P News
randall
I'm glad none has found some.
The first thing I found today was LPS. Helps to skew
you towards Th1. (T helper 1 cells)
http://www.jleukbio.org/cgi/content/abstract/77/5/626
Development and functional consequences of LPS tolerance in sinusoidal
endothelial cells of the liver
<snip>
Kupffer cells and liver sinusoidal endothelial cells (LSEC) clear
portal venous blood from gut-derived bacterial degradation products
such as lipopolysaccharide (LPS) without inducing a local inflammatory
reaction. LPS tolerance was reported for Kupffer cells, but little is
known whether sensitivity of LSEC toward LPS is dynamically regulated.
Here, we demonstrate that LSEC react to LPS directly as a function of
constitutive Toll-like receptor 4 (TLR4)/CD14 expression but gain a
LPS-refractory state upon repetitive stimulation without loss of
scavenger activity. LPS tolerance in LSEC is characterized by reduced
nuclear localization of nuclear factor-{kappa}B upon LPS rechallenge.
In contrast to monocytes, however, TLR4 surface expression of LSEC is
not altered by LPS stimulation and thus does not account for LPS
tolerance. Mechanistically, LPS tolerance in LSEC is linked to
prostanoid production and may account for cross-tolerance of
LPS-treated LSEC to interferon-{gamma} stimulation. Functionally, LPS
tolerance in LSEC results in reduced leukocyte adhesion following LPS
rechallenge as a consequence of decreased CD54 surface expression.
Furthermore, LPS tolerance is operative in vivo, as we observed by
intravital microscopy-reduced leukocyte adhesion to LSEC and improved
sinusoidal microcirculation in the liver after repetitive LPS
challenges. Our results support the notion that LPS tolerance in
organ-resident scavenger LSEC contributes to local hepatic control of
inflammation.
Key Words: liver · TLR-4 · lipopolysaccharide · cell adhesion
^^^^^^^^^^^
LPS + KuPffer cells--- on my radar--> ping
Will it ever pan out for P? More so then a mere mechanical trigger for
Th1 skewing?
I wish i had more data to tell you. We just have to wait for science to
figure out the ins and outs.
These day sunshine and topicals have been pinging too...
Whats uP on www.pubmed.com Just enter PMID # to review these hits,
Topical therapies for psoriasis: evidence-based review.
Afifi T, de Gannes G, Huang C, Zhou Y.
Division of Dermatology, Vancouver, BC.
OBJECTIVE: To review current understandings of and approaches to
topical psoriasis therapies and to assess their efficacies and adverse
effects. QUALITY OF EVIDENCE: Literature from 1987 to 2003, inclusive,
was reviewed via MEDLINE using the search term "psoriasis" combined
with "topical treatment." Articles were prioritized based on their
level of evidence, favouring double-blind, randomized controlled trials
over other comparison studies. Other studies were included where level
I research was unavailable. No level III research was included. MAIN
MESSAGE: Psoriasis is very common and causes substantial morbidity.
Because most psoriasis is mild to moderate, patients are well suited to
outpatient topical therapy. Advances in topical treatments for
psoriasis have kept pace with a rapidly evolving comprehension of its
pathogenesis, making a review of current therapies useful for those who
treat psoriasis. While research supports continued reliance on
corticosteroids as first-line therapy, comparable efficacy has been
shown for vitamin D analogues and topical retinoids, albeit with a
slight increase in adverse effects. CONCLUSION: The combination of
steroids and vitamin D analogues or topical retinoids is perhaps the
most promising current treatment. It seems to have increased efficacy
and fewer side effects.
PMID: 15856971
Sunshine in a tube to be rubbed into the P plaques. Just droP the roid
rage in the rebound phase.
This next one didn't have an abstract so I ran the related articles on
it,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Display&dopt=pubmed_pubmed&from_uid=15857477&tool=ExternalSearch
What does neurofibromatosis look like?
http://home.t-online.de/home/dr.katalinic/home_eng.htm
Whats been mentioned here,
http://groups-beta.google.com/group/alt.support.skin-diseases.psoriasis/browse_frm/thread/bf8a8e1f4b220ffb/3adeafe102702dd2?q=neurofibromatosis+psoriasis&rnum=4&hl=en#3adeafe102702dd2
Lets look at the gene, NF1,
http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=162200
http://www.ncbi.nlm.nih.gov/mapview/maps.cgi?ORG=hum&CHR=17&maps=loc-r,morbid,gene&R1=on&query=NF1&VERBOSE=ON&ZOOM=3
Far, but not to far from psors2, (but closer to keratin genes by a
mile)
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=retrieve&dopt=default&list_uids=5722
http://www.ncbi.nlm.nih.gov/mapview/maps.cgi?ORG=hum&CHR=17&maps=loc-r,morbid,gene&R1=on&query=PSORS2&VERBOSE=ON&ZOOM=3
http://www.ncbi.nlm.nih.gov/Omim/getmap.cgi?chromosome=psors2&first=+Find+&start=6961http://www.ncbi.nlm.nih.gov/mapview/map_search.cgi?taxid=9606&advsrch=off&query=602723
That went nowhere fast.
Maybe I should be looking for other P connects then P itself on this
one?
Moving on, (hehe...moveonP.org... could we get 25M from soros? What no
medical passion? At least someone would have got something for 25mill.
Perot got BC for his... lol... and we got oral spin.. it ain't no
sin...)
^^^^^^^^^^^^^^^^
Hey! Where can i buy some placebo for my P?
I'll take $100 worth, please,
A double-blind, placebo-controlled study of a commercial Aloe vera gel
in the treatment of slight to moderate psoriasis vulgaris.
Paulsen E, Korsholm L, Brandrup F.
Department of Dermatology, Odense University Hospital, DK-5000 Odense
C, Denmark.
ABSTRACT Background The Aloe vera plant has been used for an array of
ailments, including skin diseases. Recent experimental research have
substantiated the presence of biologically active compounds in the gel,
but there are few controlled, clinical trials to assess the efficacy.
Objective To test the effect of a commercial, preserved, but otherwise
untreated Aloe vera gel in psoriasis. Patients/methods Forty-one
patients with stable plaque psoriasis were included in a randomized,
double-blind, placebo-controlled right/left comparison. The study
comprised a 2-week wash-out period followed by a 4-week treatment
period with two daily applications and follow-up visits after 1 and 2
months. Results Data on 40 patients were analysed. The score sum of
erythema, infiltration and desquamation decreased in 72.5% of the Aloe
vera-treated sites compared with 82.5% of the placebo-treated areas
from week 0 to week 4, which was statistically significant in favour of
the placebo treatment (P = 0.0197). Fifty-five per cent of the patients
reported local side-effects, mainly drying up of the skin on test
areas. Conclusions The effect of this commercial Aloe vera gel on
stable plaque psoriasis was modest and not better than placebo.
However, the high response rate of placebo indicated a possible effect
of this in its own right, which would make the Aloe vera gel treatment
appear less effective.
PMID: 15857459
But if you believe that the aloe is a placebo will it work as well as
the REAL placebo used in the trials??
I hoPe not! It would be cheaPer, though.
Here's a bone for the THC crowd. But we don't know what namazi has
found without the whole paper.
Cannabinoids, loratadine and allopurinol as novel additions to the
antipsoriatic ammunition.
Namazi M.
Dermatology Department, Shiraz University of Medical Sciences, Shiraz,
Iran.
ABSTRACT As the current antipsoriatic medications are commonly
associated with deleterious side-effects, a determined search for safer
agents, which could be used alone or in combination with current
antipsoriatic drugs, would be very imperative. Psoriasis is believed to
be characterized by a type 1 cytokine pattern; interferon-gamma,
interleukin (IL)-2 and tumour necrosis factor (TNF)-alpha are
predominantly expressed in this disorder. Nitric oxide, reactive oxygen
species, histamine, leukotriene B(4), and increased keratinocyte cyclic
adenosine monophosphate/cyclic guanosine monophosphate (cAMP/cGMP)
ratio are supposed to play roles in the pathogenesis of this disorder.
Based on the immunopathogenesis of psoriasis, this paper introduces
three novel, potential treatments for this clinical conundrum: (i)
cannabinoids, which exert inhibitory effects on antigen processing and
macrophage/T-cell interaction and also on the release of IL-2,
TNF-alpha and nitric oxide from immune cells; (ii) loratadine, which is
an antihistamine capable of decreasing the cAMP/cGMP ratio and the
production of leukotriene B(4); and (iii) allopurinol, which scavenges
free radicals, inhibits the production of TNF-alpha, and downregulates
the expression of intercellular adhesion molecule-1 and P2X(7)
receptors on monocytes/macrophages, which are involved in antigen
presentation and production of the inflammatory response, respectively.
Importantly, allopurinol, especially in combination with cyclosporin,
has been shown to be effective against experimental autoimmune uveitis,
which, like psoriasis, is a cell-mediated autoimmune disorder.
PMID: 15857457
I do believe he got this one wrong,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15115315
Taking his corn (maize) oil for P seems plain old wrong to me. Unless
maize is flax in his corner of the world. To his credit he points out
the disadvantage of corn oil for Th2 conditions. That makes enough
sense for someone to get a nobel. But only if they can cure it. That
wouldn't make it easy if n-6 takes years to flip the genes to a
th2/cancer. What comes first in these things. Th1 or th2 skew or the
diet to give rise, plus a bug to trigger the mess?
Maybe he uses his abstract papers to role the cannabis?
There was a time when some thought that maybe the stuff that makes
genes didn't have their methyl caps on and that part of the dna code
was goofed with somehow. That process is called methylation and it
needs folic acid. Some would get excited and I don't know why i'm not.
But here goes,
http://www.xagena.it/news/medicinenews_net_news/7a1bb1ae4894617e33fe25166afca9d9.html
DNA hypomethylation can be reversed by intake of Folic Acid
In an article that appeared in Gastroenterology ( 2003 ) researchers at
King's College London demonstrated that low folate status and DNA
hypomethylation are associated with colorectal neoplasia.
They assessed the influence of folate status, DNA methylation, and
polymorphisms of methylenetetrahydrofolate reductase ( MTHFR 677C-->T
and 1298A-->C ), methionine synthase ( MS 2756A-->G ), and
cystathionine-beta-synthase ( CBS 844ins68 ) on risk for developing
colorectal neoplasia.
Thirty-five patients with adenoma, 28 patients with cancer, and 76
controls were recruited for a case control study.
Cancer patients had 26% lower folate status and 21% lower serum vitamin
B 12 concentration compared with controls.
[(3)H] methyl incorporation into colonic DNA was 26% higher in patients
with adenoma and 30% higher in patients with cancer compared with
controls.
High folate status was associated with decreased risk for cancer.
Colonic and leukocyte DNA hypomethylation were associated with
increased risk for adenoma and a nonsignificantly increased risk for
cancer.
These same researchers tested the hypothesis that folic acid
supplementation increases DNA methylation in leucocytes and colorectal
mucosa in patients with colorectal adenoma.
A total of 31 patients were randomised to receive either 400 µg/day
folic acid supplement ( n = 15 ) or placebo ( n = 16 ) for 10 weeks.
Folic acid supplementation increased serum and erythrocyte folate
concentrations by 81% and 57% respectively, and decreased plasma
homocysteine concentration by 12%.
Folic acid supplementation resulted in increases in DNA methylation of
31% in leucocytes and 25% in colonic mucosa.
Source: Gut, 2005
***************
So the alpha and omega of this post is LPS + the GUT..
randall... ping... piNG... pING...PING...PONG! for P.. WRONG? get the
bong!
randall
Big news for diabetics.
The gila diabetes drug will make Dr. Eng rich, rich, RICH.
http://www.signonsandiego.com/news/business/20050429-9999-1b29amylin.html
http://www.mendosa.com/monster.htm
http://www.thestreet.com/_googlen/stocks/altheachang/10220934.html?cm_ven=GOOGLEN&cm_cat=FREE&cm_ite=NA
Don't buy till your due your research,
http://news.google.com/news?hl=en&lr=&tab=gn&ie=UTF-8&q=eng+diabetes+amylin&btnG=Search+News
When are we gonna get our Dr. ENG for P? Or did we already?
Are the biologicals as good as it gets?
Or will some cocktail of low dose
fumaderm/biologicals/sunshinevitaminDinatube/MTX/roid/RxR/ make the
difference?
Time will tell.
randall...
randall
randall wrote:
> Hi,
>
>
> Big news for diabetics.
>
> Remember this,
Lets see. About 29 times?
>
Try try again.
http://groups-beta.google.com/groups?q=gila+psoriasis+forbes+evetsm&qt_s=Search
>
>
> The gila diabetes drug will make Dr. Eng rich, rich, RICH.
>
>
>
http://www.signonsandiego.com/news/business/20050429-9999-1b29amylin.html
> http://www.mendosa.com/monster.htm
>
http://www.thestreet.com/_googlen/stocks/altheachang/10220934.html?cm_ven=GOOGLEN&cm_cat=FREE&cm_ite=NA
> Don't buy till your due your research,
>
http://news.google.com/news?hl=en&lr=&tab=gn&ie=UTF-8&q=eng+diabetes+amylin&btnG=Search+News
>
>
> When are we gonna get our Dr. ENG for P? Or did we already?
We had Dr. TNF blocker and he sold it one of them?
>
> Are the biologicals as good as it gets?
Is anything ever gonna be better then what it is?
>
> Or will some cocktail of low dose
> fumaderm/biologicals/sunshinevitaminDinatube/MTX/roid/RxR/ make the
> difference?
>
> Time will tell.
Like so many have said before, if we can put a man on the moon or
in this case put some men on a new moon,
http://antwrp.gsfc.nasa.gov/apod/astropix.html
Why can't they cure P?
Because their rocket scientists and not P scientists?
You just don't need to be very far out to break gravity or know
the gravity of P if you have it. :(
Not to mention all the wind and weather down below.
The big blue keeps sPinning!
Hey! Dr Chris (wheatgrassactive.com) got some press downunder,
http://entertainment.news.com.au/story/0,10221,15123879-22809,00.html
I still use the wheatgrass spray a few times a week.
And feel that it helps enough to extol the virtues.
Blue skies, green grass.. whats not to like?
And little league baseball to watch. Ah nirvana!
Whose got the Brahma beer? ;-0
>
> randall...
randall
We've talked about using low dose naltrexone for P, before.
http://www.sciencedaily.com/releases/2005/04/050420091909.htm
There have been anecdotal stories of it helping to slow psoriasis.
I would think if you have p exacerbated by alcohol then it may
be helpful. Could be very helpful... Now if someone would test it.
Seeing that no pharma will make a dime off of it, lowers that
likely hood. So we need a college or other independent well funded
group. Like maybe the NPF (our $$$ for us... please give to them)
could look at it.
What if fumaderm and low dose naltrexone keeps you really clear?
The pharma's if they knew that would make damn sure you didn't!
Lets face it, they have to much on the line with biologicals to
even consider anything that they can't mark uP to ridiculous levels.
PLEASE give to the NPF... www.psoriasis.org
Anything with LPS/tlr-4, even the human eye, catches my attention.
Expression of toll-like receptor 4 and its associated
lipopolysaccharide receptor complex by resident antigen-presenting
cells in the human uvea.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Display&dopt=pubmed_pubmed&from_uid=15161852&tool=ExternalSearch
PURPOSE: To investigate the in vivo expression of toll-like receptor 4
(TLR4) and its associated lipopolysaccharide (LPS) receptor complex in
the human eye. METHODS: Normal human ocular tissues were evaluated for
in vivo TLR4, MD-2, and CD14 mRNA and protein expression by RT-PCR and
immunohistochemistry, respectively. The distribution patterns and
phenotypes of the cells expressing these proteins were further
characterized by confocal microscopy and double-label
immunofluorescence studies. RESULTS: Normal human uvea, retina, sclera,
and conjunctiva constitutively expressed TLR4, MD-2, and CD14 mRNA. The
protein expression of these molecules was restricted, however, to
resident antigen-presenting cells (APCs) in the normal human uvea,
consisting mainly of HLA-DR(+) dendritic cells (DCs). These APCs
endowed with the complete LPS receptor complex appeared to be
strategically positioned in perivascular and subepithelial locations
for surveying blood-borne or intraocular LPS. In contrast, other cell
types of the normal human cornea, conjunctiva, retina, and sclera did
not express TLR4/MD-2 protein in vivo as detectable by
immunohistochemistry. CONCLUSIONS: The present study demonstrates for
the first time that resident APCs in the normal human uvea express TLR4
and its associated LPS receptor complex. This has significant
implications for the understanding of normal ocular immunity as well as
unraveling the potential role of Gram-negative bacteria in the
pathogenesis of acute anterior uveitis (AAU).
PMID: 15161852
Lipopolysaccharide stimulation converts vigorously washed dendritic
cells (DCs) to nonexhausted DCs expressing CD70 and evoking
long-lasting type 1 T cell responses. .
A great variety of in vitro culture protocols for human
monocyte-derived dendritic cells (mo-DCs) has been used to generate DCs
suitable for use in immunotherapy. It is thought that activated DCs
undergo one-way differentiation into "exhausted" DCs. In the present
study, we contrived an in vitro method for facilitating expression of
CD70 by mature DCs. This was achieved by vigorous washing of mo-DCs
before exposure to lipopolysaccharide (LPS). Unexpectedly, these mature
DCs retain expression of some interleukin (IL)-12 family members after
extended periods and maintain their ability to stimulate type 1 T cell
responses. In contrast, DCs exposed to IL-4 before LPS stimulation or
LPS-stimulated DCs not exposed to washing stress before activation
failed to express CD70 and did differentiate into exhausted DCs. It is
interesting that DCs expressing CD70 (CD70(+) DCs) induced
interferon-gamma production from purified, allogeneic CD8(+) T cells
through a direct CD27-CD70 interaction. This is evidence for a pathway
resulting in generation of CD8 T effectors by B7-independent
mechanisms. These data suggest that exposure of immature DCs to LPS
stimulation contributes to their terminal differentiation into CD70(+)
DCs, which have potent ability to prolong type 1 T cell responses
through alternative pathways.
PMID: 15857939
I keep waiting for the really big break through for LPS. Is it playing
hard to catch? Or do we react slightly different then the rest of the
population.
And where do we differ from other IMID folks.
Back to P.
Corticotropin-releasing hormone (CRH) downregulates interleukin-18
expression in human HaCaT keratinocytes by activation of p38
mitogen-activated protein kinase (MAPK) pathway.
Park HJ, Kim HJ, Lee JH, Lee JY, Cho BK, Kang JS, Kang H, Yang Y, Cho
DH.
Department of Dermatology, St Mary's Hospital, College of Medicine, The
Catholic University of Korea, Seoul, Korea.
It is generally accepted that corticotropin-releasing hormone (CRH)
acts as the main coordinator of the central response to stress. Stress
or an abnormal response to stressors has been found to modify the
evolution of skin disorders, including psoriasis and atopic dermatitis.
Nevertheless, the specific pathogenic role of stress remains unknown in
skin diseases. Interleukin (IL)-18, a member of the IL-1 family, is a
key mediator of peripheral inflammation and host defense responses, and
is secreted by human keratinocytes. Here, we investigated the
regulatory effect of CRH on expression of IL-18 in skin keratinocytes.
Exposure of HaCaT cells to CRH resulted in a reduction of IL-18 mRNA
transcripts and its production was in a concentration-dependent manner.
In order to investigate whether the mitogen-activated protein kinase
(MAPK) signaling pathway is involved in the downregulation of IL-18
production, cells were pre-treated with SB203580, an inhibitor of p38
MAPK, prior to the addition of CRH. This pre-treatment blocked the
decrease in IL-18 production. In addition, CRH treatment induced rapid
phosphorylation of p38 MAPK. SB203580 were able to inhibit CRH-induced
p38 MAPK phosphorylation. CRH also inhibited production of IL-18 in
human primary keratinocytes. These results suggest that CRH regulates
IL-18 production through the MAPK signaling pathway in human
keratinocytes.
PMID: 15816833
Regulation of vascular endothelial growth factor expression by
insulin-like growth factor-II in human keratinocytes, differential
involvement of mitogen-activated protein kinases and feedback
inhibition of protein kinase C.
BACKGROUND: Vascular endothelial growth factor (VEGF) is overexpressed
in hyperproliferative diseases such as psoriasis and cancer, which are
characterized by an increased angiogenesis. It was reported that
insulin-like growth factor (IGF)-II is highly expressed during
hepatocarcinogenesis and is increased in psoriatic lesions. The
increase in IGF-II is believed to be associated with the pathogenesis
of these diseases by increasing angiogenesis. OBJECTIVES: In order to
investigate the relationship between IGF-II and angiogenesis-related
VEGF, VEGF expression in the IGF-II-treated human keratinocytes was
monitored and the IGF-II signalling pathways were examined with respect
to VEGF expression. METHODS: Northern blot analysis for the VEGF mRNA
levels and an enzyme-linked immunosorbent assay for the VEGF protein
were performed to determine if IGF-II (100 ng mL(-1)) can increase the
VEGF expression levels with or without a pretreatment with protein
inhibitors in primary normal human keratinocytes and HaCaT cells.
RESULTS: The mRNA and protein levels of VEGF by IGF-II were increased
in a time-dependent manner and reached the maximum level 2 h and 8 h
after the IGF-II treatment, respectively. However, this increase was
abrogated by pretreatment with an extracellular signal-regulated kinase
(ERK) inhibitor but not by a p38 inhibitor. The IGF-II-mediated VEGF
induction was also effectively inhibited by a pretreatment with the
tyrosine kinase inhibitor and Src inhibitor. The PI3-kinase inhibitor
also inhibited the expression of VEGF by IGF-II. However, the
phospholipase C (PLC) and protein kinase C (PKC) inhibitors did not
block the increases of VEGF mRNA level and its protein level by IGF-II,
and the PKC inhibitor instead increased VEGF expression by IGF-II.
CONCLUSIONS: These results suggest that the tyrosine kinase-Src-ERK1/2
pathway and the PI3-kinase pathway are involved in IGF-II-mediated VEGF
expression, but PKC is negatively associated in the IGF-II-mediated
VEGF expression.
PMID: 15787809
CONCLUSIONS: Taken together, our results demonstrate that the activity
of the MAPKs p38alpha, p38beta and p38delta and ERK1/2 are increased in
lesional psoriatic skin compared with nonlesional psoriatic skin, and
that clearance of psoriasis normalizes the p38 and ERK1/2 activity.
Thus, p38 and ERK1/2 might be potential targets in the treatment of
psoriasis.
PMID: 15656798
All-trans-retinoic acid induces interleukin-8 via the nuclear
factor-kappaB and p38 mitogen-activated protein kinase pathways in
normal human keratinocytes.
Retinoic acid derivatives have been used successfully for the treatment
of various dermatoses, such as psoriasis; however, topical application
of these compounds often elicits skin irritation. We hypothesized that
this irritation was as a result of the local production of
interleukin-8 (IL-8). To test this hypothesis, we investigated whether
all-trans-retinoic acid (ATRA) induced IL-8 production in normal human
keratinocytes. Stimulation with 10(-7) M ATRA enhanced IL-8 mRNA
expression and induced IL-8 production. We also studied the
intracellular signaling mechanisms of ATRA-induced IL-8 production in
keratinocytes. ATRA increased the expression of RelA (p65), RelB,
nuclear factor (NF)-kappaB2 (p52), and NF-kappaB1 (p50), and elevated
the DNA-binding activity of p65 and phosphorylation of inhibitor kappaB
(IkappaB) alpha. Introduction of a dominant-negative mutant of
IkappaBalpha completely abolished ATRA-induced IL-8 production, which
indicates that this process is NF-kappaB-dependent. We also studied the
role of the p38 mitogen-activated protein kinase (MAPK) pathway in this
phenomenon. ATRA phosphorylated the p38 MAPK, and SB202180 inhibited
ATRA-induced IL-8 production, which indicates that the p38 MAPK is also
involved in ATRA-induced IL-8 production. In summary, ATRA induces IL-8
production in both NF-kappaB- and p38 MAPK-dependent manners in normal
human keratinocytes.
PMID: 15610518
This crohn's abstract caught my eye.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15861209
Genetics of Crohn disease, an archetypal inflammatory barrier disease.
Schreiber S, Rosenstiel P, Albrecht M, Hampe J, Krawczak M.
Institute for Clinical Molecular Biology, Center for Conservative
Medicine, Christian-Albrechts-University Kiel, Schittenhelmstr. 12,
24105 Kiel, Germany.
Chronic inflammatory disorders such as Crohn disease, atopic eczema,
asthma and psoriasis are triggered by hitherto unknown environmental
factors that function on the background of some polygenic
susceptibility. Recent technological advances have allowed us to
unravel the genetic aetiology of these and other complex diseases.
Using Crohn disease as an example, we show how the discovery of
susceptibility genes furthers our understanding of the underlying
disease mechanisms and how it will, ultimately, give rise to new
therapeutic developments. The long-term goal of such endeavours is to
develop targeted prophylactic strategies. These will probably target
the molecular interaction on the mucosal surface between the products
of the genome and the microbial metagenome of a patient.
PMID: 15861209
The big D, made from the sun is on the radar,
Vitamin D analogs--drug design based on proteins involved in vitamin D
signal transduction.
Masuda S, Jones G.
Department of Biochemistry, Queen's University, Kingston, Ontario,
Canada K7L 3N6. mas...@post.queensu.ca
Vitamin D analogs have proven to be very valuable tools for the
treatment of calcium-related diseases and certain hyperproliferative
conditions such as renal osteodystrophy, psoriasis and cancer. In
general, vitamin D analogs exploit the enzymic and receptor machinery
of the 1alpha,25-dihydroxyvitamin D(3) (1alpha,25(OH)(2)D(3)) signal
transduction pathway. Key proteins in this cascade include the vitamin
D receptor (VDR), the vitamin D-binding protein (DBP) and three
cytochrome P450s (CYP27A, CYP27B and CYP24) which effect the synthesis
and breakdown of the natural hormone, 1alpha,25(OH)(2)D(3). Analogs
have been designed which reduce or enhance the importance of each of
these proteins in the signal transduction pathway. Vitamin D prodrugs
require one or more steps of activation and overcome congenital or
acquired blocks in the 1alpha-hydroxylation step. By far the biggest
class of vitamin D analogs are the VDR agonists which directly mimic
1alpha,25(OH)(2)D(3) and trigger protein conformational changes in the
receptor which lead to changes in the transcriptional machinery at
vitamin D-responsive genes. Other emerging classes of molecules include
the VDR antagonists and CYP24 inhibitors which target different events
in the cascade. This review assesses the relative importance of each of
the proteins of the vitamin D cascade, evaluates the success of these
modifications in tailoring drugs in all classes for selected disease
states and contemplates future directions for the field.
PMID: 12570725
&
Isolation and identification of 1alpha-hydroxy-24-oxovitamin D3 and
1alpha,23-dihydroxy-24-oxovitamin D3: metabolites of
1alpha,24(R)-dihydroxyvitamin D3 produced in rat kidney.
Weinstein EA, Rao DS, Siu-Caldera ML, Tserng KY, Uskokovic MR, Ishizuka
S, Reddy GS.
Department of Pediatrics, Women and Infants' Hospital of Rhode Island,
Brown University School of Medicine, Providence 02905, USA.
1alpha,24(R)-Dihydroxyvitamin D3 [1alpha,24(R)(OH)2D3], a synthetic
vitamin D3 analog, has been developed as a drug for topical use in the
treatment of psoriasis. At present, the target tissue metabolism of
1alpha,24(R)(OH)2D3 is not understood completely. In our present study,
we investigated the metabolism of 1alpha,24(R)(OH)2D3 in the isolated
perfused rat kidney. The results indicated that 1alpha,24(R)(OH)2D3 is
metabolized in rat kidney into several metabolites, of which
1alpha,24(R),25-trihydroxyvitamin D3, 1alpha,25-dihydroxy-24-oxovitamin
D3, 1alpha,23(S),25-trihydroxy-24-oxovitamin D3, and
1alpha,23-dihydroxy-24,25,26,27-tetranorvitamin D3 are similar to the
previously known metabolites of 1alpha,25-dihydroxyvitamin D3
[1alpha,25(OH)2D3]. In addition to these aforementioned metabolites, we
also identified two new metabolites, namely
1alpha-hydroxy-24-oxovitamin D3 and 1alpha,23-dihydroxy-24-oxovitamin
D3. The two new metabolites do not possess the C-25 hydroxyl group.
Thus, the metabolism of 1alpha,24(R)(OH)2D3 into both 25-hydroxylated
and non-25-hydroxylated metabolites suggests that 1alpha,24(R)(OH)2D3
is metabolized in the rat kidney through two pathways. The first
pathway is initiated by C-25 hydroxylation and proceeds further via the
C-24 oxidation pathway. The second pathway directly proceeds via the
C-24 oxidation pathway without prior hydroxylation at the C-25
position. Furthermore, we demonstrated that rat kidney did not convert
1alpha-hydroxyvitamin D3 [1alpha(OH)D3] into 1alpha,25(OH)2D3. This
finding indicates that the rat kidney does not possess the classical
vitamin D3-25-hydroxylase (CYP27) activity. However, from our present
study it is apparent that prior hydroxylation of 1alpha(OH)D3 at the
C-24 position in the 'R' orientation allows 25-hydroxylation to occur.
At present, the enzyme responsible for the C-25 hydroxylation of
1alpha,24(R)(OH)2D3 is unknown. Our observation that the side chain of
1alpha,24(R)(OH)2D3 underwent 24-ketonization and 23-hydroxylation even
in the absence of the C-25 hydroxyl group suggests that
1alpha,25(OH)2D3-24-hydroxylase (CYP24) can perform some steps of the
C-24 oxidation pathway without prior C-25 hydroxylation. Thus, we
speculate that CYP24 may be playing a dual role in the metabolism of
1alpha,24(R)(OH)2D3.
PMID: 10591152
Eicosapentaenoic acid metabolism by cytochrome P450 enzymes of the
CYP2C subfamily.
Barbosa-Sicard E, Markovic M, Honeck H, Christ B, Muller DN, Schunck
WH.
Max Delbruck Center for Molecular Medicine, Berlin, Germany.
CYP2C enzymes epoxidize arachidonic acid (AA) to metabolites involved
in the regulation of vascular and renal function. We tested the
hypothesis that eicosapentaenoic acid (EPA), a n-3 polyunsaturated
fatty acid, may serve as an alternative substrate. Human CYP2C8 and
CYP2C9, as well as rat CYP2C11 and CYP2C23, were co-expressed with
NADPH-CYP reductase in a baculovirus/insect cell system. The
recombinant enzymes showed high EPA and AA epoxygenase activities and
the catalytic efficiencies were almost equal comparing the two
substrates. The 17,18-double bond was the preferred site of EPA
epoxidation by CYPs 2C8, 2C11, and 2C23.
17(R),18(S)-Epoxyeicosatetraenoic acid was produced with an optical
purity of about 70% by CYPs 2C9, 2C11, and 2C23 whereas CYP2C8 showed
the opposite enantioselectivity. These results demonstrate that EPA is
an efficient substrate of CYP2C enzymes and suggest that n-3 PUFA-rich
diets may shift the CYP2C-dependent generation of physiologically
active eicosanoids from AA- to EPA-derived metabolites.
PMID: 15766564
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15695019
&
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15464071
That was interesting. Could it be a gene for arachidonic acid and some
liver metabolism enzyme?
Why not?
randall... enough for today? Never for P!
randall
After re-reading the crohn's abstract in the last P news (30 minutes
ago) I figured I would look into it some. Some of the crohn's genes
have been discounted for P the last few years. But the pathways my hold
some other clues.
http://visiscience.com/samples/IL-6-Signaling-in-Cronh's-d.jpg
http://groups-beta.google.com/groups?q=il-6%20%20stat3&hl=en&lr=&sa=N&tab=ig
That was good. The first hit. I'll try a kofi/il-6 search. Bingo for
il-6,
http://groups-beta.google.com/groups?hl=en&lr=&q=il-6++kofi&qt_s=Search
Back to the wider groups for il-6/P,
http://groups-beta.google.com/groups?hl=en&lr=&q=il-6++psoriasis&qt_s=Search
And going full circle back to,
http://groups-beta.google.com/groups?q=il-6%20stat6(b)%20psoriasis&hl=en&lr=&sa=N&tab=wg
LPS raises IL-6 and we have a gene for the rest of the NOT divine
comedy called P?
Is it just the LPS or some other antigen/SA?
Interleukin-6-type cytokines upregulate expression of multidrug
resistance-associated proteins in NHEK and dermal fibroblasts.
Dreuw A, Hermanns HM, Heise R, Joussen S, Rodriguez F, Marquardt Y,
Jugert F, Merk HF, Heinrich PC, Baron JM.
Department of Biochemistry, University Hospital, Aachen, Germany.
Normal human epidermal keratinocytes (NHEK) and dermal fibroblasts
express a cell-specific pattern of efflux transport proteins. Since
regulatory mechanisms for these transporters in cells of the human skin
were unknown, we analyzed the influence of inflammatory cytokines on
the expression of multidrug resistance-associated proteins (MRP1, 3, 4,
5). Using real-time PCR, RT-PCR, cDNA microarray, immunostaining and
efflux assays we demonstrated that stimulation of NHEK and primary
human dermal fibroblasts with interleukin-6 (IL-6), in combination with
its soluble alpha-receptor, or oncostatin M (OSM) for 24-72 h resulted
in an upregulation of MRP expression and activity. Both cytokines
induced a strong activation of signal transducer and activator of
transcription (STAT)1 and STAT3 as well as the mitogen-activated
protein kinase (MAPK) Erk1/2. OSM additionally activated proteinkinase
B strongly. Using the MAPK/extracellular signal-regulated kinase kinase
1-specific inhibitor U0126 we could exclude a stimulatory effect of
MAPK on MRP gene expression. Inhibition of the phosphatidylinositol
3-kinase, however, indicated that this pathway might be involved of
OSM-mediated upregulation of MRP4 in dermal fibroblasts. Several
inflammatory skin diseases show an enhanced expression of IL-6-type
cytokines. Correspondingly, upregulation of MRP expression was found in
lesional skin taken from patients with psoriasis and lichen planus.
PMID: 15654950
I feel like i'm going MR--P! As in mentally retarded due to P!
randall...Lets give it a rest... tomorrow is another day.
randall
P News yesterday went over the inflammatory cytokine IL-6, increased
by LPS (cell wall of endotoxin) that translocates in permeable (leaky)
guts and skews psoriatics towards a Th1 (T helper 1 cell) profile.
What is it to be skewed towards a Th1 profile.
A small but powerful part of the p equation. We can either block
the lps by not eating an inflammatory diet (to much meat rather
then a veggetarian fare) or try to re-balance the immune system
cytokines.
These cytokines, in balance keep us healthy and go out of balance
to bring us back to health. If you cut your finger you need
inflammation to heal the cut. Once done the cytokines go back
to a neutral posture (Th0) and all is well again. The healing is
over.
But what if the inflammatory ones like IL-6 refuse to turn off?
Then given that you have the suspected polygenetic Psoriasis
genes you build plaques. In our case Stat6(b) keeps the P fires
fired uP. But turning all of that off like blocking all your TNF
will harm you or kill you.
But there are other cytokines that will stop/slow this process and
we have mentioned it here many many times.
IL-10 is that saintly cytokine.
Don't take it from me. But should you need a new liver or kidney
you may want to find some.
Why wouldn't it help us?
http://www.news-medical.net/?id=9731
or
http://www.innovations-report.de/html/berichte/medizin_gesundheit/bericht-43925.html
<snip>
The helpful molecule, IL-10, has anti-inflammatory, immunosuppressive
and other properties that help keep blood vessels healthy. Chronic
vascular rejection, characterized by thickening of the interior lining
that eventually chokes off the blood supply, is a major cause of the
loss of function in solid organ transplants.
The study, carried out in rat models, also showed that a single
muscular injection of the molecule, interleukin-10 (IL-10), carried in
a gene delivery vector, or mechanism, could provide long-term
therapeutic effects.
Anupam Agarwal, M.D., director of the UAB Nephrology Research and
Training Center and senior author of the report, said the group found
that IL-10 was active through the heme oxygenase-dependent (HO-1)
biological pathway between cells.
"We found that one dose of IL-10 delivered using a viral vector delays
the vascular disease from occurring," Agarwal said. "If the HO-1
pathway is blocked, the protective effects of IL-10 are lost. The delay
in vascular disease shown in this study could - after more research
and possible clinical trials in human beings - offer the benefit of
at least several additional years of health for transplanted organs."
A key to the single-injection strategy, Atkinson said, "was the use of
adeno-associated virus as a way to deliver IL-10 into the body,
allowing sustained levels of the molecule to be persistently secreted
into the blood stream.
The next step will be to evaluate the treatment to try to protect
kidney transplants in non-human primates - and if successful there,
go on to clinical trials in humans, said Agarwal.
Weitere Informationen: www.uab.edu
www.vpha.health.ufl.edu
((((((((((((((((((((((((((((((())))))))))))))))))))))))))))))))))))))))))
Get those tests going and while your at it toss in some of
those psoriasis mice/rats/me, for grins.
How about those folks who deep fat fry some farm grown raised
on corn feed catfish in lard and then expect the good fat
in the fish to cure a little psoriasis plaque?
Don't go thinking that fried fish (omega-3's ) will save you,
http://msnbc.msn.com/id/7711701/
Its fried and the n:3's have died,
http://news.google.com/news?qt_s=Search&lr=&tab=gn&ie=UTF-8&q=fish+baked+broiled+fried&btnG=Search+News
And if you have the psoriasis genes suck on this weird fact,
http://news.google.com/news?qt_s=Search&lr=&tab=gn&ie=UTF-8&q=fish+arachidonic
Had you been breast fed or bottle fed with arachidonic acid (ara)/Dha
bottle formula's after 2002 you'd be much better off P wise then your
are now.
Now that you've got the P crud your better off without it. It seems
that when your born and developing your immune system does very well
with it. But once your ready to go out and procreate its a unneccessary
burden to have extra hanging around.
Or when you get old. You don't want to do the fish fry route unless
your planning on senile city.
Fatty Acid oxidation in the pathogenesis of Alzheimer's disease.
Montine TJ, Morrow JD.
Department of Pathology, University of Washington, Box 359791, Seattle,
WA 98104. tmon...@u.washington.edu.
Alzheimer's disease (AD) is the most common dementing illness of the
elderly and is a mounting public health problem.
Pharmacoepidemiological data, analytical data from human tissue and
body fluids, and mechanistic data mostly from murine models all have
implicated oxidation products of two fatty acids, arachidonic acid (AA)
and docosahexaenoic acid (DHA), in the pathogenesis of
neurodegeneration. Here we review the biochemistry of AA and DHA
oxidation, both enzyme-catalyzed and free radical mediated, and
summarize those studies that have investigated these oxidation products
as effectors of neurodegeneration and biomarkers of AD. Given the
evolving appreciation for toxicity associated with current
pharmaceuticals used to block AA and DHA oxidation, we close by
speculating on likely areas of future research directed at suppressing
this facet of neurodegeneration. If successful, these interventions are
unlikely to cure AD, but may check its explosive growth and hopefully
reduce its incidence and prevalence in the elderly.
PMID: 15855630
*********************
When are the n:6 fats good for you?
N-6 polynsaturated fatty acids confer hemodynamic stability in an
experimental model of multiple trauma.
Efstathopoulos N, Bathrellos E, Giamarellos-Bourboulis EJ, Lazarettos
J, Papalois A, Grecka P, Nikolaou V.
2nd Department of Orthopaedics, University of Athens, Medical School,
Greece.
Immunonutrition with diets enriched in polyunsaturated fatty acids
(PUFAs) are becoming mandatory for multiple trauma patients. Solutions
containing single n-6 PUFAs were administered intravenously in an
experimental model of trauma. Thirty-five rabbits were studied; 13
controls; 10 administered gamma-linolenic acid (GLA) 30 min after
fracture of the right femor; and 12 arachidonic acid (AA). Systolic,
diastolic and mean arterial pressures and heart rate were recorded;
serum levels of tumor necrosis factor-alpha (TNFalpha), malondialdehyde
(MDA) and nitrate were estimated before and after therapy. Mean
survival of controls, of animals treated with GLA and of animals
treated with AA was 0.80, 1.41 and 3.60 days, respectively.
Administration of PUFAs induced higher levels of blood pressure; that
of AA decreased serum TNFalpha and tissue bacterial load compared to
controls. Intravenous administration of n-6 PUFAs conferred hemodynamic
stability and increased survival in a model of trauma rendering further
research mandatory.
PMID: 15850717
But wouldn't you expect that AA being an inflammatory agent wouldn't
slow death due to trauma?
We (psoriatics) are loaded with it but we didn't crash our car into a
wall at 60 mph.
To much of a good thing for a trauma situation certainly doesn't bode
well for living a long life....
Or getting rid of P flakes.
Lets get the pubmed for us on this,
Secretory and cytosolic phospholipase A(2)regulate the long-term
cytokine-induced eicosanoid production in human keratinocytes.
Sjursen W, Brekke OL, Johansen B.
UNIGEN Center for Molecular Biology, Norwegian University of Science
and Technology, NTNU, Trondheim, N-7489, Norway.
The involvement of cytosolic phospholipase A(2)(cPLA(2)) and secretory
non-pancreatic PLA(2)(npPLA(2)) in release of arachidonic acid (AA)
preceding eicosanoid formation in the human keratinocyte cell line
HaCaT was examined. Interleukin 1beta (IL-1beta) and tumour necrosis
factor-alpha (TNF), phorbol myristate acetate (PMA) and calcium
ionophore A(23187)increased the extracellular AA release, and
stimulated eicosanoid synthesis as determined by HPLC analysis. The
main metabolites after stimulation with IL-1beta, PMA or A(23187)were
PGE(2), an unidentified PG and LTB(4), while TNF stimulated
HETE-production. Both cPLA(2)and npPLA(2)message and enzyme activity
were detected in unstimulated HaCaT cells. IL-1beta, PMA and TNF
increased both cPLA(2)enzyme activity and expression, but did not lead
to any increase in npPLA(2)expression or activity. The selective
npPLA(2)inhibitors LY311727 and 12-epi-scalaradial, or the
cPLA(2)inhibitor arachidonyl trifluoro methyl ketone (AACOCF(3))
reduced IL-1beta-induced eicosanoid production in a concentration
dependent manner. The results presented strongly suggest that both
cPLA(2)and npPLA(2)contribute to the long-term generation of AA
preceding eicosanoid production in differentiated, human keratinocytes.
Inhibitors against npPLA2 or cPLA2 enzymes should be useful in treating
inflammatory skin diseases, such as psoriasis. Copyright 2000 Academic
Press.
PMID: 10930295
So, will that frankincense plant fix this biblical psoriasis?
(Mentioned yesterday as boswellia serrata )
Not likely as expanded on in the last post, But it sure looks damn
good. Here's the abstract on that article posted in the beginning of
the last post,
Human genome screen to identify the genetic basis of the
anti-inflammatory effects of Boswellia in microvascular endothelial
cells.
Roy S, Khanna S, Shah H, Rink C, Phillips C, Preuss H, Subbaraju GV,
Trimurtulu G, Krishnaraju AV, Bagchi M, Bagchi D, Sen CK.
Laboratory of Molecular Medicine, Department of Surgery, The Ohio State
University Medical Center, Columbus, Ohio 43210, USA.
Inflammatory disorders represent a substantial health problem.
Medicinal plants belonging to the Burseraceae family, including
Boswellia, are especially known for their anti-inflammatory properties.
The gum resin of Boswellia serrata contains boswellic acids, which
inhibit leukotriene biosynthesis. A series of chronic inflammatory
diseases are perpetuated by leukotrienes. Although Boswellia extract
has proven to be anti-inflammatory in clinical trials, the underlying
mechanisms remain to be characterized. TNF alpha represents one of the
most widely recognized mediators of inflammation. One mechanism by
which TNFalpha causes inflammation is by potently inducing the
expression of adhesion molecules such as VCAM-1. We sought to test the
genetic basis of the antiinflammatory effects of BE (standardized
Boswellia extract, 5-Loxin) in a system of TNF alpha-induced gene
expression in human microvascular endothelial cells. We conducted the
first whole genome screen for TNF alpha- inducible genes in human
microvascular cells (HMEC). Acutely, TNF alpha induced 522 genes and
downregulated 141 genes in nine out of nine pairwise comparisons. Of
the 522 genes induced by TNF alpha in HMEC, 113 genes were clearly
sensitive to BE treatment. Such genes directly related to inflammation,
cell adhesion, and proteolysis. The robust BE-sensitive candidate genes
were then subjected to further processing for the identification of
BE-sensitive signaling pathways. The use of resources such as GenMAPP,
KEGG, and gene ontology led to the recognition of the primary
BE-sensitive TNF alpha-inducible pathways. BE prevented the TNF
alpha-induced expression of matrix metalloproteinases. BE also
prevented the inducible expression of mediators of apoptosis. Most
strikingly, however, TNF alpha-inducible expression of VCAM-1 and
ICAM-1 were observed to be sensitive to BE. Realtime PCR studies showed
that while TNF alpha potently induced VCAM-1 gene expression, BE
completely prevented it. This result confirmed our microarray findings
and built a compelling case for the anti-inflammatory property of BE.
In an in vivo model of carrageenan-induced rat paw inflammation, we
observed a significant antiinflammatory property of BE consistent with
our in vitro findings. These findings warrant further research aimed at
identifying the signaling mechanisms by which BE exerts its
anti-inflammatory effects.
PMID: 15812241
Whats missing that once put in place would fix us? Good question.
Besides sunshine which trumps everything in the cure (temporary anyway)
of psoriasis, we don't have anything that stops this
most likely polygenetic thing from flaking away.
Does psoriasis simply do its thing to soP uP the excess inflammatory
capacity of the body?
I've only speculated that about 100 times so far. One more, like one
more flake isn't gonna matter.
moving down the pathway,
Mastoparan, a G protein agonist peptide, differentially modulates TLR4-
and TLR2-mediated signaling in human endothelial cells and murine
macrophages.
Lentschat A, Karahashi H, Michelsen KS, Thomas LS, Zhang W, Vogel SN,
Arditi M.
Department of Microbiology and Immunology, University of Maryland,
Baltimore, MD 21201, USA.
Previous studies have implicated a role for heterotrimeric G
protein-coupled signaling in B cells, monocytes, and macrophages
stimulated with LPS and have shown that G proteins coimmunoprecipitate
with membrane-bound CD14. In this study, we have extended these
observations in human dermal microvessel endothelial cells (HMEC) that
lack membrane-bound CD14 and in murine macrophages to define further
the role of heterotrimeric G proteins in TLR signaling. Using the wasp
venom-derived peptide, mastoparan, to disrupt G protein-coupled
signaling, we identified a G protein-dependent signaling pathway in
HMEC stimulated with TLR4 agonists that is necessary for the activation
of p38 phosphorylation and kinase activity, NF-kappaB and IL-6
transactivation, and IL-6 secretion. In contrast, HMEC activation by
TLR2 agonists, TNF-alpha, or IL-1beta was insensitive to mastoparan. In
the murine macrophage cell line, RAW 264.7, and in primary murine
macrophages, G protein dysregulation by mastoparan resulted in
significant inhibition of LPS-induced signaling leading to both
MyD88-dependent and MyD88-independent gene expression, while
TLR2-mediated gene expression was not significantly inhibited. In
addition to inhibition of TLR4-mediated MAPK phosphorylation in
macrophages, mastoparan blunted IL-1R-associated kinase-1 kinase
activity induced by LPS, but not by TLR2 agonists, yet failed to affect
phosphorylation of Akt by phosphoinositol-3-kinase induced by either
TLR2- or TLR4-mediated signaling. These data confirm the importance of
heterotrimeric G proteins in TLR4-mediated responses in cells that use
either soluble or membrane-associated CD14 and reveal a level of TLR
and signaling pathway specificity not previously appreciated.
PMID: 15778388
Can this save us?
Thats what the tests will determine.
Something new under the sun for a good old condition.
We know the effects of the sun and 300 nm band waves.
How does a lamp compare to a laser beam at 308-nm's versus the standard
311-nm narrowband phototherapy?
Comparison of the 308-nm excimer laser and a 308-nm excimer lamp with
311-nm narrowband ultraviolet B in the treatment of psoriasis.
Kollner K, Wimmershoff MB, Hintz C, Landthaler M, Hohenleutner U.
Department of Dermatology, University of Regensburg,
Franz-Josef-Strauss-Allee 11, 93043 Regensburg, Germany.
Summary Background Psoriasis is a chronic, genetically determined
inflammatory disease, characterized by an immunomediated pathogenesis,
which affects approximately 1-3% of the population. Various modalities
have been used for psoriasis treatment, including ultraviolet (UV)
radiation. Narrowband UVB (311 nm) phototherapy is a well-established,
widely used and highly efficient treatment for psoriasis, but a big
disadvantage is that large areas of unaffected skin are irradiated
along with the psoriatic lesions. Objectives This investigation
evaluates a 308-nm excimer laser and a 308-nm excimer lamp in
comparison with 311-nm narrowband UVB in the treatment of patch
psoriasis by using two different dose-increase schemes. Materials and
methods Fifteen patients with plaque psoriasis were enrolled in the
study (first regime). Three different psoriatic lesions were treated
with the 308-nm excimer laser, the 308-nm excimer lamp or 311-nm
narrowband UVB three times per week. UVB doses were increased slowly
and stepwise (1, 1, 2, 2, 3, 3, ...multiple MEDs). Sixteen patients
were enrolled in the second regime. Two plaques were treated with the
308-nm excimer laser or with the 308-nm lamp with an accelerated scheme
(2, 2, 4, 4, 6, 6, ...multiple MEDs) three times per week. We increased
the UVB doses every second treatment (first and second regime) during
the whole treatment. If blistering occurred, the blistered plaque was
not treated on the next scheduled treatment. At every third visit and
1, 2 and 4 months after the last treatment a Psoriasis Severity Index
(PSI) score was assigned in both regimes. Results Using Friedman
analysis, the PSI scores did not show a statistically significant
difference (P > 0.05) comparing 308-nm laser therapy, 308-nm lamp
therapy and 311-nm narrowband therapy after 10 weeks in the first
regime. The mean number of treatments to achieve clearance was 24. With
the accelerated scheme, clearance could be achieved with fewer
treatments and with half the cumulative dose of the first regime.
Nevertheless, the side-effects such as blistering and crusting were
also increased. Conclusions Both 308-nm light sources can clear patch
psoriasis in a similar manner to standard phototherapy, with the
advantage of the ability to treat exclusively the affected skin and
with a reduced cumulative dose, thus perhaps reducing the long-term
risk of carcinogenicity.
PMID: 15840108
And we are finding out how powerful some oil from some
lowly plant may be. Look at this for cancer.
http://i-newswire.com/pr16148.html
Cottonseeds (gossypol) to trick Bcl-xL?
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15570010
http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=191170
Mihara et al. (2003) provided evidence that p53 translocation to
mitochondria occurs in vivo in irradiated thymocytes. Further, they
showed that p53 can directly induce permeabilization of the outer
mitochondrial membrane by forming complexes with the protective BCL-XL
(see 600039) and BCL2 (151430) proteins, resulting in cytochrome c
release. p53 was found to bind BCLXL via its DNA-binding domain.
Tumor-derived transactivation-deficient mutants of p53 concomitantly
lost the ability to interact with BCLXL and promote cytochrome c
release. The authors concluded that this finding opens the possibility
that mutations might represent 'double hits' by abrogating the
transcriptional and mitochondrial apoptotic activity of p53.
P53 may give us a clue for P.
TP53 is close to Alox12B i see,
http://www.ncbi.nlm.nih.gov/mapview/maps.cgi?ORG=hum&CHR=17&maps=loc-r,morbid,gene&R1=on&query=TP53&VERBOSE=ON&ZOOM=3
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=retrieve&dopt=default&list_uids=242
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9618483
12R-Hete again.
******************
Will we find that a low dose cocktail of IL-10, sunshine and some
fraction
of plant oil will keep us nearly clear?
Time will tell. There will come a day when some psoriatic will get
that IL-10 virus drug and he or she may clear up and his doctor will
know.
And you know before the fact, so keep your eyes open.
randall.... strange how these things get going and stoP!
randall
Hi,
Three brand new psoriasis abstracts hot off the pubmed site.
Are they really big ones?
I don't know. But I hope something in one of them will lead someone
to a cure or better drug.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15863843
The Expression of p63 during Epidermal Remodeling in Psoriasis.
Shen CS, Tsuda T, Fushiki S, Mizutani H, Yamanishi K.
Department of Pathology and Applied Neurobiology, Kyoto Prefectural
University of Medicine, Graduate School of Medical Science, Kyoto,
Japan.
Psoriasis is a skin disorder of chronic keratinization characterized by
epidermal hyperplasia, hyperkeratosis, and inflammation. However,
little is known about the mechanism (s) underlying the hyperplasia with
elongated rete ridges characteristic of psoriasis. The p63
transcription factor, a homologue of the p53 tumor suppressor, has been
implicated in the maintenance of epidermal stem cells and the
stratification of the epidermis. p63 is up-regulated in squamous cell
carcinomas with anaplasia, suggesting that it is also associated with
epidermal hyperplasia. In this study, we examined the expression of p63
in the remodeling of psoriatic epidermis. Lesional tissues from 17
psoriasis patients in various stages of plaque-type psoriasis and
normal skin tissues from five healthy subjects were examined by
immunohistochemistry using a monoclonal anti-p63 antibody. Normal
epidermis stained positively for p63 in the basal cell layer and in 2
to 4 layers of the spinous cell layer. p63 was positive in the
thickened rete ridges of the epidermis even in early psoriatic lesions.
As the epidermis elongated, p63-positive cells moved down and were
localized in the lower parts of the rete ridges where keratinocytes
densely proliferated. From these results, we suggest that p63 may be
involved in the early stage of the remodeling process of the psoriatic
epidermis as well as in the elongation of the rete ridges.
PMID: 15863843
We've had a lot of P53 around here. Not much p63 that comes to mind.
Oh for joy! :(
One more gene to scratch over. And whats a rete ridge?
http://www.footpathlab.com/photos3.htm
Oh.
I'm guessing that my rete ridges aren't uP to sPeck.
Lets look at two more pubmed hits for p and P63,
Analysis of 14-3-3sigma expression in hyperproliferative skin diseases
reveals selective loss associated with CpG-methylation in basal cell
carcinoma.
Lodygin D, Yazdi AS, Sander CA, Herzinger T, Hermeking H.
Molecular Oncology, Max-Planck-Institute of Biochemistry, Am
Klopferspitz 18A, D-82152 Martinsried near Munich, Germany.
The p53-regulated 14-3-3sigma gene encodes an inhibitor of cell cycle
progression essential for senescence and clonal evolution of
keratinocytes in vitro. Here we analysed the in vivo expression of
14-3-3sigma protein in several skin diseases, which are characterized
by hyperproliferative keratinocytes. Unexpectedly, the 14-3-3sigma
protein was expressed at high levels in psoriasis (11 of 11 patients),
condylomata acuminata (11/11), actinic keratoses (11/11) and squamous
cell carcinomas (SCC) (11/11). However, keratinocytes that had
undergone transformation to basal cell carcinoma (BCC) showed partial
(10 of 41; 24.4%) or complete (19 of 41; 46.3%) loss of 14-3-3sigma
protein expression. BCC (5/5), SCC (6/6) and actinic keratoses (7/7)
concomitantly expressed the p53-homolog p63 and 14-3-3sigma at high
levels, ruling out potential inhibitory effects of p63 isoforms on
14-3-3sigma transcription as the basis for loss of 14-3-3sigma
expression. Of 41 BCC samples isolated by laser-capture
microdissection, 28 (68.3%) showed CpG-hypermethylation of the
14-3-3sigma promoter combined with reduced or absent 14-3-3sigma
protein levels in 22 cases (78.6%). Since it has been reported that BCC
retain wild-type p16(INK4A) and here BCC with CpG-methylation of
14-3-3sigma did not show CpG-methylation of p16(INK4A) (0/17),
silencing of 14-3-3sigma may contribute to evasion of senescence in
BCC. As experimental removal of 14-3-3sigma sensitizes to DNA damage,
silencing of 14-3-3sigma may explain the high efficacy of radiation
therapy in the treatment of BCC.
PMID: 12934112
Matrix metalloproteinase-19 is expressed by keratinocytes in psoriasis.
Suomela S, Kariniemi AL, Impola U, Karvonen SL, Snellman E, Uurasmaa T,
Peltonen J, Saarialho-Kere U.
Department of Dermatology, Helsinki University Central Hospital,
Helsinki, Finland.
Keratinocyte hyperproliferation, inflammatory infiltrates,
neoangiogenesis and alterations in cytokine levels are hallmarks of
psoriatic skin. Matrix metalloproteinases (MMPs) have been associated
with the remodeling of the extracellular matrix during inflammation,
neovascularization, and malignant transformation. We have previously
shown that particularly MMP-12 is abundantly expressed by macrophages
and MMP-9 in macrophages and neutrophils of psoriatic lesions. In this
work the expression of two novel metalloproteinases, MMP-19 and MMP-28,
was investigated in psoriatic lesional and non-lesional skin. MMP-19
protein was detected by immunohistochemistry in 28/29 samples in
keratinocytes in the same regions as Ki67 (marker of proliferating
keratinocytes) and p63 (marker of keratinocyte stem cells).
Immunosignaling was also seen in endothelial cells and fibroblasts.
Furthermore, MMP-19 mRNA was upregulated in psoriatic keratinocytes and
skin as assessed by quantitative real-time polymerase chain reaction.
In lichen planus and lichenoid chronic dermatitis, MMP-19 staining was
found in keratinocytes in areas where the basement membrane was
abnormal. MMP-28 was not detected in psoriatic or non-lesional skin.
Our results suggest that keratinocytes as well as the previously
reported cell types (smooth muscle, endothelial and macrophages) can
express MMP-19 in psoriasis and lichen planus. Upregulation of MMP-19
in keratinocytes may be influenced by changes in the architecture of
the basement membrane zone.
PMID: 12735638
Maybe this next one will have more meat.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15863863
Autoantibodies other than antineutrophil cytoplasmic antibodies are not
positive in patients with psoriasis vulgaris.
Kutukculer N, Yuksel SE, Aksu G, Alper S.
Ege University Faculty of Medicine, Department of Pediatrics, Izmir,
Turkey.
There is a great deal of evidences that a link may exist between
psoriasis and autoimmunity. In this study, thirty-six patients with
psoriasis vulgaris and twenty healthy controls were screened for
antinuclear antibody (ANA), anti-ds-DNA antibodies, anti-SSA (anti-Ro),
anti-SSB (anti-La), anti-Scl-70, anti-Jo-1, rheumatoid factor (RF), C3
and C4 levels, IgG and IgM anti-cardiolipin antibodies (aCL) and
anti-neutrophil cytoplasmic antibodies (pANCA and cANCA) in order to
determine the role of autoimmunity in the pathogenesis. In addition,
the MPO-ANCA test was performed on pANCA-positive patients. In ANA
screening, one patient showed 1/80 granular positivity. No positive
results were obtained from either the study or control groups for
anti-dsDNA, anti-SSA, anti-SSB, anti-Scl-70, or anti-Jo-1
determinations. For RF, 5.8% of the patients had positive values. Both
C3 and C4 levels were found to be significantly elevated in psoriasis
patients compared to healthy controls (p<0.001). IgG-aCL and IgM-aCL
positivity was not significantly different between the two group. pANCA
was positive in 33.3% of the patients and a significant difference was
observed between study and control groups (p<0.05). MPO-ANCA was
negative in all the pANCA-positive patients. In conclusion, only serum
C3 and C4 levels and pANCA determinations showed significant
differences when compared to healthy controls. Our findings may be
evidence of associations between autoimmunity and psoriasis vulgaris.
However, more detailed studies in this field need to be done to
determine the relationship between them.
PMID: 15863863
C3 and C4. Ok. First time we saw that was in the Good article thread.
So pANCA is the next thing to look at. And we find it in gut problems
like Ulcerative colitis.
Molecular mimicry may contribute to pathogenesis of ulcerative colitis.
Kovvali G, Das KM.
UMDNJ-Robert Wood Johnson Medical School, Crohn's and Colitis Center of
New Jersey, New Brunswick, NJ 08903, United States.
Ulcerative colitis (UC) is a chronic inflammatory bowel disease with
mucosal inflammation and ulceration of the colon. There seems to be no
single etiological factor responsible for the onset of the disease.
Autoimmunity has been emphasized in the pathogenesis of UC. Perinuclear
anti-neutrophil cytoplasmic antibodies (pANCA) are common in UC, and
recently two major species of proteins immunoreactive to pANCA were
detected in bacteria from the anaerobic libraries. This implicates
colonic bacterial protein as a possible trigger for the
disease-associated immune response. Autoantibodies and T-cell response
against human tropomyosin isoform 5 (hTM5), an isoform predominantly
expressed in colon epithelial cells, were demonstrated in patients with
UC but not in Crohn's colitis. We identified two bacterial protein
sequences in NCBI database that have regions of significant sequence
homology with hTM5. Our hypothesis is that molecular mimicry may be
responsible for the pathogenesis of UC.
PMID: 15848155
Mimicry, now we're talking. But if there was one, why hasn't it
been found? Not that there aren't loads of scientists looking.
A bunch of gut hits in this pANCA site,
http://www.euroimmun.de/anca_engl.htm
If I had a gut hunch i'd say that some transcription gizmo was
going gonzo in the guts. But is it the P gut gizmo? and does it mimic?
and how does it become toPical?
****
Moving on to Vitamin D. Good thing someone is messing around with it.
Doesn't it seem like a target rich area? Sure does to me.
This study appears to be looking for a connect in folks who don't
have any family history of psoriasis. That would be a neat find and
probably tie up a bunch of loose ends, and explain others.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15864137
Vitamin D receptor gene polymorphisms, particularly the novel A-1012G
promoter polymorphism, are associated with vitamin D3 responsiveness
and non-familial susceptibility in psoriasis.
Halsall JA, Osborne JE, Pringle JH, Hutchinson PE.
aDepartment of Cancer Studies and Molecular Medicine, University of
Leicester, Leicester bDepartment of Dermatology, Leicester Royal
Infirmary, Leicester, UK.
Psoriasis is a genetically determined disease characterized by
hyperproliferation and disordered maturation of the epidermis. Th1
lymphocytes are implicated in its pathogenesis. The vitamin D receptor
(VDR) is a candidate modifying gene, having immunosuppressive effects
and being involved in anti-proliferative and pro-differentiation
pathways in keratinocytes. There is suggestive evidence that the A
allele of the A-1012G polymorphism is associated with down-regulation
of the Th1 response, via GATA-3. The F and T alleles of Fok1 and Taq1
have been associated with increased VDR activity. The present study
aimed to test the hypothesis that the A allele of A-1012G is protective
for occurrence and severity of psoriasis and enhances therapeutic
response to vitamin D analogues and that these effects would be
additive to those of Fok1 and Taq1. The study group comprised 206
psoriasis patients who had received topical calcipotriol treatment and
80 controls. There was no significant linkage disequilibrium between
any pair of the three polymorphic sites (P=0.3-0.8). The A, F and T
alleles were positively associated with calcipotriol response: AA
genotype (compared to AG/GG), odds ratio (OR)=2.18 (P=0.04); TT,
OR=1.97 (P=0.03); AAFF genotype combination, OR=4.11 (P=0.03); AATT,
OR=5.64 (P=0.005); and FFTT, OR=3.22 (P=0.01). Comparing patients
without, to patients with, a family history of psoriasis, the A allele
was under represented (P=0.01) and the AAFF genotype combination even
more so (compared to residual genotypes) (OR=0.24; P=0.005). AAFF was
also under-represented in patients without a family history compared to
controls (OR=0.31; P=0.04). There were no associations of family
history with Fok1 and Taq1. There were no associations of severity of
psoriasis with any polymorphism. In conclusion, the A-1012G, Fok1 and
Taq1 VDR polymorphisms were associated with response to calcipotriol.
A-1012G and Fok1 were associated with susceptibility to non-familial
psoriasis.
PMID: 15864137
****************************
Seems like they left room for future studies.
randall... here I am, come look at my mimics and genes in the sunlight.
randall
New abstract from a Geneticist that works with the NPF.
(Please continue to support the NPF with $$$$$ www.psoriasis.org )
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15869413
The Genetics of Psoriasis and Autoimmunity.
Bowcock AM.
Department of Genetics, Washington University School of Medicine, St.
Louis, MO 63110 bow...@genetics.wustl.edu.
Psoriasis is an inflammatory/autoimmune disease and, as with many
autoimmune diseases, is associated with alleles from the major
histocompatibility complex (MHC).With psoriasis and autoimmune disease,
the penetrance of the MHC associated alleles is never 100%, even for
monozygotic twins, because development requires additional
environmental and/or genetic modifiers. Families segregating single or
multilocus susceptibility alleles other than the MHC have also been
reported. Overlapping genetic locations of loci for different
autoimmune diseases have been known for several years and are starting
to reveal common genes or genetic variants. These include genes
normally involved in preventing spontaneous T-cell activation or
proliferation, immune synapse formation, or cytokine production via
pathways such as those mediated by NFkappaB and those involved in
thymic selection. Autoimmunity may also involve dysregulation of genes
or pathways regulated by the RUNX family of transcription factors. RUNX
is involved in hematopoietic cell development, development of T cells
in the thymus, chromatin remodeling, and gene silencing. Hence, its
effect on cells of the immune system may be due to variable changes in
gene expression and could account for variable body surface involvement
and waxing and waning of disease. Expected online publication date for
the Annual Review of Genomics and Human Genetics Volume 6 is August 30,
2005. Please see http://www.annualreviews.org/catalog/pub_dates.asp for
revised estimates.
PMID: 15869413
Is MHC the wild card for how severe your P is? Keep those bucks $$$
flowing to
the NPF and we may find out sooner rather then later. :)
This next one exonerates uvb somewhat. From San Francisco derm KOO.
UVB phototherapy and skin cancer risk: a review of the literature.
Lee E, Koo J, Berger T.
>From the University of California, Department of Dermatology, Psoriasis
Treatment Center, San Francisco, California, USA.
Abstract Background UVB phototherapy is a common treatment modality for
psoriasis and other skin diseases. Although UVB has been in use for
many decades, many clinicians are hesitant to use this type of
phototherapy because of concern over increasing the skin cancer risk.
Over the past 20 years, numerous studies have been published examining
this issue, but a consensus or analysis of the skin cancer risk is
required for the dermatologist to make an educated risk-benefit
analysis. Objective To assess the risk of skin cancer associated with
UVB phototherapy. Methods All prospective or retrospective studies were
identified in MEDLINE from 1966 to June 2002. Bibliographies were
searched to identify any additional studies examining this issue. All
studies that attempted to quantify or qualify any additional skin
cancer risk from UVB phototherapy were included. Study selection was
performed by two independent reviewers. Results Eleven studies (10 of
which concerned psoriasis patients), involving approximately 3400
participants, were included. Of note, three of the studies involved the
same cohort: members of the 16-center US Psoralen plus UVA (PUVA)
Follow-up Study. Other than the most recent Finnish study, all studies
eventually showed no increased skin cancer risk with UVB phototherapy.
One of the PUVA cohort studies examined genital skin cancers, and found
an increased rate of genital tumors associated with UVB phototherapy,
although this study has not been duplicated. Conclusion The evidence
suggests that UVB phototherapy remains a very safe treatment modality.
PMID: 15869531
Its good info. Ann Bowcock is closing in on the genes and Koo is
keeping us safe to use uvb/puva in the meantime.
randall... whats not to like?
randall
Someone out there is using the web for psoriasis.
Thank-you MP!
http://www.wpherald.com/storyview.php?StoryID=20050504-101423-6001r
(...)
Also on the federal level, the Internet has been valuable in raising
awareness of the immune disease psoriasis.
"I believe the Internet is an effective, low-cost way to show members
of Congress that their constituents care about an issue," said Michael
Paranzino, a spokesman for Psoriasis Cure Now!, a non-profit group in
Kensington, Md.
"In our case, the psoriasis community is trying to break into
Congress for the first time in recent memory, using Web tools to have
psoriasis patients write their lawmakers. We are forcing every
congressional office, for the first time in years, to figure out what
psoriasis is and how to respond to constituents writing in about it,"
Paranzino said.
(...)
How many psoriatics are there?
http://www.medicalnewstoday.com/medicalnews.php?newsid=23778
Psoriasis group calls on CDC to end confusion over number of Americans
with psoriasis
03 May 2005
How many Americans have psoriasis? Is it "as many as 7.5 million,"
"5 million" or some other number? Both of those figures have
appeared recently in media reports on psoriasis, and millions of
dollars in medical research funding may ride on the answer. To find the
answer, Psoriasis Cure Now, a patient advocacy group, today launched an
effort to get the Centers for Disease Control and Prevention (CDC) to
conduct a definitive count of Americans with psoriasis.
"No one seems to be able to agree how many Americans have psoriasis,
and this confusion may be hurting us in Congress," said Michael
Paranzino, president of Psoriasis Cure Now. "One of the most frequent
questions I get asked on Capitol Hill is how many Americans have the
disease, and the number of people impacted by a disease clearly affects
its research funding. Given that psoriasis research funding is down 8%
over the last decade as medical research funding for other diseases is
up 99%, it's time to get this question answered accurately."
The National Institutes of Health's (NIH) National Institute of
Arthritis and Musculoskeletal and Skin Diseases says that there are
"between 5.8 and 7.5 million" Americans with psoriasis, but some
reports continue to suggest there are 4.5 million or 5 million
Americans with the disease. Part of the confusion comes from studies
that exclude all children, or exclude anyone with the disease who does
not have a physician's diagnosis to back it up, even though a group of
dermatologists and primary care physicians recently surveyed by
Datamonitor estimated as many as half of psoriasis patients may be
undiagnosed.
"No one should be using figures that exclude my daughter Jessica or
the hundreds of thousands of other children who have psoriasis," said
Marielle Gagarin of Grand Rapids, Michigan, whose nine year-old
daughter has had severe psoriasis for three years. "We need the
government to determine once and for all how many Americans of all ages
have psoriasis and to commit the research funding to find a cure for
this debilitating and currently incurable disease."
Psoriasis Cure Now has launched an e-petition enabling Americans to
urge the CDC to conduct an accurate count of all psoriasis patients,
including children, as well as adults who have the disease but have not
been seen by a doctor for it. It also asks CDC to determine how many
Americans have psoriatic arthritis, another poorly-understood disease.
CDC is currently preparing to release data on psoriasis, but its study
reportedly will exclude everyone under age 20 and over age 59, meaning
millions of psoriasis patients will be missed. The e-petition letter to
CDC is available here: http://capwiz.com/psorcurenow/home .
Psoriasis is an incurable, recurring disease of the immune system that
can first strike at any age, causing dry, painful skin lesions that can
crack, bleed and itch. Many people with psoriasis also have psoriatic
arthritis, a chronic, progressive and debilitating inflammatory disease
that often causes joint pain, stiffness and swelling, as well as bone
damage.
Michael Paranzino
Psoriasis Cure Now
202-253-4863
mic...@psorcurenow.org
http://www.psorcurenow.org
^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^
Speak uP and hoPefully they will hear.
randall... Michael P sPeaks loudly! Thanks Michael.
randall
First a touching P personal story from Las Vegas and
then a possible stock pick.
http://www.klas-tv.com/Global/story.asp?S=3312481&nav=168XZZKe
Psoriasis' Affect On Intimate Relationships
May 6, 2005, 06:29 PM
We've all heard of psoriasis, but few know exactly what it is. It's a
skin condition marked by itching and burning lesions -- lesions that
can appear anywhere on the body. It's not contagious, but the nature of
psoriasis can put a strain on intimate relationships.
Henderson Rabbi Mendy Harlig developed psoriasis after moving to
southern Nevada. It became progressively worse and treatments weren't
helping. "Within 3 or 4 years it was all over my body," he said.
Rabbi Harlig has now found relief with a new injectable biologic called
Raptiva. Unfortunately, it's not a cure.
Chaya Harlig, the rabbi's wife, says, "You can say it's not a pretty
sight."
The rabbi has 4 children with wife Chaya, and number five is on the
way. Her husband's condition is impossible to ignore. Some spouses
would be turned off. But Chaya looks past it.
"There's such a strong bond, it isn't about outer appearances. And it
isn't about what's on the body. It's about what's inside a person. And
once you make that bond and connection, and it's so strong, the outer
things do not bother you when things come up like that," Chaya said.
Relationship therapist and author Ava Cadell says psoriasis can take a
toll on a relationship if the patient loses self-confidence. "In fact,
recently, there was a survey said that people with psoriasis felt
completely isolated. And they often suffer from depression too."
Rabbi Harlig adds, "It definitely looks contagious. It looks scary."
Chaya Harlig recommends, "I would say that the other spouse has to be
gentle and understanding and try to help as much as they could with
making them comfortable. Because my husband was very uncomfortable for
a very long time with it on him."
New treatments mean things are looking up. Henderson dermatologist
Johnnie Woodson is working with Rabbi Harlig.
Dr. Woodson says, "Now with the invention of the biologic medications,
we can help a lot more people. We just need to get the word out."
Two new treatments are Raptiva, an injectable, and,
http://my.webmd.com/hw/health_guide_atoz/hw215947.asp
photochemotherapy, or PUVA. PUVA is a combination of ultaviolet A (UVA)
light therapy and a psoralen medication
**************************
http://biz.yahoo.com/prnews/050506/laf060.html?.v=7
Astralis Announces Presentation of Phase II Results at 66th Society for
Investigative Dermatology Meeting
Friday May 6, 4:59 pm ET
FAIRFIELD, N.J., May 6 /PRNewswire-FirstCall/ -- Astralis Ltd (OTC
Bulletin Board: ASTR - News) announced today that the results of its
120 patient, 11 site, multi-dose Phase II clinical trial of
Psoraxine®, its product for the treatment of psoriasis, was presented
at the Society of Investigational Dermatology meeting in St. Louis, MO,
on Friday, May 6, 2005. The report authored by Dr. James Kreuger,
Professor and Medical Director of Investigative Dermatology at
Rockefeller University, and Dr. Bruce Miller, MD at Oregon Medical
Research Center, presents both PASI (Psoriasis Area Severity Index) and
patient biopsy results, respectively the primary and secondary
endpoints of the trial.
Although the six injection, twenty week trial of Psoraxine® did not
demonstrate a statistically significant clinical improvement in PASI
scores compared to placebo, the trial again confirmed the safety of the
product for human use. Upon more detailed analysis of both PASI and
biopsy results, the Company has observed specific data that has led it
to conclude that the product is active, although not at the level it
expected.
Following analysis of the clinical trial design, manufacturing process
and product formulation data, Astralis has identified several factors
including the limited number of injections used and the formulation of
the active components of the product that may have contributed to the
unexpected results of the Phase II trial. Based on these analyses, the
Company remains committed to the development of Psoraxine®, and is
embarking on a program to improve the performance of its treatment for
psoriasis.
"We continue to be encouraged by the safety profile demonstrated by the
product", remarked Dr. Jose O'Daly, Chairman and CSO of Astralis. "In
140 patients in two clinical trials in the United States no serious
adverse events related to the product were reported. The demonstrated
lack of significant side-effects in the United States trials and in
prior Venezuelan trials suggests we can continue clinical testing of
our current product, AS210, while we also work on improving its
efficacy". The most commonly reported adverse events were headache, and
injection site pain and tenderness.
With respect to the trial's overall results, Dr. Gordon Schooley, Chief
Scientific Officer of SkyePharma and a member of Astralis' Board of
Directors, said "Despite the lack of statistically significant
differences in PASI scores, the primary endpoint, the performance of a
300 microgram dose of AS210 appeared more active than either of the
other two doses of AS210. We are hopeful that changes in the protocol
such as optimizing the administration technique and dosing regimen can
improve product efficacy in the treatment of psoriasis."
James Sharpe, President & CEO of Astralis said that "Astralis continues
to believe that the results seen previously in Venezuela can be
reproduced in the United States, and feels that the Phase II data
provides important information about the active components,
formulation, dosing frequency and other variables necessary to optimize
the product's performance".
This press release may contain forward-looking statements regarding
Astralis Ltd. Clinical results may differ materially from those
described in the press release as a result of a number of factors.
There can be no assurance that PSORAXINE(TM) will be successfully
developed or manufactured, or that final results of human clinical
trials will result in the regulatory approvals required to market
products, or that final regulatory approval will be received in a
timely manner, if at all, or that patient and physician acceptance of
this product will be achieved. Astralis Ltd undertakes no obligation to
revise or update any such forward-looking statement to reflect events
or circumstances after the date of this release.
Notes to the Editor
Astralis Ltd, a biotechnology company based in New Jersey, focuses on
the research and development of novel treatments for immune system
disorders and skin diseases. Psoraxine(TM), the company's first product
candidate, is an innovative drug under development for psoriasis, and
is based on the discovery of a proprietary protein extract. For more
information, visit Astralis' web site at www.astralisltd.com.
Psoriasis
Psoriasis is a chronic, genetically based remitting and relapsing scaly
and inflammatory skin disorder that affects approximately 3% of the
world's population. Psoriasis symptoms result from the overproduction
of skin induced by blood cells associated with the immune system. These
blood cells are over- stimulated and act as though the skin was
damaged, manufacturing skin cells at a much faster rate than is
required by undamaged skin. The overproduction of skin can cause a
range of symptoms including itchy rash like patches, painful pustules
and massive inflammation.
Additional information can be obtained from:
US National Psoriasis Foundation at www.psoriasis.org
International Federation of Psoriasis Associations at
www.ifpa-pso.org
((((((((((((((((((((((((((((((((((((((((((((((((((..))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))
With Dr. Kreuger behind this and the recent price, ($.35)
http://finance.yahoo.com/q?s=astr.ob&d=t
I'm not so sure you wouldn't want to put $1,000.00 on this one.
I have a good feeling with Dr. Jose O'Daly. He seems like a real stand
up guy.
randall
randall
MsbA flips lipopolysaccharide (LPS)!!!!
But does it flip for P? Is our MsbA fliPPer broke? Bent, spent or
dented?
What will this mean for psoriasis? Toll like receptor 4 (TLr-4) may be
as important as
TLr5 and Tlr9. Those both being brought to light in recent research
with LPS and
other factors.
http://www.medicalnewstoday.com/medicalnews.php?newsid=24338
or http://www.eurekalert.org/pub_releases/2005-05/sri-ssd051105.php
Scientists at The Scripps Research Institute have solved the structure
of a protein called MsbA that is involved in resisting antibiotics and
chemotherapy.
[snip]
However, another way that bacteria resist antibiotic drugs is by using
membrane transporters -- large proteins that sit in the cell membrane
and move other molecules in and out of the cell.
One of these transporters, the structure of which is the subject of
Chang and Reyes' recent Science paper, is called MsbA. It belongs to
the ATP Binding Cassette (ABC) transporter molecule family. ABC
transporters are ubiquitous on the cell surfaces of almost all
organisms. This is one of the largest superfamilies of transporter
molecules. They transfer drugs, sugars, and peptides in organisms from
bacteria to humans.
MsbA molecules play an essential role for bacteria because they help
them build their cell walls by flipping molecules like
"lipopolysaccharide" (LPS) and "lipid A" from the inner membrane to the
outer membrane. These molecules are components of bacterial cell walls,
and flipping them from the inner to the outer membrane of bacteria is
necessary for bacterial cell growth.
The structure is important for a number of reasons. One is that solving
the structure helped Chang and Reyes to propose a mechanism by which it
works. The structure of MsbA is a dimer with two identical subunits.
These subunits stretch across the cell membrane, coming together at the
top (outside of the cell) and opening up like two outstretched arms on
the inside of the cell.
Significantly, the structure is trapped in what they call a
"post-hydrolysis" state -- basically caught in the act of flipping an
LPS molecule. "You get to see the molecule half-cocked in action, just
before the lipid is flipped outside," says Chang.
When the arms encounter LPS or lipid A, they close around the polar
part of the amphipathic molecule, flip it over, and send it through the
top to the other side of the membrane. This is most likely the same
thing that happens when other drug pumps transport antibiotics out of
the cell, and the structure of MsbA may help scientists design
compounds to block its action. Coming up with a way to block this
transporter would potentially make antibiotics more potent.
Any potential MsbA blocker might also have the dual effect of weakening
the bacteria since many different bacteria use the same transporters
for flipping LPS out of the cell and erecting a major barrier that
blocks antibiotics from entering. Blocking MsbA could prevent this.
"It's an Achilles heel," says Chang. "Without being able to flip LPS
outside, a bacteria cannot build its outer membrane."
[snip]
***********
A former poster to this group has reported that remicade and laser
treatment has
given exlnt results. So much so he suggested feigning arthritis to get
the
remicade.
***************
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15888146
Overexpression of tumour necrosis factor-alpha-converting enzyme in
psoriasis.
Kawaguchi M, Mitsuhashi Y, Kondo S.
Department of Dermatology, Yamagata University School of Medicine,
2-2-2 Iida-Nishi, Yamagata 990-9585, Japan.
Summary Background Tumour necrosis factor (TNF)-alpha-converting enzyme
(TACE) is a metalloproteinase-disintegrin that releases soluble
TNF-alpha from cells by cleaving within the extracellular domain of
membrane-bound pro-TNF-alpha. It was proposed that TNF-alpha is
involved in the pathogenesis of psoriasis, and it is therefore
suggested that TACE has important roles in psoriasis. However, it is
unclear whether TACE is expressed in psoriatic tissue. Objectives To
clarify whether TACE is expressed in psoriatic lesions and whether
expression levels of TACE mRNA are increased in lesional compared with
nonlesional psoriatic skin. Methods Skin biopsies were obtained from
patients with psoriasis. We examined the expression of TACE in
psoriatic tissues using a novel real-time quantitative reverse
transcriptase-polymerase chain reaction method and immunohistochemical
analysis. Results There was a significant rise in the level of TACE
mRNA expression in lesional psoriatic skin compared with nonlesional
skin in all patients. There was a statistically significant rise in the
level of TACE mRNA expression in lesional psoriatic skin compared with
nonlesional skin (mean +/- SD TACE/glyceraldehyde-3-phosphate
dehydrogenase ratio 0.031 +/- 0.012 vs. 0.009 +/- 0.002, P < 0.05). In
lesional psoriatic skin, immunostaining with anti-TACE antibody was
present throughout all layers of the epidermis. TACE immunostaining was
found in the cytoplasm of keratinocytes. There was staining associated
with blood vessels in the papillary dermis and perivascular
inflammatory cells. In particular, mast cells showed strong staining.
They contained numerous granules that were stained for TACE in the
cytoplasm. Conclusions The findings of the present study suggest that
elevation of TACE mRNA in psoriatic lesions is due to many cells,
particularly mast cells, that function in lesional psoriatic skin as an
important source of TNF-alpha and other cytokines.
PMID: 15888146
If your over Ten% your severe,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15888138
Get lubed with vaseline before doing UVB TL01 therapy,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15888130
UVB coaxes IL-10,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15889264
Narrowband-UVB irradiation decreases the production of pro-inflammatory
cytokines by stimulated T cells.
Sigmundsdottir H, Johnston A, Gudjonsson JE, Valdimarsson H.
Department of Immunology, Landspitali-University Hospital, Hringbraut,
101, Reykjavik, Iceland, and...@landspitali.is.
Narrow-band ultraviolet B (UVB) phototherapy is an effective treatment
for psoriasis. Owing to its limited penetration, the direct effects of
UVB are mostly restricted to cells residing in the epidermis and
papillary dermis, and are associated with epidermal depletion of
Langerhans' cells (LC) and T cells. It has been argued that the
depletion of the skin-resident T-cell population may be due to a
combination of UVB-induced apoptosis and decreased recruitment from the
blood due to lower expression of the required adhesion and homing
molecules. We have previously demonstrated that UVB treatment can alter
the expression of adhesion molecules by blood lymphocytes, and as these
can be influenced by cytokines, the aim of this study was to
investigate whether UVB irradiation can also influence the cytokine
production of circulating T cells. Four patients with active chronic
plaque psoriasis were treated daily with narrow-band 312 nm UVB
irradiation and blood samples obtained before treatment and weekly
thereafter for 2 weeks. Peripheral blood mononuclear cells (PBMCs) were
isolated and cultured with a streptococcal superantigen or a
conventional streptococcal antigen preparation, and cell culture
supernatants were assayed for various cytokines. When stimulated with
the superantigen, PBMCs from UVB-treated psoriasis patients secreted
greater amounts of the anti-inflammatory cytokine IL-10, and showed
markedly decreased production of IL-1beta, IL-2, IL-5 and IL-6 compared
to the pre-treatment values; the production of IFN-gamma, IL-8 and
IL-12p70 were also decreased but did not reach statistical
significance. Thus, the combination of UVB-induced apoptosis, increased
secretion of anti-inflammatory cytokines and decreased trafficking to
the skin may help to explain the beneficial effects of UVB treatment on
psoriasis and why disease remission can sometimes be sustained for a
prolonged period.
PMID: 15889264
Possible relations between the polymorphisms of the cytokines IL-19,
IL-20 and IL-24 and plaque-type psoriasis.
Koks S, Kingo K, Vabrit K, Ratsep R, Karelson M, Silm H, Vasar E.
[1] 1Department of Physiology, University of Tartu, Estonia [2] 3Centre
of Molecular and Clinical Medicine, University of Tartu, Estonia.
The aim of present study was to elucidate the role of the interleukin
(IL)-24 gene in predicting risk for plaque-type psoriasis and to
describe the linkage disequilibrium (LD) pattern emerging from the
genes of IL-19, IL-20 and IL-24. Genes encoding IL-19, IL-20 and IL-24
locate in the region q32 of chromosome 1. The association between the
single-nucleotide polymorphisms (SNPs) or haplotypes of the IL-24 gene
and the susceptibility of psoriasis was not found. However, a
significant protective effect of the combined haplotype CAAAC of IL-20
and IL-24 genes against plaque-type psoriasis was established (OR
0.154). Protective effect against psoriasis was also observed with
haplotype TGGGT (OR 0.591) and haplotype CGAGT (OR 0.457). Performing a
comprehensive analysis using the data regarding SNPs of IL-24 gene
together with the previously published data regarding IL-19 and IL-20
SNPs, we identified two haplotype blocks within the region q32 of
chromosome 1. The main result of the present study is that while the
IL-19/IL-20 extended haplotype CACCGGAA is a significant susceptibility
factor for psoriasis (previous study), IL-20/IL-24 haplotypes CAAAC,
TGGGT and CGAGT have a significant protective effect. Nevertheless,
family-based studies are required to confirm the impact of IL-19, IL-20
and IL-24 genes in the genetic predisposition for psoriasis.Genes and
Immunity advance online publication, 12 May 2005;
doi:10.1038/sj.gene.6364216.
PMID: 15889129
Arginase 1 overexpression in psoriasis: limitation of inducible nitric
oxide synthase activity as a molecular mechanism for keratinocyte
hyperproliferation.
Bruch-Gerharz D, Schnorr O, Suschek C, Beck KF, Pfeilschifter J,
Ruzicka T, Kolb-Bachofen V.
Research Group Immunobiology, University of Duesseldorf, Germany.
Abnormal proliferation of keratinocytes in the skin appears crucial to
the pathogenesis of psoriasis, but the underlying mechanisms remain
unknown. Nitric oxide (NO), released from keratinocytes at high
concentrations, is considered a key inhibitor of cellular proliferation
and inducer of differentiation in vitro. Although high-output NO
synthesis is suggested by the expression of inducible NO synthase
(iNOS) mRNA and protein in psoriasis lesions, the pronounced
hyperproliferation of psoriatic keratinocytes may indicate that iNOS
activity is too low to effectively deliver anti-proliferative NO
concentrations. Here we show that arginase 1 (ARG1), which
substantially participates in the regulation of iNOS activity by
competing for the common substrate L-arginine, is highly overexpressed
in the hyperproliferative psoriatic epidermis and is co-expressed with
iNOS. Expression of L-arginine transporter molecules is found to be
normal. Treatment of primary cultured keratinocytes with Th1-cytokines,
as present in a psoriatic environment, leads to de novo expression of
iNOS but concomitantly a significant down-regulation of ARG1.
Persistent ARG1 overexpression in psoriasis lesions, therefore, may
represent a disease-associated deviation from normal expression
patterns. Furthermore, the culturing of activated keratinocytes in the
presence of an ARG inhibitor results in a twofold increase in nitrite
accumulation providing evidence for an L-arginine substrate competition
in human keratinocytes. High-output NO synthesis is indeed associated
with a significant decrease in cellular proliferation as shown by
down-regulation of Ki67 expression in cultured keratinocytes but also
in short-term organ cultures of normal human skin. In summary, our data
demonstrate for the first time a link between a human inflammatory skin
disease, limited iNOS activity, and ARG1 overexpression. This link may
have substantial implications for the pathophysiology of psoriasis and
the development of new treatment strategies.
PMID: 12507903
I bring up this older abstract directly above, due to this next story.
Nitrolinoleic may be a P heart breaker. We make nitric oxide pretty
good.
http://www.pnas.org/cgi/content/full/101/32/11577
Dietary alpha-linolenic acid reduces inflammatory and lipid
cardiovascular risk factors in hypercholesterolemic men and women.
Zhao G, Etherton TD, Martin KR, West SG, Gillies PJ, Kris-Etherton
PM.
Department of Nutritional Sciences, The Pennsylvania State
University, University Park, PA, USA.
Alpha-linolenic acid (ALA) reduces cardiovascular disease (CVD)
risk, possibly by favorably changing vascular inflammation and
endothelial dysfunction. Inflammatory markers and lipids and
lipoproteins were assessed in hypercholesterolemic subjects (n = 23)
fed
2 diets low in saturated fat and cholesterol, and high in PUFA varying
in ALA (ALA Diet) and linoleic acid (LA Diet) compared with an average
American diet (AAD). The ALA Diet provided 17% energy from PUFA (10.5%
LA; 6.5% ALA); the LA Diet provided 16.4% energy from PUFA (12.6% LA;
3.6% ALA); and the AAD provided 8.7% energy from PUFA (7.7% LA; 0.8%
ALA). The ALA Diet decreased C-reactive protein (CRP, P < 0.01),
whereas
the LA Diet tended to decrease CRP (P = 0.08). Although the 2 high-PUFA
diets similarly decreased intercellular cell adhesion molecule-1 vs.
AAD
(-19.1% by the ALA Diet, P < 0.01; -11.0% by the LA Diet, P < 0.01),
the
ALA Diet decreased vascular cell adhesion molecule-1 (VCAM-1, -15.6%
vs.
-3.1%, P < 0.01) and E-selectin (-14.6% vs. -8.1%, P < 0.01) more than
the LA Diet. Changes in CRP and VCAM-1 were inversely associated with
changes in serum eicosapentaenoic acid (EPA) (r = -0.496, P = 0.016; r
=
-0.418, P = 0.047), or EPA plus docosapentaenoic acid (r = -0.409, P =
0.053; r = -0.357, P = 0.091) after subjects consumed the ALA Diet. The
2 high-PUFA diets decreased serum total cholesterol, LDL cholesterol
and
triglycerides similarly (P < 0.05); the ALA Diet decreased HDL
cholesterol and apolipoprotein AI compared with the AAD (P < 0.05). ALA
appears to decrease CVD risk by inhibiting vascular inflammation and
endothelial activation beyond its lipid-lowering effects.
PMID: 15514264
http://www.heartinfo.org/ms/news/518796/main.html
http://www.news-medical.net/?id=6167
&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15885077
Expression of hurpin, a serine proteinase inhibitor, in normal and
pathological skin: overexpression and redistribution in psoriasis and
cutaneous carcinomas.
Moussali H, Bylaite M, Welss T, Abts HF, Ruzicka T, Walz M.
Department of Dermatology, Heinrich-Heine University, Duesseldorf,
Germany.
Moussali H, Bylaite M, Welss T, Abts HF, Ruzicka T, Walz M. Expression
of hurpin, a serine proteinase inhibitor, in normal and pathological
skin: overexpression and redistribution in psoriasis and cutaneous
carcinomas.Abstract: Hurpin was identified by differential display
analysis studying UV-repressible genes in the keratinocyte cell line
HaCaT. We have previously reported that hurpin mRNA is overexpressed in
psoriatic skin compared to non-lesional or normal skin; hurpin inhibits
cathepsin L and that, after overexpression in keratinocytes, hurpin
decreases UV-induced apoptosis. To further study the expression of
hurpin, we have isolated monoclonal antibodies against hurpin and
analyzed its expression in normal and diseased skin by
immunohistochemistry (IHC). In the epidermis of normal skin, we found
hurpin to be mainly expressed in the stratum basale. In contrast, we
found an enhanced expression of hurpin in the stratum spinosum and
stratum granulosum in the majority of diseased skin samples. Within the
dermis of normal and diseased skin, hurpin was detected in sebaceous
and sweat glands, hair follicles, and endothelial cells of blood
vessels. Hurpin was localized in the cytoplasm in normal and diseased
skin. Additionally to IHC, we analyzed hurpin expression in selected
skin diseases by semiquantitative reverse-transcription polymerase
chain reaction. We found overexpression of hurpin mRNA in psoriasis,
squamous cell carcinoma (SCC), and actinic keratosis. In contrast,
expression of hurpin in melanoma and basal cell carcinoma was
comparable to that in normal skin. Overall, the strongest
overexpression was observed in SCC and psoriasis. Individual
differences in hurpin expression between patients were observed. The
increased expression and redistribution of hurpin in diseased skin
suggests its possible involvement in inflammatory processes or the
regulation of endogenous or pathogen-derived proteinase activity.
Additional studies will elucidate the physiological role of hurpin.
PMID: 15885077
http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=604445
*604445 Links
PROTEASE INHIBITOR 13; PI13
Alternative titles; symbols
SERINE PROTEASE INHIBITOR, CLADE B, MEMBER 13; SERPINB13
HURPIN
HEADPIN
Gene map locus 18q21.3
<snip>
http://www.ncbi.nlm.nih.gov/Omim/getmap.cgi?l604445
http://www.ncbi.nlm.nih.gov/Omim/getmap.cgi?d7406
http://www.ncbi.nlm.nih.gov/mapview/maps.cgi?ORG=hum&CHR=18&maps=loc-r,morbid,gene&R1=on&query=SERPINB13&VERBOSE=ON&ZOOM=3
This headpin (hurpin, serine protease inhibitor et al) does scaly skin
disease (Comel-Netherton syndrome, ichthyosis linearis circumflexa;
ILC),
http://www.scalyskin.org/content.cfm?ContentID=90&ColumnID=14
A goof in this does that?
http://www.cryst.bbk.ac.uk/PPS2/course/section10/1hle.gif
Lets check netherton's,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15606522
&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&
And moving on with other odds and ends.
http://www.medadnews.com/News/Index.cfm?articleid=237662
Phase Forward's InForm(TM) electronic data capture (EDC) solution to
manage a randomized, controlled Phase II clinical trial of its
investigational oncology drug, TNFerade(TM). The trial will assess the
clinical benefit of using TNFerade in combination with standard care
treatment in patients with locally advanced pancreatic cancer. <snip>
TNFerade causes the production of Tumor Necrosis Factor-Alpha
(TNF-alpha) directly within the tumor and is intended for use with
standard chemotherapy and/or radiation to improve the clinical outcome
for patients. Pancreatic cancer, which is very hard to control with
current treatments and can be cured only when it is found at an early
stage, is currently the lead indication for TNFerade.
Some probiotic, prebiotic, gut, crohn's info,
http://www2.rnw.nl/rnw/en/features/science/050509rf?view=Standard
http://ard.bmjjournals.com/content/vol64/suppl_2/images/large/ar31120.f2.jpeg
http://ard.bmjjournals.com/cgi/content/full/64/suppl_2/ii30
Ab TLR4 anti-cd40
http://www.jimmunol.org/cgi/content/full/162/7/3749
Some search with IL-10 added in,
http://www.jimmunol.org/cgi/content/full/171/6/3119
^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^
http://news.biocompare.com/newsstory.asp?id=78017
<sniP>
called two-photon laser-scanning microscopy, it has revealed, for
example, the dramatic difference between the random wanderings of
immature T cells and the goal-oriented, beeline movement of activated T
cells.
"This is the first time anybody has quantitated four-dimensional data -
spatial and time data - to get a picture of long-range cell migrations
through tissue," said immunologist Ellen Robey, professor of immunology
at the University of California, Berkeley. "The ability to directly
visualize cells in living tissues has changed the way immunologists
think about how cells explore their environment, how they signal to
each other, and how they migrate."
(...)
With two-photon imaging, Witt and Robey identified thymus cells they
dubbed beeliners moving nearly two centimeters - almost an inch - per
hour, which is fast in the realm of cell movement. They think that
these are cells that have received a signal committing them to be
either a helper T cell - which aids other immune cells in fighting
infections - or a killer T cell that seeks and destroys cells infected
with virus.
On the other hand, uncommitted or immature T cells, what they call
meanderers, wander slowly and apparently randomly around the outer
layer, or cortex, of the thymus, perhaps in search of that
life-altering signal.
Robey hopes to use two-photon imaging to investigate the signals
responsible for changing these meanderers into purposeful beeliners
that immediately leave the cortex for the interior medulla of the
thymus.
"We're now at the point with this technology that we can begin to look
at the movement of signaling molecules within the cells," she said.
Robey, with another colleague, Philippe Bousso, last year published a
review in the journal Immunity describing the contributions two-photo
imaging has made to the field. Robey and Witt publish their current
study in the May 3 issue of the Public Library Of Science-Biology.
Two-photon imaging is a variation on the standard technique of labeling
cells with fluorescent dye and then hitting them with a laser that
makes the dye glow and the cells light up. A certain energy or color of
laser light is needed to make the dye, in this case green fluorescent
protein, glow. But high-frequency, short-wavelength visible light, like
green, doesn't penetrate tissue as deeply as longer, redder
wavelengths.
The idea behind two-photon imaging is that if you hit a dye molecule in
a short period of time with two photons of light, each photon half the
energy needed to excite it, the dye can absorb them together and then
fluoresce. The less energetic, long-wavelength photons will go deeper
into the tissue, cause less damage and scatter less, Robey said,
essentially illuminating slices through the tissue that can be sharply
imaged and stacked to produce a 3-D image of the cells in real time.
The system they use employs an infrared laser emitting short intense
pulses of 920 nanometer-wavelength light.
In the thymus, it's possible to view cells 400 microns inside the
cortex, which is about 4/10 of a millimeter or more than a hundredth of
an inch deep. In the current study, Witt limited her viewing to about
200 microns, though she says in some tissues less dense than the
thymus, light could penetrate nearly a millimeter - deep enough to
probe cell activity in most tissues.
Witt pointed out that obtaining a movie of cell movement is just the
beginning. The human eye and brain can't pick out patterns of movement
easily, so statistical techniques are needed to identify cells with
different patterns of movement.
As an immunologist, Robey focuses on the lives of T cells produced in
the thymus and distributed via the bloodstream to the lymph nodes,
whence they move into the body's tissues. Her first use of two-photon
imaging three years ago surprised her and many immunologists because it
showed that thymocytes or immature T cells were highly mobile,
traveling thousands of microns in an hour as they explore the thymus.
The new experiments, conducted primarily by Witt, suggest that this
exploration probably is a search for a signal that will decide the
cell's fate. In their experiments on one lobe of the mouse thymus, in
fact, Witt and her colleagues saw cells, possibly those that have made
a decision on their fate, halt their wanderings and make a beeline out
of the cortex to the medulla, something immature T cells can't do.
The scenario they've reconstructed from the video and mathematical
analysis starts with immature T cells moving out of the center of the
thymus, the medulla, to the very outside edge of the cortex, where they
proliferate and fill up the cortex. At this point, Witt said, they
undergo the first of two tests to see if their surface receptors
(called T cell receptors) work properly.
Once they pass that test, they start wandering around in the cortex
looking for the second test, which is to bind precisely to a protein
called the major histocompatibility complex (MHC). These cells, the
researchers think, are the meanderers. Only about one percent of
thymocytes pass both tests, but Witt and Robey think that those that do
are the ones they see beelining out of the cortex into the medulla to
begin their two-week education to distinguish "self" from "non-self"
invader.
"To pass into the medulla they have to pass a screening test called
positive selection," Witt said. "Once they do, the cells move very
directly at a very fast speed inward toward the medulla, adopting a
polarized shape characteristic of migrating cells."
While Witt and Robey continue their two-photon imaging studies of
thymus cells and lymph cells, Witt is trying to encourage the
technology's use in biology generally.
"Immunology is just one example of a subdiscipline of biology that
stands to benefit enormously from our new ability to see in
four-dimensions - in 3-D in real time. It opens an entirely different
universe to us," Witt said.
http://news.biocompare.com/newsstory.asp?id=78452
New research on a bacterium that can survive encounters with specific
immune system cells has strengthened scientists' belief that these
plentiful white blood cells, known as neutrophils, dictate whether our
immune system will permit or prevent bacterial infections. A paper
describing the research was released today online in The Journal of
Immunology. Frank R. DeLeo, Ph.D., of Rocky Mountain Laboratories
(RML), part of the National Institute of Allergy and Infectious
Diseases (NIAID) of the National Institutes of Health, directed the
work at RML, in Hamilton, MT, in collaboration with lead author Dori L.
Borjesson, D.V.M., Ph.D., of the University of Minnesota in St. Paul.
Scientists analyzed how neutrophils from healthy blood donors respond
to Anaplasma phagocytophilum, a tick-borne bacterium that causes
granulocytic anaplasmosis in people, dogs, horses and cows. A.
phagocytophilum is carried by the same tick that transmits Lyme disease
and was first identified in humans in 1996. Human granulocytic
anaplasmosis (HGA) -- formerly called human granulocytic ehrlichiosis
-- is prevalent in Minnesota and along the East Coast. HGA typically
causes mild symptoms that include fever, muscle aches and nausea. Some
362 U.S. cases were reported to the Centers for Disease Control and
Prevention in 2003.
HGA is considered an emerging infectious disease, and Dr. Borjesson is
working to understand how it affects blood cells -- and neutrophils in
particular. "Few people know about this pathogen, but it is important
because it is transmitted by ticks and causes disease in both animals
and humans," Dr. Borjesson says.
Neutrophils, which make up about 60 percent of all white blood cells,
are the largest cellular component of the human immune system --
billions exist inside each human. Typically, neutrophils ingest and
then kill harmful bacteria by producing molecules that are toxic to
cells, including a bleach-like substance called hypochlorous acid. Once
the bacteria are killed, the involved neutrophils self-destruct in a
process known as apoptosis. Recent evidence suggests that this process
is vital to resolving human infections.
A. phagocytophilum is unusual in that it can delay apoptosis in human
neutrophils, which presumably allows some of the bacteria to replicate
and cause infection.
"This particular bacterium specifically seeks out neutrophils --
possibly the most lethal of all host defense cells -- and remarkably,
can alter their function, multiply within them and thereby cause
infection," says NIAID Director Anthony S. Fauci, M.D.
Dr. DeLeo says the findings contrast with what is known about other
bacterial pathogens, most notably Staphylococcus aureus, which is of
great interest because of its increasing resistance to antibiotic
treatment. S. aureus, often simply referred to as "staph," are bacteria
commonly found on the skin and in the noses of healthy people.
Occasionally, staph can cause infection; most are minor, such as
pimples, boils and other skin conditions. However, staph bacteria can
also cause serious and sometimes fatal infections, such as bloodstream
infections, surgical wound infections and pneumonia.
In their experiments, the research team compared the neutrophil
response to A. phagocytophilum with that of a weak strain of S. aureus.
Using microarray technology that allowed them to compare about 14,000
different human genes, the researchers discovered how the response to
A. phagocytophilum deviates from that of S. aureus, and thus permits
the HGA agent to survive.
"This study has given us a global model of how bacteria can inhibit
neutrophil apoptosis," says Dr. DeLeo. "Our next step is to look at
specific human genes or gene pathways within this model and try to
determine which of these molecules help prolong cell life following
infection." Information gathered from these and similar studies, he
adds, could help researchers develop therapeutics to treat or prevent
bacterial infections.
http://news.biocompare.com/newsstory.asp?id=78469
More on methylation
*****************************************************************
[Cytofluorimetric assay for evaluation of CD16 receptor expression and
myeloperoxidase (MPO) activity of neutrophils in patients with
psoriasis vulgaris treated with PUVA]
[Article in Polish]
Kapuscinska R, Wysocka J, Niczyporuk W, Ratomski K.
Zakladu Laboratoryjnej Diagnostyki Pediatrycznej, Akademii Medycznej w
Bialymstoku. zld...@poczta.fm
Early histological changes indicate the collecting of neutrophils in
the stratum corneum, mainly in the acute psoriasis. Fc gammaRIIIB
(CD16) is the specific functional neutrophilic receptor, which is
responsible for phagocytosis. Myeloperoxidase (MPO) is granulocyte
enzyme playing main role in metabolic activity of neutrophils. We have
evaluated CD16 expression and MPO activity of polymorphonuclear
granulocytes in the acute psoriasis vulgaris and the influence of
photochemotherapy PUVA (psoralen plus ultraviolet light of A
wavelength) treatment on these parameters. The expression of CD16 and
MPO activity were significantly higher in neutrophils of patients after
PUVA.
PMID: 15865234
Neutrophils,
http://www.cat.cc.md.us/courses/bio141/lecguide/unit1/bacpath/ekill.html
Expanded search,
http://www.mcl.tulane.edu/classware/pathology/Krause/Blood/Blood.html
granulocyte enzyme
http://connection.lww.com/Products/porth_essentials/images/11_001_000.jpg
http://www.inderm.go.th/Health/knowledge/Skin2.jpg (stratum corneum)
CD16 (aka- Fc recePtor III ) has been on the radar forever,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Display&dopt=pubmed_pubmed&from_uid=678462&tool=ExternalSearch
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8156174&dopt=Abstract
http://pathologyoutlines.com/cdmarkers.html (CD finder- click # )
http://jtcs.ctsnetjournals.org/cgi/content/abstract/129/5/1137
MPO- myeloperoxidase
http://www.chmeds.ac.nz/research/freerad/tony.htm
C3-->C3a C5a etc,
http://connection.lww.com/Products/porth_essentials/images/08_012_000.jpg
MHC II
http://connection.lww.com/Products/porth_essentials/images/08_005_000.jpg
Skin healing (remember with P the process doesn't stop)
http://connection.lww.com/Products/porth_essentials/images/09_009_000.jpg
&&&&&&&&&&&&&&&&&&
Adenosine A2A activation during early reperfusion attenuated lung
inflammation and preserved pulmonary function in this model of lung
transplantation. ATL-146e and similar compounds could play a
significant role in improving outcomes of pulmonary transplantation.
H'mmmm,
http://www.biotechjournal.com/Journal/aug2002/augRes3text.htm
DM and DO shape the repertoire of peptide-MHC-class-II complexes.
Karlsson L.
Johnson & Johnson Pharmaceutical Research and Development, 3210
Merryfield Row, San Diego, CA 92121, USA. lkar...@prdus.jnj.com
The presentation of antigenic peptides by MHC class II molecules is
essential for activation of CD4+ T cells. The formation of most
peptide-MHC-class-II complexes is influenced by the actions of two
specialized accessory proteins--DM and DO--located in the
endosomal/lysosomal system where peptide loading occurs. DM removes
class-II-associated invariant-chain peptide (CLIP) from newly
synthesized class II molecules, but by now it is clearly established
that this is only a special case of the general peptide-editing
function of DM. Recent data have begun to explain the molecular basis
for the editing activity. The other accessory protein, DO, modulates DM
activity in vitro, but the physiological importance of DO is unclear.
New evidence from several laboratories has provided clues that may soon
change this.
PMID: 15653313
Functionally divergent T lymphocyte responses induced by modification
of a self-peptide from a tumor-associated antigen.
Hess AD, Thoburn CJ, Miura Y, Bright EC.
The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins
University, 1650 Orleans Street, Room 489, Baltimore, MD 21231, USA.
adh...@jhmi.edu
The N- and C-terminal flanking domains of the invariant chain peptide,
CLIP, have remarkable immunological properties. Addition of these
flanking domains to a foreign peptide antigen increases its immunologic
potency. The present studies evaluated whether altering a peptide
ligand from the tumor-associated antigen c-neu with the flanking
domains of CLIP could modify the systemic immune response. The results
indicate that the immunogenicity of an MHC class II restricted peptide
(NEU) derived from c-neu was significantly altered by addition of the
flanking domains from CLIP. Interestingly, selective modification of
the peptide with either the N- or the C-terminal flanking domains
resulted in functionally divergent systemic immune responses.
Immunization of normal F344 rats with the NEU peptide modified with the
N-terminal domain of CLIP (N-NEU) resulted in an immune response
primarily consisting of type 1 (IL-2, IFNgamma) cytokine producing T
cells. On the other hand, type 2 (IL-4) cytokine responses were largely
predominant following immunization with the self-peptide modified with
the C-terminal flanking domain (NEU-C). The functionally divergent
responses elicited by the modified self-peptides were accompanied by
significant changes in the expression of the CD28/CTLA4/B7 family of
co-stimulatory molecules. Immunization with the N-NEU peptide led to
enhanced expression of CD28 in the antigen-specific, CD4+ T cell
compartment while expression of B7.1 was dramatically reduced in
antigen-specific CD8+ T cells. Comparatively, expression of CTLA4 was
down-regulated in the antigen-specific CD4+ T cell compartment
following immunization with NEU-C peptide. The N-NEU peptide also had a
direct effect on dendritic cells leading to the up-regulation of B7.1
expression. Taken together, functionally divergent systemic immune
responses can be elicited by strategically altering a self-peptide
ligand with the N- and C-terminal flanking domains of CLIP. Moreover,
changes in expression of co-stimulatory molecules that are required for
T cell activation and T cell-T cell communication may account for the
polarization of the immune response elicited by the chimeric peptides.
PMID: 15721842
P - HLA-dr, ( www.pubmed.com keywords hla-dr + psoriasis --248 hits)
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15854134
In vitro culture of skin-homing T lymphocytes from inflammatory skin
diseases..
Bang K, Lund M, Mogensen SC, Thestrup-Pedersen K. In vitro culture of
skin-homing T lymphocytes from inflammatory skin diseases.Abstract: We,
in this study, describe how T lymphocytes in a skin biopsy can
proliferate in vitro for up to 3 months by using T-cell growth factors
- interleukin-2 (IL-2) and IL-4 yielding approximately 100-160 million
T lymphocytes within 1 month. We established cell lines from three
tuberculin skin tests, four positive patch tests, 15 of 16 biopsies
from atopic dermatitis (AD), 15 of 19 biopsies from mycosis fungoides
(MF), 12 of 24 biopsies from psoriasis vulgaris, which was
significantly less than AD (P < 0.05), and with a reduced cumulative
number of lymphocytes (P < 0.05). Omitting IL-2 and IL-4 led to
immediate halt of proliferation. Blood mononuclear cells from patients
and biopsies from healthy persons never gave cell lines. All cells were
T lymphocytes expressing CD45RO(+), HLA-DR(+) and CD150. The CD7
expression was significantly increased in cell lines from AD (P <
0.05). T-cell receptor beta-chain studies by using reverse
transcription-polymerase chain reaction showed that all T lymphocytes
had access to the skin compartment. Single-stranded conformational
analysis showed clonally expanded T cells numbering between 40 and 60
clones. After approximately 2 months of growth, the mean CD4(+) :
CD8(+) ratio was for AD 1.20, MF 0.65 and psoriasis 0.85. Patients with
AD treated with cyclosporin-A had almost no growth of CD8(+) cells in
vitro. Our findings indicate a changed homeostasis among skin-homing
lymphocytes for in vitro culture. Our culture system of skin-homing T
lymphocytes leads to a prominent cellular expansion allowing for a
range of studies of in vivo activated skin T lymphocytes.
PMID: 15854134
HLA-DO transduced in human monocyte-derived dendritic cells modulates
MHC class II antigen processing.
Through the regulation of human leukocyte antigen (HLA)-DM (DM) in B
cells, HLA-DO (DO) modulates positively or negatively the presentation
of specific peptides. Transduction of DO into human blood
monocyte-derived dendritic cells (MoDC) has been proposed as a mean of
modifying the peptide repertoire of major histocompatibility complex
class II molecules. However, maturation of DC induced by inflammatory
stimuli or possibly the adenoviral vector itself triggers acidification
of vesicles and shuts down transcription of the class II transactivator
gene as well as de novo biosynthesis of class II-related molecules and
DM activity. In these conditions, it is unclear that transduced DO
could alter the peptide repertoire. Our Western blot and reverse
transcriptase-polymerase chain reaction analyses revealed that human DC
derived from blood monocytes express small amounts of DOalpha.
Transduction of DObeta alone resulted in the accumulation of a small
pool of DO in DM(+) CD63(+) vesicles and at the plasma membrane of
mature DC. The cell-surface increase in class II-associated invariant
chain peptide (CLIP)/class II complexes is in line with an inhibitory
role of DO on DM. Cotransduction of DOalpha and DObeta only slightly
increased CLIP and DO levels at the cell surface. Together with the
fact that a large fraction of transduced DO remains in the endoplasmic
reticulum, this suggests that DM is limiting in these conditions. DO
expression did not affect a mixed lymphocyte reaction but reduced
presentation of the exogenous gp100 antigen to a specific T cell clone.
These results show that transduced DO modulates antigen presentation in
human mature MoDC, evoking the possible use of this chaperone for
immunotherapy.
PMID: 15817706
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15795121
And on the radar since 1982,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6173446&dopt=Abstract
<snip> Interestingly, the cytokine profiles of the CLIP-reactive T
cells closely correlated with the onset and progression of disease.
Levels of type 1 cytokines, particularly IFN-gamma mRNA production
assessed by quantitative polymerase chain reaction (PCR), were dominant
during acute SGVHD, whereas chronic SGVHD was associated with type 2
cytokine mRNA production. Although there was a dramatic polarization
with respect to cytokine production, only subtle changes in antigen
specificity were detected. Of additional interest, autoreactive T cells
producing IL-10 mRNA were detected in both acute and chronic SGVHD,
suggesting that this cytokine may play an important but perhaps
paradoxical role in both the onset and progression of this experimental
autoaggression syndrome.
PMID: 15808545
How about a invariant chain (CIITA) with HLA-DR pubmed search. OK
323 hits. Loads of plenty! Fully understanding it may shed p light.
Whoops
that should be a hla-dr CIITA for 98 hits.
Ok. So I scream about IL-10 being the saviour of P. Lets see. Same
search with IL-10.
Three hits. And this one shines that light,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12047752
Regulation of major histocompatibility complex class II synthesis by
interleukin-10.
Morel AS, Coulton G, Londei M.
The Kennedy Institute of Rheumatology Division, Imperial College of
Science, Technology and Medicine, Faculty of Medicine, London, UK.
We have shown previously that interleukin-10 (IL-10) blocks the
development and T-cell stimulatory capacity of human monocyte-derived
dendritic cells, without apparently down-regulating the surface
expression of co-stimulatory molecules or human leucocyte antigen (HLA)
molecules. In the majority of donors (60%), the cell surface levels of
HLA-DR actually increased upon IL-10 treatment. Here we have shown that
IL-10 does not regulate HLA-DR transcription as assessed by polymerase
chain reation. Epifluorescence microscopy analysis showed that IL-10
primarily increased the intracellular pool of HLA-DR. In fact, IL-10
directly increased HLA-DR protein synthesis. However, IL-10 did not
significantly alter the synthesis of invariant chain (Ii), which plays
a crucial role in the assembly, transport and loading of newly formed
HLA class II molecules, nor the amount of Ii reaching the cell-surface.
In contrast, IL-10 increased the amount of HLA-DR-bound Iip33 shortly
after the HLA-DR complex assembly. We postulate that, upon IL-10
treatment, immature Ii-associated HLA II molecules can still transit to
the cell surface as they do in immature dendritic cells and recycle to
the intracellular space, where they accumulate. A higher proportion of
Ii-associated HLA-DR, coupled to increased membrane recycling, may
contribute to the lower T-cell stimulatory capacity of IL-10-treated
dendritic cells.
PMID: 12047752
Interesting. More? Please!
Enhanced production of IL-10 by dendritic cells deficient in CIITA.
Yee CS, Yao Y, Xu Q, McCarthy B, Sun-Lin D, Tone M, Waldmann H, Chang
CH.
Department of Microbiology and Immunology, University of Michigan
Medical School, Ann Arbor, MI 48109, USA.
Dendritic cells (DC) are professional APCs that play a critical role in
regulating immunity. In DC, maturation-induced changes in MHC class II
expression and Ag presentation require transcriptional regulation by
CIITA. To study the role of CIITA in DC, we evaluated key cell
functions in DC from CIITA-deficient (CIITA(-/-)) mice. The ability to
take up Ag, measured by fluid phase endocytosis, was comparable between
CIITA(-/-) and control DC. Although CIITA(-/-) DC lack MHC class II,
they maintained normal expression of costimulatory molecules CD80,
CD86, and CD40. In contrast, CIITA(-/-) DC activated with LPS or CpG
expressed increased IL-10 levels, but normal levels of TNF-alpha and
IL-12 relative to control. Enhanced IL-10 was due to greater IL-10 mRNA
in CIITA(-/-) DC. Abeta(-/-) DC, which lack MHC class II but express
CIITA normally, had exhibited no difference in IL-10 compared with
control. When CIITA was cotransfected with an IL-10 promoter-reporter
into a mouse monocyte cell line, RAW 264.7, IL-10 promoter activity was
decreased. In addition, reintroducing CIITA into CIITA(-/-) DC reduced
production of IL-10. In all, these data suggest that CIITA negatively
regulates expression of IL-10, and that CIITA may direct DC function in
ways that extend beyond control of MHC class II.
PMID: 15661876
Modulation of IFN-gamma-induced immunogenicity by
phosphatidylethanolamine-linked hyaluronic acid.
Yard BA, Yedgar S, Scheele M, van der Woude D, Beck G, Heidrich B,
Krimsky M, van der Woude FJ, Post S.
V. Medizinische Klinik, Klinikum Mannheim, University of Heidelberg,
Germany.
BACKGROUND: The present study was conducted to examine the possibility
of modulating interferon (IFN-gamma)-induced immunogenicity by a novel
compound that is composed of a PLA2 inhibitor linked to hyaluronic acid
(HYPE). METHODS: HYPE was tested for its effect on IFN-gamma-induced
expression of MHC class I, class II, and intercellular adhesion
molecule (ICAM-1) in cultured endothelial and renal proximal tubular
cells by flow cytometric analysis (FACS) as well as its ability to
influence T cell activation in mixed lymphocyte reaction (MLR) or after
mitogen stimulation. RESULTS: In FACS, a profound inhibition in MHC
class I and ICAM-1 staining was observed in stimulated or unstimulated
cells that were incubated with HYPE. This was not due to
down-regulation of antigen expression and only occurred when monoclonal
antibodies, but not when polyclonal antibodies, were used. HYPE
inhibited the induction of MHC class II in both cell types after
IFN-gamma stimulation in a dose-dependent manner. Moreover, the
induction of class II transactivator (CIITA) was completely inhibited
under these conditions, most likely because it blocked the binding of
IFN-gamma to the cell membrane. Addition of HYPE to MLR inhibited the
proliferation of T cells and the secretion of interleukin (IL)-2,
IFN-gamma, and IL-10. This was not observed when HYPE was added
together with anti-CD3 or phytohemagglutinin (PHA). CONCLUSION: Our
study provides experimental evidence that HYPE has immunosuppressive
features. This makes the compound an interesting candidate as an
immunosuppressive drug, not only in organ transplantation, but also in
diseases where IFN-gamma is overexpressed.
PMID: 11923705
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12422218
The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and
reverses paralysis in central nervous system autoimmune disease.
Youssef S, Stuve O, Patarroyo JC, Ruiz PJ, Radosevich JL, Hur EM, Bravo
M, Mitchell DJ, Sobel RA, Steinman L, Zamvil SS.
Department of Neurology and Neurological Sciences, Beckman Center for
Molecular Medicine, Stanford University, Stanford, California 94305,
USA.
Statins, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase
inhibitors, which are approved for cholesterol reduction, may also be
beneficial in the treatment of inflammatory diseases. Atorvastatin
(Lipitor) was tested in chronic and relapsing experimental autoimmune
encephalomyelitis, a CD4(+) Th1-mediated central nervous system (CNS)
demyelinating disease model of multiple sclerosis. Here we show that
oral atorvastatin prevented or reversed chronic and relapsing
paralysis. Atorvastatin induced STAT6 phosphorylation and secretion of
Th2 cytokines (interleukin (IL)-4, IL-5 and IL-10) and transforming
growth factor (TGF)-beta. Conversely, STAT4 phosphorylation was
inhibited and secretion of Th1 cytokines (IL-2, IL-12, interferon
(IFN)-gamma and tumour necrosis factor (TNF)-alpha) was suppressed.
Atorvastatin promoted differentiation of Th0 cells into Th2 cells. In
adoptive transfer, these Th2 cells protected recipient mice from EAE
induction. Atorvastatin reduced CNS infiltration and major
histocompatibility complex (MHC) class II expression. Treatment of
microglia inhibited IFN-gamma-inducible transcription at multiple MHC
class II transactivator (CIITA) promoters and suppressed class II
upregulation. Atorvastatin suppressed IFN-gamma-inducible expression of
CD40, CD80 and CD86 co-stimulatory molecules. l-Mevalonate, the product
of HMG-CoA reductase, reversed atorvastatin's effects on
antigen-presenting cells (APC) and T cells. Atorvastatin treatment of
either APC or T cells suppressed antigen-specific T-cell activation.
Thus, atorvastatin has pleiotropic immunomodulatory effects involving
both APC and T-cell compartments. Statins may be beneficial for
multiple sclerosis and other Th1-mediated autoimmune diseases.
PMID: 12422218
Will any of this cure us? I hope so. I'm tried of waiting . .... So the
cure must
be close.
randall
randall
Loads of BIG P news today! ImPortant stuff too.
All the world is a P hole when feeling flaky.
HoPe abounds,
Remicade (Adalimumab) approved for PsA (psoriatic arthritis),
http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=109&STORY=/www/story/05-17-2005/0003633502&EDATE=
A nice abstract to go with the above,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15838232
And as mentioned in P news yesterday. One creative psoriatic suggests
you persuade your derm you may have some PsA to get this stuff. He is
as well cocktailing in some laser treatments. And looking really clear.
Cool.
Ok cool hand luke, your next. (I can eat eat 50 eggs and suffer no P!)
http://www.cologne-conference.de/i/photos/Filmbilder/Werkschau/Cool-Hand-Luke.jpg
(if i ate 50 egg yolks, the P joke would be all over me)
http://www.nostalgiacentral.com/images_movie/coolhand_10.jpg
When it comes to arachidonic acid in those yolks, I muST
resPect its authority,
http://www.astro.hr/personal_pages/Overview/People/Cartman_sp.jpg
On to the glitter of sitcom & tinsel town.
Hollywood, king of queens tackles psoriasis in finale this week,
http://webwire.com/ViewPressRel.asp?SESSIONID=&aId=2620
KENSINGTON, Md., May 17 -- In real life, Hollywood stars dare not say
the word. Despite more than 2 percent of adults having the disease,
virtually no one in Hollywood will admit having psoriasis, a
non-contagious, incurable immune system disease. But tomorrow night on
the season finale of CBS-TV's "King of Queens," Jerry Stiller's
character Arthur will face his psoriasis with the help of Stiller's
real-life wife, guest star Anne Meara. "Psoriasis Cure Now," a patient
advocacy group, is hoping this fictional portrayal will end the silence
in Hollywood about this misunderstood, under-researched and often
debilitating disease.
"Jerry Stiller is a comic genius, and no doubt he will make us laugh
about this most unlikely of subplots, psoriasis," said Michael
Paranzino, president of Psoriasis Cure Now. "But while we are all
laughing, let's also remember that for 6.5 million Americans young
and old, psoriasis is not funny, but is both physically and emotionally
painful." <snip>
*************
Well this didn't take long! The British aren't affraid to mention it,
http://www.contactmusic.com/new/xmlfeed.nsf/mndwebpages/ecclestons%20doctor%20who%20hell
(I wonder if British MP, galloway has some? He certainly knew more then
the CIA and Blair about weapons of mass distruction. Gosh, he should
have stoPPed those planes from hitting us as well. And maybe he knows
how to cure us?)
(Back to the UK hollywood and P!)
The hectic filming schedule for DOCTOR WHO took such a toll on star
CHRISTOPHER ECCLESTON, his face became "disfigured" and his mind kept
conjuring up images of the Tardis.
(Whats that? Lets google. OK
http://www.davidwyatt.me.uk/photos/glasgow&birmingham/Tardis-type%20police%20box.JPG
) (OK, I see this box can cause P? Ow, the stress of it. )
The movie actor - who announced in March (05) he's quitting the TV show
after one series - has helped launch the time-travelling hero back to
popularity, but he admits the gruelling shoot drove him to the brink of
insanity.
Eccleston was particularly disturbed by haunting visions of the Tardis,
the deceptively large police box he uses to travel through time.
He says, "You can't have a life. You can't socialise. It's like having
a Tardis in your skull and every time you open your mouth you see a
Tardis.
"There were days when I got psoriasis, I got eczema. My face blew up in
the DALEK (evil robots) episode. I looked literally disfigured with
tiredness and poor skin."
17/05/2005 14:04
(Hey Chris! Talk to mP Galloway today. He's got all the answers down
pat. )
This cop box show sounds like some king of Hitchhiker's guide to the
Galaxy takeoff only going backwards.
Just what we need. Pure fantasy with real psoriasis prone actor's
bemoaning
the itch. Could we have a P reality show in the making?
Will the Brits beat the hollywooders on this one?
After-all the P word is outa the box!
With all this notoriety the bucks should pore in for research?
Thanks for the fish!
Click:
Exclusive Clip: "So Long and Thanks for All the Fish" - The world's
dolphins perform a musical number for the opening of the film
http://movies.yahoo.com/feature/thehitchhikersguidetothegalaxy.html
DolPhins being the second smartest inhabitants on this dirt ball,
may have a few P answers.
Like eat only raw fish for your psoriasis and thanks for the fish.
(Maybe we could do a sitcom tragedy with fliPPer?)
*****************************************
P improves for women on the estrogen patch? And when pregnant due
to estrogen? Some percentage gets better during pregnancy,
http://my.webmd.com/content/Article/106/108034.htm
I can hear some of you guys now. Hey Doc! Can you find an off label
use to put me on some low dose estrogen patch?
Oh sure. If your not worried about growing some nice knockers to
go with your P! yuk yuk
***********************************
Turmeric comes to the rescue,
http://www.rednova.com/news/health/150207/turmeric_helps_clear_up_psoriasis_on_scalp/
Sounds good to me. Time for my proflora shake.
I believe.
Hey, does this make it a P placebo? I sure hoPe so.
************************************
http://www.pharmalive.com/News/index.cfm?articleid=240488&categoryid=15
GenPat77's Novel Approach to Immune Disorder Therapy Supported by
Presentations at Medical Conferences
BERLIN, May 17, 2005 /PRNewswire/ -- GenPat77, a company focused on the
discovery of innovative immune modulatory products, announced today the
presentation of encouraging preclinical data on its TIRC7 program at
the Federation of Clinical Immunology Societies (FOCIS) annual meeting
(May 12-16, Boston, USA) and its CEACAM1 program at Digestive Disease
Week (May 14-19, Chicago, USA). TIRC7 and CEACAM1 are proteins involved
in the activated immune response. GenPat77 is developing therapeutic
strategies targeting these proteins for immune disorders such as
rheumatoid arthritis and inflammatory bowel disease.
"These data confirm earlier research with each of these immune targets.
In arthritis, there are a growing number of patients that are not
responding to anti-TNF treatment. This preliminary data suggest that
targeting TIRC7 not only exerts an effect alone but also synergizes
with anti-TNF therapy. Our research with CEACAM1 confirms that it is a
potential therapeutic target for inflammatory bowel disease," noted
Nalan Utku, MD, CEO of GenPat77 and an investigator in the studies.
"GenPat77 and its collaborators are already moving forward with
additional studies to move both programs towards evaluation in clinical
trials."
At the FOCIS meeting, GenPat77 and collaborators at Humboldt
University, Berlin, Germany, and Brigham and Women's Hospital, Boston,
USA revealed that anti-TIRC7 mAb therapy may offer a novel therapeutic
strategy for rheumatoid arthritis. Studies in mice with
collagen-induced arthritis showed that antibody targeting of TIRC7
demonstrated significant therapeutic efficacy as both a monotherapy and
in combination with a TNF-alpha receptor-Ig-fusion protein. Anti-TIRC7
mAb treatment also significantly inhibited memory T cell function and B
cell numbers.
GenPat77, along with scientists from Humbolt University, Berlin,
Germany, Keio University, Tokyo, Japan and Brigham and Women's
Hospital, Boston, USA, showed that TIRC7 was up-regulated in tissues
isolated from patients with rheumatoid arthritis and kidney rejection
following transplantation in a separate presentation at the FOCIS
meeting. In peripheral blood lymphocytes, the over expression of TIRC7
was observed strongly in resting memory T cells but less so in naive
and effector/memory cells. Combined, this data supports the potential
role of TIRC7 as a therapeutic target in a number of immune disorders.
Studies with CEACAM1 presented at DDW demonstrated its role in the
suppression of experimental murine colitis. In mice, administration of
CEACAM1 fusion protein promoted suppression in the proliferation of T
cells and maintained low Th1-type cytokine responses following
challenge with Staphylococcal enterotoxin B (SEB) compared to control.
The researchers concluded that induction of immune tolerance seems to
be one of the major mechanisms behind the suppression in murine colitis
seen with CEACAM1 therapy.
GenPat77 is focused on the discovery of innovative immune modulatory
products for rheumatoid arthritis, multiple sclerosis, inflammatory
bowel disease and the prevention of transplant rejection. Based on a
fundamental understanding of the human immune system, GenPat77 is able
to target key proteins in the immune cascade and appropriately modulate
the immune response according to each specific indication. The company
was founded in Berlin, Germany (1998) based on exclusively licensed
intellectual property rights on immune related targets from Brigham and
Women's Hospital, an affiliate hospital of Harvard Medical School,
Boston, USA. The company has licensed TIRC7, a novel molecule involved
in immune regulation, to MedImmune for development of biologics and
small molecule drugs. For further information visit the company's
website at http://www.genpat77.com/.
( I certainly hoPe they get this gut thing down PAT. It may helP P.)
Next gut check,
********
Crohn's and Humira,
http://www.xagena.it/news/medicinenews_net_news/b8043b9b976639acb17b035ab8963f18.html
Their response and side effects look similar to what psoriatics
experience with these TNF blockers.
*********
If some of your really do have gut problems related to P. Here's your
chance to get a gut
check,
http://www.news-medical.net/?id=10135
*******
On to more mundane toPics. Like solving JXSterns P symmetry equations.
Koebner phenomenon in lupus erythematosus with special consideration of
clinical findings.
Ueki H.
Kawasaki Medical School, 577 Matsushima Kurashiki-city, Okayama,
701-0192 Japan.
The isomorphic response of Koebner can be observed not only in
psoriasis, but also in other diseases, such as lichen planus and some
systemic diseases including LE (lupus erythematosus) or sarcoidosis.
Several clinical findings in LE skin were presented and discussed in
this review. The mutually-interactive-, negative-, and internal-Koebner
phenomena were introduced and discussed with some speculative views.
Many forms of environmental stress on the skin were reported as
provocating factors of the Koebner phenomenon, including trauma,
scratching, UV-exposure, and various types of dermatitis. Clinical
observations of the nature, localization, and movement of lesions
should be carefully made. The pathophysiology of the Koebner phenomenon
may be classified into two steps. A first non-specific inflammatory
step and a second disease-specific step. The inflammatory products
released from the first step would be targeted in the second step. In
the first step, there could be many substances including cytokines,
stress proteins, adhesion molecules, or autoantigens translocated from
intra-cellular areas. In the second step after latent periods, there
may be disease-specific reactions, including ones by T-cells, B-cells,
autoantibodies, and immune deposits, under the restriction of genetic
backgrounds. The Koebner phenomenon may prove useful in understanding
the pathophysiology of diseases of unknown origin.
PMID: 15893715
Whats all the big bang about P anyway?
Some Poor soul caught the P daily double,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15893039
P and luPus both for one person? YeP.
Count your blessings.
What did Voltaire say?
"for private misfortunes are for the public good."
Or was that Pangloss? How about Newsweek sParking some private
mishaPPPPPs? Their Bush hatred kills peoPle half way around the
world now. Tisk tisk the idiot PiPsweek!
The good Doctor pangloss would say something like, without it we
couldn't
cure it. Or some other rubbish.
But look on the bright side. It would give Cunegonde the oPPortunity to
rub some cream on Candides P.
randall... P is philosoPecal to me, when feeling blue&silvery.
randall
> Hi,
>
[snip]
>
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15838232
When these abstract links break. Just copy and paste the PMID# (at the
end
of the broken link) back into the empty search box. And you have
your abstract. Like magic.
Don't forget to watch king of queens to-nite. So we
can discuss how they handle arthurs psoriasis.
Should be interesting. Maybe.
> Hollywood, king of queens tackles psoriasis in finale this week,
> http://webwire.com/ViewPressRel.asp?SESSIONID=&aId=2620
>
> KENSINGTON, Md., May 17 -- In real life, Hollywood stars dare not say
> the word. Despite more than 2 percent of adults having the disease,
> virtually no one in Hollywood will admit having psoriasis, a
> non-contagious, incurable immune system disease. But tomorrow night
on
> the season finale of CBS-TV's "King of Queens," Jerry Stiller's
> character Arthur will face his psoriasis with the help of Stiller's
> real-life wife, guest star Anne Meara. "Psoriasis Cure Now," a
patient
> advocacy group, is hoping this fictional portrayal will end the
silence
> in Hollywood about this misunderstood, under-researched and often
> debilitating disease.
>
> "Jerry Stiller is a comic genius, and no doubt he will make us laugh
> about this most unlikely of subplots, psoriasis," said Michael
> Paranzino, president of Psoriasis Cure Now. "But while we are all
> laughing, let's also remember that for 6.5 million Americans young
> and old, psoriasis is not funny, but is both physically and
emotionally
> painful." <snip>
>
> *************
>
More remicade revelations. Fake some PsA and tell us how you do
Plaque wise. Please.
(HOW does one fake PsA? Well. If your me, all you have to do is eat
pork and egg yolks and soy bean oil everyday and in no time at all, the
p is
worse and all the finger joints are stiff and swollen. Bingo a ticket
to
remicade Rx... ;-)
http://www.businessweek.com/ap/financialnews/D8A561A82.htm?campaign_id=apn_home_down
MAY. 17 5:22 P.M. ET Johnson & Johnson Inc. said Tuesday that
regulators approved its Remicade drug to reduce symptoms of psoriatic
arthritis, creating a competitor for Amgen Inc.'s blockbuster arthritis
drug Enbrel, which until now was the sole therapy approved to treat the
skin lesions and joint swelling associated with the autoimmune
disorder.
The two drugs already compete as treatments for other inflammatory
diseases such as rheumatoid arthritis and ankylosing spondylitis. But
Enbrel, which is sold by Amgen and Wyeth, has been the only drug
approved for psoriatic arthritis since 2002. Enbrel is also approved to
treat the joint damage associated with the disease.
Psoriatic arthritis affects about one million Americans, according to
J&J unit Centocor, which makes Remicade. The disease usually occurs
when someone already suffering from psoriasis, a chronic skin condition
in which the immune systems attacks the body's own cells, develops
joint swelling and pain. Its cause is unknown, although genetics may be
a factor.
Enbrel's psoriatic indication in much broader than the "signs and
symptoms" treatment approval that Remicade received and Amgen
spokeswoman Nurha Hindi said the drugmaker does not yet see Remicade as
a challenge to its dominance in the market.
"This can be a very destructive disease with serious joint damage,"
Hindi said. "Enbrel is the only treatment approved to stop that joint
damage and most patients see little or no joint destruction for a
continuous two years on therapy."
Centocor spokesman Michael Parks said the company has "very good" data
supporting Remicade's ability to treat joint damage that it plans to
submit later this year.
Both treatments belong to a class of drugs called "TNF inhibitors,"
which block a protein that regulates inflammation. Another major drug
in the group, Abbott Laboratories' Humira, is approved to treat
rheumatoid arthritis and is currently in trials for psoriatic
arthritis. Amgen's Hindi said that Enbrel has a different mechanism of
action than both Remicade and Humira.
"There are real safety considerations based on these modes of action,"
Hindi said. "Enbrel is a soluble TNF receptor, meaning it works like a
the body's natural receptors. Remicade is a monoclonal antibody that is
not natural to the body, so it results in different safety
indications."
However, "the labels are very much the same," said Centocor spokesman
Michael Parks. "What differentiates us from Enbrel is the higher level
of clearance that we're seeing in our clinical trials." About a third
of patients in the Centocor trial saw skin clearance of 90 percent or
more. Parks said Enbrel's data does not appear to be as strong for this
measure, though trials between the companies are not directly
comparable. Amgen's Hindi said about 70 percent of Enbrel patients saw
a 75 percent skin clearance over two years of monitoring.
"What's also important to bear in mind is that there was a survey
conducted by the National Psoriasis Foundation late last year that
found people with psoriasis or psoriatic arthritis that have even a
little bit of skin involved said that has a huge impact on their
quality of life," Parks said.
Remicade, which is also approved to treat Crohn's disease, posted sales
of $2.41 billion in 2004, up from $1.73 billion in 2003.
Enbrel posted sales of $1.9 billion in 2004, up from $1.3 billion in
2003. Thousand Oak, Calif.-based Amgen said it does not break out sales
according to treatment use. The drug is also approved to treat juvenile
rheumatoid arthritis, an indication that Remicade lacks.
In September, the European Union approved Remicade to treat active and
progressive psoriatic arthritis in patients who have not responded to
other drugs. It was approved as a combination treatment along with the
standard treatment for the disease, an immuno-suppressant called
methotrexate. Enbrel was approved for psoriatic arthritis in Europe in
2002, Hindi said.
Arthritis is more common in psoriasis sufferers than in the general
population and about one in 20 people with the skin condition develop
arthritis, according to the National Institutes of Health.
Shares of New Brunswick, N.J.-based Johnson & Johnson rose 27 cents to
close at $67.91 on the New York Stock Exchange, while Wyeth Co. shares
fell 32 cents to close at $44.23. On the Nasdaq, Amgen shares fell 9
cents to close at $62.90. Abbott Labs shares fell 6 cents to close at
$49.41 on the NYSE.
*****
I see the word inhibitor attached to many TNF's now. Lets compare
inhibitors to blockers.
http://news.google.com/news?auth=DQAAAGgAAABCE5CcPkVt9K9YR7W9Vd28G_SXzyP4c1SH2h7RjVpDCMUmsTzORruDKWo49cRwswR7mEwd_a_rwr6UCrw4r2JtgIYn9fcH7KDI3fGW4pg5FVaM2ZCVQTfrJJEh3TlPpHJ744qDKX1mllKkb51f4QeB&lr=&tab=gn&ie=UTF-8&scoring=d&q=tnf+inhibitors&btnG=Search+News
Well, at the moment I did this, inhibitors had 19 and blockers received
21 hits. What these drugs
actually do is somewhat more complex then what these words connote.
Good day.
Or bad day if your TNF is increasing!
******
If you drink booze, you may not want to eat fish. Alcohol and gut
permeability
alert.
Cut this bait!
http://www.news-medical.net/?id=10149
<snip>
Alcohol-Induced Changes in Gut Permeability and Liver Injury are
Influenced By Sex and Dietary Fatty Acids (Abstract 182)
Maintaining safe limits of alcohol intake can mean different things, as
females are more susceptible to liver injury at much lower doses than
their male counterparts and, as a result, may suffer more extensive
liver disease if they drink the same amount as a man. In this study,
researchers at the University of Pittsburgh School of Medicine and the
Veterans Affairs Medical Center used animal models to analyze the
differences in liver injury between the sexes due to chronic alcohol
ingestion, using two diets that vary in carbohydrate and fatty acid
content. One diet contained fish oil while the other contained a
mixture of vegetable oils.
Alcohol-induced liver injury (ALI) can involve damage that ranges from
mild to quite severe: fatty liver (fat buildup in liver cells),
alcoholic hepatitis (an inflammatory condition) or cirrhosis
(replacement of normal tissue with fibrous scar tissue).
Male and female rats were divided into groups and given either no
alcohol (IC) or alcohol (AF) in a higher carbohydrate diet (LDC) or a
low-carb, higher fat diet (NFO) for a total of eight weeks. Researchers
determined injury to the intestine by measuring bacterial translocation
and blood endotoxin levels, and also the degree of liver injury.
Previous reports have shown that endotoxins, which are bacterial
products that can escape from the intestine, appear to be a major
factor in the development of ALI.
Female rats fed alcohol in the high fat fish oil (NFO) diet had
significantly greater bacterial translocation (escape of bacteria from
the GI tract to abdominal lymph nodes, in this example), higher blood
endotoxin levels and more severe liver injury than male rats on the
same diet or rats of either sex on the LDC diet (two-fold increase in
total change), based on their intake of unsaturated fatty acids and
alcohol. These results indicate that the intestines of the females had
become permeable as a result of the alcohol-fish oil combination in the
diet.
All rats that ingested alcohol demonstrated some degree of fatty change
in their livers, but liver inflammation was evident only in females fed
the NFO diet, and both female and male rats on the LDC diet showed
fatty liver only, without bacterial translocation nor elevation of
endotoxin levels.
"Our research suggests that women should be cautious about the amount
of alcohol they consume, since they highly susceptible to more severe
liver injury than men and thus to potentially serious complications,"
said Patricia Eagon, Ph.D., of the University of Pittsburgh and
Pittsburgh VA Medical Center and lead author of the study. "Our work
also shows that in females, alcohol in the diet along with fish oil
injures the intestine, which causes release of factors that contribute
to liver injury."
****************
StoPPing IL-1 at the source, sorta.
http://www.rednova.com/news/health/150468/tracking_the_trail_of_disease_roots/
Tracking the Trail of Disease Roots
Scientists at the Novartis Institute for BioMedical Research (NIBR) in
the United States are focusing on molecular pathways in the human body
as an organizing concept in the search for novel, but more effective
medicinal compounds.
Researchers have discovered that various diseases may share the same
molecular pathways.
Traditional pharmaceutical development has relied heavily on
identifying appropriate drug "targets," such as single genes or
proteins.
But, following the decoding of the human genome, researchers have found
that interacting pathways of proteins may be at the root of several
diseases.
New approaches have thus been developed to search for new compounds
which target critical nodes within the signalling pathways to alter the
disease-causing mechanism.
Dr Mark Fishman, president of NIBR, and his team have instituted
several new fundamental discovery platforms, ranging from those focused
on specific gene families to those intended to identify "drugable
nodes" or integrate key molecular pathways that cause disease.
The new compounds will enter full-scale clinical development only after
successfully completing "proof-of-concept" trials.
"All of our drug discovery efforts begin and end with the patient. By
focusing early on the experience of patients alongside a commitment to
understanding the mechanism of action of a particular disease, our
science is geared towards improving both the patient's medical
condition as well as their quality of life," said Fishman.
"We are harnessing the power of the genome to invent a 'new grammar' of
drug discovery that will translate breakthroughs in biology and
chemistry into innovative medicines for patients," he said.
For example, the scientists recently completed a successful proof-
of-concept trial of a novel antibody, ACZ885, for inflammatory
conditions.
This trial examined patients with a rare inherited inflammatory
condition called Muckle-Wells Syndrome, which is manifested by rash,
aching joints, fever and migraine-like headaches.
All of these symptoms were relieved within days by a single injection
of the antibody, directed to an inflammatory signal known as IL-1 beta.
NIBR has expanded its oncology research activities to include other
mechanisms of action, particularly inhibition of cell
proliferation/survival pathways and activation of cell death pathways.
One approach being studied is exposing cancer cells to a first-
in-class SMAC mimetic, which is a small molecule that blocks the
protein which causes cells to die. Multiple cancer models have shown
that this compound has reduced the size of tumours in animals.
Founded three years ago, NIBR is a global pharmaceutical research
organization of Novartis dedicated to research into finding new drugs.
Thus far, it has produced breakthrough therapies for treating cancer
and schizophrenia.
************
I wonder if we spun our blood, would we flare faster, due to NGF's?
http://www.newscientist.com/article.ns?id=dn7375
****
A test i'm prepared to avoid. Now if they could take out the TNF while
sPinning
that plasma, i'm game....
And if stinging nettles drops TNF 20%. I may as well try that soon.
Certainly easier to eat nettles then have someone sPin your blood.
randall....THE BIG SpIN!
randall
randall wrote:
> Don't forget to watch king of queens to-nite. So we
> can discuss how they handle arthurs psoriasis.
>
I watched it. Seemed stuPid enough for a TV sitcom. But not very funny.
Arthur gets some new P meds and tries them out on a
friends mom who is hoping that arthur has love designs on her
as they are both single/lonely? Arthur plies her unknowingly with
his p meds to see if she has any undesirable side effects.
When she discovers his surreptitious tests, the real heartbreak
of psoriasis unfolds as these two are not slated to be a
couPle. The non-paramour flies out in a rage feeling the
sting of betrayal.
All very not funny. Cept for the fact that the non-paramour
is arthurs (jerry stillers) real life wife.
Chuckle chuckle...
> > Hollywood, king of queens tackles psoriasis in finale this week,
> > http://webwire.com/ViewPressRel.asp?SESSIONID=&aId=2620
> >
> > KENSINGTON, Md., May 17 -- In real life, Hollywood stars dare not
say
> > the word. Despite more than 2 percent of adults having the disease,
> > virtually no one in Hollywood will admit having psoriasis, a
> > non-contagious, incurable immune system disease. But tomorrow night
> on
> > the season finale of CBS-TV's "King of Queens," Jerry Stiller's
> > character Arthur will face his psoriasis with the help of Stiller's
> > real-life wife, guest star Anne Meara. "Psoriasis Cure Now," a
> patient
> > advocacy group, is hoping this fictional portrayal will end the
> silence
> > in Hollywood about this misunderstood, under-researched and often
> > debilitating disease.
> >
> > "Jerry Stiller is a comic genius, and no doubt he will make us
laugh
> > about this most unlikely of subplots, psoriasis," said Michael
> > Paranzino, president of Psoriasis Cure Now. "But while we are all
> > laughing, let's also remember that for 6.5 million Americans young
> > and old, psoriasis is not funny, but is both physically and
> emotionally
> > painful." <snip>
Now for some real P news. Funny or not here it comes.
http://www.medicalnewstoday.com/medicalnews.php?newsid=24699
(...)
The third pilot, led by Alice Pentland, M.D., chair of the URMC
Department of Dermatology, will examine whether stress and lack of
sleep precede bursts of psoriasis in patients in her dermatology clinic
(...)
University of Rochester Medical Center
http://www.urmc.rochester.edu
You may want to check with getting involved in their tests if you live
nearby.
******************
You can learn a lot from a worm. Like how to stay young.
http://www.newscientist.com/channel/being-human/mg18624991.400
(...)
researchers at Massachusetts
General Hospital in Boston worked out what the daf-2 gene does. They
found that it specifies a cell-surface receptor that recognises a
signalling protein called IGF-1 (insulin-like growth factor 1). Like
many such receptors, daf-2 turned out to be at the apex of a powerful
signalling cascade. When IGF-1 binds to the receptor, it transmits a
message to the inside of the cell, switching on another gene, daf-16,
which Kenyon's group found could also influence longevity. It turned
out
that daf-16 codes for a "suppressor" protein that binds to genes and
turns them off. Mutations in daf-2 apparently extend life by
suppressing
this suppression, keeping numerous genes active that would otherwise be
switched off.
But which genes was daf-2 affecting? Kenyon's group tried to find out
using one of the latest technologies for probing gene expression:
microarrays or "gene chips" that pack huge numbers of short DNA
sequences onto a glass slide. By taking RNA molecules - the direct
transcriptions of any gene - from living cells and seeing which DNA
sequences these bind to, microarrays can tell you which genes are
active. Kenyon's idea was to compare gene expression in normal C.
elegans with that of long-lived daf-16 mutants, and two years ago she
showed that mutations in daf-16 affect more than 300 genes.
(...)
IGF-1, keyworded with P brings 16 pubmed hits,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15140223&query_hl=1
Enter ( IGF-1 and P... ) for the rest of those.
Checking Daf-2 signalling brings up this curious abstract,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15850715&query_hl=2
Delta(6) & (5) enzymes have been on my radar. And are again now. As
well as Daf-7.
What all this daf talk means is simple. Some of us with P, simPly look
better then our non P Peers, as we age!
I know i do. I look marvelous everywhere I don't have P. :)
A little grayer but with nice smooth non P skin and far less wrinkles.
What about those creaks and pains as we age? Well, if you not willing
to stop eating inflammation inducing foods. (To much meat, salt etc and
not enough fruits/veggies/whole grains etc)
Then go the remicade way to block TNF for arthritis and psoriasis.
(Wow! Three posts in a row touting remicade! I'm so bad. )
http://www.pharmaceutical-business-review.com/article_news.asp?guid=17309F64-AF64-47FA-8538-8C523020D619
Centocor's Remicade gets ninth FDA OK
The FDA has approved Centocor and Schering-Plough's Remicade to reduce
the signs and symptoms of active arthritis in patients with psoriatic
arthritis, making this the drug's ninth indication.
19 May 2005, 08:27 GMT - Data from a trial named IMPACT 2 served as the
primary basis for the approval. In the trial, significant improvements
in both American College of Rheumatology and psoriasis area severity
index scoring criteria were observed in Remicade-treated patients as
early as week two, with further improvements through 24 weeks.
At week 14, 58% of Remicade-treated patients experienced at least 20%
improvement in arthritis symptoms, according to the American College of
Rheumatology scoring criteria (ACR 20) versus 11% of placebo-treated
patients. At week 24, 27% of Remicade-treated patients experienced at
least 70% improvement (ACR 70) versus 2% of placebo-treated patients.
Additionally, at week 24, 60% of Remicade-treated patients experienced
at least 75% improvement from baseline in psoriasis, as assessed by
psoriasis area severity index (PASI 75) versus 1% of placebo-treated
patients. At week 24, more than one-third (39%) of patients receiving
Remicade achieved PASI 90, a dramatic improvement in psoriasis
symptoms. No patients receiving placebo achieved a PASI 90 response at
week 24.
Importantly, patients in the Remicade group also experienced decreased
symptoms of dactylitis and enthesopathy, two common disease
manifestations causing pain and swelling.
In addition to this indication, Remicade has achieved approvals in the
treatment of such inflammatory diseases as Crohn's disease, rheumatoid
arthritis, and ankylosing spondylitis.
**************
I was a little hot on tanning awhile back. It was winter, raining and
the sun was scarce I suPPose. That tanning booth was a kind resPite
from a wintry
... who am i kidding? I live in freaking paradise...
The other side of tannning, THE DARK SIDE
http://www.auburnpub.com/articles/2005/05/19/opinion/my_view/myview01.txt
Tanning is not a healthy pursuit
By Dr. Jeffrey R. LaDuca
I am outraged at the recent article, "Tanning's light side,"
prominently appearing on the front of the "health" section of the
paper. The author had called my office asking for an interview to
discuss the "benefits of tanning." As I was literally too busy
diagnosing and treating skin cancers, I failed to reply. Additionally,
I saw no benefits to tanning other than the financial rewards to the
proprietors of those tanning salons.
The article touches on several aspects of tanning but fails to mention
any opposing views, and any reliable supporting facts. Sunburns are in
fact bad for the skin and cause damage to the blood vessels, elastic
fibers and collagen. But chronic and cumulative ultraviolet light does
far more damage. Chronic ultraviolet light exposure causes severe
breakdown of collagen and elastin and is a major cause of wrinkles.
Ultraviolet light is also known to be a significant risk factor for
skin cancers. The incidence of malignant melanoma is on the rise. And
malignant melanomas are occurring in younger and younger patients. I
have personally diagnosed melanoma in an 18-year-old patient, a
17-year-old patient, and a 15-year-old patient. Early stage malignant
melanoma is very treatable and can be cured, but advanced stage
melanomas are nearly always fatal. One person dies of malignant
melanoma in the United States every hour.
Vitamin D deficiency may very well be on the rise. And I agree that
sunlight is important for the skin to produce the vitamin, but only a
few minutes of sunlight each day are required for this to happen
adequately in healthy people. Tanning is not required.
Patients seen in orthopedic and endocrinology offices are there for a
reason, and may be more at risk for Vitamin D deficiency. It may turn
out that not all people can use sunlight the same way to manufacture
Vitamin D, and that this small subset of patients may need additional
ultraviolet light. But to state that we all could benefit from tanning
is irresponsible.
Even Lisa Doyle, the physicians' assistant interviewed in the prior
article, states that 15 minutes of sunlight three times a week is
adequate. And 15 minutes of sunlight is not the same as 15 minutes of
tanning. Tanning parlors provide a lot more ultraviolet light in the
same amount of time.
Tanning and sunlight can be beneficial for some dermatology patients.
Psoriasis is usually better in the summer months. But there are some
psoriasis patients for which tanning is contraindicated.
Tanning is a multi-million dollar industry with very few limitations
placed on it. There is an FDA warning on tanning and the risks of skin
cancers. In addition to skin cancers, I have seen fungal and herpes
infections contracted from tanning parlors.
Tanning under the age of 18 should be illegal. In 20 years, when tan
teens grow into young adults, there will be an epidemic of skin
cancers. For more information on skin cancers visit www.aad.org
LaDuca is a dermatologist in Auburn
&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&
I posted this boozy story yesterday. Bears repeating. While some of
us should avoid the tanning booth. All of us and most of the women
should
at least try to avoid alcohol.
http://drkoop.com/newsdetail/93/525777.html
Booze May Hit Women's Livers Harder
Rat study suggests gender differences, especially with high-fat diets.
Rat study suggests gender differences, especially with high-fat diets
WEDNESDAY, May 18 (HealthDay News) -- A study in rats suggests that
females metabolize alcohol differently in their bodies and may be more
susceptible to alcohol-related liver damage than males, especially if
they also consume a high-fat diet.
"Our research suggests that women should be cautious about the amount
of alcohol they consume, since they're highly susceptible to more
severe liver injury than men, and thus to potentially serious
complications," study author Patricia Eagon, of the Pittsburgh School
of Medicine and the Pittsburgh Veterans Affairs Medical Center, said in
a prepared statement.
Her team used a rat model to analyze differences in liver damage
suffered by females and males due to chronic alcohol ingestion.
The rats were divided into two groups and given either no alcohol or
alcohol, and either a diet high in carbohydrates or a low-carb,
high-fat diet for eight weeks. The high-carb diet contained a mixture
of vegetable oils, while the high-fat diet contained fatty fish oils.
Researchers assessed the degree of the rats' liver injury and measured
levels of bacteria in the lymph nodes, as well as blood levels of
compounds called endotoxins.
Previous research found that endotoxins -- bacterial products that
escape from the intestine -- appear to be a major factor in the
development of alcohol-induced liver injury.
The study found that female rats given alcohol and fed the high-fat
diet had much greater escape of bacteria from the gastrointestinal
tract to abdominal lymph nodes, higher blood endotoxin levels, and more
severe liver damage than male rats on the same diet or rats of either
sex on the high-carb diet.
This suggests the intestines of the female rats became more permeable
as a result of the combination of alcohol and high-fat fish oil, the
researchers explained.
All the rats given alcohol showed some degree of fatty changes in their
livers. However, liver inflammation was only evident in those females
that were given alcohol and fed the high-fat fish oil diet.
The study shows "that in females, alcohol in the diet along with fish
oil injures the intestine, which causes release of factors that
contribute to liver injury," Eagon said.
The findings were presented Tuesday at the annual Digestive Disease
Week 2005 meeting in Chicago.
More information
The American Liver Foundation has more about alcohol and liver damage
(www.liverfoundation.org )
****************
TNF du jour, If you skew towards Th1 and psoriatics do. Then you also
make to much IFN-gamma, IL-6 as well as TNF.
http://inet.uni2.dk/~iirrh/IIR/04MO/MO.htm
And all this leads to excess iNOS,
http://www.sigmaaldrich.com/Area_of_Interest/Life_Science/Cell_Signaling/Scientific_Resources/Pathway_Slides___Charts/Inductible_Nitric_Oxide_Synthase__iNOS_.html
& maybe a P gene,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12507903&dopt=Abstract
And that takes us back to P News,
http://groups-beta.google.com/groups?hl=en&lr=&q=iNOS+psoriasis+freaking+NOS+AA+LPS+TH1+th2+P&qt_s=Search
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15898287&query_hl=1
http://groups-beta.google.com/groups?hl=en&lr=&q=il-12+il-23+ranhub11&qt_s=Search
Whats a psor head to do?
Take a low tech bath?
Old fashioned sodium bicarbonate baths for the treatment of psoriasis
in the era of futuristic biologics: an old ally to be rescued.
Verdolini R, Bugatti L, Filosa G, Mannello B, Lawlor F, Cerio RR.
Dermatology Unit, St Andrew's Hospital, London, UK.
rverd...@hotmail.com
BACKGROUND: For centuries, medicated baths have been one of the first
lines of treatment for psoriasis. Even today, with sophisticated
immunosuppressive treatments available, Dead Sea salts and spa waters
are recognized to be beneficial in the management of psoriatic
patients. OBJECTIVE: To assess statistically the efficacy of sodium
bicarbonate (NaHCO3) baths in psoriasis patients. Methods: Thirty-one
patients with mild-moderate psoriasis were admitted to this study;
Nineteen patients were treated with sodium bicarbonate baths and
compared with twelve patients who were administered a placebo.
Assessments were made on days 0 and 21. RESULTS: Almost all patients
who used NaHCO3 reported a statistically valuable improvement. NaHCO3
baths reduced itchiness and irritation; in general, the patients
themselves recognized a beneficial impact on their psoriasis, so much
so that they have continued to bathe in NaHCO3 even after the end of
the study. CONCLUSION: We maintain that even with sophisticated
immunosuppressive and highly specific anti-cytokine and anti-chemokines
treatments available for the treatment of psoriasis, an older and often
forgotten treatment can still play a role.
PMID: 15897164
How about nettles, as mentioned by evetsm the other day. Poria cocos
(fu ling, PC) could be cocktailed in for added clout,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=1306145&query_hl=5
While the PC slows TNF it also kicks up IL-10 (IL-10 being good for P)
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12568282&query_hl=5
So, if you want paradise or heaven on earth.
Remicade/laser beams or nettle extract with Fu Ling (poria cocos- PC)
may
be in your future.
I know whats in mine.
Lets do the pathways and see whats current.
NF-kappa-B kinase alpha and beta (IKKa and IKKb or NF- IKappa) and
affects on inflammation,
http://www.sciencedaily.com/releases/2005/05/050502121411.htm
Inhibitors (Thanks to kofi on sci.life-extension for this exlnt link)
http://people.bu.edu/gilmore/nf-kb/inhibitors/#top
Kappa stuff from our group,
http://groups-beta.google.com/group/alt.support.skin-diseases.psoriasis/search?group=alt.support.skin-diseases.psoriasis&q=kappa&qt_g=1&searchnow=Search+this+group
http://groups-beta.google.com/group/alt.support.skin-diseases.psoriasis/search?group=alt.support.skin-diseases.psoriasis&q=nf-kb&qt_g=1&searchnow=Search+this+group
And from the web,
http://www.google.com/search?hl=en&lr=&q=Nf-kappa+psoriasis&btnG=Search
http://www.google.com/search?hl=en&lr=&q=Nf-kappa-b+psoriasis&btnG=Search
The med. diet is good for your heart. How about for P? Try it
and find out and then let us all know.
http://www.sciencedaily.com/releases/2005/05/050507094823.htm
We can use the data and it just may save someone's life. Thats a good
thing, we like to think.
And if the life you save is your own. Then you'll think so too. then
again you
won't know if your dead.
Thnk about that one.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8821518&query_hl=1
[Anti-inflammatory effect of Urtica dioica folia extract in comparison
to caffeic malic acid]
[Article in German]
Obertreis B, Giller K, Teucher T, Behnke B, Schmitz H.
Strathmann AG, Hamburg.
Urtica dioica extract is a traditionary used adjuvant therapeutic in
rheumatoid arthritis. The antiphlogistic effects of the urtica dioica
folia extract IDS 23 (Extractum Urticae dioicae foliorum) and the main
phenolic ingredient caffeic malic acid were tested concerning the
inhibitory potential on biosynthesis of arachidonic acid metabolites in
vitro. The caffeic malic acid was isolated from Urtica folia extract
using gel exclusion- and high performance liquid chromatography and
identified by mass spectroscopy and nuclear magnetic resonance.
Concerning the 5-lipoxygenase products IDS 23 showed a partial
inhibitory effect. The isolated phenolic acid inhibited the synthesis
of the leukotriene B4 in a concentration dependent manner. The
concentration for halfmaximal inhibition (IC50) was 83 microns/ml in
the used assay. IDS 23 showed a strong concentration dependent
inhibition of the synthesis of cyclooxygenase derived reactions. The
IC50 were 92 micrograms/ml for IDS 23 and 38 micrograms/ml for the
caffeic malic acid. Calculating the content in IDS 23 the caffeic malic
acid is a possible but not the only active ingredient of the plant
extract in the tested assay systems. It is demonstrated that the
phenolic component showed a different enzymatic target compared with
IDS 23. The antiphlogistic effects observed in vitro may give an
explanation for the pharmacological and clinical effects of IDS 23 in
therapie of rheumatoid diseases.
PMID: 8821518
If Urtica dioica extract (nettle extract) works on arthritis and P, i'd
be haPPy.
Suppression of tumor necrosis factor-alpha, interleukin-1 beta,
interleukin-6 and granulocyte-monocyte colony stimulating factor
secretion from human monocytes by an extract of Poria cocos.
Tseng J, Chang JG.
Department of Biology, National Taiwan Normal University, Taipei, ROC.
Fu-Ling, the sclederma of Poria cocos (Schw.) Wolf, has long been used
as a sedative and diuretic. However, data in this report suggest that
Fu-Ling is a potential suppressor of cytokine secretion from human
peripheral blood monocytes under in vitro condition. Monocyte culture
medium containing 10% of Fu-Ling extract significantly inhibited
secretion of TNF-alpha, IL-beta, IL-6 and GM-CSF from the monocyte
monolayer. However, as Fu-Ling extract content was gradually reduced,
cytokine secretion was augmented in comparison with the cytokine
secretion in drug-free controls. This augmentative effect resulted from
the trace amount (1.24 ng/ml in 0.62% of Fu-Ling extract) of
lipopolysaccharide (LPS) which contaminated the Fu-Ling extract during
the preparation process, since TNF-alpha, IL-1 beta and IL-6 secretion
induced by 0.62% Fu-Ling extract could be significantly inhibited by
polymyxin B, an LPS inhibitor. Furthermore, the amounts of TNF-alpha
IL-1 beta and IL-6 induced by 1 ng/ml of LPS without the presence of
drug were more than that induced by 0.62% of Fu-Ling extract. Thus,
cytokine secretion induced by LPS contamination (1.24 ng/ml) in the
Fu-Ling extract was partially suppressed by 0.62% of the Fu-Ling
extract itself. GM-CSF secretion in the medium containing 0.62% of
Fu-Ling extract was not induced by LPS since: a) GM-CSF induced by
0.62% Fu-Ling extract could not be inhibited by polymyxin B; b) LPS at
1 ng/ml showed no activity indicating induction of GM-CSF secretion.
PMID: 1306145
There you go....Or should I say, we go? I go?
randall... just gone.
randall
Got dairy fractions?
http://www.dairyreporter.com/news/news-ng.asp?n=60115-advitech-seeks-new
Canadian sweet dairy whey extract XP-828L being tested in second trial
for mild
to moderate psoriasis. Looks like a riP-off of randall's proflora
whey, to me. <G>
<snip>
Advitech acquired the exclusive rights to the technology behind
XP-828L, which is intended first and foremost to help alleviate mild to
moderate psoriasis, when it entered into an agreement with French firm
Pierre Jouan Biotechnologie in 2003.
It originally hoped to roll out the product by the end of 2004, but
decided to delay whilst it carries out a program of placebo-controlled
clinical trials, the results of which are expected to give the product
weight with dermatologists, as well as just with natural products
suppliers.
Advitech's double-blind, placebo-controlled clinical study on XP-828L
for mild to moderate psoriasis will be completed in mid-June and the
results - expected to confirm the findings of a first clinical trial
involving 11 patients over a 112-day period in early 2004 - made public
on July 1.
An in vivo study is also underway at Université Laval investigating
the use of the ingredient for inflammatory bowel disease.
On 4 May the newly public-traded company released its financial results
for 1Q 2005. Its net loss stood at C$671,269, or C$0.01 per share,
compared with C$267,378 at the same point in 2004.
The 128.4 percent increased loss was explained by reduced sales of
Lactium, Advitech's bioactive ingredient from dairy proteins
(C$157,000 compared with C$406.4 last year), R&D expenses associated
with XP-828L and sales and marketing expenses during
pre-commercialization for the product.
(I don't know what happened in their first P trial. If this one turns
out
positive, an investment in this canadian corP may be in order. It's
about
time we made a buck, even a canadian one, on this p thang.)
*******
If you can't get humans, the third smartest inhabitants on planet earth
(according to Hitchhiker's guide to the galaxy) to take proflora whey,
feed it to the animals they consume?
http://www.thepigsite.com/LatestNews/Default.asp?AREA=LatestNews&Display=9422
<G>
*****
Atopic genes overlap with P, (Knew it! My head has some atoPia!)
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15902388&query_hl=1
The genetics of atopic dermatitis: recent findings and future options.
Hoffjan S, Epplen JT.
Department of Human Genetics, Ruhr-University, Universitatsstrasse 150,
44801, Bochum, Germany, sabine....@ruhr-uni-bochum.de.
Atopic dermatitis (AD) is a chronic pruritic skin disease affecting up
to 15% of children in industrialized countries. AD belongs to the group
of allergic disorders that include food allergy, allergic rhinitis, and
asthma. A multifactorial background for AD has been suggested, with
genetic as well as environmental factors influencing disease
development. Genome-wide screens for AD have been completed in four
different populations to date. Interestingly, the susceptibility
regions identified for AD show little overlap with asthma
susceptibility regions, suggesting that, at least in part, separate
genes might be involved in the pathogenesis of the different atopic
disorders. Instead, some of the identified regions overlap with
susceptibility regions for psoriasis, another chronic skin disease.
Thus, genes expressed in the skin might play an important role in AD
pathogenesis, in addition to genes influencing atopic diatheses.
Although no veritable "AD gene" has been identified by positional
cloning to date, examples from other complex genetic disorders such as
asthma show that this goal is likely to be reached in the near future.
Candidate gene studies, on the other hand, have identified 19 genes
that were shown to be associated with AD in at least one study. The
results of genome-wide screens as well as candidate gene studies are
evaluated here in detail.
PMID: 15902388
You know when they find the exact genes, they can get really serious
with trying how to figure out how to fix us without killing us.
Calcium at play in this next one,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15902381&query_hl=1
[Severe Erythrodermic Psoriasis in a Patient with 22q11 Deletion
Syndrome.]
[Article in German]
Preiss JC, Zouboulis CC, Zeitz M, Duchmann R.
Medizinische Klinik I (Gastroenterologie, Infektiologie,
Rheumatologie), Charite-Universitatsmedizin Berlin, Campus Benjamin
Franklin, Berlin.
BACKGROUND: : Erythrodermic psoriasis is a severe manifestation of
psoriasis and can be triggered by several factors. CASE REPORT: : A
35-year-old man was admitted with severe, almost generalized
exfoliative, oozing erythrodermic psoriasis, fever, and cramping of
hands and legs. He was under systemic treatment with acitretin.
Laboratory examination revealed a marked hypocalcemia as a consequence
of primary hypopara thyroidism as well as hypalbuminemia. After
normalization of the serum calcium and albumin levels, cutaneous
symptoms and fever rapidly improved. No infectious etiology could be
found. Hypoparathyroidism together with a right-sided aorta was caused
by a 22q11 deletion syndrome. CONCLUSION: : Epidermal cell
proliferation and formation of intercellular junctional components of
the epidermis are strongly calcium-dependent. Furthermore, carriers
like albumin are necessary for the transportation of acitretin in the
peripheral tissue. This case report suggests that calcium can be
involved in psoriasis pathogenesis at least in a subgroup of patients
and that systemic retinoids exhibit insufficient effectiveness under
low serum albumin levels.
PMID: 15902381
Lets see now, calcium ions are in the pathways. Gosh, who knew?
I know that ED does from a quick group google. Try Ca+ or is that
Ca++?
KNOW THY DERM!
A good derm should be well versed in cocktailing, rotating, LASERS, etc
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15900797&query_hl=1
Combining traditional agents and biologics for the treatment of
psoriasis.
Cather JC, Menter A.
Baylor University Medical Center, Dallas, TX, USA.
Psoriasis patients deserve long-term control of their disease with
optimal safety. Traditional agents (methotrexate, cyclosporine,
retinoids, and photochemotherapy [PUVS]), although providing excellent
short-term control, may produce acute or chronic toxicities, thus
limiting their usage. Dermatologists are well versed in combination and
rotational therapies for psoriasis, using these and other agents. With
the advent of biologic therapies (three currently approved, and others
pending), the potential for safer long-term psoriasis control is being
realized. A review of the literature, plus our personal experience in
using combinations of traditional agents and biologics, is presented.
PMID: 15900797
Anything else?
why yes! A nice simple cure would be nice.
How about megamin? Sounds like mega-BS to me. LOL
Which guarantee's someone will try it and then be to embarassed
to report their negative results. lol
Can we find one person not ashamed to try it and then report back?
Sure, why not. Won't be the last time a flim flam landed here.
randall....
randall
randall wrote:
>
> why yes! A nice simple cure would be nice.
>
> How about megamin? Sounds like mega-BS to me. LOL
>
> Which guarantee's someone will try it and then be to embarassed
> to report their negative/(+) results. lol
>
> Can we find one person not ashamed to try it and then report back?
>
> Sure, why not. Won't be the last time a flim flam landed here.
>
Ok ok, lets get to the details.
First you do an author search. Its easy. You click the
guy/gals name on the groups at deja.com (find the group
by keywording psoriasis with some other word, like randall)
Then click open a thread and click the persons name.
For A.. @ A. A
you get 75,800 hits,
http://groups-beta.google.com/groups?enc_author=i8ir6gUAAABGKvQMJgJuc2Kp592lmpVv
Why this person choose a bogus email address is their first
strike. Trying to hide your identity and provide a product (a spamy one
at that) is not a good idea.
But,
Then use the search box and put in megamin or psoriasis.
Bingo-- this person hasn't posted much and the two posts to the
group are most likely not even the same person.
At this point you can look up the provider/owner of the link they
posted.
Go to whois.com (i usually do a web search of whois.com and try a
different whois search engine each time)
Just enter the url link (getmegamin . com ) in their box and click go.
And then you know who they are,
This one came back:
Registrant:
Velebit Informatika International velem...@zg.htnet.hr
+385.12334766
Velebit Informatika International
Trg J. F. Kennedya 6a
Zagreb,HR,HR 10000
Domain Name:getmegamin.com
Record last updated at 2005-02-24 06:08:10
Record created on 2005/2/24
Record expired on 2006/2/24
Domain servers in listed order:
ns1.mojsite.com ns2.mojsite.com
Administrator:
Name-- DNS Admin
EMail-: (dom...@plus.hr)
tel --: +385.52380870
org: PLUS hosting
Istarska 36
Pula,Istra,HR 52100
Technical Contactor:
Name-- DNS Admin
EMail-: (dom...@plus.hr)
tel --: +385.52380870
org: PLUS hosting
Istarska 36
Pula,Istra,HR 52100
Billing Contactor:
Name-- DNS Admin
EMail-: (dom...@plus.hr)
tel --: +385.52380870
org: PLUS hosting
Istarska 36
Pula,Istra,HR 52100
Registration Service Provider:
name: PLUS hosting
tel: +385.52380870
fax: +385.52210685
web:http://www.plus.hr
provider each time
(And the company i used to do the search let me know that
I can buy all the other domains on this one. like .org, .biz etc
are all availabe to be used for a fee...)
**********************************************
Then you can search this owner info or look for abuses
from their other links.
Which I'm not about to take any more time on.
But you get the idea by now. So you can do it.
One thing I notice is that,
Novatech isn't a name connected with their products.
Its a computer hardware maker and not a pill company.
Novatech isn't on any web or group pages other then this one, that i
can
find.
Now that is strange. And another big warning signal.
Either their nano nonsense is a well kept secret or
a marketing ploy to seParate your $$$ from your bank
accounts.
****************
**************
Next--- the sunday P funnies. :)
P word watch. Some writers like to use P in their articles.
(Some famous writers actually became writers due to it.)
This week P and starwars does an odd hookuP...
Check it out,
(...)
Some villains just have too much power. Red Sox President Larry
Lucchino didn't call the Yankees the "Evil Empire" because he thought
Steinbrenner looked like Darth Vader. In the 1960s and '70s, Wilt
Chamberlain was so physically imposing, he was considered a villain
wherever his teams played. Shaq has the physical gifts, but the Heat
center is too much of a goofball to be a good villain.
The biggest villain in sports isn't even a person. It's TV. It's
responsible for games that end after midnight, too many commercials,
long-winded announcers, the heartbreak of__psoriasis__ and global
warming.
(...)
*****
Return of the fall guy: The farce be with you
http://ydr.com/story/mike/70518/
NEWS ITEM: The White House criticized Newsweek for damaging America's
image in the Islamic world and demanded that the newsweekly "help
repair the damage" done by its discredited report that Korans were
tossed into toilets at the Guantanamo Bay terror prison. "The image
of the United States abroad has been damaged; there is lasting damage
to our image because of this report," said White House press
secretary Scott McClellan.
* * *
The White House ripped Newsweek magazine this week for a now
discredited report that quoted an anonymous source as saying that
Anakin Skywalker transformed into Darth Vader after suffering from a
near fatal bout with psoriasis.
The report was blamed for widespread rioting among fanatical followers
of the "Star Wars" movie franchise, resulting in what witnesses
described as the senseless destruction of several boxes of Jujubes and
Junior Mints.
"This report, which Newsweek has now retracted and said was wrong,
has had serious consequences," said White House press secretary Scott
McClellan. "Popcorn was spilled because of this report and there is
lasting damage to the image of 'Star Wars' because of it."
The brief story quoted an anonymous source as saying that Skywalker was
turned to the dark side, not because he was lured by the unlimited
power offered by the dark side of the Force and was seriously injured
when Obi-Wan Kenobi found out Skywalker had had an illicit relationship
with Jar-Jar Binks, but because he had "a really bad skin problem."
The magazine printed the item after submitting it to two movie
executives for a response, receiving no response.
The White House claimed the report was responsible for the rioting
among Star Wars fans, which administration sources suggested broke out
after radical dermatologists denounced the "Star Wars" franchise
for its "complete and total disrespect of quality skin care" and
its failure to attach the "Star Wars" brand to a line of skin-care
products.
But in a briefing after the violence had broken out, Gen. Richard B.
Myers, chairman of the Joint Chiefs of Staff, had said that the senior
commanders believed the protests were unrelated to skin care and
dermatology and allegations of psoriasis plaguing Anakin Skywalker.
"They thought it was not at all tied to the article in the
magazine," Myers said.
The chairman said the rioting began after theaters sold out early shows
of the new "Star Wars" movie via Internet sales, leaving some who
had camped out for weeks to be first in line to see the film out in the
cold.
"We have reason to believe that this is the work of a small group of
fanatics and began when those dressed up like Darth Vader began
ridiculing those wearing Jar-Jar Binks costumes," Myers said. "And
then, the guys dressed up like Wookies got involved, and the situation
spiraled out of control."
Nonetheless, the White House continued its attacks on Newsweek,
criticizing the magazine for causing disturbances that disrupted
essential industries and threatened lives.
"During the rioting among 'Star Wars' fans, the nation's video
gaming and Internet porn industries suffered severe losses,"
McClellan said.
Segments of the video gaming industry reported a sharp decline in sales
and analysts predicted it would take several weeks for the industry to
recover. Also, unemployment among women named Brandyne was reported to
hit a five-year high.
McClellan also suggested that the magazine run stories that reflect
"Star Wars" in a positive, non-psoriasis-related light.
"Now, it's not my position to tell them what to print and what not
to print," McClellan said. "But I'm telling them what to print to
undo the damage caused by the first report, which was based on an
anonymous source, as are a lot of stories that come from the White
House."
Changing the subject, McClellan also told reporters that the White
House was investigating other instances where Newsweek might be
responsible for bad things.
"What we're saying is that Newsweek bears responsibility for a
variety of things that a lot of people try to blame on the people who
are actually responsible," McClellan said.
The White House also said Newsweek was responsible for:
# Rioting in Afghanistan and Pakistan, even though the magazine was
unsure whether it had any circulation in those countries and was even
translated into whatever language the people there speak.
# The failure to find weapons of mass destruction in Iraq.
# Steroid use in Major League Baseball.
# The fact that it's nearly impossible to get Thai food delivered on
weekends.
"We believe Newsweek is responsible for all of these things and many
more that we can't think of right now at the moment," McClellan
said. "Oh, oh, oh. Traffic jams on the Beltway? Newsweek's
fault."
Mike Argento, whose column appears Mondays and Thursdays in Living and
Sundays in Viewpoints, can be reached at 771-2046 or at mi...@ydr.com.
Read more Argento columns at ydr.com/mike.
*****
I liked the second one better then the first. More creative and clever.
And the H Of P is so drool. Wasn't it a marketing ploy to get one
to use nanotechnology to separate your $$$ from your bank accounts?
Or a comedy thing to get yucks and not bucks?
Or a way to simply Piss us off?
Have a nice sunny day and get naked and stick your P in the suns
face. It can deal with it....
randall
randall
The last P news (including the P sunday funnies!) had a revealing look
at the latest P flim flam. Provided nanotechnology is flim flam for
P...
and how you can search anyone or thing on he web.... you get so
much for so little on this group....Not to mention we have each other.
Back to megananotechnologyvitamins from serbia? Wasn't it?
To be fair.
We don't actually know that getmegamin.com is a fraud.
Here is medical news from last week dealing with anything even remote
to P. I lean towards cardio and diabetes as those are big overlaPs for
P...
A bunch of stuff related or not to P.
Nanotech news, (Yep thats right, real news for nanotechnology)
http://www.medicalnewstoday.com/medicalnews.php?newsid=24410
If you have a binge drinking problem or just drink to much. And any
amount can be
considered to much if you psoriasis. Eat kudzu to lower the cravings.
NO, really,
http://www.medicalnewstoday.com/medicalnews.php?newsid=24669
I can see naked psoriatics digging up the south for this tenacious
herbal root and eating it like crazy... Should we do a trial of psors
in the south with this root? Could be another hot business to
sell this root all over the country...
Back to recent P highlights. I still take glucosamine and chondrotin
as a precursor to HA btw.
HA news,
http://www.medicalnewstoday.com/medicalnews.php?newsid=24805
New polysaccharide may help combat multidrug resistance in cancer
20 May 2005
In a recent study published in the Journal of Biological Chemistry,
scientists report that a molecule previously thought to play a purely
structural and inert role in cells is actually involved in multidrug
resistance in cancer. Using antagonists for this molecule, the
researchers were able to sensitize drug resistant breast cancer cells
to chemotherapeutic drug treatment.
The research appears as the "Paper of the Week" in the May 27 issue of
the Journal of Biological Chemistry, an American Society for
Biochemistry and Molecular Biology journal.
Multidrug resistance is very common in most types of cancers, making it
one of the leading problems in cancer therapy. It is often caused by an
increase in the cell's production of proteins that transport drugs out
of the cell, preventing the drugs from combating cancer.
Previously, Dr. Bryan P. Toole and his coworkers, Drs. Suniti Misra and
Shibnath Ghatak, of the Medical University of South Carolina noticed
that small pieces, or oligomers, of a polysaccharide called hyaluronan
were able to sensitize drug-resistant breast cancer cells to several
different chemotherapeutic drugs. He believed that the polysaccharide
oligomers were binding to a receptor for hyaluronan (called CD44) and
preventing it from initiating a signaling cascade that would result in
drug resistance.
"It is very surprising that hyaluronan is involved in drug resistance,"
admits Dr. Toole. "Most scientists think of hyaluronan as a structural
and inert molecule. In adult tissues it plays two roles. First, it
assists in tissue hydration and in biophysical properties such as
resilience. Second, it forms a template to which matrix proteins attach
and form important extracellular structural complexes."
Hyaluronan also accumulates around the outside of cells during disease
processes such as early atherogenesis, persistent inflammation, and
cancer. In recent years, however, hyaluronan has also been shown to
induce signaling pathways in inflammatory, embryonic and cancer cells.
In their current Journal of Biological Chemistry paper, Dr. Toole and
his colleagues report on further studies which indicate that hyaluronan
increases the cellular production of a multidrug transporter protein by
binding to CD44. They discovered that antagonist molecules that bind to
hyaluronan and prevent it from interacting with CD44 were able to
sensitize multidrug resistant breast cancer cells to chemotherapeutic
drugs. The researchers also found that increasing hyaluronan synthesis
in cells increased resistance to drug treatment.
"Our work indicates that hyaluronan antagonists, for example small
hyaluronan oligomers, reverse the malignant properties of cancer cells,
including proliferation, invasiveness, and drug resistance," explains
Dr. Toole. "Hyaluronan oligomers are non-toxic, non-immunogenic, and
readily applicable to several proliferative disease processes,
especially cancer. We are hoping that hyaluronan antagonists can be
used in conjunction with chemotherapy such that much lower and less
toxic doses of chemotherapeutic agents can be used."
The Journal of Biological Chemistry's Papers of the Week is an online
feature which highlights the top one percent of papers received by the
journal. Brief summaries of the papers and explanations of why they
were selected for this honor can be accessed directly from the home
page of the Journal of Biological Chemistry online at www.jbc.org.
The American Society for Biochemistry and Molecular Biology (ASBMB) is
a nonprofit scientific and educational organization with over 11,000
members in the United States and internationally. Most members teach
and conduct research at colleges and universities. Others conduct
research in various government laboratories, nonprofit research
institutions, and industry.
Founded in 1906, the Society is based in Bethesda, Maryland, on the
campus of the Federation of American Societies for Experimental
Biology. The Society's primary purpose is to advance the sciences of
biochemistry and molecular biology through its publications, the
Journal of Biological Chemistry, The Journal of Lipid Research,
Molecular and Cellular Proteomics, and Biochemistry and Molecular
Biology Education, and the holding of scientific meetings.
For more information about ASBMB, see the Society's website at
http://www.asbmb.org.
Contact: Nicole Kresge
nkr...@asbmb.org
301-634-7415
American Society for Biochemistry and Molecular Biology
http://www.asbmb.org
***********
Mouth plaque contributes to heart attack,
http://www.medicalnewstoday.com/medicalnews.php?newsid=24792
Yikes... Get those mouths cleaned uP. See your dentist regularly.
**********************
2 out of 100 get P, 1 out of 12 gets diabetes. So one would expect
overlaps between
the two and they do. but what is happening with diabetes and how can
you avoid it?
http://www.medicalnewstoday.com/medicalnews.php?newsid=24525
Drug help for those with crohn's and gut problems,
http://www.medicalnewstoday.com/medicalnews.php?newsid=24691
*******
Some day, finding the P genes will lead to a cure. So anything that
advances that quest deserves our resPect...
Genetic prize for advancing the state of the art on gene targeting,
http://www.medicalnewstoday.com/medicalnews.php?newsid=24383
(...)
Before gene targeting, researchers could not pinpoint how a specific
gene worked, which was very frustrating," said Dr. Jennifer L. Howse,
president of the March of Dimes. "Dr. Capecchi and Dr. Smithies,
working independently, made a technological breakthrough that
completely revolutionized biomedical research and our ability to study
human disease and development. We're reaping the benefits every day
with advances in genetic medicine."
Gene targeting is now practiced routinely by thousands of scientists
all over the world, enabling them to address the most complex and
critical biological problems, including the causes and treatment of
birth defects and many other disorders, such as cancer, diabetes, and
atherosclerosis.
(...)
Immune news,
www.medicalnewstoday.com/medicalnews.php?newsid=24383
Funds for the awards come from trusts established by John G. and
Frances C. Searle. Mr. Searle was President of G.D. Searle & Co., of
Skokie, Illinois, a research-based pharmaceutical company. The 393
Searle Scholars have shared over $69,780,000 in grants since the
program began in 1981. This year, 15 scholars were chosen from 193
applications by recently appointed assistant professors at 122
universities and research institutions nationwide. Nominated applicants
come from all branches of the biomedical and chemical sciences. <snip>
http://www.medicalnewstoday.com/medicalnews.php?newsid=24614
<>Weakened T-cell receptor signals change T-cell lineage, Fox Chase
study
Understanding the development of critical components of the immune
system can lead to scientific and medical advances in stimulating
desirable immune responses and halting unwanted ones -
The immune system is a marvel of versatility, creating a variety of
cells that develop in different ways to protect the body. To carry out
these tasks, immune cells follow a career path that forks at various
points in their development. In a report in the May 2005 issue of
Immunity, Fox Chase Cancer Center scientists led by immunologists David
L. Wiest, Ph.D. and Dietmar J. Kappes, Ph.D., show that cell-receptor
signaling strength influences which course certain immature immune
cells will take, suggesting a flexible new model for commitment to one
lineage or another.
The first, most basic career choice made by precursors of the adaptive
arm of the immune system is whether to adopt the B-cell or T-cell fate.
Both originate from stem cells in the bone marrow, but B cells mature
there while T cells migrate to the thymus gland, which governs their
development.
"The recognition and destruction of invading pathogens by T lymphocytes
is essential to the ability of humans to resist disease," said Wiest.
"T cells recognize these invaders by means of a surface structure
called the T-cell antigen receptor complex, or TCR."
Two distinct lineages of T cells utilize distinct types of TCR
complexes. One lineage employs pairs of TCR proteins termed alpha-beta
while the other uses the TCR gamma-delta pair of proteins. The
alpha-beta and gamma-delta pairs of proteins represent the "eyes" of
the TCR complex and enable these distinct types of T cells make unique
contributions to our ability to resist disease.
The more numerous T cells of the alpha-beta lineage provide protection
against infectious diseases either by helping B cells generate
antibodies against external agents (helper T cells) or by directly
attacking and destroying cells infected by foreign invaders (killer T
cells). Gamma-delta T cells migrate from the thymus to epithelial
tissues such as skin and the linings of the lung. While their precise
role remains poorly understood, they perform vital protective
functions. Certain lung infections easily cleared from normal
laboratory mice are a death sentence for those lacking gamma-delta T
cells.
Despite their clear importance in resisting disease, the processes
controlling the generation of gamma-delta T cells have remained
mysterious until recently. As Robert Frost put it, Wiest pointed out:
"Two roads diverged in a wood, and I--
I took the one less traveled by,
And that has made all the difference."
"Gamma-delta T cells represent the road less traveled," Wiest said.
"However, the role of the TCR in determining lineage is controversial,
particularly whether different forms of TCR predetermine a cell's fate
and whether or not their signals control the choice."
In the new study, Wiest and his colleagues use several models to
manipulate the signaling strength of the gamma-delta TCR. A strong
signal, produced in the presence of a specific binding substance, or
ligand, directs immature T cells almost exclusively to the gamma-delta
lineage. However, weakening the signal promotes alpha-beta lineage
development.
"The signal strength determines the level of expression of early growth
response (Egr) proteins, with cells choosing the gamma-delta lineage
expressing far greater quantities of Egr proteins than those adopting
the alpha-beta lineage," explained Wiest. "Egr proteins regulate which
cellular genes are turned on or off so we think that high-level
expression of Egr proteins instructs cells to express the set of
cellular genes necessary to become a gamma-delta T cell."
Understanding the development of critical components of the immune
system can lead to scientific and medical advances in stimulating
desirable immune responses and halting unwanted ones.
"Although their precise function is still unclear, delta-gamma T cells
seem to form the first line of response against external
disease-causing agents, including bacterial infections, tissue damage
and stress," Wiest said. "Laboratory mice unable to make delta-gamma T
cells heal skin injuries more slowly.
"Immune surveillance, the body mechanism that detects potential cancers
and destroys them before their presence is evident to us, may be one
function of the delta-gamma lineage, since gamma-delta T cells appear
to be particularly adept at combating skin cancers," Wiest added.
In addition to Wiest and Kappes, Fox Chase co-authors of the new
Immunity paper include postdoctoral fellow Mariëlle C. Haks, Ph.D.
(currently at Leiden University Medical Center in The Netherlands),
graduate student Juliette Lefebvre, postdoctoral associate Jens Peter
H. Lauritsen, Ph.D., research associate Michael Carleton, Ph.D. (now at
Rosetta Inpharmatics in Seattle), and scientific technician Michele R.
Rhodes, along with Toru Miyazaki, M.D., Ph.D., of the University of
Texas Southwestern Medical Center's Center for Immunology in Dallas.
Grants from the National Institutes of Health and an appropriation from
the Commonwealth of Pennsylvania helped support this work along with a
Fox Chase Cancer Center Board of Directors Postdoctoral Fellowship and
a stipend from the Netherlands Organization of Scientific Research for
Haks.
Fox Chase Cancer Center was founded in 1904 in Philadelphia as the
nation's first cancer hospital. In 1974, Fox Chase became one of the
first institutions designated as a National Cancer Institute
Comprehensive Cancer Center. Fox Chase conducts basic, clinical,
population and translational research; programs of prevention,
detection and treatment of cancer; and community outreach. For more
information about Fox Chase activities, visit the Center's web site at
http://www.fccc.edu or call 1-888-FOX CHASE.
Contact: Karen Carter Mallet
Karen....@fccc.edu
215-728-2700
Fox Chase Cancer Center
http://www.fccc.edu
****************************
stoPPing evolution of little itty bitty bugs,
http://www.medicalnewstoday.com/medicalnews.php?newsid=24716
A team of scientists at The Scripps Research Institute and the
University of Wisconsin have demonstrated a new way of fighting
antibiotic resistance: by stopping evolution.
In the June issue of the open-access journal PloS Biology, the team
describes how a protein called LexA in the bacterium Escherichia coli
promotes mutations and helps the pathogen evolve resistance to
antibiotics. The scientists also show that E. coli evolution could be
halted in its tracks by subjecting the bacteria to compounds that block
LexA. Interfering with this protein renders the bacteria unable to
evolve resistance to the common antibiotics ciprofloxacin and
rifampicin.
"If you inhibit this pathway, the bacteria cannot evolve," says Scripps
Research Assistant Professor Floyd Romesberg, Ph.D., who led the study.
<snip>
****
http://www.medicalnewstoday.com/medicalnews.php?newsid=24694
Hydroxycitric acid slows glucose uptake, cuts insulin peaks/valleys
In this obesity-obsessed world, the dream ingredient must be something
that tastes good enough to be a condiment or flavoring and yet somehow
helps us keep our weight down. Consider hydroxycitric acid (HCA), known
variously as Brindle berry or Malabar tamarind, which is used in Indian
and Thai food as a condiment and flavoring agent.
In Indian folk medicine as a dried powder or tea it's indicated as a
laxative and for rheumatism. As Malabar tamarind, it can substitute for
lime, and in Ceylon it's used along with salt to cure fish.
For HCA, though, the other half of the taste-benefit formula is much
less clear. Animal studies suggest HCA may reduce food intake followed
by weight loss, but no controlled human trials have shown either
effect. Nevertheless, many people seem to believe HCA will help them
lose weight. It's sold by vitamin and other specialty shops as Citrimax
or Citrin, and is a featured ingredient in such dietetic aids as
Herbalife's "Snack Defense" tablets. <snip>
***********
http://www.medicalnewstoday.com/medicalnews.php?newsid=24617
Nutrition Gene Key in Regulating Immune System
18 May 2005
A gene that signals a yeast cell to make bread rise and mice to eat a
better diet also helps selectively silence the immune system,
researchers have found.
The finding may help explain how a mother avoids rejecting a
genetically foreign fetus and provides a new target for treatments to
help the immune system ignore other desirables like a transplanted
organ.
"Think of this like a radio transmitter and a receiver," says Dr.
David H. Munn, pediatric hematologist-oncologist at the Medical College
of Georgia and lead author of the study in the May issue of Immunity.
The transmitter is indoleamine 2,3-dioxygenase, or IDO, an enzyme
particularly expressed in places such as the gastrointestinal tract and
tonsils where the immune system routinely meets up with foreign
substances it might want to ignore.
Drs. Munn, Andrew L. Mellor and Simon J. Conway published a Science
article in 1998 showing IDO's role in protecting the fetus from
rejection by the mother's immune system during pregnancy. Later they
learned that tumors and persistent viruses such as HIV may hijack this
mechanism to shield themselves from immune attack.
They knew IDO degraded tryptophan, an amino acid essential to the
survival of T cells. They weren't so certain what happened at the
receiving end.
The researchers wondered if T cells exposed to IDO might simply starve
to death without enough trytophan, one of nine essential amino acids
attainable only through food. "If the T cells are just starving, then
you don't need a receiver. They just die. But the T cells didn't seem
to be dying. They seemed to be rendered selectively non-responsive,"
says Dr. Munn. "That sounded more like the T cell was participating
in this process."
So the researchers started looking at the few genes known to respond to
amino acid levels and found GCN2.
GCN2 is present and active in many cells, but its major sites of action
are unknown and its role in T cells was unexplored, Dr. Munn says.
"GCN2 is a nutrition sensor in yeast," says Dr. Munn. GCN2 helps
yeast know when it has sufficient nutrition to grow; bread keeps rising
until yeast run out of nutrition. A paper published in March in Science
explores GCN2's role in mammalian survival by enabling mice to sense
they need to eat a well-balanced diet to stay healthy.
Dr. Munn contacted Dr. David Ron, a professor of medicine and cellular
biology at New York University School of Medicine's Skirball Institute,
studying the nutritional aspects of the gene. Dr. Ron, a co-author on
the Immunity paper, shared a GCN2 knockout mouse he developed and
helped the MCG researchers study the gene's role in T cells.
When these knockout mice were exposed to IDO, their T cells simply
ignored it.
The researchers had found a receiver and possibly more.
"No one had known any gene specifically targeted by IDO, and now we
have one," says Dr. Munn. "We had not known how T cells were turned
off. We didn't know if the T cells just were never activated, or if
they were actively suppressed by IDO. They all look like resting T
cells. Now we do know that there are differences."
MCG researchers want to know more about how GCN2 puts T cells to sleep.
"Whatever it's doing doesn't appear to be killing the T cells. It
would be nice to be able to mimic the effect of IDO by using a drug
that activates this pathway." Now that they have a knockout,
comparative studies with regular mice can determine other genes that
might be impacted downstream of GCN2.
Another big question is whether T cells deactivated by this system can
be reactivated. Knowing the role of the GCN2 gene makes it easier for
scientists to watch what happens to the T cells affected by IDO in a
living organism.
"We know that IDO itself is an important pathway. Evidence is
emerging that IDO seems to contribute to several important regulatory
processes in the immune system," Dr. Munn says of findings from labs
across the country. "But there has been a question in the field about
how the IDO expressed in one cell can signal to neighboring T cells.
Here's our first evidence of one way it may do so. By giving you a
target in the T cell that IDO is talking to, it helps you understand
the system better and we think it also may give us another target for
drugs to try to intervene in the system."
The studies were funded by the National Institutes of Health and the
Carlos and Marguerite Mason Trust.
**************
http://www.medicalnewstoday.com/medicalnews.php?newsid=24566
Sugar "Addiction" a Sign of Hunger, Not Usually Lack Of Control
18 May 2005
Consistent cravings or indulging in sweets is usually a sign that a
person has gotten too hungry rather than a sugar addiction, said sports
nutritionist Nancy Clark, M.S., R.D. With millions of people trying to
lose weight, strategies to control food intake are extremely important.
Clark says active people who are weight conscious can tame their own
"cookie monster" by following a few simple tips to fend off
temptation.
"People who get too hungry tend to crave sweets," said Clark. "To
prevent these cravings, eat enough wholesome foods at breakfast and
lunch, along with a healthy afternoon snack, and voila, you will no
longer crave sweets, nor miss them." <snip>
****************
http://www.medicalnewstoday.com/medicalnews.php?newsid=24437
Vitamin D - More May Be Better
Vitamin D has long been known to help keep your bones in good shape.
The May issue of Mayo Clinic Health Letter covers new research that
shows vitamin D may play a much bigger role in overall health.
Several recent studies have considered the effects of low vitamin D on
health aside from bones. In a controlled study of elderly women, those
taking vitamin D and calcium had much better leg strength and fewer
falls than the women taking only calcium. Another study, of patients
ages 10 to 65 with musculoskeletal pain, found 93 percent were
deficient in vitamin D. <sniP>
*****************
Ok,,,
done for now. But i have some P stuff left, so look for another post in
minutes
not days/hours/months /years/decades...
randall..Thank God for medical research! Now cure us... already.
randall
This P news will be boring... But what the heck. P bores me.
So skiP this P skin post if your not in a scientific mood.
As I search the latest google news for something that may point
the way to the P cure, i'm driven by the thought of all of us with
clear skin and haPPy smiles on our faces. :)
Today this lowly little protein got some press and I jumPed
all over it.
http://www.medicalnewstoday.com/medicalnews.php?newsid=24933
Annexin 1 protein.
(Same thing next link, ) I do this in case a link expires or breaks in
case
you didn't know.... So don't open every link. Scan and if you feel
interested
then open it and peel that onion.
http://www.eurekalert.org/pub_releases/2005-05/ajop-ppd051305.php
Protein prevents detrimental immune effects of bacterial sepsis London,
UK -- The anti-inflammatory protein annexin 1 may protect patients from
the detrimental effects of severe inflammatory response syndrome, as
reported by researchers at Barts and the London, Queen Mary's School of
Medicine and Dentistry. The paper by Damazo et al., "Critical
protective role for annexin 1 gene expression in the endotoxemic murine
microcirculation," appears in the June issue of The American Journal of
Pathology and is accompanied by a commentary.
Severe inflammatory response syndrome, or SIRS, occurs when the body's
response to an overwhelming infection becomes uncontrolled. The very
immune response meant to clear the pathogen and its toxins actually
causes damage to the host's own tissues when it goes into overdrive,
releasing too many immune signals. Thus, the immune response must be
carefully controlled to prevent damage to the host.
Damazo et al. studied this balancing act by analyzing the effects of
the bacterial toxin LPS on normal and annexin 1 knockout mice. Annexin
1 was chosen because it appears to be involved in the resolution phase
of the immune response: its expression on white blood cells impairs
their ability to bind blood vessel walls, preventing their transit from
the blood to other organs.
When normal mice were treated with LPS, the immune system induced a
steady migration of white blood cells from the blood into affected
tissues. However, mice deficient for annexin 1 exhibited a dramatic
release of white blood cells from blood vessels, ultimately leading to
100% mortality by 48 hours.
The researchers characterized the expression of annexin 1 and found
that the gene was activated as early as 1.5 and 6 hours after LPS
administration, with levels returning to normal by 24 hours. Higher
levels of markers of inflammation, and of organ injury, were measured
in annexin 1 deficient animals. Altogether, these findings implied that
the protective effects of the annexin 1 pathway were activated in the
first few hours following toxin administration. In fact, when annexin 1
knockout mice were given small doses of human recombinant annexin 1 in
the first 24 hours following LPS treatment, survival increased to 60%.
<sniP>.
Sirs and real problems with endotoxin (LPS) came to light as a result
of
the post by JXStern a few years ago. That thread is called the Good
article post.
Since then i've built on the immune ramifications of this endotoxin for
inflammation.
Back to the article above,
What is annexin 1?
Ok, here are some of its aliases:
S100 CALCIUM-BINDING PROTEIN A10; S100A10
Alternative titles; symbols
CALPACTIN I, LIGHT CHAIN; CAL1L
CALPACTIN I, p11 SUBUNIT; CLP11
ANNEXIN II LIGAND; ANX2LG
ANNEXIN II, LIGHT CHAIN
p11
http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=114085
http://www.ncbi.nlm.nih.gov/Omim/getmap.cgi?l114085
&
Brings up the fatty acid binding protein (E-FABP),
http://www.biochemj.org/bj/339/0419/bj3390419.htm
^^^^
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12704215&query_hl=1
S100 protein subcellular localization during epidermal differentiation
and psoriasis.
Broome AM, Ryan D, Eckert RL.
Department of Physiology, Case Western Reserve University School of
Medicine, Cleveland, Ohio 44106, USA.
S100 proteins are calcium-activated signaling proteins that interact
with target proteins to modulate biological processes. Our present
studies compare the level of expression, and cellular localization of
S100A7, S100A8, S100A9, S100A10, and S100A11 in normal and psoriatic
epidermis. S100A7 and S100A11 are present in the basal and spinous
layers in normal epidermis. These proteins appear in the nucleus and
cytoplasm in basal cells but are associated with the plasma membrane in
spinous cells. S100A10 is present in basal and spinous cells, in the
cytoplasm, and is associated with the plasma membrane. S100A8 and
S100A9 are absent or are expressed at minimal levels in normal
epidermis. In involved psoriatic tissue, S100A10 and S100A11 levels
remain unchanged, whereas, S100A7, S100A8, and S100A9 are markedly
overexpressed. The pattern of expression and subcellular localization
of S100A7 is similar in normal and psoriatic tissue. S100A8 and S100A9
are strongly expressed in the basal and spinous layers in
psoriasis-involved tissue. In addition, we demonstrate that S100A7,
S100A10, and S100A11 are incorporated into detergent and reducing
agent-resistant multimers, suggesting that they are in vivo
transglutaminase substrates. S100A8 and S100A9 did not form these
larger complexes. These results indicate that S100 proteins localize to
the plasma membrane in differentiated keratinocytes, suggesting a role
in regulating calcium-dependent, membrane-associated events. These
studies also indicate, as reported previously, that S100A7, S100A8, and
S100A9 expression is markedly altered in psoriasis, suggesting a role
for these proteins in disease pathogenesis.
PMID: 12704215
OK, so these are calcium signalling proteins. Lets look at the
overexpressed ones,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15749908&query_hl=2
IL-22 inhibits epidermal differentiation and induces proinflammatory
gene expression and migration of human keratinocytes.
Boniface K, Bernard FX, Garcia M, Gurney AL, Lecron JC, Morel F.
Laboratoire Cytokines et Inflammation, UPRES EA 3806, Pole Biologie
Sante, Universite de Poitiers, Poitiers, France.
IL-22 belongs to a family of cytokines structurally related to IL-10,
including IL-19, IL-20, IL-24, and IL-26. In contrast to IL-10, IL-22
has proinflammatory activities. IL-22 signals through a class II
cytokine receptor composed of an IL-22-binding chain, IL-22RA1, and the
IL-10RB subunit, which is shared with the IL-10R. In the present study,
we show that short-term cultured human epidermal keratinocytes express
a functional IL-22R but no IL-10R. Accordingly, IL-22 but not IL-10
induces STAT3 activation in keratinocytes. Using a cDNA array screening
approach, real-time RT-PCR, and Western blot analysis, we demonstrate
that IL-22 up-regulates, in a dose-dependent manner, the expression of
S100A7, S100A8, S100A9, a group of proinflammatory molecules belonging
to the S100 family of calcium-binding proteins, as well as the matrix
metalloproteinase 3, the platelet-derived growth factor A, and the
CXCL5 chemokine. In addition, IL-22 induces keratinocyte migration in
an in vitro injury model and down-regulates the expression of at least
seven genes associated with keratinocyte differentiation. Finally, we
show that IL-22 strongly induces hyperplasia of reconstituted human
epidermis. Taken together, these results suggest that IL-22 plays an
important role in skin inflammatory processes and wound healing.
PMID: 15749908
We only have three hits (now 4) in our group for IL-22,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15308104
And two more similar ones.
moving on to checking for S100A7 in the p ng,
http://groups-beta.google.com/group/alt.support.skin-diseases.psoriasis/search?group=alt.support.skin-diseases.psoriasis&q=+S100A7+%28psoriasin%29+&qt_g=1&searchnow=Search+this+group
Using keyword psoriasin is useless as its the name of a P product and
returns 35 hits.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15740587&query_hl=2
S100A7 does return 66 hits in pubmed, but not one with keyword LPS in a
search.
So lets try S100A9 (calgranulin-B) with LPS... Ok .. bingo
We get 6 hits. And the importance of IL-10 appears to rear its head.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15699168&query_hl=4
Regulation of S100A8 by glucocorticoids.
Hsu K, Passey RJ, Endoh Y, Rahimi F, Youssef P, Yen T, Geczy CL.
Inflammatory Diseases Research Unit, School of Medical Sciences,
University of New South Wales, Sydney, New South Wales, Australia.
S100A8 (A8) has roles in inflammation, differentiation and development
and is associated with oxidative defense. Murine A8 (mA8) is
up-regulated in macrophages, fibroblasts, and microvascular endothelial
cells by LPS. Glucocorticoids (GCs) amplified LPS-induced mA8 in these
cells. Relative to stimulation by LPS, GCs increased mA8 gene
transcription and mRNA half-life. Enhancement required new protein
synthesis, IL-10 and products of the cyclooxygenase-2 pathway, and both
ERK1/2 and p38 MAPK. Protein kinase A positively and protein kinase C
negatively regulated this process. Promoter analysis indicated
element(s) essential for LPS and dexamethasone enhancement colocated
within the region -178 to 0 bp. In the absence of glucocorticoid
response elements, NF1 motif at -58 is a candidate for mediation of
enhancement. Gel shift analysis detected no differences between LPS-
and LPS/dexamethasone-treated complexes within this region. GCs
increased constitutive levels of A8 and S100A9 (A9) mRNA in human
monocytes. The synovial membrane of rheumatoid patients treated with
high dose i.v. methylprednisolone contained higher numbers of
A8/A9-positive macrophages than pre- or posttreatment samples. Results
support the proposal that A8 has anti-inflammatory properties that may
be independent of hetero-complex formation with A9 and may also enable
localized defense in the absence of overriding deleterious host
responses.
PMID: 15699168
&
Blockade of S100A8 and S100A9 suppresses neutrophil migration in
response to lipopolysaccharide.
Vandal K, Rouleau P, Boivin A, Ryckman C, Talbot M, Tessier PA.
Centre de Recherche en Infectiologie, Centre de Recherche du Centre
Hospitalier Universitaire de Quebec, Universite Laval, 2705 Boulevard
Laurier, Sainte-Foy, Quebec, Canada G1V 4G2.
Recently, proinflammatory activities had been described for S100A8 and
S100A9, two proteins found at inflammatory sites and within the
neutrophil cytoplasm. In this study, we investigated the role of these
proteins in neutrophil migration in vivo in response to LPS. LPS was
injected into the murine air pouch, which led to the release of S100A8,
S100A9, and S100A8/A9 in the pouch exudates that preceded accumulation
of neutrophils. Passive immunization against S100A8 and S100A9 led to a
52% inhibition of neutrophil migration in response to LPS at 3 h
postinjection. Injection of LPS was also associated with an increase in
peripheral blood neutrophils and the presence in serum of S100A9 and
S100A8/A9. Intravenous injection of S100A8, S100A9, or S100A8/A9
augmented the number of circulating neutrophils and diminished the
number of neutrophils in the bone marrow, demonstrating that S100A8 and
S100A9 induced the mobilization of neutrophils from the bone marrow to
the blood. Finally, passive immunization with anti-S100A9 inhibited the
neutrophilia associated with LPS injection in the air pouch. These
results suggest that S100A8 and S100A9 play a role in the inflammatory
response to LPS by inducing the release of neutrophils from the bone
marrow and directing their migration to the inflammatory site.
PMID: 12928412
H'mmmm, maybe this will move the scientists towards a few genes that
respond
to LPS. Or don't detox it or flip it right. A story about a protein
that flips LPS was
done a few days back. Try the 16th.
Il-10 seems to rear its head again and a better understanding of theTh2
phenotype should help us to understand whats going on. This next
article on race horses/asthmatics/meatpackers and athletes training in
cold weather should help.
http://www.medicalnewstoday.com/medicalnews.php?newsid=24959
How about safe Sunshine and vitamin D again. Talk about medical
conflicts unfolding.
Big cancer versus big sunshine coming to light,
http://www.cbn.com/cbnnews/Wire/050523e.asp
Government information: for this article,
http://ods.od.nih.gov/factsheets/vitamind.asp
As to the psoriatic and his/her th1 skew due to what trigger or LPS,
http://bbid.grc.nia.nih.gov/geneimages/113.Th1andTh2cells.jpeg
We still need to know how to bring back more IL-10 to slow that
sPin.
It won't be easy,
http://tnf.cellzome.com/map.php
So back to the races as in horses again,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15906271&query_hl=2
<snip> A significant effect of LPS stimulation over time was seen on
TNFalpha, IL-1beta, IL-10 and IFN-gamma production. (note: The
Betafectin(R) PGG-Glucan in this trial failed to stoP the TH1 skew)
(...)
PMID: 15906271
As an aside to that note:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9617896&dopt=Abstract
&
Certainly beta 1,3 glucan (beta glucan) has been touted to no end,
http://www.mothernature.com/Library/Ency/Index.cfm/Id/2805007
If it doesn't skew you to a TH1 profile. What good is it, if you have a
TH2 (cancer for instance)
condition???
Wow, flim flam and tricky sugars. Once again. And no mention of
megavitamins. :)
Lets see how,
245,000 hits for keyword: [ beta 1,3 glucan ]
http://www.google.com/search?hl=en&lr=&scoring=d&q=beta+1%2C3+glucan&btnG=Search
67,600 hits for keywords: [ beta 1,3 glucan cancer ]
http://www.google.com/search?hl=en&lr=&scoring=d&q=beta+1%2C3+glucan+cancer&btnG=Search
Now do a simple google news search of beta glucan,
http://news.google.com/news?hl=en&lr=&scoring=d&tab=wn&ie=UTF-8&q=beta+glucan&btnG=Search+News
Someone is under the impression that its an immunity booster thing.
StoPPing LPS and recall that it comes from endogenous sources (us-- our
own guts via permeability) is number one on my radar. Yet I can't help
but feel that P inflammation is due
to a window of sorts and happens often enough to maintain the plaques
or even grow
them periodically. And no beta 1,3 glucan is even gonna spur psoriasis
on let alone stop cancer.
So, back to what works under the sun and why....
Time to give it a rest. Till then,
randall...But P doesn't rest or does it?
randall
randall wrote:
This link broke. I'll try it again.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15740587&query_hl=2
>
>
> S100A7 does return 66 hits in pubmed, but not one with keyword LPS in
a
> search.
> So lets try S100A9 (calgranulin-B) with LPS... Ok .. bingo
> We get 6 hits.
>
More info on S100A8 or was that S100A 9?
Back to the gene map,
http://www.ncbi.nlm.nih.gov/Omim/getmap.cgi?d446
(Look towards the bottom and "S100 calcium-binding protein A8
(calgranulin A) "
and in the comments column, "over-expressed in 1q21-linked
psoriasis"...
Moving down the gene from ~148.77 (S100A10) to about 150.19,
http://www.ncbi.nlm.nih.gov/mapview/maps.cgi?ORG=hum&CHR=1&maps=loc-r,morbid,gene&R1=on&query=S100A8&VERBOSE=ON&ZOOM=3
http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=123885
Other alias time.
Lets do it,
*123885 S100 CALCIUM-BINDING PROTEIN A8; S100A8
Alternative titles; symbols
CYSTIC FIBROSIS ANTIGEN; CFAG
CALGRANULIN A; CAGA; CGLA
S100A8/S100A9 COMPLEX, INCLUDED
CALPROTECTIN, INCLUDE
****from this link, above,
"Psoriasis (see 177900) is an inflammatory skin disorder characterized
by keratinocyte hyperproliferation and altered differentiation. Linkage
analyses have identified at least 7 distinct disease susceptibility
regions. PSORS4 (603935) maps to chromosome 1q21, within the epidermal
differentiation complex (EDC; 601588), a cluster that contains 13 genes
encoding S100 calcium-binding proteins. Semprini et al. (2002) analyzed
S100 gene expression in psoriatic individuals from 2 large pedigrees
characterized by linkage studies, 1 linked and 1 unlinked to the 1q21
locus. The analyses demonstrated that only the 1q21-linked family had
upregulation of S100A8, S100A9, and, to a lesser extent, S100A7
(600353) and S100A12 (603112). Later studies confirmed
S100A8/S100A9-specific overexpression in 1q-linked pedigrees.
30 MEDLINE Neighbors
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=DocSum&list_uids=12384771,12704215,15191538,10190323,8618063,8938441,15598222,8985590,12923069,12664160,15656815,15740587,15703480,12777802,7591220,9920416,8530009,11463791,10973813,15185146,15838637,15213155,11867565,11001818,8341667,15086546,12366693,15149869,11260185,9693957
Calprotectin
Calprotectin, the complex of S100A8 and S100A9, is a major calcium- and
zinc-binding protein in the cytosol of neutrophils, monocytes, and
keratinocytes. Although serum concentrations of calprotectin are raised
in many inflammatory conditions, they are generally lower than 10 mg/L.
Sampson et al. (2002) reported greatly elevated serum concentrations in
5 patients with hyperzincemia and hypercalprotectinemia (194470), a
seemingly novel disorder of zinc metabolism. All 5 patients presented
with recurrent infections, hepatosplenomegaly, anemia, and evidence of
systemic inflammation. Cutaneous inflammation was present in 3, and 3
presented in infancy with severe growth failure. As no structural
defects in the S100A8 or S100A9 subunits of calprotectin were detected,
Sampson et al. (2002) suggested that the hypercalprotectinemia was
caused by a defect in its metabolism. 30 MEDLINE Neighbors
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=DocSum&list_uids=12480428,11865286,15209531,12808281,12626582,15778088,11463791,10551823,10571075,10066369,12553726,8245468,15476267,12928412,12645005,10344284,15642721,11867565,10443460,12137245,15149869,7481561,9262226,9000536,9210089,9514426,10534107,15481316,8035402,10725790
http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=177900
And more six degrees of separation? Nope, about one or two.
More interesting p helpers? You be the judge.
Blocking protein with proteins,
http://www.genpromag.com/ShowPR~PUBCODE~018~ACCT~1800000100~ISSUE~0505~RELTYPE~PRO~PRODCODE~00000000~PRODLETT~AF.html
Filling the Niches in Candidates for Protein-Protein Interactions
· Researchers have had a tough time identifying, let alone
developing, small molecule inhibitors of protein-protein interactions.
But as scientists report an expanding repertoire of potential drug
candidates, this nascent field may be on the verge of a growth spurt.
· By Leslie Pray, PhD
More realistically, says graduate student Joseph Rodgers, lead author
of the study, a better understanding of this protein-protein
interaction will lead to novel treatment for diabetes. If the
interaction could be blocked, the excess glucose production that is so
damaging in diabetic patients could be reduced.
That is the kind of targeting that has led many biotech and
pharmaceutical companies to invest in the study of protein-protein
interactions, including the development of inhibitors that target those
interactions. The global market for protein interaction technology and
therapeutics is expected to reach $50 billion by 2010.
Perhaps the best known protein-protein interaction inhibitor is
Herceptin (trastuzumab), an antibody that binds to the extracellular
domain of the human epidermal growth factor receptor 2 protein, HER-2.
Herceptin was approved by the FDA in 1998 for use against breast
cancer, because clinical trial data showed a longer time to disease
progression, a reduced risk of death, and other positive results in
women with HER-2-positive metastatic breast cancer who received
Herceptin in addition to standard chemotherapy, compared to women who
received chemotherapy only.
Last year, Herceptin was the third biggest-selling drug for Genentech,
San Francisco, bringing in close to half a billion dollars. Antibodies
are the fastest-growing segment of the prescription drug market, but
they have their problems. Antibodies are expensive and difficult to
manufacture; they can't be taken in pill format (they can only be
administered as injections or infusions); and they aren't
cell-permeable, which means they can't be used to block intracellular
interactions.
Enter small-molecule inhibitors of protein-protein interactions, which
are not only cheaper and easier to manufacture than antibodies, but
they also are cell-permeable. So far, scientists have only identified a
couple dozen potential small-molecule protein-protein interaction
inhibitors (SMPPIIs), almost all of which have been published within
the last two years. Although few SMPPIIs have reached clinical trials
and none have reached the marketplace, all promise novel therapeutic
treatments for a range of human ailments, from cancer to HIV/AIDS.
<snip>
****
"The hunt for inhibitors of protein-protein interactions has been going
on in a low-level way for a long time. But as certain targets get to be
better characterized and are shown to be effectively inhibited by small
molecules, it is going to expand. There are a number of viable
approaches to screening for inhibitors. Comfort with this target class
is going to come more from biological validation than from technology.
- Michelle Arkin, PhD, senior scientist, Sunesis Pharmaceuticals Inc.
*****
Protein-Protein Interactions and New Antibiotics?
Earlier this year, Andrew Emili, PhD, University of Toronto, Canada,
and colleagues published a paper on protein interactions in Escherichia
coli [G. Butland et al., Nature, vol. 433, pp. 531-537 (2005)]. The
study was remarkable, say several leaders in the field, because it was
the first large-scale analysis of protein complexes in a bacterium. As
Tracy Palmer, PhD, of the John Innes Centre, Norwich, UK, wrote,
"Expect a mad scramble across the globe as every microbial biochemist
maniacally checks the supplementary information to see what their
favorite protein interacts with . . ."
Using a modified yeast-based tandem affinity purification (TAP)
procedure for isolating protein complexes, the research team purified
648 different affinity-tagged E. coli proteins to homogeneity. They
used mass spectrometry to identify the proteins' interacting partners.
Eighty-five percent of the validated interactions were new (i.e., not
described in select databases). Most of the proteins had just a few
interacting partners, whereas others-the "hubs"-had far greater
numbers of connections. Of course, scientists have been seeing the same
in eukaryotes, but this was the first time a prokaryote's whole-cell
protein network had been linked together.
The data serve as a starting point for understanding not just how a
bacterial cell is designed, but how it functions. "We don't understand
how cells are designed," says Emili. "But if we understood the circuit
board, the logical relationships of all the components, it wouldn't be
so random. To figure out how cells work is a daunting and perhaps
irrational task, but if we are ever going to look at the genome and
make accurate predictions, that's the way we have to go."
Even more exciting, Emili says, the map provides information that may
be helpful in elucidating the evolutionary relationships of microbial
protein interactions and networks, particularly if the data can be
analyzed in combination with the extant wealth of comparative genomic
data on prokaryotes. If the same interacting proteins are found in
different species, what does that tell us about how these networks have
evolved?
If some of those pathways turn out to be broadly conserved, microbial
protein mapping could facilitate the discovery of broad-range
antibiotics. Currently, only about 30 bacterial proteins are targeted
by prescription antibiotics, and antibiotic resistance has emerged as a
major global public health problem. Although Emili is not involved with
the pharmaceutical aspects of the research, he says that others are
exploring the possibillity of using the information to find new
bacterial drug targets. Whether these targets would ever be suitable
for SMPPIIs remains to be seen.
***************
http://www.genpromag.com/images/0505/pro2.jpg
How to block IL-2 with a small protein diagram.
Looking good.
****
http://news.biocompare.com/newsstory.asp?id=80129
Scientists have uncovered a new method the immune system uses to label
foreign invaders as targets to be attacked. Researchers showed that the
immune system can brand foreign proteins by chemically modifying their
structure, and that these modifications increased the chances that
cells known as lymphocytes would recognize the trespassers and attack
them.
"Now that we know that some T cells need to see these types of
modifications to identify an invader, we can see if incorporating such
changes into the proteins is helpful for vaccination," says senior
author Emil R. Unanue, M.D., the Edward Mallinckrodt Professor and head
of Pathology and Immunology.
The finding may also be relevant to autoimmune conditions where the
immune system erroneously attacks healthy tissues. Such disorders
include rheumatoid arthritis, multiple sclerosis and type 1 diabetes.
"We show in this study that during some infections, these same types of
modifications can be made to our own proteins, potentially leading to T
cell attacks on the self," says Unanue.
Unanue and colleagues, who publish their results on May 31 in the
Proceedings of the National Academy of the Sciences, conducted their
studies in mice and in cultures of mouse cells. Jeremy Herzog, a
research associate in Unanue's lab, did many of the experiments and was
the lead author of the study.
T cells belong to a class of immune cells known as thymic-lymphocytes,
which in turn are a component of the branch of the immune system known
as adaptive immunity. This branch responds to pathogens after they
interact with the other major branch, the innate immune system. T cells
kill pathogens or produce molecules like cytokines that stop their
growth.
Scientists have known for some time that a second class of innate
immune system cells known as antigen-presenting cells helps T cells
determine what to attack. They do this by displaying fragments of
proteins they have picked up on their surfaces for inspection by T
cells. Fragments of proteins are called peptides.
Researchers also knew that when antigen-presenting cells are activated
by inflammatory factors or microbial products, they start putting out
chemically unstable compounds such as nitric oxide and superoxide.
Together, these compounds generate peroynitrate, a highly potent
chemical that modifies many proteins.
Unanue's group showed that this chemical modifies the peptides
presented by antigen-presenting cells in several distinct ways. For
example, they attach a nitrate group to the amino acid tyrosine in the
peptides, changing it to nitrotyrosine.
Unanue's lab then showed that these changes increased the chances that
various types of T cells would react to the modified peptides shown to
them by antigen-presenting cells.
Unanue's group is working to substantiate their findings and explore
their potential relevance to different areas of biomedical research. He
notes that insulin-producing beta cells, the pancreatic cells attacked
by T cells in type 1 diabetes, also generate reactive compounds similar
to those made by antigen-presenting cells.
"The beta cells could therefore be modifying their own proteins in the
same way that antigen-presenting cells are modifying foreign proteins,"
he says. "We're now investigating whether such modifications can cause
T cells to attack the beta cells."
Damaging oxidative reactions are also believed to play a role in
atherosclerosis. Scientists suspect oxidative damage in the blood
vessel walls may lead to immune reactivity that contributes to
narrowing and stiffening of blood vessels.
******
randall...ok not that boring now.
randall
Hi,
The cosmetic industry seems to be using the nanotechnologi sales tag.
GEE! NO gi!
nanogi! for nanoP? NoPe?
http://www.cosmeticsdesign.com/news/news-ng.asp?n=60204-nanotechnologi-ups-efficacy
Nanotechnologi ups efficacy of tanning pill
24/05/2005 - Preliminary studies find that a nanotech drug delivery
system has been developed to increase the efficacy of a prescription
tanning agent for fair-skinned people, reports Phil Taylor and Simon
Pitman.
The delivery vehicle, called BioSilicon and developed by Australian
nanotechnology company pSivida, BioSilicon's porous nanostructure
effectively stores an active compound in tiny pockets that release
minute amounts of drug as the silicon dissolves.
The study, performed by pSivida in collaboration with another
Australian company EpiTan, compared four BioSilicon formulations
containing the tanning agent Melanotan (alpha-melanocyte stimulating
hormone) to EpiTan's implantable formulation, currently in clinical
development.
Epitan has evolved as one of the world's leading dermatologist in the
fight against skin cancer. Currently the company owns the branding
rights to topical products for eczema, psoriasis and acne, but one of
the next steps could well be a move into cosmetics products for people
who want to tan but without having to sunbathe.
Melanotan is designed to promote the formation of the skin pigment
melanin in the skin without exposure to ultraviolet light, and thereby
protect fair-skinned people in sunny climates from developing skin
cancer. Previously the drug has been delivered as a daily injection
that required significantly higher quantities. As with any
pharmacological agent, it is preferable to limit the amount delivered
to reduce the risk of side effects
Data obtained from the in vivo study conducted at the Institute of
Medical and Veterinary Science in Adelaide, South Australia, indicated
that a single injection of BioSilicon loaded with Melanotan released
the active drug over a sustained, 14-day period.
In February, EpiTan announced that it had filed a patent application
for discoveries surrounding the increased efficacy (i.e. increase in
melanin) of Melanotan when given at significantly lower dose levels in
a sustained manner. This patent covers the collaboration work by EpiTan
and pSivida.
The next stage of development will progress towards a commercially
viable version of this formulation. Meanwhile, the implantable version
of Melanotan is scheduled to be available in 2007, after the successful
completion of clinical trial programs and registration with the
relevant regulatory authorities around the world.
"The outcome of this collaboration could lead to a second-generation
injectable Melanotan product," said Iain Kirkwood, EpiTan's
managing director. "It would give consumers further choice as to how
they could have Melanotan administered. They could now conceivably have
the choice of a solid implant or a liquid injection."
BioSilicon has also shown promise in a proof-of-principle study looking
at its ability to deliver localised radiotherapy to tumours in the form
of implantable beads, a procedure known as brachytherapy.
Why hasn't the immunce system been figured out?
Seems to be giving up those secrets day by day now,
http://news.biocompare.com/newsstory.asp?id=80036
Fox Chase Study Shows That Weakened T-Cell Receptor Signals Change
T-Cell Lineage
5/17/2005
###
In addition to Wiest and Kappes, Fox Chase co-authors of the new
Immunity paper include postdoctoral fellow Mariëlle C. Haks, Ph.D.
(currently at Leiden University Medical Center in The Netherlands),
graduate student Juliette Lefebvre, postdoctoral associate Jens Peter
H. Lauritsen, Ph.D., research associate Michael Carleton, Ph.D. (now at
Rosetta Inpharmatics in Seattle), and scientific technician Michele R.
Rhodes, along with Toru Miyazaki, M.D., Ph.D., of the University of
Texas Southwestern Medical Center's Center for Immunology in Dallas.
Grants from the National Institutes of Health and an appropriation from
the Commonwealth of Pennsylvania helped support this work along with a
Fox Chase Cancer Center Board of Directors Postdoctoral Fellowship and
a stipend from the Netherlands Organization of Scientific Research for
Haks.
Fox Chase Cancer Center was founded in 1904 in Philadelphia as the
nation's first cancer hospital. In 1974, Fox Chase became one of the
first institutions designated as a National Cancer Institute
Comprehensive Cancer Center. Fox Chase conducts basic, clinical,
population and translational research; programs of prevention,
detection and treatment of cancer; and community outreach. For more
information about Fox Chase activities, visit the Center's web site at
www.fccc.edu or call 1-888-FOX CHASE.
randall
While trying to look out for the guy with a penchant for trying to
manage his
own health and deal with his P, this next site's author has come up
many
times.
His advice on vitamin C and lower iron intake in some situations, i've
used
in my own regimen to lower P. Also HA, NaC, IP-6 and more nutrients and
supplements are mentioned on his new site.
If your a nut for this stuff. It should help out.
I've posted half a dozen Bill Sardi articles previously. I feel he's
looking out for the little guy.
And has many tips and things to try to achieve better health. And now
he has a new site.
http://www.knowledgeofhealth.com/
How about a new low carb sugar?
Look for this in your store or in your foods.
Shugr, World's First Natural, Zero-Calorie Sweetener, Announces Shugr
5X and Shugr 10X; Highly Efficient Format Now Available for Commercial
Users
LOS ANGELES--(BUSINESS WIRE)--April 28, 2005--Shugr,(TM) the world's
first natural, zero-calorie sweetener that tastes, cooks and bakes like
cane sugar, is now available to commercial users in two highly
efficient new formats: Shugr 5X(TM) and Shugr 10X.(TM) The two new
products were announced this week by the manufacturer and marketer of
Shugr, Swiss Research, Inc. of Los Angeles, CA, a Health Sciences Group
company (OTCBB:HESG).
"Since our initial announcement of Shugr, commercial manufacturers have
flooded us with requests," said Loren Miles, CEO of Swiss Research,
Inc. "We recently announced our partnership with DNP International Co.,
Inc, in Irvine, CA, one of the world's leading distributors of
commercial ingredients. Now, we can provide Shugr to commercial users
in two highly efficient new formats, Shugr 5X and Shugr 10X, equivalent
to five times and ten times the intensity of cane sugar."
Miles noted that Shugr 5X and Shugr 10X are ideal formats for
formulating cookies, desserts, beverages, baked goods - even
compressible tablets. Economical and yet a close match to cane sugar,
Shugr 5X and Shugr 10X dissolve easily and demonstrate good binding
properties as well as great taste.
(...)
*******
Do you wish to make your brain work better?
A risky deal but one may feel and look better with these suggestions,
Make your brain work better special,
http://www.newscientist.com/channel/health/mg18625011.900
*****
Whats it al about when it comes to the immune system?
The P immunity thing goes on and on like the energizer bunny.
But why?
Well no one has the exact pathway nailed down. But some of us
feel that LPS (endotoxin from gut flora in you right now is that source
of craP that keeps TNF-alpha running steady) is that culPrit.
So, news on LPS stays on the radar every day.
Here's a current one,
http://ajp.amjpathol.org/cgi/content/abstract/166/6/1607
(...)
Lipopolysaccharide (LPS) markedly activated the AnxA1 gene in
epithelial cells, neutrophils, and peritoneal, mesenteric, and alveolar
macrophages-cell types known to function in ex-perimental
endotoxemia. Administration of LPS to AnxA1-deficient mice produced a
toxic response characterized by organ injury and lethality within 48
hours, a phenotype rescued by exogenous application of low doses of the
protein. In the absence of AnxA1, LPS generated a deregulated cellular
and cytokine response with a marked degree of leukocyte adhesion in the
microcirculation. Analysis of LPS receptor expression in AnxA1-null
macrophages indicated an aberrant expression of Toll-like receptor 4.
In conclusion, this study has detailed cellular and biochemical
alterations associated with AnxA1 gene deletion and highlighted the
impact of this protective circuit for the correct functioning of the
homeostatic response to sublethal doses of LPS.
One more gene that may conncet with those pesky P genes. Sure we don't
have
them all figured out. But most of us may differ as to how they produce
their effects
anyway. So time will tell and so will I.
IN previous posts C5a was mentioned and this link will help you
put that into perspective in some possible p pathways.
Enjoy,
C5a and a bunch of diagrams from medscape
(see last figure for C5a and all of them for LPS)
http://www.medscape.com/content/2003/00/45/36/453656/453656_fig.html
C5a in inflammatory response,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Display&dopt=pubmed_pubmed&from_uid=15638737&tool=ExternalSearch
And a new drug for asthma that takes advantage of this C5a pathway,
http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=109&STORY=/www/story/05-12-2005/0003597731&EDATE=
randall... have a nice sunny day.
randall
Don't read this next article unless you want to know how depression can
put
you in a dark place. And what the author thinks of say P and cancer in
regards to it. (you have to read the whole article to get to what i've
posted
below and its a long one)
Are P and C, pc to depression? What if your depressed just because and
you
don't have P or C?
http://www.sfgate.com/cgi-bin/article.cgi?f=/c/a/2005/05/29/RVG9FCS23I1.DTL&type=books
Disorder or disease? Myths make depression hard to define
When Prozac came onto the market almost 20 years ago, it helped raise
the question "Is depression a disease?" Since then, Prozac has been
followed by a series of antidepressants that target the brain's
"feel-good" neurotransmitters. Some 20 million people are now taking
the meds, and a whole new genre of literature, the depression memoir,
has sprouted up alongside the analytical books examining the condition
and its cure. We've come a long way, and the conversation now centers
on a much more refined question:
"But is depression really a disease?"
(...)
Perhaps, in a compromise that will please no one but the poets,
depression is a disease and also more than a disease and also less than
one. Though they share many aspects, the experience of this illness is
different from that of, say, psoriasis or pulmonary cancer. It affects
our moods, not our skin or our lungs. It is also blotched with gray
areas that spill over into everyday life: You don't get little
fragments of things that feel kind of like cancer the way you get hints
of depression, in the form of grief or despair.
(...)
*****
What does this author mean? P and C are *different* then the dis-ease
called depression?
Ones in the brain as the others are topical or eating your alive?
Heck! Some of us get a little depressed. Without any outlets to vent.
I would imagine that many psoriatics have the big D over P or simply
due to P.
And feel like we're being eaten alive whether we have cancer or
psoriasis.
In C one would go through all five stages
of coping with death: denial, anger, bargaining, depression and
acceptance.
(Kubler-Ross ... ).
At least with P you don't die like many do with C. So what?
We work our way to depression and fight our way back to anger? Or move
forward to accePtance?
The latter seems to be the most reasonable choice.
In the words of Rodney King. "Can't we all just get along?"
And that would include us with our P ridden conditions?
Getting along with my P now and moving on to real P news.
May 23rd and 24th, P news dealt with S100A8/S100A9. This next abstract
shows the continuing work in this arena and the likely hood of pay dirt
for
us. Cure wise that is,
http://content.febsjournal.org/cgi/content/abstract/272/11/2811
FGF-2, IL-1{beta} and TGF-{beta} regulate fibroblast expression of
S100A8
Farid Rahimi, Kenneth Hsu, Yasumi Endoh and Carolyn L. Geczy
Inflammatory Diseases Research Unit, School of Medical Sciences,
University of New South Wales, Sydney, Australia
C. Geczy, Inflammatory Diseases Research Unit, School of Medical
Sciences, The University of New South Wales, Sydney, NSW 2052,
Australia Fax: + 61 293851389 Tel: + 61 293851599 E-mail:
c.g...@unsw.edu.au Website: http://www.med.unsw.edu.au/
Growth factors, including fibroblast growth factor-2 (FGF-2) and
transforming growth factor-{beta} (TGF-{beta}) regulate fibroblast
function, differentiation and proliferation. S100A8 and S100A9 are
members of the S100 family of Ca2+-binding proteins and are now
accepted as markers of inflammation. They are expressed by
keratinocytes and inflammatory cells in human/murine wounds and by
appropriately activated macrophages, endothelial cells, epithelial
cells and keratinocytes in vitro. In this study, regulation and
expression of S100A8 and S100A9 were examined in fibroblasts. Endotoxin
(LPS), interferon {gamma} (IFN{gamma}), tumour-necrosis factor (TNF)
and TGF-{beta} did not induce the S100A8 gene in murine fibroblasts
whereas FGF-2 induced mRNA maximally after 12 h. The FGF-2 response was
strongly enhanced and prolonged by heparin. Interleukin-1{beta}
(IL-1{beta}) alone, or in synergy with FGF-2/heparin strongly induced
the gene in 3T3 fibroblasts. S100A9 mRNA was not induced under any
condition. Induction of S100A8 in the absence of S100A9 was confirmed
in primary fibroblasts. S100A8 mRNA induction by FGF-2 and IL-1{beta}
was partially dependent on the mitogen-activated-protein-kinase pathway
and dependent on new protein synthesis. FGF-2-responsive elements were
distinct from the IL-1{beta}-responsive elements in the S100A8 gene
promoter. FGF-2-/heparin-induced, but not IL-1{beta}-induced responses
were significantly suppressed by TGF-{beta}, possibly mediated by
decreased mRNA stability. S100A8 in activated fibroblasts was mainly
intracytoplasmic. Rat dermal wounds contained numerous S100A8-positive
fibroblast-like cells 2 and 4 days post injury; numbers declined by 7
days. Up-regulation of S100A8 by FGF-2/IL-1{beta}, down-regulation by
TGF-{beta}, and its time-dependent expression in wound fibroblasts
suggest a role in fibroblast differentiation at sites of inflammation
and repair.
Keywords: FGF-2; fibroblasts; interleukin-1{beta}; S100A8 gene;
TGF-{beta}.
randall..... have a nice ray! And may the C not be with you!
Steve Cassidy
ranh...@aol.com (randall) wrote:
> Heck! Some of us get a little depressed. Without any outlets to vent.
> I would imagine that many psoriatics have the big D over P or simply
> due to P.
Very good point - but you miss something out. Cancer is a "noble" disease.
It attracts massive interest and near-limitless funding. Psoriasis isn't
noble, and the medical profession would rather ignore it if they could.
That makes a very considerable difference to the nature of the depression.
randall
Thanks!
I only wish my disease was more noble then. Or do I?
Besides being a royal pain in the rear?
Hey! I refuse to be depressed. There are bigger things and
questions the last few days. We need to ratchet up the
the BIG QUESTIONS. Like making a difference for the world
or something.
A nice short resPite from *it* was achieved watching Englishman Dan
Wheldon beat Danica Patrick to the Indy finish line. I barely
thought about it all day, come to think of it. CePt for the
way he gargled down all that milk. lol
GLUG, glug... still have that one on my mind. Should i cut back
on my milk intake?.... lol
Less dairy helps in my case. I think?
But what haPPens when your brain is amPed out on P and can't
rest?
Is P a brain strain due to active ADD? Maybe restless glial cells?
Should I take some thalidomide? I'm sure not going to have any
more kids without having my private parts put in extreme jeoPardy! :(
That should give one some mental pause. lol
And the big T does work to ease dePression. See Mathias's link in the
dermazinc post today?
But shouldn't one take his dePression into his own hands?
We all can't be like Leonardo Da Vinci, hand wise. How about
brain wise?
This was found in P News today,
http://www.timesleader.com/mld/timesleader/living/health/11771395.htm
(...)
Andrew B. Newberg of Penn and other neuroscientists have found that
meditative practice can train the mind and reshape the brain. Others
have found that regular meditation can lower blood pressure and heart
rates, decrease anxiety and depression, and help control chronic pain.
According to last month's Harvard Mental Health Letter, meditation
techniques have been used to relieve discomfort in patients with
___psoriasis___, irritable bowel syndrome, and fibromyalgia. A
combination of meditation, yoga and diet change has been claimed to
reverse coronary artery disease.
The newsletter also reported that depressed patients treated with a
mindfulness-based cognitive therapy were only half as likely to relapse
as patients getting traditional counseling and medication. Cognitive
therapy focuses on recognizing distorted beliefs about one's self and
replacing them with realistic ones.
(...)
*********
A segue from the web, same toPic,
http://www.quietmindfdn.org/Is%20Buddhism%20Good%20for%20Your%20Health.htm
Ok, ok... so you want the ultimate meditation pill.
Sitting and clearing the brain of all those thoughts is to hard?
Sorry the kids have ruined the GHB triP for us oldsters. Their Xstasy
is our lost,
http://news.google.com/news?hl=en&lr=&tab=wn&ie=UTF-8&q=ghb+raPe&btnG=Search+News
But if i had C, i'd put that C right back into X-c-stasy and me.
Back to the real world as the kids have turned theirs uPside down.
You can try GABA instead,
http://www.raysahelian.com/gaba.html
Pnews- gaba sleep kw's,
http://news.google.com/news?q=%20gaba%20sleep&hl=en&lr=&sa=N&tab=wn
*************
Moving on biologically, as it does make sense to lower
depression. I know when i was over 50% pasi i was a mess mentally.
And if you need a jolt to block TNF-alpha so be it.
(I'll stick to my mellow yellow whey! as in proflora good gut bugs.)
Large Raptiva three year study--shows 75% clearances
http://www.medicalnewstoday.com/medicalnews.php?newsid=25273
(...)
More than 3,500 patients in the U.S. and Europe have been included in
Raptiva® trials to date, creating the largest existing database of
patients taking part in studies with a biological therapy for
psoriasis.
About the 36-month phase IIIb open-label study
This three-year study is the longest study of psoriasis patients
receiving continuous treatment with a biologic treatment. In this
study, 339 patients received Raptiva® weekly for an initial 12 weeks,
and patients with a PASI 50 response or a static Physician's Global
Assessment response of 'mild' or 'better' after 12 weeks of
treatment were eligible to continue on a once-weekly maintenance dose
of 1 mg/kg Raptiva® for 12-week periods starting at week 13. A total
of 290 subjects entered this second phase of the study. For each
successive three-month period of treatment, dropouts during that period
were analyzed using their last available PASI assessment but were
excluded from the subsequent cohorts.
Adverse events in this study were similar to what has been observed in
previous clinical trials of Raptiva® and include headache,
non-specific infection (e.g. common colds), chills, pain, nausea,
weakness, and fever, all of which diminished after the first 1 - 2
doses. Further, there was no evidence of accumulation or cumulative
toxicity.
(...)
'Sweet' diagnostics kit developed to help bowel disease sufferers
In her early 30s, Cathy Richards is spunky, successful and outgoing.
What most people wouldn't know is that for nearly a year of her life
she was attached to a bag into which her stool and urine drained.
Doctors were dumbfounded as Cathy lay in the hospital for a week while
her rectum was prodded with tubes in sensitive areas. While the doctors
were pouring barium milkshakes down her throat, her parents tried to
convince the hospital that their teenage daughter had Crohn's disease.
It took a year, but finally doctors agreed.
Today Cathy and millions of others like her won't have to wait a year,
or even a month, for a diagnosis. That's because the Israeli company
Glycominds has developed a diagnostic blood test kit which quickly
enables differential diagnosis between Crohn's disease, ulcerative
colitis and irritable bowel syndrome.
Today, instead of endless enemas, X-rays, and humiliating colonoscopies
a patient can give a small vial of blood which can be analyzed in the
lab within an hour. What normally takes months or years can now be
ascertained by a doctor within days. In the best case, a person may
only have to modify their diet. In the worst, parts of the colon may
need to be removed.
(...)
Glycominds worked for seven years on the IBDX kit which cracks the code
of a complex form of sugars in the body called glycans which can be
used to diagnose chronic intestinal disease.
(...)
There are two million US doctor visits a year for bowel-related
complaints with symptoms as mild as diarrhea and bloating to blood in
the stool. Only about 5-6% of these people will go on to be diagnosed
with the inflammatory types of Crohn's and ulcerative colitis and be
treated accordingly.
The rest of the people are categorized under the rubric of Irritable
Bowel Syndrome (IBS) - a condition that affects approximately 10-20
percent of the general population and is one of the most common
disorders seen by primary care physicians.
Until now, there has been no one test that gives doctors the confidence
to distinguish the inflammatory bowel diseases (IBDs) of ulcerative
colitis and Crohn's disease from Irritable Bowel Syndrome (IBS).
Glycominds hopes to be able to make invasive diagnostic testing a thing
of the past.
The problem in diagnosing bowel disease up until now is that doctors
didn't have a sure fire tool to measure the complex signals given off
by the immune system in Inflammatory Bowel Diseases which are
auto-immune diseases.
Glycominds measures indicators called biomarkers which point to disease
activity and show in advance what other tests, such as Magnetic
Resonance Imaging, can only show after deterioration in the intestines
has taken place. The company's IBDX kit can help push a doctor to begin
aggressive treatments earlier or it can help a doctor be sure that a
patient does not need therapy at all.
(...)
*****
Whats in your colon? Is something in there bugging you?
Is it a wheat thing? How do you know?
Are those Bm's outa whack for any reasons?
I'm of the oPinion that LPS can translocate from the gut,
and raise p severity like crazy,
and you may not have much noticeable dysfunction down there.
OTOh many here have shared their *real* gut problems in relation to
some degrees of P severity.
What do you do then? Try dieting?
****
http://www.seacoastonline.com/news/05292005/health/44909.htm
(...)
Some factors in the diet may have the potential to help reduce
symptoms. These include antioxidants, a gluten-free diet, foods
containing active cultures, omega 3 fatty acids and a lower intake of
saturated fat.
The immune system depends on a number of nutrients. This means focusing
on a healthy diet to reduce inflammation. A key category of nutrients
is antioxidants. These are found in fruits, vegetables and other
plant-based foods and should make up a high percentage of foods
consumed. Antioxidants from foods appear to be a better choice than
just taking antioxidant supplements.
Gluten-free diets appear to benefit some individuals who have
inflammatory illnesses, including psoriasis. One study showed
improvement in psoriasis after following a gluten-free diet for three
months. Avoiding all gluten, means not consuming anything that contains
wheat, barley, rye and oats (the oats may not be a problem directly but
may have become contaminated with wheat during processing). This
involves good label reading for hidden sources of gluten, such as the
term "modified food starch" or foods containing malt (which could be
from barley or wheat). For further information, check out
www.celiac.ca, www.gluten.net, www.csaceliacs.org or the book
"Gluten-Free Diet" by Shelly Case.
(...)
One of the best dietary approaches for psoriasis, as well as for other
inflammatory diseases, is modifying the type of fats eaten. Increasing
the intake of omega-3 fatty acids and decreasing intake of omega-6
fatty acids may be helpful. Our current food sources tend to include
many foods containing omega-6 fatty acids.
Omega 3s, such as fish oils, may even allow for reduced intake of
anti-inflammatory medications for psoriasis. The level of intake needed
for the positive effect probably needs to come from fish oil
supplements plus dietary sources and not just from diet. Other food
sources of omega-3s are flaxseed oil and nuts. The effect is enhanced
by reducing the intake of other fats in the diet (saturated and trans
fat), including limiting portion sizes of meat.
Another advantage of trying some of these dietary approaches to
psoriasis, such as adding antioxidants and omega-3 fatty acids, is that
they can benefit other medical conditions like heart disease. A diet
high in fruits, vegetables, whole grains, legumes, nuts, seeds, fatty
fish, and moderate in other animal proteins is really what we should
all be consuming for optimal health.
(...)
(This gal is good. The only place I differ with her is eating
probiotics
etc to try to establish a colony of good flora in the colon. I'm of the
opinion, due to many many years of trying to do just that, that the
www.thewholewhey.com implant is the best, fastest most reasonable way
to fix a broke down alkaline colon. And return it to a fresh slightly
acidic clean burning machine again.)
Lets look at the other finish line denizen and how your
can be a winner too.
****
When is a horse not a horse? Lets ask Mr. Ed,
Why of course a horse is like a man when he can tell your his
problems. Duh!
http://www.thehorse.com/viewarticle.aspx?ID=780
Butt what LPS problems does he have? You ask.
Ok, straight from the horses gut.
(...)
One characteristic of Gram negative bacteria such as Salmonella is the
presence of "endotoxin." The endotoxin is part of the bacterial cell
wall and is technically called the lipopolysaccharide component or LPS.
The significance of this is that the effects of endotoxin on the body
are great. The main effects are to decrease blood pressure and to
decrease blood flow throughout the body. When you hear from your
veterinarians that your horse appears "toxic" or is suffering from
"endotoxemia," it means the horse is showing clinical signs that can be
attributed to the negative effects of endotoxin. Endotoxic "shock" is a
potential component of Salmonella infection that can greatly complicate
treatment.
Known associated "risk factors" for the development of salmonellosis in
horses are co-existing gastrointestinal disease, concurrent disease
and/therapy with antibiotics, transportation, and dietary change. Most
"outbreaks" of Salmonella occur in summer and autumn--this might be
related to the seasonal increase in risk factors (competition,
transportation, and irregular feeding).
A previous report in the Journal of the American Veterinary Medical
Association noted that intravenous antibiotic therapy or a combination
of oral and intravenous antibiotic therapies increased the chance of
developing salmonellosis by 6.4 and 10 times, respectively.
The defense mechanisms of the gastrointestinal system are complex.
There is "local" immune system function, but in addition the "normal
gastrointestinal microbial flora" plays an important role in protecting
against invading pathogens. The horse's colon or hind gut is
essentially a vat of bacteria. Much of the digestive process is based
on the normal population of bacteria (flora) digesting the raw fiber
(hay) that would otherwise be indigestible--without bacteria,
forage-eating animals would not be able to digest plant material.
The protective nature of this normal population of digestive bacteria
is called "competitive inhibition," as the few would have to compete
with the many in order to survive. So, if only a few pathogenic
organisms are ingested, there is a good chance they will be "competed
out of existence" before causing disease. But, as the amount of
pathogen ingested increases, there is an increasing chance it will
establish an infection and cause disease--the pathogen thus reaches an
infective dose.
As can be imagined, the bacterial "microenvironment" is very
complicated and reaches a working balance dependent on numerous
microorganisms and other factors. This delicate balance can easily be
disrupted by sudden feed changes. As with any finely tuned fermentation
process (e.g., beer, wine, pickle, or sauerkraut making), very subtle
changes can really mess up the process. Changes in the carbohydrate
content (e.g., sudden excessive grain feeding) can rapidly alter the
fermentation process in the gastrointestinal tract and therefore alter
the competitive inhibition action. These changes decrease the defense
mechanisms of the normal microbial flora and can actually "select" for
an increasing number of disease-causing organisms in the
gastrointestinal tract.
It is therefore extremely important to avoid sudden feed
changes--especially with respect to concentrates (grain). A horse's
diet should be maintained as consistently as possible and include an
adequate amount of fiber (hay or grass). Any changes in feeding habit
should be made gradually and a great effort should be made to avoid
playing "musical feeds," especially during times of other concurrent
stresses. Bringing your horse's normal feed with him to shows and
events might reduce one of the overall stress factors. Many horses
which are ultimately confirmed to have Salmonella have a history that
includes transportation in the week preceding the development of
disease and/or a recent change in feeding habit.
(...)
******
Here's some meat for thought.
Ever wonder how much more comPlicated the human gut is?
Isn't it obvious by now?
Well it should be.
http://www.emsl.pnl.gov/docs/cbbb/index.html
(kywords: LPS Ca2+, N-acetyl-glucosamine, P042 )
*****
Getting to technical again and we've had every LPS abstract
and news story in the last year, haven't we?
Sorry, guess i need some GABA.
Or I could get my kicks on route 66?
"Lady and gentlemen! Start your engines"
randall... and their off
randall
I was pondering my previous post.
DeeP thinking in the shower with my hands all over my
p plaques rubbing and removing plaque -ish skin.
And I came to the conclusion that my mental and physical
states are intricately linked. And i'm better with a dry demeanour.
If I make merry with the falstaff (rip- falstaff beer/2005 btw),
and expand my girth with to much mirth.
Then I won't be happier as slowly advancing P plaques will dictate the
blues.
Next I thought about how much I enjoyed the INdy 500. A really exciting
race.
I hardly knew who Danica Patrick was at the start. By the end she was
the
comeback rooky and a huge underdog with a shot. I increasingly found
myself
rooting for her. Despite David Letterdude being an owner. ;-0
The excitement carried over to running the google news on indy. And
a few image shots. And then instead of delving into p once more,
I found myself looking up Douglas Adams. I've listened to that
Dolphin trailer, Thanks for the fish, about a dozen times after seeing
"The Hitchhikers Guide to the Galaxy" recently.
http://movies.yahoo.com/feature/thehitchhikersguidetothegalaxy.html
Not ever knowing anything about Douglas Adams drove me to
google the craP outa him. I loved his flick H2G2.
And though we've lost his physical presence, you should go see the
movie and support his site, now run by the BBC, H2G2.
Right here,
http://www.bbc.co.uk/h2g2/guide/
And if you enjoy it as much as I. You'll find yourself laughing out
loud...
randall... and then you can google 42, P and ?
randall
SulPhur8!
Good one Aim!
http://www.texasbeautysupplies.com/sulmedanhair.html
I just may have to cocktail this one into the Head mix.
My latest twist and not sure if its whats working. But chewing
about 80mg.s of aspirin with half a tablespoon of cod liver oil
and then taking a few costco fish oil softgels. Think sushi,
mackerel/SAba when doing this. Just do the sake as a mental
construct and not actually. And then a quick tablespoon of
flax seed oil as a chaser. Not so bad once you get used to it. :)
As to P news. Do you want the good news or the bad news first?
P Genes or antioxidants?
Lets try the GENES behind P. Or are they?
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15923274&query_hl=2
Analysis of RUNX1 Binding Site and RAPTOR Polymorphisms in Psoriasis:
____ No ____Evidence for Association Despite Adequate Power and
Evidence for Linkage.
(YIKES!)
Stuart P, Nair RP, Abecasis GR, Nistor I, Hiremagalore R, Chia NV, Qin
ZS, Thompson RA, Jenisch S, Weichenthal M, Janiga J, Lim HW,
Christophers E, Voorhees JJ, Elder JT.
University of Michigan, United States.
INTRODUCTION: We further assessed the psoriasis susceptibility locus
PSORS2 located on distal chromosome 17q by linkage and association
techniques, focusing on previous reports of allelic association between
psoriasis and SNPs mapping to a RUNX1 binding site between the SLC9A3R1
and NAT9 genes, and to the third intron of the RAPTOR gene. METHODS:
579 pedigrees containing 1,285 affected individuals were genotyped for
three SNPs immediately flanking and including the RUNX1 binding site,
and for three SNPs in the third intron of the RAPTOR gene. In addition,
274 of these pedigrees were also genotyped for 32 microsatellite
markers spanning chromosome 17, with marker density greatest in the
vicinity of PSORS2. Data were analyzed using nonparametric multipoint
linkage and family-based association methods. RESULTS: We identified a
linkage peak mapping 1.7 cM distal to the RUNX1 binding site (LOD =
2.26-2.73, depending upon statistic used). However, we found no
evidence for association to individual SNPs or haplotypes in either of
the previously-identified peaks of association. Power analysis
demonstrated 80% power to detect significant association at genotype
relative risks of 1.2 (additive and multiplicative models) to 1.5
(dominant and recessive models) for the RUNX1 binding site, and 1.3 to
1.4 for the RAPTOR locus under all models except dominant. DISCUSSION:
Our data provide no support for the previously-identified RUNX1 binding
site or for the RAPTOR locus as genetic determinants of psoriasis,
despite evidence for linkage of psoriasis to distal chromosome 17q.
PMID: 15923274
Oh!
What a drag!
Just when you hoPed that they had a hold of the cats tail, it turns on
them.
Is it possible that we are simply the 2% on the bell curve that exhibit
a higher
degree of being Th1? We just have excess ability to react to anything
foreign including ourselves? We live in a perPetual no mimics or mimes
zone?
Th1 makes TNF-alpha and for P you block it and then your not dePressed.
*****^^^^^^^^********^^^^^^^^********^^^^^^^^***********^^^^^^^^^*********^^^^^
Ok, what's a possibility in the suPPlement world?
I've tried PS, the supplement before. Maybe i'll cocktail it with
whats going down my gut currently,
http://www.medgadget.com/archives/2005/05/celacade_immune.html
Same article at forbes,
http://www.forbes.com/home/free_forbes/2005/0606/085.html
part II: http://www.forbes.com/home/free_forbes/2005/0606/085_2.html
(from the first link on celacade_immune)
Celacade technology by Mississauga, Ontario based Vasogen, Inc., an
immune modulation therapy to treat chronic heart failure. This therapy
is "using a modified sample of a patient's own blood to trick the
immune system into fighting cardiac inflammation."
The company describes some details of this treatment:
Our Celacade™ technology, currently in phase III clinical
development for the treatment of chronic heart failure and peripheral
arterial disease, is being developed to target the chronic inflammation
associated with cardiovascular disease. Our Celacade technology is
designed to deliver oxidative stress to a sample of a patient's own
cells during a brief outpatient procedure, which is administered
monthly. During the procedure, a small sample of blood is collected
into our Celacade single-use disposable cartridge, exposed to
controlled oxidative stress using our Celacade medical device
technology, and then re-administered to the patient intramuscularly.
Oxidative stress is a factor known to induce cell apoptosis, or
programmed cell death. During apoptosis, signalling molecules,
including phosphatidylserine (PS), normally present on the inner
surface of the cell membrane, become exposed on the cell surface. The
PS molecules interact with specific PS receptors on the surface of
antigen presenting cells (APCs) of the immune system, including
macrophages and dendritic cells. The interaction with macrophages leads
to an up-regulation in the production of the anti-inflammatory
cytokines IL-10 and TGF-β. Dendritic cells that interact with
apoptotic cells remain immature and, in the presence of
anti-inflammatory cytokines such as IL-10 and TGF-β, cause the
differentiation of some naive T cells to regulatory T cells. These
traffic through the tissues and inhibit inflammatory cells such as T1
cells by a process that includes cell-cell interaction and the
production of anti-inflammatory cytokines by the regulatory T cells.
The end result is a reduction in tissue levels of inflammatory
cytokines such as TNF-α, IL-6, IFN-γ, and IL-1β, and a
down-regulation of chronic inflammation.
^^^^^^^^^^
I may have used PS in the past. but not with whats going on now. It may
be a helPer? If they say down-regulation of chronic inflammation, i'm
game.
This next one looks really interesting. An oil fraction! Didn't we
get all jiggy over those down under scientists working with this area?
Slowing down TNF-alpha with an antioxidant,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15920037&query_hl=2
Antiinflammatory Effects of Tetradecylthioacetic Acid Involve Both
Peroxisome Proliferator-Activated Receptor {alpha}-Dependent and
-Independent Pathways.
Dyroy E, Yndestad A, Ueland T, Halvorsen B, Damas JK, Aukrust P, Berge
RK.
Institute of Medicine, Section of Medical Biochemistry, University of
Bergen, Haukeland University Hospital, Bergen; and the Research
Institute for Internal Medicine, Section of Endocrinology, and Section
of Clinical Immunology and Infectious Diseases, Medical Department,
Rikshospitalet, University of Oslo, Oslo, Norway.
OBJECTIVE: Tetradecylthioacetic acid (TTA) is a hypolipidemic
antioxidant with immunomodulating properties involving activation of
peroxisome proliferator-activated receptors (PPARs). Human endothelial
cells express PPARs. We hypothesized that TTA could modulate
endothelial cell activation at least partly through PPAR-related
mechanisms. METHODS AND RESULTS: We explored this hypothesis by
different experimental approaches involving both in vitro studies in
human endothelial cells (HUVECs) and in vivo studies in humans and
PPAR-alpha(-/-) mice. Our main findings were as follows: (1) TTA
suppressed the tumor necrosis factor alpha-induced expression of
vascular cell adhesion molecule 1 (VCAM-1) and interleukin 8 (IL-8) in
HUVECs. (2) No TTA-mediated attenuation of VCAM-1 and chemokine
expression was seen in the liver of PPAR-alpha(-/-) mice. (3) Whereas
TTA markedly enhanced PPAR-alpha-target genes in the liver of
wild-type, but not of PPAR-alpha(-/-), mice, no such effect on
PPAR-alpha-target genes was seen in HUVECs. (4) The relevance of our
findings to human disease was suggested by a TTA-mediated
downregulation of serum levels of soluble VCAM-1 and IL-8 in psoriasis
patients. CONCLUSIONS: We show that TTA has the ability to attenuate
tumor necrosis factor alpha-mediated endothelial cell activation,
further supporting antiinflammatory effects of this fatty acid,
possibly involving both PPAR-alpha-dependent and -independent pathways.
PMID: 15920037
And TTA has been in this group before,
http://groups-beta.google.com/groups?q=+Tetradecylthioacetic+acid+%28TTA%29&qt_s=Search
And sliPPed right under the radar. Not like you can run down to your
pharm or supplement store and grab some up. Or can you?
Lets look at the web and see,
http://atvb.ahajournals.org/cgi/content/full/17/11/3255
(...)
This fatty acid analogue was effectively able to reduce in a dose
dependent manner the formation of 8-hydroxydeoxyguanosine from
2-deoxyguanosine with ascorbic acid as the radical producer. TTA bound
copper(II) ions and did not reduce copper(II) to copper(I). It failed
to scavenge the 1.1-diphenyl-2-picrylhydrazyl radicals. The results
suggest that the modification of LDL in the lipid and protein moieties
can be significantly reduced by TTA. This acid may exert its
antioxidant effect partially through metal ion binding and through free
radical scavenging. <snip>
What does it mean?
I don't know yet. We need more data,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11971945&dopt=Abstract
Tetradecylthioacetic acid prevents high fat diet induced adiposity and
insulin resistance.
Madsen L, Guerre-Millo M, Flindt EN, Berge K, Tronstad KJ, Bergene E,
Sebokova E, Rustan AC, Jensen J, Mandrup S, Kristiansen K, Klimes I,
Staels B, Berge RK.
Department of Clinical Biochemistry, University of Bergen, Haukeland
Hospital, N-5021 Bergen, Norway.
Tetradecylthioacetic acid (TTA) is a non-beta-oxidizable fatty acid
analog, which potently regulates lipid homeostasis. Here we evaluate
the ability of TTA to prevent diet-induced and genetically determined
adiposity and insulin resistance. In Wistar rats fed a high fat diet,
TTA administration completely prevented diet-induced insulin resistance
and adiposity. In genetically obese Zucker (fa/fa) rats TTA treatment
reduced the epididymal adipose tissue mass and improved insulin
sensitivity. All three rodent peroxisome proliferator-activated
receptor (PPAR) subtypes were activated by TTA in the ranking order
PPARalpha > PPARdelta > PPARgamma. Expression of PPARgamma target genes
in adipose tissue was unaffected by TTA treatment, whereas the hepatic
expression of PPARalpha-responsive genes encoding enzymes involved in
fatty acid uptake, transport, and oxidation was induced. This was
accompanied by increased hepatic mitochondrial beta-oxidation and a
decreased fatty acid/ketone body ratio in plasma. These findings
indicate that PPARalpha-dependent mechanisms play a pivotal role, but
additionally, the involvement of PPARalpha-independent pathways is
conceivable. Taken together, our results suggest that a TTA-induced
increase in hepatic fatty acid oxidation and ketogenesis drains fatty
acids from blood and extrahepatic tissues and that this contributes
significantly to the beneficial effects of TTA on fat mass accumulation
and peripheral insulin sensitivity.
PMID: 11971945
And synergistic with dex,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1968766&dopt=Abstract
Synergistic actions of tetradecylthioacetic acid (TTA) and
dexamethasone on induction of the peroxisomal beta-oxidation and on
growth inhibition of Morris hepatoma cells. Both effects are
counteracted by insulin.
Norrheim L, Sorensen H, Gautvik K, Bremer J, Spydevold O.
Institute of Medical Biochemistry, University of Oslo, Norway.
(1) The relation between the effects of the sulfur-substituted fatty
acid analogue, tetradecylthioacetic acid (TTA), dexamethasone and
insulin on enzyme induction and growth rate was studied in Morris
hepatoma 7800 C1 cells in culture. (2) The activities of the
cynanide-insensitive palmitoyl-CoA oxidase and palmitoyl-CoA hydrolase
were induced about 2-fold by 50 microM TTA after 72 h of treatment.
Catalase was less induced and NADPH-cytochrome-c2 reductase,
glucose-6-phosphate dehydrogenase and lactate dehydrogenase were
unaffected by the fatty acid analogue. (3) Dexamethasone (250 nM)
induced the same enzymes as did TTA, but was a less efficient than 50
microM TTA. However, in combination their effects were more than
additive, resulting in 4-7-fold increases. (4) Insulin (400 nM)
counteracted the inductive effects of both TTA and dexamethasone on all
enzymes except for lactate dehydrogenase, which was induced by the
combination of all three compounds. (5) TTA inhibited the growth rate
of the cells, and this effect was potentiated by dexamethasone and
counteracted by insulin. (6) The enzyme inductions were similar in
exponential and plateau phases of growth, indicating that these
processes were independently affected by the three compounds.
PMID: 1968766
Modulation of rat liver apolipoprotein gene expression and serum lipid
levels by tetradecylthioacetic acid (TTA) via PPARalpha activation.
Raspe E, Madsen L, Lefebvre AM, Leitersdorf I, Gelman L,
Peinado-Onsurbe J, Dallongeville J, Fruchart JC, Berge R, Staels B.
U325, INSERM, Departement d'Atherosclerose/U325 INSERM, Institut
Pasteur de Lille, 59019 Lille, France.
3-Thia fatty acids are modified fatty acids that promote hepatic
peroxisome proliferation and decrease serum triacylglycerol,
cholesterol and free fatty acid levels in rats. In vivo administration
of tetradecylthioacetic acid (TTA) to rats led to a significant
decrease in liver apolipoproteins apoA-I, A-II, A-IV, and C-III mRNA
levels, and to an increase of liver acyl-CoA oxidase (ACO), carnitine
palmitoyltransferase-II, and 3-hydroxy-3-methylglutaryl coenzyme A
synthase (HMG-CoA synthase) mRNA levels and activities. By contrast, no
significant changes of lipoprotein lipase (LPL) mRNA levels were
detected in rat epididymal adipose tissue. Liver carnitine
palmitoyltransferase-I, apoB, apoE, and LDL receptor mRNA levels were
not significantly affected. When tested in vitro, TTA increased rat ACO
and carnitine palmitoyltransferase-I mRNA levels in primary rat
hepatocytes and also LPL mRNA levels in 3T3-L1 preadipocytes. TTA also
enhanced the transcriptional activity of chimeras containing the DNA
binding domain of the yeast transcription factor Gal4 fused to the
ligand binding domain of either human PPARalpha or human PPARgamma. The
effect depended on the concentration tested and the cell type.In
conclusion, our data suggest that in vitro, TTA activates both
PPARalpha and PPARgamma, but the latter with much lower affinity. TTA
affects serum lipid levels in vivo in rats by acting mainly on the
liver via PPARalpha where it decreases the liver expression of genes
involved in vascular lipid transport and increases the expression of
genes involved in intracellular fatty acid metabolism. -Raspe, E., L.
Madsen, A-M. Lefebvre, I. Leitersdorf, L. Gelman, J. Peinado-Onsurbe,
J. Dallongeville, J-C. Fruchart, R. Berge, and B. Staels. Modulation of
rat liver apolipoprotein gene expression and serum lipid levels by
tetradecylthioacetic acid (TTA) via PPARalpha activation.
PMID: 10553013
Sulfur-substituted and alpha-methylated fatty acids as peroxisome
proliferator-activated receptor activators.
Larsen LN, Granlund L, Holmeide AK, Skattebol L, Nebb HI, Bremer J.
Institute of Basic Medical Sciences, Department of Biochemistry,
University of Oslo, Norway. l.n.l...@medisin.uio.no
FA with varying chain lengths and an alpha-methyl group and/or a sulfur
in the beta-position were tested as peroxisome proliferator-activated
receptor (PPAR)alpha, -delta(beta), and -gamma ligands by transient
transfection in COS-1 cells using chimeric receptor expression
plasmids, containing cDNAs encoding the ligand-binding domain of
PPARalpha, -delta, and -gamma. For PPARalpha, an increasing activation
was found with increasing chain length of the sulfur-substituted FA up
to C14-S acetic acid (tetradecylthioacetic acid = TTA). The derivatives
were poor, and nonsignificant, activators of PPARdelta. For PPARgamma,
activation increased with increasing chain length up to C16-S acetic
acid. A methyl group was introduced in the alpha-position of palmitic
acid, TTA, EPA, DHA, cis9,trans11 CLA, and trans10,cis12 CLA. An
increased activation of PPARalpha was obtained for the alpha-methyl
derivatives compared with the unmethylated FA. This increase also
resulted in increased expression of the two PPARalpha target genes
acyl-CoA oxidase and liver FA-binding protein for alpha-methyl TTA,
alpha-methyl EPA, and alpha-methyl DHA. Decreased or altered metabolism
of these derivatives in the cells cannot be excluded. In conclusion,
saturated FA with sulfur in the beta-position and increasing carbon
chain length from C9-S acetic acid to C14-S acetic acid have increasing
effects as activators of PPARalpha and -gamma in transfection assays.
Furthermore, alpha-methyl FA derivatives of a saturated natural FA
(palmitic acid), a sulfur-substituted FA (TTA), and PUFA (EPA, DHA,
c9,t11 CLA, and t10,c12 CLA) are stronger PPARalpha activators than the
unmethylated compounds.
PMID: 15825830
The metabolic syndrome and the hepatic fatty acid drainage hypothesis.
Berge RK, Tronstad KJ, Berge K, Rost TH, Wergedahl H, Gudbrandsen OA,
Skorve J.
Institute of Medicine, The Lipid Research Group, Haukeland University
Hospital, University of Bergen, 5021 Bergen, Norway.
rolf....@med.uib.no
Much data indicates that lowering of plasma triglyceride levels by
hypolipidemic agents is caused by a shift in the liver metabolism
towards activation of peroxisome proliferator activated receptor
(PPAR)alpha-regulated fatty acid catabolism in mitochondria. Feeding
rats with lipid lowering agents leads to hypolipidemia, possibly by
increased channeling of fatty acids to mitochondrial fatty acid
oxidation at the expense of triglyceride synthesis. Our hypothesis is
that increased hepatic fatty acid oxidation and ketogenesis drain fatty
acids from blood and extrahepatic tissues and that this contributes
significantly to the beneficial effects on fat mass accumulation and
improved peripheral insulin sensitivity. To investigate this theory we
employ modified fatty acids that change the plasma profile from
atherogenic to cardioprotective. One of these novel agents,
tetradecylthioacetic acid (TTA), is of particular interest due to its
beneficial effects on lipid transport and utilization. These
hypolipidemic effects are associated with increased fatty acid
oxidation and altered energy state parameters of the liver. Experiments
in PPAR alpha-null mice have demonstrated that the effects
hypolipidemic of TTA cannot be explained by altered PPAR alpha
regulation alone. TTA also activates the other PPARs (e.g., PPAR delta)
and this might compensate for deficiency of PPAR alpha. Altogether,
TTA-mediated clearance of blood triglycerides may result from a lowered
level of apo C-III, with a subsequently induction of hepatic
lipoprotein lipase activity and (re)uptake of fatty acids from very low
density lipoprotein (VLDL). This is associated with an increased
hepatic capacity for fatty acid oxidation, causing drainage of fatty
acids from the blood stream. This can ultimately be linked to
hypolipidemia, anti-adiposity, and improved insulin sensitivity.
PMID: 15733731
Effects of structural changes of fatty acids on lipid accumulation in
adipocytes and primary hepatocytes.
Granlund L, Larsen LN, Nebb HI, Pedersen JI.
Institute of Basic Medical Sciences, Department of Nutrition,
University of Oslo, P.O.B. 1046 Blindern, 0316 Oslo, Norway.
Conjugated linoleic acids (CLAs), tetradecylthioacetic acid (TTA),
eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are all
shown to differently affect lipid homeostasis. Additionally, previous
studies have shown that introducing a methyl group in the molecule
potentiates the hypolipidemic effect of EPA. The objective of this
study was to determine how cis9,trans11 CLA, trans10,cis12 CLA, TTA,
EPA and DHA affect lipid accumulation in 3T3-L1 adipocytes and in
cultured primary rat hepatocytes, and to what extent changes in
cis/trans configuration or introducing a methyl group in the molecules
influence their way of affecting lipid accumulation in these cells. Our
results show that trans10,cis12 CLA is highly specific in preventing
lipid accumulation in adipocytes, and that small structural changes in
the molecule (changing to trans/trans or introducing an alpha-methyl
group) totally abolish this effect and up-regulate the expression
levels of adipogenic marker genes towards control levels. Furthermore,
all the fatty acids increased hepatic lipid accumulation, whereas the
lipid content was normalized after adding an alpha-methyl group into
the molecules. Taken together, our data demonstrate that the various
fatty acids are highly specialized molecules, and that small structural
changes markedly alter their way of affecting lipid accumulation in
adipocytes and hepatocytes.
PMID: 15708350
(one thing is for sure. My tests with CLA showed that it has the
ability to flare
the craP outa me. And it did in short order. Certainly a trigger for
me. :( )
Immunomodulating effects of 3-thia fatty acids in activated peripheral
blood mononuclear cells.
Aukrust P, Wergedahl H, Muller F, Ueland T, Dyroy E, Damas JK, Froland
SS, Berge RK.
Section of Clinical Immunology and Infectious Diseases, Research
Institute for Internal Medicine, Rikshospitalet, Oslo, Norway.
BACKGROUND: 3-thia fatty acids such as tetradecylthioacetic acid (TTA)
are modified fatty acids that have been suggested to change the plasma
profile from atherogenic to cardio protective. Because of its
interaction with peroxisome proliferator activated receptor (PPAR) we
hypothesized that TTA also could have immunomodulatory properties.
Based on the suggested role of inflammation in atherogenesis, any
immunomodulating effects of TTA would be of particular interest for the
potential use of this fatty acid in atherosclerotic disorders.
MATERIALS AND METHODS: We examined if TTA could modulate proliferation
and the release of cytokines from peripheral mononuclear cells (PBMCs)
taken from five healthy blood donors. RESULTS: Our main findings were:
(i) TTA had several effects on cytokine release from activated PBMCs
with a marked increase in interleukin (IL)-10 accompanied by a
reduction in IL-2 possibly favouring anti-inflammatory net effects.
(ii) These cytokine-modifying effects were found in both T cells and
monocytes when cultured separately. (iii) Tetradecylthioacetic acid
increased the cytokine stimulating effects of tumour necrosis factor
alpha with a particularly enhancing effect on IL-10. (iv)
Tetradecylthioacetic acid significantly suppressed PBMC proliferation,
and this antiproliferative property did not involve enhanced apoptosis
or necrosis. (v) These immunomodulatory effects of TTA were accompanied
by a marked down-regulation of PPARoad mRNA expression, the most
abundant PPAR subtype in PBMCs. CONCLUSIONS: Our findings show potent
immunomodulatory effects of TTA in activated PBMCs, possibly involving
PPAR-related mechanisms.
PMID: 12713457
^^^^
So much for TTA. I hope it turn out to be a real possibilty for us. And
not
just a way to keep lab rats healthy.
Moving on to LPS du jour and G-CSF signalling.
G-CSF modulates LPS-induced apoptosis and IL-8 in human microvascular
endothelial cells: involvement of calcium signaling.
Schneider EM, Lorenz I, Ma X, Weiss M.
Sektion Experimentelle Anaesthesiologie, Department of Clinical
Anaesthesiology, University Clinic, 89075 Ulm, Germany.
marion.s...@medizin.uni-ulm.de
Microvascular endothelial cells (mECs) circulate at higher numbers in
patients with severe sepsis and hemophagocytic syndromes. Although
these blood mECs might stem from damaged microvasculature, they are
perfectly viable and lead to the establishment of cell lines. Such mECs
were cultured in low-dose human serum pools (0.5%) and MEM-alpha
medium. Antigenic profiling revealed the expression of CD36, factor
VIIIa, CD95-ligand, and CD44, but also CD146. We studied the
antioxidative effect of the hematopoietic growth factor G-CSF(1) after
in vitro stimulation with LPS from E. coli 0111:B4; the growth factor
appeared to exhibit a protective effect on organ function in patients
with SIRS. mECs were stimulated with 1 micro g/mL of LPS for 24 h and
48 h with and without G-CSF (3x10(3) U/mL) preincubation. After 24 h,
supernatants of the stimulated mEC were tested for IL-8 by ELISA, and
cells were tested for hemoxygenase-1 (HO-1, Hsp32) by
immunohistochemistry and flow cytometry using OSA110 (mAb, Stressgene).
Stimulation with LPS upregulated IL-8 by a factor of 2 to 10 in mEC.
Preincubation with G-CSF markedly downregulated the LPS-induced IL-8
secretion (20-50%), but IL-6 production was not affected. Upon 48 h of
LPS stimulation, mECs developed massive signs of apoptosis and
concomitant caspase 3 activation. Caspase 3 activity induced by LPS (24
h) or by staurosporin (6 h) was found to be dramatically downregulated
by the G-CSF preincubation protocol.
PMID: 15033698
Granulocyte colony-stimulating-factor-induced psoriasiform dermatitis
resembles psoriasis with regard to abnormal cytokine expression and
epidermal activation.
Mossner R, Beckmann I, Hallermann C, Neumann C, Reich K.
Department of Dermatology, Georg-August-University Gottingen, Germany.
Psoriasis is a chronic inflammatory skin disorder characterized by
accumulation of Th1-type T cells and neutrophils, regenerative
keratinocyte proliferation and differentiation, and enhanced epidermal
production of antimicrobial peptides. The underlying cause is unknown,
but there are some similarities with the immunologic defense program
against bacteria. Development of psoriasiform skin lesions has been
reported after administration of granulocyte colony-stimulating factor
(G-CSF), a cytokine induced in monocytes by bacterial antigens. To
further investigate the relation between this type of cytokine-induced
dermatitis and psoriasis, we analyzed the cutaneous cytokine profile
[tumor necrosis factor-alpha (TNF-alpha), interferon-gamma,
transforming growth factor-beta1 (TGF-beta1), interleukin-10 (IL-10),
IL-12p35 and p40, and IL-8] and expression of markers of epidermal
activation [Ki-67, cytokeratin-16, major histocompatibility complex
(MHC) class II, intercellular adhesion molecule-1 (ICAM-1)] in a
patient who developed G-CSF-induced psoriasiform dermatitis by using
quantitative real-time reverse transcriptase-polymerase chain reaction
and immunohistology. The histologic picture resembled psoriasis with
regard to epidermal hyperparakeratosis and the accumulation of
lymphocytes in the upper corium. CD8(+) T cells were found to
infiltrate the epidermis which was associated with an aberrant
expression of Ki-67, cytokeratin-16, MHC class II, and ICAM-1 on
adjacent keratinocytes. As compared to normal skin (n = 7), there was
an increased expression of TNF-alpha, IL-12p40, and IL-8, a decreased
expression of TGF-beta1, and a lack of IL-10, similar to the findings
in active psoriasis (n = 8). Therefore, G-CSF may cause a lymphocytic
dermatitis that, similar to psoriasis, is characterized by a
pro-inflammatory Th1-type cytokine milieu and an epidermal phenotype
indicative of aberrant maturation and acquisition of non-professional
immune functions.
PMID: 15186319
Differential effects of IL-10 on prostaglandin H synthase-2 expression
and prostaglandin E2 biosynthesis between spleen and bone marrow
macrophages.
Shibata Y, Nishiyama A, Ohata H, Gabbard J, Myrvik QN, Henriksen RA.
Department of Biomedical Sciences, Florida Atlantic University, Boca
Raton, FL 33431-0991, USA. yshi...@fau.edu
Different populations of mononuclear phagocytes (MO) show considerable
diversity of cellular function including prostaglandin E2 (PGE2)
biosynthesis. Certain bacterial components enhance PGE2 biosynthesis
differentially in selected populations of MO. Interleukin (IL)-10 is
proposed to inhibit modulation of PGE2 biosynthesis by down-regulating
prostaglandin G/H synthase-2 (PGHS-2) expression. To assess whether
IL-10 regulates PGE2 biosynthesis and PGHS-2 expression, splenic and
bone marrow MO were isolated from IL-10-deficient (IL-10(-/-)), C57Bl/6
[wild-type (WT) control], and Balb/c (comparison control) mice and were
treated with lipopolysaccharide (LPS) and/or interferon-gamma
(IFN-gamma) as a model of bacterial inflammation. LPS-induced PGHS-2
expression was similar for splenic MO isolated from the three strains
of mice. However, PGE2 released by LPS-treated splenic MO was
significantly higher in IL-10(-/-) and Balb/c than in WT cells. In the
presence of LPS and IFN-gamma, PGHS-2 expression and PGE2 release by
IL-10(-/-) and Balb/c splenic MO were enhanced compared with
stimulation with LPS alone or IFN-gamma alone. However, there was no
significant increase in PGE2 release from WT splenic MO treated with
LPS plus IFN-gamma despite increased PGHS-2 expression. In sharp
contrast, PGHS-2 expression and PGE2 release by bone marrow MO were
greatly enhanced in IL-10(-/-) cells compared with control cells. Our
results indicate that IL-10 regulation of MO PGE2 biosynthesis and
PGHS-2 expression is compartment-dependent and that PGE2 production is
not linked directly to PGHS-2 levels. Furthermore, our findings
emphasize strain-specific differences between C57Bl/6 and Balb/c mice,
and Balb/c appears more similar to the IL-10(-/-) than to the C57Bl/6
with respect to prostanoid production.
PMID: 15657087
Glycosylated or non-glycosylated G-CSF differently influence human
granulocyte functions through RhoA.
Mattii L, Azzara A, Fazzi R, Carulli G, Chimenti M, Cecconi N,
Galimberti S, Petrini M.
Department of Human Morphology and Applied Biology, University of
Pisa, Pisa, Italy.
Granulocyte function may be altered after in vivo G-CSF administration
and this has been related to both an immaturity of mobilized cells and
to a defect in F-actin polymerization. In this paper we show that in
resting Filgrastim (non-glycosylated G-CSF)-pulsed cells, F-actin
polymerization, membrane-linked RhoA and cell polarization are enhanced
compared to those found in resting Lenograstim (glycosylated
G-CSF)-cells. The basal hyper-activation of RhoA could be responsible
for the morphological and functional modifications of
Filgrastim-mobilized cells. Moreover, Filgrastim-mobilized cells, but
not Lenograstim-mobilized cells, are unable to correctly respond to LPS
stimulation, as demonstrated by minor further RhoA activation and cell
elongation.
PMID: 15916805
Granulocyte colony-stimulating factor decreases tumor necrosis factor
production in whole blood: role of interleukin-10 and prostaglandin
E(2).
Agnello D, Mascagni P, Bertini R, Villa P, Senaldi G, Ghezzi P.
"Mario Negri" Institute for Pharmacological Research, Milan, Italy.
Previous reports have indicated that the administration of granulocyte
colony-stimulating factor (G-CSF) decreases ex vivo tumor necrosis
factor (TNF) production in humans. In this study, we report that daily
pretreatment of mice with G-CSF for three days decreases ex vivo
lipopolysaccharide (LPS)-induced TNF production in whole blood.
Conversely, production of interleukin-10 (IL-10) and prostaglandin E(2)
(PGE(2)) is increased. The inhibitory effect of G-CSF pretreatment on
TNF production is partially reversed by addition of an anti-IL-10
antibody, and completely reversed by combined addition of anti-IL-10
antibody and the cyclooxygenase (COX) inhibitor, ketoprofen. These
results suggest that G-CSF decreases TNF production in this
experimental model by increasing production of IL-10 and PGE(2), which
are both known inhibitors of TNF production.
PMID: 15627641
http://ajpcell.physiology.org/cgi/content/short/00387.2003v1 (full
text available)
Selective activation of STAT3 in human monocytes stimulated by G-CSF:
implication in inhibition of LPS-induced TNF-alpha production.
Nishiki S, Hato F, Kamata N, Sakamoto E, Hasegawa T, Kimura-Eto A,
Hino M, Kitagawa S.
Department of Physiology, Osaka City University Medical School,
Asahi-machi, Abeno-ku, Osaka 545-8585, Japan.
Lipopolysaccharide (LPS) induced tumor necrosis factor (TNF)-alpha
production in human monocytes, which was dependent on activation of
extracellular signal-regulated kinase (ERK), p38, c-Jun NH(2)-terminal
kinase (JNK), and nuclear factor (NF)-kappa B. LPS-induced TNF-alpha
production was inhibited by granulocyte colony-stimulating factor
(G-CSF) and interleukin (IL)-10. G-CSF, like IL-10, exerted the
inhibitory effect even when simultaneously added with LPS. Among the
signaling pathways, signal transducer and activator of transcription 3
(STAT3) was selectively activated in monocytes stimulated by G-CSF or
IL-10. G-CSF-mediated inhibition of LPS-induced TNF-alpha production as
well as G-CSF-induced STAT3 phosphorylation and suppressor of cytokine
signaling 3 mRNA expression were prevented by pretreatment of monocytes
with AG-490, an inhibitor of Janus kinase 2. G-CSF did not affect
LPS-induced activation of ERK, p38, JNK, and NF-kappa B, indicating
that G-CSF affects the pathway downstream or independently of these
signaling molecules. G-CSF-induced, but not IL-10-induced, STAT3
phosphorylation was attenuated in the presence of LPS. These findings
suggest that G-CSF, like IL-10, inhibits LPS-induced TNF-alpha
production in human monocytes through selective activation of STAT3,
and the immunomodulation observed in vivo by G-CSF administration may
be partly ascribed to the direct effect of G-CSF on monocyte functions.
PMID: 14736711
Gov clinical trial of G-CSF on crohn's
http://www.clinicaltrials.gov/ct/gui/show/NCT00025805
OMIM
http://www3.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=138970
Map
http://www.ncbi.nlm.nih.gov/Omim/getmap.cgi?l138970
(click the ideas links- the light bulbs!)
Other ideas,
http://www.bioscience.org/knockout/ref/lieschk.htm
***********
Now if I could add some TTA to my fish oil aspirin morning cocktail and
uPregulate IL-10 somehow. And lower LPS translocation. Then who knows?
Maybe those P Genes would not misbehave....
randall....
JXStern
On 1 Jun 2005 12:21:36 -0700, "randall" <ranh...@aol.com> wrote:
>Is it possible that we are simply the 2% on the bell curve that exhibit
>a higher
>degree of being Th1? We just have excess ability to react to anything
>foreign including ourselves? We live in a perPetual no mimics or mimes
>zone?
I don't think it's that simple, cuz just any old reaction wouldn't
necessarily turn up on the skin, etc.
I think that it's just combinatorics, eg, genes, but like this, that
exactly what lipids and markers you have on your skin cells depend on
dozens or hundreds of genes, and are further affected by what
pathogens you run into, while exactly what signals your immune system
looks for are governed by hundreds and thousands of genes, and when
you have one gene for skin cells, and another gene for immune actions,
and they overlap (as they should not), then congratulations, you've
got psoriasis! Could be hundreds or thousands or millions of such
possible combinations. Perhaps large classes of them will have some
features in common, evolution being very conservative in some such
things (or we wouldn't share 80% of our genome with yeasts and
dandelions, not to speak of weasels and Republicans). But hmm, I
wonder by this very logic, if the idea of there being specific
psoriasis genes is ever going to work out. Not if my description is
accurate. Skin gene #abcde will occur in x% of the population, and
immune gene #wxyz will occur in y% of the population, and (100-x) *
(100-y) % of the population will not have psoriasis FROM THAT GENE
COMBINATION, but you'll have to sum over zillions of such combinations
if you want overall odds, and for some you'll need their pathogen
exposure history as well! And, oh, there probably ARE some genes that
make you more violently Th1 for a given stimulus, that could pass for
a psoriasis-related gene although it's actually far more general, and
probably helpful more often than not.
And, y'know, like that.
J.
ps - don't start on me about the "Republicans", the original of the
joke used whatever ethnic group you care to make fun of, but we can't
do that anymore can we?
randall
We are not devo!
We are Pevo!
Crack that whiP!
First take a wiff of oxytocin before reading this!
Warning! Got it? ok continue,
I certainly wouldn't coP to this,
http://fusionanomaly.net/devo.html
Not very cute youthfool nihilists,
http://www.qwantz.com/fanart/nihilism.jpg
And what the hell is that p2p Hash thing on their toP menu?
If I were a popPy,
http://www.atpm.com/7.07/flowers-ii/images/poppy.jpg
I certainly wouldn't be imPressed by,
http://paranoia.lycaeum.org/marijuana/images/waterfall-buds.jpg
Even if it was made into a nice hash.
Back to the p2p hash thingy,
It's to the far right of the eye in the triangle telex thing.
And whats with that?
http://watch.pair.com/mason.html
http://watch.pair.com/mason.html#seal
Are they truly concerned with the eye of horus?
http://amun.com/eng/horus_e.html
Or are they the all knowing? Or simple money loving
students? With a cache of nihilistic nonsense?
Youth part II, we are into ourselves!
Aren't they all?
Well. I know I was. Hey that reflection is fading!
The looking pool does that.
As one psor to another psor, its just Pevo to me.
Psor 2 psor + PC ='s pevo (not P evil, though it's toPical!)
Would devo be de-evolving then?
http://www.nearingzero.net/screen_res/nz326.jpg
Make my P do that and i'm a believer!
Hey hey we're the monkeys!
2001 here we come,
Thusly,
JXStern wrote:
> Was: P News 6/1/2005 12:21PM
>
> On 1 Jun 2005 12:21:36 -0700, "randall" <ranh...@aol.com> wrote:
>
> >Is it possible that we are simply the 2% on the bell curve that exhibit
> >a higher
> >degree of being Th1? We just have excess ability to react to anything
> >foreign including ourselves? We live in a perPetual no mimics or mimes
> >zone?
>
> I don't think it's that simple, cuz just any old reaction wouldn't
> necessarily turn up on the skin, etc.
>
OH!
> I think that it's just combinatorics, eg, genes, but like this, that
> exactly what lipids and markers you have on your skin cells depend on
> dozens or hundreds of genes, and are further affected by what
> pathogens you run into, while exactly what signals your immune system
> looks for are governed by hundreds and thousands of genes, and when
> you have one gene for skin cells, and another gene for immune actions,
> and they overlap (as they should not), then congratulations, you've
> got psoriasis! Could be hundreds or thousands or millions of such
> possible combinations. Perhaps large classes of them will have some
> features in common, evolution being very conservative
The dirty trick is in the genes,
http://www.nearingzero.net/screen_res/nz125.jpg
>in some such
> things (or we wouldn't share 80% of our genome with yeasts and
> dandelions, not to speak of weasels and Republicans).
Beware of suPer bugs,
http://www.nearingzero.net/screen_res/nz149.jpg
> But hmm, I
> wonder by this very logic, if the idea of there being specific
> psoriasis genes is ever going to work out. Not if my description is
> accurate. Skin gene #abcde will occur in x% of the population, and
> immune gene #wxyz will occur in y% of the population, and (100-x) *
> (100-y) % of the population will not have psoriasis FROM THAT GENE
> COMBINATION, but you'll have to sum over zillions of such combinations
> if you want overall odds, and for some you'll need their pathogen
> exposure history as well!
Oh you boys with big brains!
http://www.ratpackstlouis.com/VosSavant2.jpg
You make me so curious.
> And, oh, there probably ARE some genes that
> make you more violently Th1 for a given stimulus, that could pass for
> a psoriasis-related gene although it's actually far more general, and
> probably helpful more often than not.
>
> And, y'know, like that.
>
No!
> J.
>
> ps - don't start on me about the "Republicans", the original of the
> joke used whatever ethnic group you care to make fun of, but we can't
> do that anymore can we?
PC isn't even PC anymore in a quantum universe.
http://www.physik.uni-frankfurt.de/~jr/gif/cartoon/lars0896.gif
or
http://www.nearingzero.net/screen_res/nz103.jpg
But sticking with stars in our own galaxy,
http://antwrp.gsfc.nasa.gov/apod/astropix.html
And crediting those political stars isn't so easy.
If they be dogs and cats so much the easier to follow.
We say up and down, right and left, light and dark,
and yet when it comes to politics we are suPPosed to
fall into one camP or another? No way. Nonsense.
Or do lemming genes show up there?
http://www.stevecolgan.com/Portfolio/Lemmings%20(Fortean%20Times).jpg
& did he have P,
http://www.buriedaliveillustrations.com/cartoons/lemmings.jpg
Yet how does one truly know,
http://www.nearingzero.net/screen_res/nz095.jpg
When the sPin machines warP your understandings,
http://www.nearingzero.net/screen_res/nz109.jpg
Take the pol salad du jour,
http://i.timeinc.net/b2/images/mag/dec2003_34a_225x165.jpg
add the olive oil laden new-mans
http://www.newmansown.com/NEWimages/4a14lightitalian.gif
And P wise your ok.
But what haPPens with Berstein's vegetable dressing, mainly soybean
oil,
http://www.birdseyefoods.com/images/corp/ourBrands/brands_bernsteins.jpg
Well even a bird dawg can name that P flare. And Wood ward know if the
Beaver was covered in P or not? He had the crystal ball and scriPt
to work over and over.
June may have a problem being so middle class.
But don't hiss just yet,
http://www.wilsonsalmanac.com/toons/jan25_hiss_an.gif
In the Court of Public Opinion, one man's hissteria is anothers
McCarthyism,
http://www.s-t.com/daily/11-96/11-16-96/a07wn050.htm
And so a future prez found a pumP-kin,
http://www.law.umkc.edu/faculty/projects/ftrials/hiss/hissimages.html
Looks like a dirty little commie to me,
http://www.law.umkc.edu/faculty/projects/ftrials/hiss/nixonfilm.jpg
Who thought with their head when the HEART ruled?
http://news.google.com/news?hl=en&lr=&tab=in&ie=UTF-8&q=alger+hiss+nixon++felt&btnG=Search+News
And what dirty trick was played and why,
http://www.watergate.com/silentcoup/14.htm
Why think with your head when you have this guy,
http://www.watergate.com/silentcoup/13.htm
Follow the bucks and even though bernstein's is cheaper due
to inferior ingredients he still made a ton of green on this
caPer. Though woodward made more. Lots mo.
You can hear dick rolling over in his grave talking with
these dudes. "Can you even believe that hilly billy was doing
the legal thing on us and bill would get a blow job right where
we were standing"???
http://www.watergate.com/silentcoup/1.htm
And felt was doing the garage thing with bernstein&woodward and
making those jerks rich?
And dick is rolling over murmuring,
Hey SATAN once this guy gets here,
http://www.freenorthkorea.net/archives/freenorthkorea/saddam_indignant.jpg
Let me know. I'm running for head of the union down here.
I need a strawman that will light things uP and turn the polls my way.
Who knew,
http://www.thezreview.co.uk/posters/posterimages/insidedeepthroat.jpg
I'm not a crook, but please NO jews in the FBI,
http://www.newsmax.com/archives/ic/2005/6/2/134011.shtml
Did Bill bust a liP,
http://www.newsmax.com/articles/?a=1999/6/23/165603
http://www.newsmax.com/articles/?a=1999/3/1/233307
Hillary get outa the closet before 2008,
http://www.trosch.org/wom/hillary.html
http://www.american-partisan.com/cols/2001/king/qtr1/0222.htm
Isn't the bernstein/wardwood thing just love actually?
http://www.cah.utexas.edu/db/dmr/image_lg.php?variable=e_wm_0202
Not,
http://www.newstohughes.com/images/love_actually_graph.jpg
And Dean knew what he was trying to hide?
http://www.watergate.com/stories/deepthroat.asp
And liddy knew too,
http://www.watergate.com/stories/liddy.asp
What has dirty tricks and thinking with your head instead of
your heart have to do with it?
I bet dick is still wondering why he didn't use his head instead.
http://www.rightwingnews.com/interviews/liddy.php
(...)
John Hawkins: Yeah, that's how it always seems to go. Now in your
newest book, you say that Watergate was actually "not to repair a
telephone tap but to collect dirt on an alleged call-girl ring at the
DNC headquarters" and that the Watergate burglars were looking for
photos of John Dean's wife. Can you elaborate on that a bit?
G. Gordon Liddy: It's a very long, detailed story and after I
publicized it, I and a lot of other people were sued by John Dean and
his wife. It took 8 years to get them to court and when we finally did,
they dropped the charges.
John Dean thereafter procured a woman named Ida "Maxie" Wells and
provided her with his lawyer. She did sue and we had a trial in which
all of these issues were aired and I won.
Briefly, here's what happened. Back in those days, the FBI was
investigating 3 different call-girl rings that were operating at the
time in Washington DC. One of them was operating out of the Columbia
Plaza apartments which is across the street from the Watergate.
According to the supervising assistant district attorney, whose name
was John Rudy, he was told by the FBI that they had established a
connection with the ring to a person in the Democratic National
Committee headquarters. That person was described as either a secretary
or as an administrative assistant and a female. When the Democrats
themselves found the wiretap that everybody supposed was on Mr.
O'Brien, there was never any wiretap on Mr. O'Brien, the wiretap was on
the phone used by that woman. The burglars, when they were apprehended,
were not anywhere near Mr. O'Brien's office. They were clustered around
the desk of that woman, they had set up the photographic equipment on
the desk of that woman. The way the call-girl ring operated was by a
photographic brochure with pictures of the girls (in it). John Dean
knew that, this was a John Dean operation. The question then comes to
mind; "Well how would John Dean, counsel to the President, know
something like that"? Well, that's because his then paramour, now his
wife, Maureen, when she was not shacked up with John, was the roommate
of the madame.
John Hawkins: (Chuckles)
G. Gordon Liddy: Of course, we knew the identity of the madame, her
name was Heidi Rikan. She was a German national and she operated under
the street name of Cathy Dieter. When Maureen Dean wrote her book,
'Mo': A Woman's View of Watergate, which was sort of autobiographical,
she included her wedding pictures to John. There, one of her
attendants, in all her glory, was the madame. So, that's how John found
out. But, you can read all about it in the book!
John Hawkins: I look forward to doing that. You know one of the things
that has always puzzled me about Watergate, was that as we now know,
Nixon absolutely buried McGovern in 1972. So, I've always wondered why
anyone in the Nixon White House thought it was necessary to do
something like Watergate. Can you shed some light on that subject?
G. Gordon Liddy: Well sure. Now remember when all of this was; this was
prior to the Democrats having selected their candidate. No one knew who
the candidate was going to be. Before he broke down in front of the
Union Leader Office, Mr. Muskie was thought to be very Lincolnian and
to be a strong candidate. We never knew whether or not Ted Kennedy
would make a try and despite his Chappaquiddick troubles, it was
thought that he would be a potent foe. So the political intelligence
apparatus was set into effect because no one knew who the candidate was
going to be.
(...)
****
And think about it. Dick Nixon and Dick Morris are both Dicks.
And were in the oval egg-head office.
Whats the odds?
http://chaos.swarthmore.edu/courses/phys6_2004/cartoons/dice.jpg
But, why a dick
http://www.nearingzero.net/screen_res/nz147.jpg
The whole stick is like a 50's B grade movie,
http://www.nearingzero.net/screen_res/nz159.jpg
And since this isn't particle physics the next big discovery
could be right around the corner,
http://www.nearingzero.net/screen_res/nz179.jpg
And since a nonbeliever will never be elected prez for
obvious reasons,
http://www.eegah.com/photo1.htm
We can only Pray for good not bad men,
http://www.learnersonline.com/weekly/lessons04/week4/012604-2.jpg
http://www.iun.edu/~wostnw/history/images/Mother_Teresa.jpg
Are you still here?
OK,
So you are actually addicted to P news and you need your fix?
Ok,
Here you go,
http://biz.yahoo.com/prnews/050602/to257.html?.v=6
MARKHAM, ON, June 2 /PRNewswire/ - Cytochroma Inc. today announced
results from a Phase Ia clinical study for CTA018, a novel vitamin D
analog developed for the treatment of psoriasis. The study, involving
17 healthy subjects with mild to moderate plaque psoriasis, was
designed to characterize the local efficacy and safety of three
concentrations of CTA018. Results indicate that all three doses appear
to reduce the severity of psoriasis plaques with no local tolerability
concerns. The Company is currently concluding a Phase Ib study with
CTA018 to assess the drug's systemic safety and pharmacokinetics
(...)
CTA018 is a novel vitamin D analog with a dual mechanism of action. It
is a strong activator of the vitamin D signaling pathway and also a
potent inhibitor of CYP24 activity (the enzyme responsible for the
breakdown of vitamin D). CTA018 was designed by Prof. Gary H. Posner
and is protected under patents and patent applications exclusively
licensed to Cytochroma Inc. from the Johns Hopkins University.
(...)
Cytochroma Inc. is a specialty drug development company targeting
hyperproliferative disorders, autoimmune diseases and chronic kidney
disease. The company is currently focused on developing and
commercializing innovative vitamin D analogs, significantly having a
dual mechanism of action, which address major medical needs in the
treatment of psoriasis, secondary hyperparathyroidism, multiple
sclerosis and cancer. For more information, please visit
www.cytochroma.com.
******
GroPep Limited (GRO) today advised that it had been granted a patent in
in Japan for the active ingredient of its developmental psoriasis drug,
PP0102. The company also announced that a seventh biopharmaceutical
product has obtained regulatory approval by the Food and Drug
Administration (FDA) in the United States.
On the Japan patent GroPep's Vice President of Commercial Operations,
Mr Gregory Moss-Smith, said that with the equivalent patents had
already been granted in the USA and Europe, and that the Japanese
patent completes coverage of the most valuable potential markets.
The paten is until January 16, 2016, with the potential to extend this
term by an additional 5 years, the company said.
"The patent news is significant because Japan is a major
pharmaceutical market and grant of the patent provides the company with
a patent monopoly," noted the groups press statement.
Exclusive, worldwide rights to the patent were obtained by GroPep in
2002 through a licence from the Northern Sydney and Central Coast Area
Health Service (NSCCH).
The patent (Japanese Patent No. 3,665,342 - "Novel Peptide") is
based on research conducted at the Royal North Shore Hospital by
Professor Nick Manolios.
The PP0102 active ingredient has potential application in other
autoimmune diseases, including asthma, with the company filing an
International Patent application on the use of the active ingredient
for the treatment of asthma on 27th May 2005.
****
http://www.healthopedia.com/news/article.php?id=526027
HURSDAY, June 2 (HealthDay News) -- A protein called tumor necrosis
factor (TNF) is linked with a deficiency of male sex hormones in people
with rheumatoid arthritis, according to a European study.
The finding may give researchers new insights into the underlying
causes of this common, debilitating disorder.
TNF is involved in multiple cell functions and is also known to provoke
destructive inflammation. It's believed that male sex hormones --
androgens -- play an important role in helping fight inflammation in
rheumatic diseases, including various forms of arthritis and lupus. In
this study, researchers took a closer look at TNF's impact on androgen
production.
Specifically, researchers at University Hospital Regensburg, in
Germany, focused on TNF's role in the conversion of a biologically
inactive compound, dehydroepiandrosterone sulfate (DHEAS), to the more
biologically active DHEA -- the steroid hormone "parent" of androgen,
estrogen and testosterone.
They analyzed samples of inflamed synovial tissue from the knee joints
of 37 people with either rheumatoid arthritis or osteoarthritis. Levels
of both DHEAS and DHEA were much lower among the rheumatoid arthritis
patients than patients with (non-rheumatic) osteoarthritis, the team
reported in the June issue of Arthritis & Rheumatism.
The researchers also found evidence that TNF inhibits the activity of
steroid sulfatase, an enzyme that plays a crucial role in DHEAS-to-DHEA
conversion.
"This is the first study to demonstrate that the conversion of DHEAS to
DHEA is decreased in patients with rheumatoid arthritis as compared
with that in patients with osteoarthritis," noted leading contributor
Claudia Weidler.
*****
Funny how they name these things P this and that and when the drug gets
to the market, provided it makes it. It becomes some cool name.
Like,
Bezelebub juice
randall... finally possessed by being clear.
randall
If that last one didn't take the starch outa love, you need more
oxytocin. :)
What did that person say about vanity/fair and love and politics?
Right. Alls fair! And Olly olly in-come-free.
Next,
Lemming cream or for real P meds?
Topical cream that blocks cox-2 made from the ginseng root?
http://www.01sante.com/version-1/toutes_therapeutiques/images/ginseng.jpg
Hey! I loss my roots,
http://www.ginsengboard.com/ginseng%20plant%201.jpg
No wait. Their still there, under ground sucking up nutrients in mother
earth.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15914323&query_hl=1
Effect of ginsenoside Rb1 and compound K in chronic oxazolone-induced
mouse dermatitis.
Shin YW, Bae EA, Kim SS, Lee YC, Kim DH.
College of Pharmacy, Kyung Hee University, 1, Hoegi, Dongdaemun-ku,
Seoul 130-701, South Korea.
During the screening program to discover antipsoriatic agents from
natural products, ginseng was found to show inhibitory activity in
oxazolone-induced mouse ear dermatitis. Therefore, the effects of a
main constituent ginsenoside Rb1 isolated from ginseng and its
metabolite compound K on oxazolone-induced mouse ear dermatitis were
investigated. Compound K at concentrations of 0.02% and 0.05% also
potently suppressed mouse ear swelling by 54% and 76% at 16 days,
respectively, although ginsenoside Rb1 did not significantly show the
inhibitory activity. The compound K also significantly reduced the
levels of mRNA of cyclooxygenase (COX)-2, IL-1beta, TNF-alpha,
IFN-gamma and IL-4 increased in oxazolone-applied mouse ears. Based on
these findings, the compound K may improve contact dermatitis or
psoriasis by the regulation of COX-2 produced by macrophage cells and
interferon-gamma and IL-4 induced by Th cells.
PMID: 15914323
So, you get some ginseng and squeeze the ginsenoside Rb 1 outa it and
put that into a cream designed to only be used in the P plaque patch?
Bring it on.
http://www.iums.ac.ir/publications/journals/ijpt/v3n2/040302030.htm
And you could eat the rest of that nasty manly root for some
extracuricular activities?
And if that doesn't do it, it may have placebo effects. ;-0
Quick! Change my Qi, MAN!
http://www.quickchange.com/ginsengstore/
In case someone wants to grow their own. Figure on four years to 80
plus for the good stuff.
Know thy root,
http://www.ginsengboard.com/Know.htm
Here's a biz op, grow some for us to rub into our P patches,
http://corn.agronomy.wisc.edu/AlternativeCrops/Ginseng.htm
Move to marathon, wiscosin and find some real estate. Grow that stuff
and then beware of those willing to coPy your efforts with inferior
root,
http://www.jsonline.com/bym/news/may04/228350.asp
Hey this stuff is really cool! look,
(...)
Herbalists across China attribute near-mystical qualities to
Wisconsin's ginseng as a therapy for healing mind, body and spirit.
Doctors prescribe it for everything from chronic fatigue and diabetes
to daily stress, the flu, forgetfulness, hangovers and impotence.
The Chinese use Taoist philosophy to describe the difference between
Wisconsin's species of ginseng and the traditional Chinese and Korean
varieties: The human body, like the universe, is composed of opposing
natural forces - yin and yang - that eternally strive to balance one
another. Yin is darker, softer and cooler like night, and has the life
energy of a woman; yang represents brightness and hardness and has the
hot rush of masculine energy, according to Chinese medicine and
philosophy.
Wisconsin-grown ginseng provides the Chinese with a cooling yin tonic
that they cannot find in the hot yang grades from Korea or China.
Wisconsin root is also gentler and better-suited to older folks, who
constitute the biggest group of ginseng consumers as they strive to
push the boundaries of longevity.
(...)
"American ginseng grown in China is called 'China white,' and it's
considered by the Chinese as inferior," Beyfuss said. "That's why those
with fewer scruples label their product as 'Wisconsin ginseng' even if
they use Chinese-grown American ginseng, or Korean ginseng, or mix some
real Wisconsin root in with whatever else they could snap up on the
market."
(...)
With the Chinese becoming flush with US dollars this looks like a
golden oPPortunity.
http://www.explorewisconsin.com/countypages/marathon.html
http://www.gotginseng.com/About_Ginseng/about_ginseng.cfm
http://www.gotginseng.com/Finding_Wild_American_Ginseng_/finding_wild_american_ginseng_.cfm
http://attra.ncat.org/attra-pub/ginsgold.html
And if your into cheese. Your there dude.
<>CAVEAT EMpTOR (ginseng my screw up your CYP-450 liver enzymes and any
drugs you may be on. Either making the dosage more or less.... This
should be checked for any herb against any
meds your on... best to beware then DEAD)
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15898829&query_hl=2
Ok, lets yin and yang our way on to big pharma's answer to curing P.
This next abstract is some stuff to block the stuff right after the TNF
receptors?
And also cool tnf receptor- protein thingy,
http://www.hprd.org/interactor_map?selectedtab=TNF+Receptor+1
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15914319&query_hl=1
Effects of the kinase inhibitor CGP41251 (PKC 412) on lymphocyte
activation and TNF-alpha production.
Si MS, Reitz BA, Borie DC.
Transplantation Immunology Laboratory, Department of Cardiothoracic
Surgery, Stanford University School of Medicine, 300 Pasteur Drive,
Stanford, CA 94305-5407, United States.
CGP41251 is a serine/threonine and tyrosine kinase inhibitor that is a
novel anticancer agent. Because the kinases that CGP41251 inhibits play
important roles in T lymphocyte activation, we hypothesized that this
compound may have useful immunomodulatory properties. Here we
characterized the in vitro immunomodulatory effects of CGP41251. The
effects of CGP41251 on lymphocyte proliferation, expression of T cell
activation surface markers, and intracellular calcium response in
peripheral blood mononuclear cells (PBMC's) were measured.
Intracellular IL-2, TNF-alpha, IFN-gamma expression in CGP41251-treated
T cells stimulated by lectin was measured by flow cytometry. CGP41251
inhibited lectin-induced lymphocyte proliferation and upregulation of
activation surface markers with a 50% inhibitory concentration (IC(50))
of 0.1 muM. CGP41251, at micromolar concentrations, blunted the
intracellular calcium response during PBMC activation. CGP41251
inhibited TNF-alpha production by T cells with an IC(50) of 0.5 muM and
did not significantly inhibit the production of IL-2 or IFN-gamma. In
conclusion, CGP41251 potently inhibits T lymphocyte activation and
function and interferes with the proximal part of the T cell activation
pathway. The ability of CGP41251 to selectively block T cell TNF-alpha
production warrants the evaluation of this compound on other, e.g.,
monocyte, immune cells and in immunological conditions that are
characterized by high TNF-alpha levels such as psoriasis and
inflammatory bowel diseases.
PMID: 15914319
http://www.copewithcytokines.de/cope.cgi?008902
*****
And another anti-inflammatory,
Effect of chunghyuldan in chronic oxazolone-induced mouse dermatitis.
Wee SS, Shin YW, Bae EA, Kim DH.
College of Pharmacy, Kyung Hee University.
To evaluate the antipsoriatic effect of Chunghyuldan (CHD,
Daio-Orengedokuto in Japanese), which exhibited anti-inflammatory and
antiischemic actions, the inhibitory activity of CHD metabolized with
and without human intestinal microflora was investigated in
oxazolone-induced mouse ear dermatitis. The CHD and metabolized CHD
(MCHD) at concentrations of 0.1% also potently suppressed mouse ear
swelling by 52.7% and 63.2% at 16 d, respectively. The antipsoriatic
effect between CHD and MCHD was not significantly different, although
that of CHD weakly increased by the metabolism of human intestinal
microflora. Both CHD and MCHD also potently reduced the mRNA levels of
cyclooxygenase (COX)-2, interferon (IFN)-gamma and IL-4 increased in
oxazolone-applied mouse ears, but weakly inhibited that of IL-1beta and
TNF-alpha. Based on these findings, CHD may improve contact dermatitis
or psoriasis by the regulation of COX-2 produced by macrophage cells
and IFN-gamma and IL-4 produced by Th cells.
PMID: 15930749
But i can't figure out what this plant looks like.
randall...
randall
See if you sPot what I found funny.
http://www.nbc4.tv/health/4562786/detail.html
New Psoriasis Treatment May Be Cheaper, Better
A new treatment might be the solution that millions of people who
suffer from psoriasis have been waiting for.
Psoriasis can be crippling, NBC4's Dr. Bruce Hensel reported. Many
people who suffer pain and embarrassment all year long travel to tar
baths in the Middle East for treatment.
A new solution may be cheaper, better and produce fewer side effects.
For Kris Kaluger, choosing what to wear on warm days always presented a
challenge.
"You tend to wear longer pants, T-shirts, going to the gym, things like
that," Kaluger said. "I owned a lot of pants and a lot of long-sleeve
T-shirts.
<sniP>
For Kaluger, the psychological toll was even worse than the actual
condition.
"It can psychologically cripple you, it really can, it can beat you
down to the point where you do not leave your home," Kaluger said.
Up until now, treatments included creams, ultraviolet light and pills,
but those can damage the skin or internal organs.A new treatment
targets the problem at the source."These biologic agents target a
specific pathway in your immune system to inhibit psoriasis," Yamauchi
said. "It's much more safe, without the side effects associated with
the pills.
"Kaluger uses Raptiva, a once a week drug that blocks the cells that
activate psoriasis beneath the skin.
The drug is self-administered by injection. Kaluger says he was nervous
about giving himself shots at first but quickly got used to it.
After a month on Raptiva, Kaluger's psoriasis cleared up completely.
And one of the first things he did was buy a pair of shorts.
"I feel fantastic," Kaluger said. "I feel happy to (be) out here,
running, with shorts on.
"Raptiva is one of several recently approved biologic therapies on the
market. Ask your dermatologist which treatment is right for you.
*****
*****
Yeah for shorts!
HiP hiP hooray for raPtiva!
Boo for those tar baths!
I wonder if they suPPly feathers after you bathe?
randall...
randall
P News from around the world. Plus a little extra now and then.
http://www.wilmingtonstar.com/apps/pbcs.dll/article?AID=/20050606/ZNYT04/506060350/1004/LOCAL
(...)
"I was at the prime of my life and it's like a bomb fell on me," she
said.
The attack was the physiological equivalent of friendly fire. Ms. Perez
has lupus and hemolytic anemia. Both are autoimmune diseases, in which
the person's immune system, meant to defend against germs, instead
directs its fury against the person's own tissues.
There are at least 80 autoimmune diseases, ranging from familiar ones
like rheumatoid arthritis, psoriasis, multiple sclerosis and Type 1
diabetes to more obscure ones like pemphigus vulgaris. They affect 5 to
8 percent of the American population, or up to 23.5 million people, say
estimates from the National Institutes of Health. Patient advocacy
groups often give much higher estimates, and there is evidence that the
incidence of some of the diseases is increasing.
(...)
http://www.israel21c.org/bin/en.jsp?enDispWho=Articles%5El1009&enPage=BlankPage&enDisplay=view&enDispWhat=object&enVersion=0&enZone=Health
Foam, sweet foam.
There isn't anything quite like it for skin treatments. It gets the job
done, without the messy and sticky remains associated with creams,
lotions, ointments and gels.
Foams are also easy to use, easily spread and absorbed, and leave the
skin hydrated and nourished. With those choices, it's no surprise that
foam is quickly becoming the choice of topical application for
consumers and pharmaceutical companies alike.
While pharmaceutical giants worldwide recognize the value of foams and
mousses as a more efficient delivery system, most lack the expertise to
create foam for themselves. That's why Foamix, a small privately held
company in Israel, is currently surfing a wave of foam to success.
(...)
*****
This next one is,
A little off toPic, but higher levels of IL-10 would lower our Th1 skew
and
mean less TNF-alpha to have to block.
http://www.news-medical.net/?id=10727
In a presentation at the 2nd ESMO Scientific & Educational Conference
(ESEC) in Budapest, Hungary, Dr. Uwe Langsenlehner and colleagues from
Medical University Graz in Austria showed that a specific genetic
variation in a cytokine gene is associated with lower breast cancer
risk.
Cytokines are molecules that act as signals between cells. The authors
were examining the cytokine IL 10, which is involved in the development
of various tumors.
"In breast cancer risk, IL-10 may be a two-edged sword," Dr.
Langsenlehner said. "On one hand, higher IL-10 levels could facilitate
development of cancer by supporting tumor escape from the immune
response. On the other hand, the anti-angiogenic effects of IL-10 are
supposed to prevent or reduce tumor growth and spread."
Specifically, the Austrian team examined a particular genetic
arrangement, or haplotype, in the promoter region of the gene, which
has been associated with increased IL-10 expression. The researchers
call this the TCATA haplotype.
In a study comparing 500 women with breast cancer against 500 health
controls, they found that breast cancer patients were significantly
less likely to have two versions of the TCATA haplotype.
"Our study suggests that high levels of IL-10 may be protective against
breast cancer," Dr. Langsenlehner said. "The mechanism for this remains
to be determined, but may likely include anti-angiogenic functions of
IL-10. If this result can be confirmed in additional studies,
determination of IL 10 genotypes may help to obtain a more precise
individual breast cancer risk profile."
*******
How do the drugs of the future get made? Should I invest in this
company?
http://www.signonsandiego.com/uniontrib/20050603/news_1b3arena.html
(...)
"It's tough because investors don't care about your technology right
now. They're just concerned about results," Lief said. "But you can't
get good results unless you've got the technology to get the job done.
And this does not happen by magic."
Arena focuses solely on G-protein coupled receptors, or GPCRs, a large
family of proteins in the body that are involved in virtually every
biological process, from memory to blood pressure regulation and
metabolism. There are more than 500 such receptors.
The receptors respond to signals from the body or the environment and
tell cells how to respond, Dan Connelly, the company's director of
biology, explained. For example, GPCRs tell the cells whether to
release insulin from the pancreas, a process that doesn't work properly
in people with diabetes.
The company selects key biological processes, like those involved in
diabetes or obesity, and then identifies the receptors that regulate
them. It then tries to discover small-molecule drugs that are able to
modulate the processes.
The company developed tests that allow it to screen about 200,000
molecules an hour, Connolly said. The test signals success by turning a
darker or lighter color, a scientific process borrowed from the skin of
a frog that turns different colors in different light.
Arena has used this technology to narrow the candidates in its pipeline
and do extensive preclinical work on drug candidates, said Noah, the
analyst. Rather than rush to try the therapies on humans, the company
seems to take great pains to first do a lot of testing on animals and
collect reams of data about efficacy and side effects, he said.
Lief said he thinks what sets Arena apart from other companies is its
ability to choose compounds that are selective, meaning they hit the
receptor they need to and not others. Hitting unwanted receptors can
cause side effects.
"Historically, compounds are nonselective. It is like using a blowtorch
to treat something when what you really want is a finely sharpened
scalpel," Lief said.
For instance, the company's obesity compound hits a receptor in the
brain that affects a feeling of fullness after meals. It is the same
receptor that was targeted by the diet drug combination fen-phen, which
was very popular in the 1990s. The problem was that fen-phen hit a
second receptor located in the heart and caused cardiac problems.
Noah, the Granite analyst, said he thinks that because of the scare
from fen-phen, concerns about serious side effects from Arena's drug
are already factored into share prices. Arena shares closed at $6.54
yesterday, giving the company a total stock valuation of $230.6
million.
(...)
****
What are small molecules?
http://www.genpromag.com/ShowPR.aspx?PUBCODE=018&ACCT=1800000100&ISSUE=0502&RELTYPE=PR&ORIGRELTYPE=CVS&PRODCODE=00000000&PRODLETT=L
&
http://www.netsci.org/Science/Compchem/feature14h.html
Group background,
http://groups-beta.google.com/groups?q=gpcrs+psoriasis&qt_s=Search
****
I liked this page so here it is,
Anti-ros
http://www.sigmaaldrich.com/Area_of_Interest/Biochemicals/Enzyme_Explorer/Cell_Signaling_Enzymes/Superoxide_Dismutase.html
***
And for those of you that wonder where I believe a possible cure for
autoimmune
conditions may reside. This next one is right up your colon. As I've
had luck with
the proflora whey routine to grow out good gut flora, I can't help but
think that science
will make some inroads, eventually.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15932503&query_hl=3
New Lactobacillus acidophilus isolates reduce the release of leptin by
murine adipocytes leading to lower interferon-gamma production.
Bleau C, Lamontagne L, Savard R.
Departement des Sciences Biologiques, Universite du Quebec a Montreal,
Montreal, Quebec, Canada.
Summary Leptin produced by adipocytes increases Th1-dependent
immunostimulation and autoimmune diseases. Lactobacilli are known to
promote or suppress Th1 responses according to the isolates. We have
investigated whether the sensitivity of Suriss Jim Lambert (SJL) mice
to Th1-dependent immune diseases, when compared with C57BL/6 mice, may
be modulated by selected lactobacilli able to decrease leptin release
by adipocytes. White adipocytes were isolated from both C57BL/6 and SJL
mice and incubated with bacterial extracts from new CBA4P and TPA3P
isolates of Lactobacillus acidophilus and L. rhamnosus 9595 (LR), or
with conditioned media (CM) from lactobacillus-treated macrophages.
Immunomodulation induced by supernatants of treated adipocytes was
determined by metabolic activity of syngenic splenic lymphocytes.
Leptin produced by adipocytes, tumour necrosis factor (TNF)-alpha and
interleukin (IL)-1beta by macrophages, and IFN-gamma and IL-4 by
lymphocytes were quantified by enzyme-linked immunosorbent assay
(ELISA) tests. Results revealed that supernatants from CBA4P- and
LR-treated adipocytes decreased the metabolic activity of lymphocytes
from SJL mice, whereas adipocytes incubated with CM from CBA4P-treated
macrophages showed no stimulation of lymphocytes. Such effects
correlated with leptin levels. Lower levels of leptin were produced by
adipocytes from SJL mice in the presence of CBA4P and LR extracts.
Lymphocytes from SJL mice produced low levels of IFN-gamma when
incubated with supernatants from CBA4P-treated cells. Such
immunosuppressive effects were dependent on levels of TNF-alpha and
IL-1beta produced by lactobacillus-treated macrophages. Taken together,
these results suggest that the CBA4P isolate reduces levels of leptin
in SJL mice, leading to lower IFN-gamma production. Therefore, the
CBA4P isolate of L. acidophilus is a promising new probiotic strain for
the control of Th1 inflammatory diseases.
PMID: 15932503
******
And the good think is you can have a new slightly acidic colon in less
then a month.
And be doing it yourself, no medicine just food suPPlements, you beam
with pride
that you can control the gut denizens that indirectly control you.
If you have a sweet tooth, it may not be the oral cavity dictating that
craving.
The flora inside the Gi tract may be sending signals to your brains.
YIKES!
So get with it already. If you think for two seconds that alkalinity
has anything
to do with something health wise, then start with changeing it in your
colon.
randall....
Fizziwig2
"variation in a cytokine gene is associated with lower breast cancer risk"
Twenty years or so ago it was mentioned on a "Tomorrows World" (a BBC tv
programme) that Psoriasis sufferers were less likely to get breast cancer -
according to current research at the time.
Skeats
"randall" <ranh...@aol.com> wrote in message
news:1118072722....@g43g2000cwa.googlegroups.com...
randall
I'm all for saving the Breasts! And the rest of the package that goes
with em. EsPecially the curvy hiPs,
http://news.google.com/news?q=curvy%20hips&hl=en&lr=&sa=N&tab=gn
It makes sense. High TNF-alpha levels mean less tumours. TNF (Tumor
necrosis
factor) eats tumors. Since we have to much TNF we have less cancer.
Lady Andy posted the first exlnt paper on it in this group. This may be
it,
(you have to go about 65% of the way down the page to get to the meat)
http://www.signalsmag.com/signalsmag.nsf/657b06742b5748e888256570005cba01/59d864e70a7d28db88256b020013fa6b?OpenDocument&Highlight=0,tnf
Or was it,
http://www.signalsmag.com/signalsmag.nsf/0/1F7CC7BB37E6D89C88256CD3001A92AD
Well, one of these,
http://groups-beta.google.com/groups?q=signals+magazine&qt_s=Search&enc_author=lGf0thcAAAB_ICtCdboV5Lpy7-tCSMv4Xwmjf647Ff9pzzml4Om-hQ
I hope she finds her way back here again. :)
Nevertheless, thats where this idea of Th1 (T helper one cells) gets
its history.
These cytokines and chemokines may be small molecules. But their
powerful. And getting it just right is an art our derms are only now
learning.
We all need to be patient as we all have different levels of TNF-alpha
and
some of us simply don't respond at all to the biologicals.
P being a situation where the body primes and churns out activated TH1
cells and thus TNF, means your possibly less likely to get cancer, a
th2 driven situation.
Then again, agressive treatment with biologicals which block/bind/halt
TNF may
turn that around.
Plus the meds for P generally being potent. They can induce other
adverse effects.
http://groups-beta.google.com/groups?q=iatrogenics%20database%20psoriasis&hl=en&lr=&sa=N&tab=wg
Anyway building on the info thats reported in the BBC and other news
outlets
helps to understand the path of the P pathways.
Now, if we can get some gut flora that pumPs out those exact small
molecules
that makes this thing go away!!
That will be a fine day.
And worth waiting for.
Untill then,
randall... :) in the rays
I
randall
Thanks again skeats for your comments. I'm like those primed Th1 cells.
Since we're talking about TNF, curvy hiPs and other cool things.
It doesn't take much and the cascade goes over the toP!!
Lets go find the genes that go with them! TNF not hips. ;-)
Here's one that came out last week from the UK, in pubmed. But it seems
to connect
with other auto- immune questions and less directly with psoriasis.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15934099&query_hl=2
Association between the PTPN22 gene and rheumatoid arthritis and
juvenile idiopathic arthritis in a UK population: Further support that
PTPN22 is an autoimmunity gene.
Hinks A, Barton A, John S, Bruce I, Hawkins C, Griffiths CE, Donn R,
Thomson W, Silman A, Worthington J.
University of Manchester, Manchester, UK.
OBJECTIVE: The protein tyrosine phosphatase N22 (PTPN22) gene exhibits
regulatory activities for both T cells and B cells. A missense
single-nucleotide polymorphism (SNP) within this gene (rs2476601) has
recently been associated with 4 autoimmune diseases: rheumatoid
arthritis (RA), systemic lupus erythematosus, autoimmune thyroid
disease, and type 1 diabetes mellitus, all of which are T cell-mediated
and associated with the elaboration of autoantibody. The aim of this
study was to investigate associations of the missense SNP of PTPN22 in
a number of autoimmune diseases in the UK population, including RA,
juvenile idiopathic arthritis (JIA), psoriasis, psoriatic arthritis
(PsA), and multiple sclerosis (MS), some of which have not been
examined previously. METHODS: The PTPN22 missense SNP was genotyped in
886 RA, 661 JIA, 279 psoriasis, 455 PsA, and 379 MS patients and in 595
healthy controls. Association with the PTPN22 SNP was analyzed by
chi-square test as implemented in Stata software. RESULTS: There was a
significant association between the PTPN22 SNP and RA (P = 1.8 x
10(-8)) and JIA (P = 0.0005). In contrast, no association with
psoriasis, PsA, or MS was detected. CONCLUSION: We replicated the
findings of a previous association with RA and identified a novel
association with JIA. Together with previous data showing associations
with other autoimmune diseases, our findings provide further evidence
that the PTPN22 gene plays a role in the pathogenesis of a subgroup of
autoimmune diseases.
PMID: 15934099
This gene is really getting looked at recently, (13 studies in last few
months)
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Display&dopt=pubmed_pubmed&from_uid=15934099
Ok, so whats in the groups?
http://groups-beta.google.com/groups?q=PTPN22&qt_s=Search
Wouldn't you know. <g>
And what does PTPN22 do?
http://www.dsi.univ-paris5.fr/genatlas/fiche1.php?symbol=PTPN22
(...)
Basic function:
# tyrosine phosphatase, non receptor, involved in regulation of the
function of protooncogene CBL in the T-cell receptor signaling pathway
# playing a role in regulating the immune system and the development
of the autoimmunity
Running entrez is the fatest way to understand a gene, or protein etc
http://www.ncbi.nlm.nih.gov/gquery/gquery.fcgi?term=PTPN22
Some of you wonder how I churn these things out so fast. That last
one is the secret. That and some creativity and you can really get
to the maker's plan fast.
And now you have more info then you can grasP.
Try keyword P, then TNF plus whatever. Er, LPS for grins.
I just did it but didn't take time to look at any of it. I can imagine
it would be a huge review of everything i've posted here.
Sorry for that little segue, but some of you think i know something.
lol
I can hardly take credit for the real hero's. Those folks on the front
lines
of research....
And back to PTPN22, one easily finds a diabetes type one correlation,
http://www.google.com/search?hl=en&lr=&q=PTPN22+diabetes+type+&btnG=Search
Particulary among all the groups of humans that don't get P.
Oh Well it does tell and show a few more pieces of the Puzzle.
randall...immunity, its an itch! Till Th0 days roll around anywhey!
randall
P news from around the world and in your backyards.
Beware of quacks bearing needles(s) meds,
http://news.scotsman.com/latest.cfm?id=4658556
You can't eat your choP suey and sue him today? Without his bolting
for the high road to china?
Talk about a blunt needle and bad aPProach.
***
Speaking of china.
http://www.biotecheast.com/modules.php?op=modload&name=News&file=article&sid=942&topic=2
Taipei-based drug discovery company AbGenomics Corporation announced
Monday that it had licensed its antibody 168 to German pharmaceutical
company Boehringer Ingelheim International GmbH. The two companies held
a signing ceremony to mark the occasion in Taipei.
(...)
"Discovered by AbGenomics, AB168 is a promising drug candidate.
Together with Boehringer Ingelheim's expertise in biotech R&D and
manufacturing, I'm sure that this relationship will be mutually
beneficial to both companies," said Wilgenbus. "We consider this kind
of partnership-with smaller biotech companies-an important part of
our drug development pipeline."
(...)
I wonder what it does for P? Let's see,
http://www.abgenomics.com/technology/technology.htm
Ok,
http://www.abgenomics.com/Antibody168/Antibody168.htm
Ok, got it. It's a mab.
At pubmed.com using keywords: Monoclonal Antibody
There are an astounding 167,908 hits!
Add in keyword: psoriasis
And there are 672 hits.
Thats a lot of mab. See yesterdays p news for what they do.
Those signal magazine pages clearly explain them.
*****
How about a garlic cream rich in sulfur from Dr. Gruenwald in Kuala
Lumpur?
Isn't that where these towers are?
http://www.globalgeografia.com/album/malaysia/kuala_lumpur.jpg
The link says so. I have to go see these some time.
Back to the cream,
http://www.nst.com.my/Current_News/NST/Tuesday/BodySoul/20050606164035/Article/indexb_html
(...)
Dr Gruenwald and his team of researchers have also conducted studies
with great success using allicin (in the form of liquid, powder and
cream) on some problem bacteria, such as the staphylococcus aureus,
salmonella typhimurium, escherichia coli 0157 and helicobacter pylori.
The staphylococcus aureus is involved in 95 per cent of eczema cases.
It causes secondary infection in these cases and prevents topical
steroids from working. This bacteria is also present in most cases of
acne and in psoriasis. The allicin kills the bacteria.
The Allisure cream, as it is called, is also effective in healing bed
sores.
The allicin used for the Bio-Allisure supplement is extracted from
garlic grown in China, Egypt and Spain. This is because the allicin
level is higher when the garlic is grown in hot, dry conditions.
Dr Gruenwald is also the president of Phytopharm Consulting, a business
consulting company for herbal medicine, dietary supplements and
functional foods, and the chief scientific officer of InQpharm Natural
Synergies which has an office in Kuala Lumpur.
He is a leading figure in nutraceuticals and has under his belt more
than 180 scientific publications in the field of phytotherapy, dietary
supplements, cardiovascular disease and arteriosclerosis.
InQpharm's chief medical officer Dr Christof Jaenicke, who was also
present at the Bio-Allisure launch, spoke of how allicin can be used
topically. "It has a light, lovely smell. If you have bacteria on the
skin, it will knock off the staph. aureus."
According to him, you cannot overdose on Bio-Allisure. "You can take
9,500 capsules a day and you will still be alive!"
You can also give it to children.
(...)
Or you can give it uP! And eat it fresh.
***
If you P acts like acne or some other atopic condition it may do
something. I'd rather eat my garlic with shrimP.
I'll find my favorite shrimP dish,
http://www.cdkitchen.com/recipes/recs/435/Gambas_al_Ajillo_Garlic_Shrimp47472.shtml
Nope that isn't quite it. I like mine outa the pan with a baguette to
diP uP the luscious pan liquor.
Here it is,
http://www.post-gazette.com/food/20000810spanish1a.asp
Wait. Does this one have some italian parsley? And i like about three
heads of garlic in
chunks. You can smush them some to release the good stuff, about twenty
minutes prior to cooking. So prepare the garlic prior to letting the
shrimp go towards room temP. And they'll both hit the oil perfectly
ready for cooking.
YummmmO!
I know whats cooking in my kitchen to-nite.
If you lean toward the vegetarian venue. You could bake the garlic
heads
and squeeze them out onto that baguette and do some salad on the side.
Then rub the garlic on you and have a party.
*****
http://www.newswire.ca/en/releases/archive/June2005/07/c8576.html
(...)
Funds will be used to finance the company's
R&D, including formal preclinical development of its WBI-1001 compound
against
psoriasis.
(...)
http://www.welichem.com/disease.asp
*****
randall...choP choP i'm off to the shrimP store! Got the Point!
randall
Whaz uP with the P viral thing?
http://photos1.blogger.com/img/198/1552/640/parisvirus.jpg
Being the right gender you may not have any problems with that
exPosure.
Howard huge medical and viral hide and seek,
http://www.hhmi.org//news/ganem3.html
(...)
Sullivan soon found the target of the plentiful SV40 microRNA. It
effectively targeted the messenger RNA for a protein known as T
antigen, leading to its cleavage. "SV40 may be the world's most
studied virus," Sullivan said, "and T antigen is its most studied
part."
When SV40 enters a cell, it produces T antigen, which functions to
trigger viral DNA replication. Unfortunately for the virus, T antigen
also serves as a target for immune (T) cells, which can destroy
infected cells and prevent the virus from spreading.
Conveniently, the microRNA that targets T antigen is made late in the
infectious cycle, just when T antigen is no longer essential for virus
replication. Further experiments showed that cytotoxic immune cells
were more likely to kill cells infected with a mutant virus that cannot
make the microRNA than the normal virus. Thus, microRNA-induced
reductions in T antigen expression promote escape from antiviral T
cells without affecting virus growth.
"Viruses can use the host RNA inference machinery, which is often
speculated to have evolved as an antiviral mechanism, to generate small
RNAs that serve their own purposes - the latest chapter in the long
cat-and-mouse game known to virologists as host-virus coevolution,"
the researchers conclude in their Nature article.
(So these viral dudes can be sneaky little pests! But are they in a P
pathway? That
will come in time. And you can search the group. KW- virus psoriasis )
Or use the one uP above.
******
HLA & P from a
http://news.biocompare.com/newsstory.asp?id=82608
The great physical diversity that evolution has forged in human beings
is in evidence wherever we look, but the genes exhibiting the greatest
diversity at the DNA level happen to function in a wholly invisible
process: immunity. Genes encoding the Human Leukocyte Antigen (HLA)
proteins are among the most diverse in the human genome, and scientists
have proposed a number of hypotheses to explain why. This week,
researchers report new findings that support the idea that the striking
diversity of HLA genotypes in humans is shaped to a significant degree
by the different sets of pathogenic species encountered by different
human populations around the world.
The findings are reported in the June 7 issue of Current Biology by Dr.
Franck Prugnolle and colleagues at the University of Cambridge.
HLA class I proteins are critical players in the recognition of
antigens--bits of foreign protein derived from invading pathogens--and
in the presentation of the antigens on the surfaces of cells. HLA
proteins and the antigens they present are recognized by specialized
immune cells, resulting in immune responses that combat disease. But
why should HLA genes be so diverse? Numerous factors could contribute,
but a leading idea has been that pathogens themselves play a role. Past
work had offered clues to this effect--for example, individuals with
some HLA genotypes are more susceptible (or more resistant) to some
pathogens than others. If different versions of HLA proteins can
influence how the immune system deals with a particular pathogen, it
follows that, in theory, HLA genes should evolve to deal most
effectively with the various antigens humans encounter.
This kind of evolution, leading to diverse HLA genotypes in which
individuals possess two different versions, or alleles, of the various
HLA genes, forms the basis for the idea of "pathogen-driven balancing
selection," or PDBS.
In their new work, the researchers set out to test the PDBS hypothesis
by analyzing HLA sequences from 61 native human populations worldwide
and comparing the degree of HLA diversity to the number of different
pathogens known to be present in each population's geographic region.
Because other factors, such as a population's migratory history, could
influence genetic diversity in a general way, the authors also compared
HLA diversity with the general genetic diversity expected for the
population's location (this research group previously showed close
correlation between diversity and location along ancient colonization
routes).
The authors found that although human colonization history accounted
for a certain degree of HLA diversity (as it does for other genes as
well), the "local" richness of pathogen diversity also correlated
significantly with the HLA diversity exhibited by individual
populations, supporting the PDBS hypothesis. High HLA diversity tended
to correlate with high pathogen diversity. In addition, the authors
found that this correlation was especially strong for a particular type
of HLA gene, HLA B. This finding is in agreement with past
immunological and genetic studies showing that not all HLA class I
proteins play identical roles and suggesting that pathogens--notably,
viruses--may exert stronger evolutionary pressure on HLA B than on
other HLA genes
HLA II and P,
With over 1000 hits on pubmed this is the most recent,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15908298&query_hl=6
It could be going in the right direction. I hope so anyway. And if its
a gene thing then surely HLA and MHC will be in there somewhere.
*****
If it not be viral and due to bacteria and that could be from the cell
wall of
endotoxins (aka- LPS) , then where do we find the critical P pathways?
Lets tackle the biggest question for humans on dirt ball earth.
Escuse me, but wouldn't these bacteria solve the energy problems?
http://news.biocompare.com/newsstory.asp?id=82590
(...)
Some of these bacteria produce methane that accumulates in "gas
hydrates" - a super concentrated methane ice that contains more
carbon than all conventional fossil fuels and, therefore, a potentially
enormous energy source. However, we know little about gas hydrates as
they melt during recovery due to the fall in pressure.
(...)
"DNA analysis of deep sediments has shown diverse bacterial
populations, including major new types, but we have been unable to
culture them and this might be because we have not been able to keep
them at the very high pressures which they need to survive," said
Professor Parkes.
(...)
(You may not do well living on the moon. Poor little ancient bacteria
forced to live in an alien enviroment. Whoa nellie, check out this next
part. SPeaking of aliens.)
As well as studying potentially the deepest organisms on Earth this
research might also throw light on the mystery of the Bermuda Triangle
by finding out more about the behaviour of the mysterious hydrates.
One theory now suggests that when the covering of "methane ice" which
exists over much of the seabed of the Bermuda Triangle becomes
unstable; this causes instability of the sea and an explosive mixture
of air and methane above. Any ships or planes travelling over the area
could sink or catch fire.
"So ancient, deep-sediment bacteria may be a key to sustainable energy
in the future and to explaining a few disasters," said Professor
Parkes.
(The answer is out there. Or right inside of you and the out there came
into you
a zillion years ago.)
****
So Duh, dudes! This planet had to figure out how to make us long before
we were able to wiPe our own behinds.
****
Prions. Weird bent proteins that may or not do very bad things,
http://www.nih.gov/news/pr/jun2005/niaid-02.htm
*****
What haPPens when stem cells have sex?
http://www.sciencedaily.com/releases/2005/05/050520172757.htm
(...)
Rothman explained that cell fusion is analogous to the melding of soap
bubbles, and the process is involved in creating many of our organs,
including muscles, bones, and placentas. "When a cell fuses with
others, it loses its individuality," said Rothman. "But it can also
adopt a new career, either productive, as when stem cells regenerate
organs, or sinister, as in cancer metastasis."
Fusion is the process that allows a sperm to fertilize an egg; it also
allows a cancer cell to join with a normal cell. The discovery by
Rothman and his co-authors reveals that the inappropriate joining of
cells by fusion is naturally prevented by a familiar protein, called
vacuolar ATPase, acting in an entirely unanticipated context. The
discovery suggests new avenues for pharmaceutical companies to develop
drugs to enhance organ regeneration by stem cells, prevent cancer
progression, and control fertility.
The protein, vacuolar ATPase, was already known to make certain
compartments inside a cell become more acidic, an essential function in
cell biology. Now it is understood that the protein also works on the
surface of the cell to prevent cell fusion. "The protein is in an
unexpected place, doing an unexpected job," said Rothman. "This finding
might make it possible to develop new methods, and new drugs, for
controlling cell fusion."
Rothman studies the nematode worm C. elegans as a model organism. His
research group looks at genetic mutations to see what effect they
cause. From that information they can determine which genes are
involved in certain biological processes. The mutation they found in
this discovery is one that causes a large number of cells to fuse with
each other. Normally these cells would not fuse.
He describes his approach in working with worm mutations as similar to
figuring out how a machine, such as a car, is put together. "It's as if
we reach in and remove a part of the car and then try to drive it, to
see if it still works," said Rothman. "We pull out the radio and the
car still works fine. But when we take off a wheel, the car doesn't
move straight at all. We take out the brakes and everything is fine
until you have to stop."
A few years ago a protein that allows for cell fusion, called EFF-1,
was discovered by other laboratories using similar strategies,
explained Rothman. The new discovery makes known a protein that
prevents cell fusion from happening inappropriately. "It's as if we now
have a yin and yang of cell fusion," he said.
*****
Whoops my shrimP are ready. And to think that this one is going out
un-edited.
randall... some things are more imPortant then P....
randall
Raisin d'etre,
http://www.forbes.com/lifestyle/health/feeds/hscout/2005/06/08/hscout526141.html
(,,,)
Wu's study, funded by the California Raisin Marketing Board, found that
raisins are particularly high in a plant-based compound called
oleanolic acid, which inhibited two species of cavity- and
plaque-causing bacteria in lab analyses that her team performed.
But oral health experts don't expect dentists to start handing out
packets of raisins to their patients anytime soon.
"Raisins (due to their high sugar concentration) are among the most
cavity-promoting foods we have ever encountered," asserted William H.
Bowen, a professor of dentistry, microbiology & immunology and
environmental medicine at the University of Rochester School of
Medicine & Dentistry.
"So no matter what beneficial agents are in there, they're obviously
not sufficient to overcome the harmful effects of the raisins to
promoting cavities," he added.
Bruce J. Paster, senior staff member and professor in the department of
oral and developmental biology at The Forsyth Institute at Harvard
University's School of Dental Medicine, urged caution in interpreting
the findings. "Although the results are promising," he said, "you would
need a study to show that eating raisins reduced cavities and/or gum
disease."
Tooth decay occurs when foods containing sugars and starches are
frequently left on the teeth, according to the American Dental
Association. Bacteria in the mouth feed on these substances, producing
acid that can destroy tooth enamel. Plaque is the sticky film of
bacteria on teeth that can cause the enamel to break down and cause
cavities unless it is removed by regular brushing and flossing.
Using chemical analyses, Wu and her colleagues found raisins may not be
the dental demons they're made out to be. The team identified five
specific compounds in Thompson seedless raisins that are known
"phytochemicals," or plant-based substances that protect against human
disease.
One of the most powerful is oleanolic acid. At a concentration of 31
micrograms per milliliter, this substance prevented the bacteria
Streptococcus mutans, a major cause of cavities, from adhering to tooth
surfaces. At 62 micrograms per milliliter, it inhibited growth of
Porphyromonas gingivalis, a leading cause of periodontal disease, the
study found.
(...)
******
I don't know about you. But i'm thinking that raisins may be helping to
move the oral lps into the gut for translocation once in the small
intestines. May explain trigger effects that I've noticed over the
years.
Yet at non flarish times of year i can eat them without problems.
Lets see what the exPerts on this group have to say,
http://groups-beta.google.com/groups?hl=en&q=raisins+psoriasis&qt_s=Search
Well I only read a few and arginine and iron pop right uP for me.
Soaking them in Gin and actually eating them would seem to be a double
negative and surely aggravate the skin.
Mine anyway. But a hell of a test to try out, should you need a reason.
*****
Yet who am I to say your tests won't show the oPPosite. I'm going to
cocktail them with this next one. ;-)
A Red Delicious aPPle a day keeps the oxidants away,
http://www.sciencedaily.com/releases/2005/05/050523234141.htm
(...)
Researchers have long known that apples are a good source of
antioxidants, a group of chemicals that scavenge and neutralize
unstable molecules called free radicals. Free radicals, which can wreak
havoc on cells and tissues, appear to play a role in the onset of heart
disease and prostate, colon and other cancers.
Polyphenols ? phytochemicals that act like astringents ? are major
sources of antioxidants in apples, but which polyphenols are most
active in the fruit has perplexed scientists. Tsao and his colleagues
used three different laboratory measures to evaluate polyphenol
activity in apples that are popular in Canada: Red Delicious, McIntosh,
Cortland, Northern Spy, Ida Red, Golden Delicious, Mutsu and Empire
apples. However, the researchers did not include a number of other
apples popular in the United States including Gala, Granny Smith,
Jonathan, York, Stayman and Rome. All of the apples used in the study
were grown on the same farm under similar conditions.
The researchers found:
* Polyphenols were five times more prevalent in the skin than the
flesh of the apples.
* Two polyphenols, epicatechin and procyanidin B2, were the greatest
contributors to total antioxidant activity of the apples. Procyanidins
accounted for about 60 percent of the antioxidant activity in the peel
and 56 percent in the flesh.
(...)
(APPles, raisins and thou under the bough... whoops forgot the
wine/bread)
*****
Time to go find a nice dark red delicious aPPle. Waiting in the frig
for me.
Darn the thing is rotten around the core. Wouldn't you know it.
I may as well eat as much of the skin as possible. I wonder if i have
some
raisins in there?
YeP. And in the time it took to find them and usher some into the oral
cavity.
The apple is turning brown quickly. No wonder the skin has the anti-ros
stuff in it. Otherwise you'd have to make apple sauce every time you
bought them. And if you do, avoid the cinnamon, as it does flare you.
If your like me.
*****
And the piece de resistance,
some HA to cool the P plaques. And <SAVE THE BREASTS>!
http://www.sciencedaily.com/releases/2005/05/050520171743.htm
(...)
The research appears as the "Paper of the Week" in the May 27 issue of
the Journal of Biological Chemistry, an American Society for
Biochemistry and Molecular Biology journal.
Multidrug resistance is very common in most types of cancers, making
it one of the leading problems in cancer therapy. It is often caused by
an increase in the cell's production of proteins that transport drugs
out of the cell, preventing the drugs from combating cancer.
Previously, Dr. Bryan P. Toole and his coworkers, Drs. Suniti Misra
and Shibnath Ghatak, of the Medical University of South Carolina
noticed that small pieces, or oligomers, of a polysaccharide called
hyaluronan were able to sensitize drug-resistant breast cancer cells to
several different chemotherapeutic drugs. He believed that the
polysaccharide oligomers were binding to a receptor for hyaluronan
(called CD44) and preventing it from initiating a signaling cascade
that would result in drug resistance.
"It is very surprising that hyaluronan is involved in drug
resistance," admits Dr. Toole. "Most scientists think of hyaluronan as
a structural and inert molecule. In adult tissues it plays two roles.
First, it assists in tissue hydration and in biophysical properties
such as resilience. Second, it forms a template to which matrix
proteins attach and form important extracellular structural complexes."
(...)
*****
Who would have thought that drug-resistant breast cells would have
lead to this discovery?
Oh well, two birds with on stone.
And once the P genes are found, they can take care of the women without
the BIG O genes,<>
http://www.newscientist.com/article.ns?id=dn7481
*****
randall.... I knew SC would like that last one.
randall
Some drugs are good drugs that go bad. Side effect wise.
We've seen many of those the last few years, due to the time
it takes for the whole story to unfold.
But what if the risk benefits ratio is so great and those nasty side
effects can be
dealt with?
Don't we all do that with our decisions when it comes to which
treatment/drugs?
It comes down to choice and with full knowledge of rare side effects,
don't
you want the oPtions?
But if 2 people outa 2 million drop dead, can a way be found to help
them?
http://www.rednova.com/news/health/155121/case_offers_hope_ms_drug_could_return_to_market/
Case Offers Hope MS Drug Could Return to Market
The future of a revolutionary treatment for multiple sclerosis may
hinge on a single patient who survived a rare but potentially fatal
side effect that wreaks havoc in the brain, doctors report today.
The drug, Tysabri, was pulled from the market in February by its maker,
Biogen Idec and Elan Corp., after two patients died of a brain disease
seen mostly in AIDS patients. That a patient survived suggests that,
with early diagnosis and treatment, doctors may be able to avert brain
damage in Tysabri patients, salvaging the drug for those who need it.
"Stopping therapy may prevent the disease," says Burt Adelman, vice
president of drug development for Biogen. He says the firm hopes to
find an approach to Tsyabri therapy that will protect patients and
bring the drug back to market.
Doctors feared that the Tysabri disaster could derail a new generation
of drugs that represent medicine's best hope of treating autoimmune
diseases.
"There are huge implications," says Igor Koralnik, director of the
HIV/Neurology Center at Boston's Beth Israel Deaconess Medical Center.
"These drugs are the wave of the future to treat conditions as diverse
as asthma, psoriasis, rheumatoid arthritis, Crohn's disease, multiple
sclerosis and other autoimmune diseases."
The drugs are clever knock-offs of natural infection-fighters called
antibodies. The man-made versions target immune system or cancer cells
that cause disease. Tysabri attacks renegade white blood cells that
damage nerves in patients with multiple sclerosis.
(...)
I don't know what this stock did, but i bet it made someone money on
the
rebound. :)
See! some rebounds aren't bad things. ;-)
*****
Its a skin biz! But will folks get skinned again?
Older and mellower with a considerably thicker skin . . .
(Filed: 11/06/2005)
The founder of collapsed dermatology company Bioglan is back in
business and unbowed by its demise. But this this time he's more
subdued, writes Rosie Murray-West
(...)
The company has bought a spun-out business from Sheffield University
that is developing treatments for eczema and psoriasis, but when it
floated it only had the rights to one product, and the patent on it ran
out before York planned to launch it.
The whole premise might sound a bit flaky to you, but Sadler, who has
been obsessed by skincare since his early days as a drug salesman, can
happily talk skin for hours.
(...)
I like the way this guy sounds! He's a Brit with wit! Will he see the
toP again?
*****
On to pubmed time. Not much there. But what is deals with P genes. So
lets take a look.
If you read this first post, in this next link, from the NPF regarding
VEGF you'll understand this recent pubmed abstract a little better,
http://groups-beta.google.com/groups?q=VEGF+psoriasis&qt_s=Search
Human Mast Cells Express Corticotropin-Releasing Hormone (CRH)
Receptors and CRH Leads to Selective Secretion of Vascular Endothelial
Growth Factor.
Cao J, Papadopoulou N, Kempuraj D, Boucher WS, Sugimoto K, Cetrulo CL,
Theoharides TC.
Departments of Biochemistry and Pharmacology and Experimental
Therapeutics, Tufts University School of Medicine, and Departments of
Obstetrics and Gynecology and Internal Medicine, Tufts-New England
Medical Center, Boston, MA 02111.
Mast cells are critical for allergic reactions, but also for innate or
acquired immunity and inflammatory conditions that worsen by stress.
Corticotropin-releasing hormone (CRH), which activates the
hypothalamic-pituitary-adrenal axis under stress, also has
proinflammatory peripheral effects possibly through mast cells. We
investigated the expression of CRH receptors and the effects of CRH in
the human leukemic mast cell (HMC-1) line and human umbilical cord
blood-derived mast cells. We detected mRNA for CRH-R1alpha, 1beta, 1c,
1e, 1f isoforms, as well as CRH-R1 protein in both cell types.
CRH-R2alpha (but not R2beta or R2gamma) mRNA and protein were present
only in human cord blood-derived mast cells. CRH increased cAMP and
induced secretion of vascular endothelial growth factor (VEGF) without
tryptase, histamine, IL-6, IL-8, or TNF-alpha release. The effects were
blocked by the CRH-R1 antagonist antalarmin, but not the CRH-R2
antagonist astressin 2B. CRH-stimulated VEGF production was mediated
through activation of adenylate cyclase and increased cAMP, as
evidenced by the fact that the effect of CRH was mimicked by the direct
adenylate cyclase activator forskolin and the cell-permeable cAMP
analog 8-bromo-cAMP, whereas it was abolished by the adenylate cyclase
inhibitor SQ22536. This is the first evidence that mast cells express
functional CRH receptors and that CRH can induce VEGF secretion
selectively. CRH-induced mast cell-derived VEGF could, therefore, be
involved in chronic inflammatory conditions associated with increased
VEGF, such as arthritis or psoriasis, both of which worsen by stress.
PMID: 15944267
And as stated many many times, angiogenic factors have broad
imPlications for cancer and psoriasis,
http://www.biocarta.com/pathfiles/h_vegfPathway.asp
http://www.gene.com/gene/research/focusareas/vascular/
And with all the research in these areas inflammatory chronic
conditions
are slowly being figured out.
Well, fast if you think in earth time. It took billions of years to
make us and now
we're looking at the plans closer and closer.
&&&&&&&&&&&&&
Study of Alanine-73 and Aspartate-9 of HLA-C Locus in Saudi Psoriasis
Patients, Using Sequence-specific Primers (PCR-SSP).
Abanmi A, Harthi FA, Agla RA, Khan HA, Tariq M.
Department of Dermatology and Research Center, Armed Forces Hospital,
Riyadh, Saudi Arabia. rkh_re...@yahoo.com.
Alanine at residue 73 (Ala-73) and aspartate at residue 9 (Asp-9) are
characteristic to both Cw6 and Cw7 alleles of HLA-C gene and have been
suggested as possible markers for psoriasis vulgaris (PsV). However,
the results from various ethnic groups/populations are contradictory
and inconclusive. In this study, an attempt has been made to examine
the association between HLA-C (Ala-73 and Asp-9) and susceptibility to
PsV among Saudi patients. Genomic DNA was extracted from 25 Saudi PsV
patients and 75 control subjects. Polymerase chain reaction (PCR) was
performed to amplify HLA-C sequences using earlier reported primers,
C133P and C243PR. Sequence-specific primers were used to specifically
detect nucleotide coding for Ala-73 and Asp-9 in all the subjects. The
results showed significantly higher frequency of Asp-9 (84.0 % versus
61.3 %) in PsV patients as compared to controls (p < 0.05, 2-tailed
Fisher's exact test). The frequencies of Ala-73 among PsV patients (92
%) and controls (88 %) did not differ significantly.
PMID: 15943912
Just click the related articles link on that last one,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Display&dopt=pubmed_pubmed&from_uid=15943912&tool=ExternalSearch
And you can see the prior research in this area.
Or to get a better feel for it. Go to the groups and use the search
box.
And pop in HLA or MHC or both of those terms.
Or use pubmed from one of those links and try it out there.
randall...
randall
P News has been in other threads the last few days.
All this heated debated about P and food only makes me hungry.
Can't our genes just all get along? APParently not,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15955105&query_hl=18
Inverse Regulation of the Nuclear Factor-kappaB Binding to the p53 and
Interleukin-8 kappaB Response Elements in Lesional Psoriatic Skin.
(...)
Genes are an imPortant thing to discovering your ROOTS,
One day your the Queen of talk TV and have a billion bucks in the
bank,
http://www.news24.com/Images/Photos/2005061221332712_oprah.jpg
and the next your a Zulu,
http://www.news24.com/News24/South_Africa/News/0,,2-7-1442_1720183,00.html
Queen Outa Africa?
http://news.bbc.co.uk/2/hi/africa/4096706.stm
Well. If she isn't, she certainly looks like one to me.
At some Point we all came outa Africa in the last 100,000 years. Sorry
OPrah your not the only one with roots from the rift river valley.
Five million years ago our fore fathers/mothers stoPPed
swinging from a branch and stood uP. Or something like that.
That had to stand up, to see if they where gonna be eaten by some big
cat.
And while some human descendants have little to no P we all are still
very much alike.
Even though the funky monkey genes that make P are playing hard to get.
We will
find them. Or we hoPe that they will be found. Don't worry your
prayers will
be answered some how.
I feel very positive about the future and curing P.
Lets go half way around the world from Africa now.
You could have gone south and become a zulu,
and they maintain a greater variation in their DNA then anyone on
this dirtball,
http://www.sas.upenn.edu/African_Studies/Map_Satellite/Earth_Africa_10689.gif
Or gone the other direction and had the whole world to inhabit.
And at 5 million years old, we are really quite young,
http://en.wikipedia.org/wiki/History_of_Africa
Lets ziP on over to The Land of the Rising Sun.
http://www.staycurious.net/countries/japan.html
Are we turning Japanese?
http://www.lyricsfreak.com/v/vapors,-the/143701.html
http://www.andipantz.com/andipantz/Images/JapaneseWallpaperMagnolias.jpg
Will this one break the bank on the devo Pevo thread?
http://groups-beta.google.com/group/alt.support.skin-diseases.psoriasis/search?hl=en&group=alt.support.skin-diseases.psoriasis&q=devo+whip+it&qt_g=1&searchnow=Search+this+group
Hey, WhiP it is cool, but Japan is cooler.
What we have in Japan is a really nice experiment with genes.
A huge homegenous DNA pool without many western ones till recently.
What does that show for caucasians and Japanese and P?
The P genes came about a long time ago?
And they are different. But how?
Are we or they turning? Here's a Samurai moment,
http://www.zenunbound.com/lastsamurai.html
And the science from all around the stinking World.
I really stink so!
Oh? You think so?
Corneodesmosin (CDSN) gene association with psoriasis vulgaris in
Caucasian but not in Japanese populations.
Ameen M, Allen MH, Fisher SA, Lewis CM, Cuthbert A, Kondeatis E,
Vaughan RW, Murakami H, Nakagawa H, Barker JN.
St. John's Institute of Dermatology, Kings College, London.
Summary PSORS1 on chromosome 6p21.3, which contains the MHC, is a major
susceptibility locus for psoriasis vulgaris. This region is
characterized by strong linkage disequilibrium and contains the
corneodesmosin (CSDN) gene, an attractive candidate for psoriasis
susceptibility based on its putative biological function in
keratinocyte adhesion, and HLA-Cw6, an established marker for psoriasis
susceptibility. We compared two genetically independent populations in
order to define the major psoriasis susceptibility gene, a British
Caucasian population comprising parent-offspring trios analysed by the
transmission disequilibrium test (TDT) and a Japanese case-control
population. All individuals were investigated for CDSN polymorphism
(+619, +1236, +1240 and +1243) and HLA-C association. Our data confirms
strong association with HLA-Cw6 and CDSN allele 5 (+619T, +1240G,
+1243C) in the Caucasian cohort (TDT, P = 5.4 x 10(-6)) and in addition
defines this region further by identifying a high-risk CDSN haplotype
(allele 5 and +1236T, P = 8.5 x 10(-8)). In contrast no association was
observed in the Japanese cohort for any HLA-C or CDSN alleles. This
data supports a role for the CDSN gene in Caucasian populations with
psoriasis. However the lack of association with HLA-Cw6 and CDSN
alleles in Japanese psoriasis patients may be because Japanese patients
exhibit a form of psoriasis similar to late onset or Type II psoriasis
vulgaris in contrast to early onset or Type I disease characterizing
our Caucasian population.
PMID: 15953084
Good old type II psoriasis. Don't any of the Japanese onset early with
P???
I really wanna know?
I can't figure this out. Without learning some foreign language?
Or you may want to check out bablefish.
H'mmm that study had a dichotomy with ,
Human leucocyte antigen (HLA)-Cw*0602 and it was in that last Krueger/
Bowcock article.
Time to bring it back uP again?
Sure its toPical.
Much the same as reading and understanding a foreign language.... lol
And soon we will have a chip in our brains to do that. Google and Intel
will take over by then.
&&&&&&
&&&&&&
Recall the GREAT SCIENTIFIC ARTICLE,
http://ard.bmjjournals.com/cgi/content/full/64/suppl_2/ii30/F1
>From here,
http://ard.bmjjournals.com/cgi/content/full/64/suppl_2/ii30
Which begs for this once again,
http://ard.bmjjournals.com/content/vol64/suppl_2/images/large/ar31120.f2.jpeg
How does one slow the iDC's from firing uP P?
(the mother nature way really works best. But this a real science thing
and gives the pharma's
their due....or is it?)
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15950746&query_hl=2
Immunosuppressive agents mediate reduced allostimulatory properties of
myeloid-derived dendritic cells despite induction of divergent
molecular phenotypes.
Duperrier K, Velten FW, Bohlender J, Demory A, Metharom P, Goerdt S.
Department of Dermatology, Venereology and Allergology, University
Medical Center Mannheim, Ruprecht-Karls-University of Heidelberg,
Theodor-Kutzer-Ufer 1-3, 68135 Mannheim, Germany.
Immunosuppressive drugs such as glucocorticoids (dexamethasone (Dexa)),
cyclosporin A (CsA) and tacrolimus (Tacro) have been shown to impair
differentiation and/or function of immunostimulatory dendritic cells
(DC(ims)). Phenotypes and functions of the resultant myeloid dendritic
cells, however, have not yet been thoroughly elucidated. We show here
that all DC subsets generated by treatment with immunosuppressive
agents exhibited considerably reduced allostimulatory properties as
measured in the primary mixed lymphocyte reaction
(tacrolimus>cyclosporin A>dexamethasone, used at equimolar
concentrations). In the MLR, all these DC subsets furthermore inhibited
secretion of the T-helper type 1 cytokine IFN-gamma; in addition,
DC-Tacro and, less so, DC-CsA induced the T-helper type 2 cytokine
IL-4. Upon FACS analysis, DC-Tacro and DC-CsA exhibited phenotypic
features similar to DC(ims). In addition, DC-CsA and, to a smaller
extent, DC-Tacro were characterized by increased mRNA expression of the
novel costimulatory molecule B7-H2 (ICOS-ligand). In contrast,
dexamethasone induced the generation of DC characterized by decreased
expression of CD83 and CD86, by de novo expression of plasmacytoid and
myeloid cell markers CD123 and CD14, respectively, and by sustained
expression of Toll-like receptor 2. Interestingly, activation of
DC-Dexa with a specific TLR2 ligand induced a strong up-regulation of
IL-10 along with TNF-alpha and IL-6, a combination of cytokines that
allow amplification of regulatory DC populations. In conclusion,
myeloid DC induced by dexamethasone as well as by CsA or tacrolimus
show reduced allostimulatory properties; however, they are equipped
with different molecular repertoires to exert these functions.
PMID: 15950746
How many agents can you hit IT with before things downstream go
iatrogenic on you?
WE know you can beat P to a crisP and it just keeps coming back.
Pass the DEX and the TEX as well as the MtX. I'm gonna go CYCLO on my
P... hehe
How do i find a rhyme for tacro?
I know....
As these little itty bitty bugs in us are not macro!
Fighting micro with
Small molecules to blast, smaller waller gutter bugs.
Fresh from your Pharma to you and their not free.
Heck they are quite smug about the pricey price as
we all know that sciene stuff is dicey pricey
and never ending when you don't have a cause.....
Or even a clue as to what mother nature is truely uP too.
****
And you get free stuff like that from me.? LOL
Dicey Pricey... i like that.
Can't these cyto-UN-kines just all get along? Even dead and dying cells
make proteins
that sPur on life and are in the P pathways. HMGB1 uPregulates CD83.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15944249&query_hl=2
Release of High Mobility Group Box 1 by Dendritic Cells Controls T Cell
Activation via the Receptor for Advanced Glycation End Products.
Dumitriu IE, Baruah P, Valentinis B, Voll RE, Herrmann M, Nawroth PP,
Arnold B, Bianchi ME, Manfredi AA, Rovere-Querini P.
Cancer Immunotherapy and Gene Therapy Program, Clinical Immunology
Unit, H. San Raffaele Scientific Institute, Milan, Italy.
High mobility group box 1 (HMGB1) is an abundant and conserved nuclear
protein that is released by necrotic cells and acts in the
extracellular environment as a primary proinflammatory signal. In this
study we show that human dendritic cells, which are specialized in Ag
presentation to T cells, actively release their own HMGB1 into the
extracellular milieu upon activation. This secreted HMGB1 is necessary
for the up-regulation of CD80, CD83, and CD86 surface markers of human
dendritic cells and for IL-12 production. The HMGB1 secreted by
dendritic cells is also required for the clonal expansion, survival,
and functional polarization of naive T cells. Using neutralizing Abs
and receptor for advanced glycation end product-deficient (RAGE(-/-))
cells, we demonstrate that RAGE is required for the effect of HMGB1 on
dendritic cells. HMGB1/RAGE interaction results in downstream
activation of MAPKs and NF-kappaB. The use of an ancient signal of
necrosis, HMGB1, by dendritic cells to sustain their own maturation and
for activation of T lymphocytes represents a ___________profitable
evolutionary mechanism________.
PMID: 15944249
Who profits and who gets screwed in this death and dying deal???
Did mother nature leave some easter eggs for us to use?
Besides the patented dirt fungus from norway or snoraway.
How about some of this herbal stuff in the next abstract?
http://sinobest.en.ec21.com/co/s/sinobest/img/oimg_010620085318.jpg
Chinese herbs are cool. And you can grow them, if you wish.
Catch a worm and go fish if thats not your dish.
Botanical source: from Triptergium wilfordii Hook F.
Hooking into this abstract,
Triptolide affects the differentiation, maturation and function of
human dendritic cells.
Zhu KJ, Shen QY, Cheng H, Mao XH, Lao LM, Hao GL.
Department of Dermatology and Venereology, Sir Run Run Shaw Hospital,
Medical College, Zhejiang University, Hangzhou 310016, PR China.
Triptolide is a purified component from a traditional Chinese herb
Tripterygium wilfordii Hook F. It has been shown to have
anti-inflammatory and immunosuppressive activities by its inhibitory
effect on T cells. But the effect of triptolide on dendritic cells (DC)
is unknown. Dexamethasone (Dex) is a classic immunosuppressive agent
known to suppress the immune response at different levels and has
recently found to modulate the development of DC, thereby influencing
the initiation of the immune response. In this study, we investigated
the affect of triptolide on the differentiation, maturation and
function of DC differentiated from human monocytes (MoDC) in vitro in
the presence of GM-CSF and IL-4. Dex was included in the study as a
reference. Our data show that both triptolide and Dex prevented the
differentiation in immature MoDC by inhibiting CD1a, CD40, CD80, CD86
and HLA-DR expression but upregulating CD14 expression, as well as by
reducing the capacity of MoDC to stimulate lymphocyte proliferation in
the allogeneic mixed lymphocyte reaction. They blocked the maturation
of MoDC as totally blocked induction of CD83 expression and absent
upregulation of CD40, CD80, CD86 and HLA-DR. In addition, higher
concentration of triptolide (20 ng/ml) and 10(-6) M Dex induced
apoptosis in MoDC as measured by expression of APO2.7 and DNA
fragmentation (TUNEL assay). However, the phagocytic capacity of MoDC
was enhanced by triptolide but not Dex. Therefore, the suppression of
DC differentiation, the function in immature DCs as well as the
inhibition of DC maturation by triptolide may explain some of its
immunosuppressive properties. It is suggested that DCs are a primary
target of the immunosuppressive activity of triptolide.
PMID: 15953568
This triPtolide is a trip and so is the company that sells it. They
have more
herbs and things,
http://sinobest.en.ec21.com/2/Triptolide_99_.html
I know you know that i can't get away from these herbs.
Still, i have't tried kalawalla. I know i must.
click their menu on the left side to see more.
^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^
This next chinese herb increases CD83 (not a good thing for P) and most
likely helps to
fight the Th2 condition known as cancer!
It does help to understand the P and C pathways in regards to Th1 and
Th2 conditions.
Lets check it out. I love this stuff.
Polysaccharide purified from Ganoderma lucidum induced activation and
maturation of human monocyte-derived dendritic cells by the NF-{kappa}B
and p38 mitogen-activated protein kinase pathways.
Lin YL, Liang YC, Lee SS, Chiang BL.
*Graduate Institute of Clinical Medicine, College of Medicine, National
Taiwan University, Taipei, Republic of China; Graduate Institute of
Biomedical Technology, College of Medicine, Taipei Medical University,
Taiwan, Republic of China; and Department of Biochemistry, National
Yang-Ming University, Taipei, Taiwan, Republic of China.
Ganoderma lucidum, a fungus native to China, has been widely used to
promote health and longevity in the Chinese. The polysaccharide
component with a branched (1-->6)-beta-D-glucan moiety of G. lucidum
(PS-G) has been reported to exert anti-tumor activity and activation of
natural killer cells. In this study, we investigated the effects of
PS-G on human monocyte-derived dendritic cells (DC). Treatment of DC
with PS-G resulted in the enhanced cell-surface expression of CD80,
CD86, CD83, CD40, CD54, and human leukocyte antigen (HLA)-DR, as well
as the enhanced production of interleukin (IL)-12p70, p40, and IL-10
and also IL-12p35, p40, and IL-10 mRNA expression, and the capacity for
endocytosis was suppressed in DC. In addition, treatment of DC with
PS-G resulted in enhanced T cell-stimulatory capacity and increased T
cell secretion of interferon-gamma and IL-10. Neutralization with
antibodies against Toll-like receptor (TLR)-4 inhibited the
PS-G-induced production of IL-12 p40 and IL-10, suggesting a vital role
for TLR-4 in signaling DC upon incubation with PS-G. Further study
showed that PS-G was able to augment inhibitor of kappaB (IkappaB)
kinase and nuclear factor (NF)-kappaB activity and also IkappaBalpha
and p38 mitogen-activated protein kinase (MAPK) phosphorylation.
Further, inhibition of NF-kappaB by helenalin and p38 MAPK by SB98059
prevented the effects of PS-G in the expression of CD80, CD86, CD83,
CD40, CD54, and HLA-DR and production of IL-12p70, p40, and IL-10 in
various degrees. Taken together, our data demonstrate that PS-G can
effectively promote the activation and maturation of immature DC,
suggesting that PS-G may possess a potential in regulating immune
responses.
PMID: 15894585
Hey! Ganoderma lucidum is aka Reishi or ling zhi.
http://www.fungitobewith.org/The%20weird%20and%20the%20wonderful.htm
And it is an immune enhancer. I would think you'd want to avoid it. Let
us know what
haPPens if you don't.
Lets look at the P group for it,
http://groups-beta.google.com/groups?hl=en&q=reishi+psoriasis&qt_s=Search
Hey J and I have the same thoughts. And son nguyen used it for some
help for his P.
Where has he been? It's been awhile since he's posted. He's like so
many that comes
around gets on a kick and reports back about it in six months or so.
And then there are folks that never go away. lol
Even if you wish I would.
%%%%%%
%%%%%%
This next one has been around for a while,
http://groups-beta.google.com/group/alt.support.skin-diseases.psoriasis/search?group=alt.support.skin-diseases.psoriasis&q=cellcept&qt_g=1&searchnow=Search+this+group
Or known by its doctorly name,
http://groups-beta.google.com/group/alt.support.skin-diseases.psoriasis/search?group=alt.support.skin-diseases.psoriasis&q=Mycophenolate+Mofetil&qt_g=1&searchnow=Search+this+group
Mycophenolate Mofetil: A Dermatologic Perspective
http://www.medscape.com/viewarticle/505756?src=hp33.lead (free sign up
needed)
(...)
Page 2 of 10
*****
Mechanism of Action
Mycophenolate mofetil selectively and noncompetitively inhibits inosine
monophosphate dehydrogenase (IMPDH) in the de novo purine synthesis
pathway. This enzyme facilitates the conversion of inosine
monophosphate to xanthine monophosphate, an intermediate metabolite in
the production of guanosine triphosphate. As MMF results in the
depletion of guanosine nucleotides, it impairs RNA, DNA and protein
synthesis.[9]
The purine bases, adenosine and guanosine, may be synthesized through
two pathways: the de novo purine synthesis pathway, and the
hypoxanthine-guanine phosphoribosyl transferase salvage pathway. As
lymphocytes lack the salvage pathway, MMF selectively inhibits
lymphocyte proliferation and antibody formation. Moreover, MMF
preferentially blocks the type II isoform of IMPDH, predominantly
located on lymphocytes; thus, it also holds potent cytostatic effects
on T and B cells.[9] Herein lies the selective advantage of this
immunosuppressive agent.
Mycophenolate also prevents the glycosylation of lymphocyte and
monocyte glycoproteins that are involved in adhesion to endothelial
cells. It may further inhibit the recruitment of leukocytes to sites of
inflammation and impair antigen presentation.[10] While it does not
inhibit early events in the activation of human peripheral blood
mononuclear cells (i.e., IL-1 and IL-2 production), MMF blocks the
coupling of these events to DNA synthesis and proliferation.[9]
(...)
Page 7 of 12
Multiple case reports suggest that MMF is an effective treatment option
for psoriasis.[16-20] In a study of 11 patients with stable plaque-type
psoriasis, the efficacy of MMF was measured using the Psoriasis Area
and Severity Index (PASI) score.[21] Patients initially received MMF 1g
twice daily for 3 weeks followed by 0.5g twice daily. Within 3 weeks of
therapy, there was a reduction in PASI of between 40% and 70% in seven
of the 11 patients. Only one patient achieved a reduction in PASI of
<25% from baseline. After 6 weeks, there was further improvement in six
patients. However, PASI worsened in four patients when MMF was tapered
to the lower dosage.
In a two-center, prospective, open-label clinical trial, 23 patients
with moderate to severe psoriasis were treated with MMF 2-3g/day for 12
weeks.[22] In the 18 patients who completed the study, the PASI was
reduced by 24% (p<0.001) at 6 weeks and by 47% (p<0.001) at 12 weeks.
Moreover, MMF appeared to have a beneficial effect on patients
suffering from psoriatic arthritis. The treatment was well tolerated:
five patients developed nausea, one patient experienced periorbital
edema and pruritus, and one patient had a transient leukopenia. Thus,
MMF monotherapy appears to be an effective treatment for patients with
moderate-to-severe, plaque-type psoriasis.
Page 8
Dermatitis
In a pilot study of 10 patients with severe refractory atopic
dermatitis, MMF was increased to a dose of 2g/day.[23] After 12 weeks
of therapy, the median scores for disease severity (SCORAD index)
improved by 68%. These findings were associated with a significant
decrease in serum IgE and a shift in the T-helper (Th)-1 to Th2
cytokine ratio.
In another study of 10 patients with moderate-to-severe atopic
dermatitis, MMF was administered at 2g/day for a month and tapered to
1g/day.[24] In a 20 week follow-up period, there was a 74% reduction in
the SCORAD index as compared with baseline (p<0.01). Dyshidrotic eczema
and chronic actinic dermatitis have also responded to MMF therapy
^^^^^^^
Good old read drugs! Don't you love them? When nothing else works?
And your feeling down and blue?
*****
*****
Who is the guy that founded Pscore cure now? What's he like at home?
http://www.rednova.com/news/health/156458/daddys_home_to_stay/
Boring!, being Mister Mom is cool uP to a point. Michael get out
and take the kids with you.
gEt the bugs for P... Time to cure it..
*******
You could just try to hibernate like an alaskan ground squirrel,
http://www.betterhumans.com/News/News/tabid/61/News/776/Default.aspx
Or get jiggy with the GABA and feeling no pain,
http://www.med.umich.edu/opm/newspage/2005/neuropathicpain.htm
randall
P news from the google news search engines.
Killer new P cocktail?
Or really cool idea out their in pharma land?
http://www.medadnews.com/News/index.cfm?articleid=249388
24 hits for dexamethasone for this group.
(4 hits for DEX... randall likes to rhyme it with tex)
http://groups-beta.google.com/group/alt.support.skin-diseases.psoriasis/search?group=alt.support.skin-diseases.psoriasis&q=dexamethasone&qt_g=1&searchnow=Search+this+group
45 hits for dexa and psoriasis on all groups,
http://groups-beta.google.com/groups?q=dexamethasone+psoriasis&qt_s=Search
And bingO, we may have a groovy new p drug, made from two different
ones.
JXStern's ultimate P cocktail? could be.
Lets post the whole thing from medanews.com
Ok!
^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^
Senesco Technologies Reports Results of Pre-Clinical Cytokine Study
Versus a Steroid and a TNF Inhibitor
NEW BRUNSWICK, N.J.--(BUSINESS WIRE)--Jun 17, 2005 - Senesco
Technologies, Inc. ("Senesco" or the "Company") (AMEX:SNT) reported
today the results of a series of mouse experiments which compared the
Company's proprietary Factor 5A technology to two approved drugs:
dexamethasone and Enbrel(R) (etanercept). Dexamethasone is a
glucocorticoid (catabolic steroid) reported to be stronger than
prednisone, and Enbrel(R) (etanercept) made by Amgen Inc., which has
been approved for treatment of rheumatoid arthritis, psoriasis and
other diseases, is a soluble tumor necrosis factor ("TNF") receptor
which acts to reduce inflammation by binding TNF to make it inactive.
TNF is a cytokine, which are proteins produced by cells of the immune
system as part of the body's defenses against infection and disease.
Overproduction of certain cytokines can cause inflammation, swelling or
damage to joints or organs.
In the Company's pre-clinical experiments, mice were injected with
___LPS_____, an agent used to induce inflammatory response. Cytokine
levels were then measured in the four experimental groups of mice:
those that received a control treatment, those that received a single
dose of Senesco's Factor 5A siRNA, those that received a single dose of
dexamethasone and those that received a single dose of Enbrel(R).
Relative to the control treatment, dexamethasone treated mice had TNF
levels decrease approximately 90%. Senesco siRNA treated mice had TNF
levels decrease approximately 75%. Three different cytokines were
measured in mice that received Enbrel(R). Interleukin 1-alpha decreased
approximately 50% with Enbrel(R) treatment as compared to approximately
35% with Senesco's siRNA. Interleukin-6 decreased approximately 98%
with Enbrel(R) as compared to approximately 82% with the Senesco siRNA
and Interferon-gamma decreased approximately 93% with Enbrel(R) as
compared to approximately 87% with Senesco's siRNA.
Dr. Charles A. Dinarello, a member of Senesco's Scientific Advisory
Board and in whose laboratory at the University of Colorado Medical
School these mouse studies were conducted, commented, "Senesco's siRNA
decreased levels of several important inflammatory cytokines in these
animal tests to levels comparable to the decreases seen with the
presently used doses of corticostreroids and anti-TNF therapies such as
Remicade(R), Humira(R) and Enbrel(R)."
Bruce C. Galton, Senesco's president and CEO, stated, "We continue to
build in-vivo data on our technology's role in cytokine production and
control. Our ongoing pre-clinical research will seek to ascertain the
most effective dosing regimens for Senesco's siRNA. Such pre-clinical
information is helpful so that inflammatory cytokine levels are
controlled yet still allow for a proper response to infections."
Enbrel(R) is the registered trademark of Amgen, Inc.
Remicade(R) is the registered trademark of Centocor, Inc.
Humira(R) is the registered trademark of Abbott Laboratories
About Senesco Technologies, Inc.
Senesco takes its name from the scientific term for the aging of plant
cells: senescence. The Company has developed technology that regulates
cell life. Delaying cell breakdown in plants extends freshness after
harvesting, while increasing crop yields and resistance to
environmental stress for flowers, fruits and vegetables. The Company
believes that its technology can be used to develop superior strains of
crops without any modification other than delaying natural plant
senescence. Senesco has undertaken preclinical research in certain
areas of human health.
Accelerating apoptosis may have applications to development of cancer
treatments. Delaying apoptosis may have applications to certain
diseases such as glaucoma, ischemia and arthritis, among others.
Senesco partners with leading-edge companies and earns research and
development fees for applying its technology to enhance its partners'
products. Senesco is headquartered in New Brunswick, New Jersey, and
utilizes research laboratories at universities and research centers
throughout North America.
Certain statements included in this press release are forward-looking
statements within the meaning of the Private Securities Litigation
Reform Act of 1995. Actual results could differ materially from such
statements expressed or implied herein as a result of a variety of
factors, including, but not limited to: the development of the
Company's gene technology; the success and the timing of the Company's
studies and preclinical trials; the approval of the Company's patent
applications; the successful implementation of the Company's research
and development programs and joint ventures; the success of the
Company's license agreements; the successful conversion of the
Company's letter of intent into a license agreement; the acceptance by
the market of the Company's products; competition and the timing of
projects and trends in future operating performance, as well as other
factors expressed from time to time in the Company's periodic filings
with the Securities and Exchange Commission (the "SEC"). As a result,
this press release should be read in conjunction with the Company's
periodic filings with the SEC. The forward-looking statements contained
herein are made only as of the date of this press release, and the
Company undertakes no obligation to publicly update such
forward-looking statements to reflect subsequent events or
circumstances.
Contact Senesco Technologies, Inc. Bruce Galton, 732-296-8400
bga...@senesco.com or Investor Relations Contacts: Lippert/Heilshorn &
Associates Kim Sutton Golodetz, 212-838-3777 kgol...@lhai.com
^^^^^^^^
BravO! This is one cocktail I should have had in the back of my mind.
Dexa with any biological. Cruiser may be interested in Dexa for his
antibotic treatment as well...
Kevin Reed, who is a scientist, mentioned it in his self treatment
post, that can be obtained above,
Under the post by Elsie Reed. Entitled " Dalalone and Valisone works!
Four or five posts down on the first page.
While Kevin is advocating self treatment, most if not all of you should
consult with your derm.
You can copy this stuff to show your derm.
************************
****************************
http://www.rednova.com/news/health/156416/management_of_heatstroke_and_heat_exhaustion/
Good old simple heat allows more intestinal permeability,
(If you hang out in a hot hot tub drinking rum all day, its no surprise
if you flare up....)
(...)
Medications and Substances that May Contribute to Heat-Related Illness
The term thermal maximum was developed to measure the magnitude and
duration of heat that cells can encounter before becoming damaged.
Human thermal maximum has been established as a core body temperature
of approximately 42C (107.6F) for between 45 minutes and eight hours.15
Cellular destruction occurs more quickly and completely at higher
temperatures. Inflammatory factors are released and gastrointestinal
permeability increases, which may allow endotoxins into the
circulation.16 Hematologic and endothelial changes resembling
disseminated intervascular coagulation also occur.17
(...)
The face of the future? Small drugs to work directly on the cytokines.
B cell ---> T helper cell
http://pathmicro.med.sc.edu/bowers/act-1.jpg
http://pathmicro.med.sc.edu/bowers/coop-2.jpg
Both of above jpg's from here:
http://pathmicro.med.sc.edu/bowers/cell-mediated.htm
******
Bacteria made to pump the right or missing cytokines back
into you!! Yes. This is high tech and could be really great.
We will watch this stuff closely.. Here it is,
http://www.nature.com/drugdisc/news/articles/nbt0605-645.html
& or
http://www.nature.com/news/2005/050531/pf/nbt0605-645_pf.html
Genetically engineered bacteria made biotech drugs possible. Now, they
are becoming drugs in their own right, Monya Baker reports.
On April 30 this year, two Florida patients received a unique mouth
rinse. Using a cotton swab, a dentist painted billions of genetically
modified live bacteria of the species Streptococcus mutans onto their
pearly whites. If all goes as planned, these bacteria, which lack the
gene to make enamel-eroding lactic acid, will replace their naturally
occurring, acid-making counterparts, which cause tooth decay.
Besides S. mutans, a number of strains of live bacteria are being
developed as therapies. A Lactococcus Lactis strain, engineered to
secrete a therapeutic protein, has already been tested in patients with
Crohn disease at the University of Amsterdam; in April, trial results
were submitted for publication. Also that month, Osel of Santa Clara,
California, began phase 2 trials using a proprietary, naturally
occurring strain of live Lactobacillus crispatus to treat recurrent
urinary tract infection and recurrent bacterial vaginosis. Other
academics and companies are exploring genetically modified bacteria
against cancer and infectious diseases.
As drugs, bacteria offer several advantages: compared with therapeutic
proteins, they are easier to grow, purify and store; although
engineering them to express (or not express) a particular gene takes
expertise, it needs to be done only once. But along with their
convenience and versatility, bacteria reproduce and evolve, making them
hard to predict. That creates tricky regulatory issues, and most
investors are keeping their distance. But even without venture backing,
the field is progressing steadily through the clinic.
Living therapies
The first dose of engineered S. mutans comes two years after the US
Food and Drug Administration (FDA) placed Alachua, Florida-based
Oragenics' clinical trial on hold for safety concerns. The current
seven-day trial requires bacteria with additional engineering. The gene
for alanine racemase is deleted, which makes the bacteria dependent on
D-alanine for their growth. During the clinical trial, they are
supplied with the nutrient in a mouth rinse applied twice-daily. And,
just in case the bacteria must be eliminated quickly, all patients
enrolled in the trial must wear dentures, which can be removed should
problems arise. When the trial is over, patients will rinse their
mouths with an antibiotic and be monitored, along with their spouses,
for three months.
Oragenics hopes that eventually the bacteria will become a routine part
of dentistry, a one-time treatment applied to children's teeth before
they start getting cavities. CEO Chuck Soponis acknowledges no one has
any specific idea what ill health effects the bacteria might cause. The
strain does not make a recombinant protein or displace other species of
bacteria living on the tongue and gums. Still, he says, the FDA is
right to be cautious. ?You're putting a genetically modified bacteria
that's going to be in people's mouths for a lifetime, and that hasn't
been done before.?
Using live bacteria, or probiotics, to promote health is already common
in Japan and becoming increasingly so in Europe. In fact, about 30
probiotic prescription products are sold in Japan. Far more common are
products sold without prescriptions as so-called functional foods. The
Japanese company Yakult Honsha of Tokyo sells 25 million bottles a day
of a fermented milk drink, each one boasting that it contains 8 billion
live Lactobacillus casei strain Shirota, which allegedly make for a
more healthful gut flora. However, the efficacy of these
over-the-counter products is uncertain, and they can't command the high
prices of prescription drugs.
Investors hang back
In general, companies seeking funding for live bacteria therapies will
have an even harder time finding funding than other biotechnology
startups, according to Irena Melnikova, research manager at consulting
firm Life Sciences Insights of Framingham, Massachusetts. ?This is
something very novel,? she says, ?and when you start talking about
putting live bacteria in humans, there's a negative first reaction.?
In fact, neither Oragenics nor Osel are accessing traditional venture
capital (VC) sources to fund their programs. Oragenics went straight to
the public markets, listing the company on the Toronto Venture Exchange
in June 2003, and moving it to the American Stock Exchange in May last
year. Though Osel began in 1998 with money from the founders and has
received funding from government agencies including the National
Institutes of Health, it has relied mainly on private investors who are
not venture capitalists, according to the company's president Ralph
Levy. ?The VC community does not have a model which our product fits
into,? he says. ?Small molecules and antibodies, they've seen that;
live bacteria they don't understand.?
Oragenics is also pursuing an antibiotic and an over-the-counter
probiotic, both stemming from research by the company's CSO and
cofounder Jeff Hillman. The probiotic is a proprietary mixture of three
naturally occurring bacteria expected to prevent periodontal disease
when taken daily. Oragenics plans to partner with larger oral care
companies and get the product on the market in Europe and Asia sometime
next year and use revenues from probiotics sales to partly finance
development of its genetically modified bacteria, which will be
marketed as a prescription drug administered by dentists.
Osel's Levy is quick to distance himself from the nonprescription
marketplace. He doesn't even like the term 'probiotic.' ?The easy route
is just manufacturing it and putting it in a store. My market is the
physician who's going to write a script to treat a patient,? he says.
Levy thinks venture capitalists will be more forthcoming with funding
once phase 2 results are available. ?When we have the data, they'll be
where I need them to be.?
Producing drugs in situ
As an academic, Lothar Steidler, a molecular biologist at Cork
University in Ireland, bypassed many corporate headaches while still
moving a live bacteria therapy into clinical trials. The work began
about ten years ago when Steidler, then at Belgium's Ghent University,
was looking for an inexpensive source of cytokines?soluble protein
regulators of the immune system. Steidler and his colleagues acquired
all sorts of expression systems to make cytokines in-house, and
routinely scanned the literature for more. ?We bumped into Lactococcus
because I met someone at a conference and he had a nice poster,? says
Steidler, who eventually created Lactococcus that secreted human
interleukins 2, 6 and 10 (IL-2, IL-6, IL-10) as well as trefoil
factors. As a production system the bug was disappointing; its output
was a hundredth to a thousandth that of Escherichia coli, says
Steidler. ?But what immediately struck our minds was that the product
was soluble and was fully biologically active.? Most cytokines do not
require glycosylation to be active, and so don't need to be made in
eukaryotic cells. In Lactococcus cultures, soluble cytokines could be
recovered from the supernatant with its secretion leader clipped off
correctly. In other words, says Steidler, ?The material you got for
IL-10 was indistinguishable from the eukaryotic product.? Furthermore,
people have safely eaten Lactococcus in cheese and yogurt for thousands
of years. Perhaps, Steidler's team thought, patients could safely
consume it as a drug.
The technology seemed especially applicable to inflammatory bowel
disease, in which the immune system erroneously attacks the gut,
causing chronic discomfort and frequent diarrhea. IL-10 tends to quiet
the immune system, but administering the cytokine orally is
problematic, as its activity is rapidly destroyed by acid in the
stomach. Given intravenously, the cytokine spreads through the entire
body, where it can actually rouse the immune system. But Lactococcus
taken by mouth could travel through the stomach and secrete IL-10
exactly where it was needed, along the intestinal wall. ?We're still
surprised at the simplicity,? says Steidler. In two separate mouse
models of colitis, treatment with the bacteria either prevented disease
onset or dramatically reduced its severity1. The mice suffered no
obvious adverse effects.
In an unusual move, the University of Amsterdam approached Steidler
about putting the bacteria into clinical trials. But the therapy was
not ready for people yet. ?You can't just release genetically modified
bacteria in the environment without precaution,? says Steidler. The
research team needed a way to prevent the engineered bacteria from
growing outside the body, so they decided to insert IL-10 into the
locus normally occupied by the gene for thymidylate synthase2, which is
essential for DNA synthesis, and hence required for growth.
The modified Lactococcus can readily absorb thymidine from the
nutrient-rich gut, but quickly depletes any available in the
environment; its viability decreases about a millionfold within 60
hours after the source of thymidine is removed.
To obtain permission to run trials in Holland, explains Steidler,
researchers must publish trial plans in newspapers and the Royal
National Library in The Hague. That way the general public can question
trials before they start. However, no one raised concerns during that
process, he says. Although that may seem surprising, given widespread
objection to genetically modified food in Europe, attitudes toward
transgenic plants do not predict attitudes toward transgenic therapies.
The technology is currently covered under 45 patents owned by Flanders
Inter university Institute for Biotechnology (VIB) of Zwijnaarde,
Belgium, which is working with Steidler to commercialize the
technology. VIB director Rudy Dekeyser says the group is looking both
at corporate partners to collaborate on clinical development, as well
as venture capitalists to start a new company.
But even if the technology finds corporate backing, that doesn't mean
that other companies developing live bacteria will necessarily have an
easier time, says IDC's Melnikova, ?It's always hard to be the first,
but each individual therapy will be considered on its individual
merits.?
Bacteria take on cancer
Several groups are looking for ways to use microbes against cancer, and
in fact, the naturally occurring bacteria, bacillus Calmette-Guerin, is
standard therapy for a type of bladder cancer. Still most work in this
area uses viruses rather than bacteria. Viruses had a head start
because they can target specific cells, according to David Bermudes,
director of microbiology at Vion in New Haven, Connecticut. Still, he
says, bacteria offer several practical advantages. ?A virus depends on
the cell to deliver its payload. Bacteria are self-contained
factories.? Moreover, bacteria can carry more genetic material, be
controlled with antibiotics and ?are a joy to manufacture compared with
viruses.?
Vion has already taken a cancer-fighting bacteria through three phase 1
trials. It chose bacteria for their ability to grow preferentially in
tumors, an advantage that molecular biologists were slow to recognize,
says Bermudes. The company's genetically modified Salmonella
typhimurium makes cancer drugs potent at the site of the tumor,
allowing a less toxic prodrug to be administered. As it grows in
tumors, the engineered S. typhimurium expresses an E. coli enzyme for
cytidine deaminase, which converts nontoxic 5-fluorocytosine (5-FC) to
the anticancer drug 5-fluorouracil (5-FU)3. In mouse studies, the
treatment, called TAPET-CD, slowed tumor growth by as much as 95%.
In mice, the bacterium also has some ability to target tumor cells even
without cytidine deaminase. Vion tested versions of S. typhimurium
lacking the enzyme in phase 1 trials and found that although the
bacteria found their way to tumors, the therapy had no antitumor
activity. ?It was a commercial failure, but a scientific success
because you've shown that you can make a bacteria that's safe for
systemic administration that targets tumors,? says Bermudes. Human
trials with TAPET-CD showed conversion of 5-FC to 5-FU in two of three
patients, but were stopped for what Bermudes calls ?nonmedical
reasons.? Vion is focusing efforts on a small molecule anticancer drug
now in phase 2 trials.
Cerus of Concord, California, looked at both viral and bacterial
vectors before deciding to engineer Listeria monocytogenes as a cancer
vaccine. As one of the deadliest food-borne bacteria, it seems a
surprising choice for a vaccine vector, but microbiologists have a long
history of finding ways to attenuate pathogens, and L. monocytogenes
had key advantages, according to Tom Dubensky, head of vaccine
development at Cerus. The bacteria is easy to grow and elicits a potent
immune response. Also, unlike many other microbes, it is not
neutralized by antibodies, so repeated vaccinations are more likely to
be effective. In fact, a clinical trial of 20 healthy volunteers showed
that a genetically attenuated strain of L. monocytogenes could still
prompt an immune response without serious side effects.
Wild-type L. monocytogenes enters liver cells and spreads from cell to
cell by sending bacteria-filled protrusions into neighboring cells,
thus avoiding the immune system. Cerus's engineered bacteria lack this
ability, but they can still enter antigen-presenting cells and
stimulate an immune response4. Although Cerus's first-generation L.
monocytogenes works by boosting only innate immunity, researchers have
also created a way to stimulate adaptive immunity. ?We spent a lot of
time learning how to program L. monocytogenes to secrete antigen from
the bacterium within the antigen-presenting cell,? recalls Dubensky.
The next-generation of L. monocytogenes vectors make mesothelin, a
tumor marker present in many ovarian and prostate cancers; Cerus has a
joint project with MedImmune of Gaithersburg, Maryland, using its
proprietary EphsA2 antigen as well. Cerus hopes to file an
investigational new drug application by the end of this year for its
first-generation L. monocytogenes against colorectal cancer that has
metastasized to the liver. Dubensky expects close scrutiny from the FDA
but thinks that for cancer patients that have not benefited from other
therapies, the risk-benefit calculations favor experimental therapies.
?While there is risk to being the first use in man, these are people
for whom there are no other options.?
Bert Vogelstein, an oncologist at Johns Hopkins University in
Baltimore, uses a version of Clostridium novyi that lacks the gene to
make alpha-toxin. This spore-forming bacteria germinates in oxygen-poor
tumors and turns them to mush within18 hours. Ruptured cells from the
dying tumor prompt an immune response that trains the immune system to
attack remaining cancer cells5. The therapy has been tried in mice,
rats, and rabbits; in one in three animals the tumor is destroyed
without additional drugs. Odds of vanquishing the tumor improve if
anticancer drugs are given as well. Vogelstein thinks the therapy is
promising, but is adamant that it is not ready to be tested in humans.
Toxicities so far seem acceptable, he says, but the immune response
elicited can be so strong that it harms the host.
Cautious yet optimistic
Whether liquifying tumors or pushing out harmful bacteria,
live-bacteria therapies can exploit mechanisms impossible for small
molecule and protein drugs, and can even be engineered to deliver drugs
where the body needs them. But for all this, they present unpredictable
and unquantifiable risks. As Vogelstein says, ?The agent is new and
it's self-replicating. The dose that we give and the dose that we get
are not the same.? Vion's Bermudes says skepticism is warranted, but so
is hope, particularly for patients who have no other options. ?Ten
years ago, everybody said antibody therapies don't work. Where are the
products? Now there are almost twenty products on the market.?
References
1. Steidler, L. et al. Treatment of murine colitis by Lactococcus
lactis secreting interleukin-10. Science 289, 1352?1355 (2000).
2. Steidler, L. et al. Biological containment of genetically modified
Lactococcus lactis for intestinal delivery of human interleukin 10.
Nat. Biotechnol. 21, 1785?1789 (2003).
3. Nemunaitis, J. et al. Pilot trial of genetically modified,
attenuated Salmonella expressing the E. coli cytosine deaminase gene in
refractory cancer patients. Cancer Gene Ther. 10, 737?744 (2003).
4. Brockstedt, D.G. et al. L. monocytogenes-based cancer vaccines
that segregate immunogenicity from toxicity. Proc. Natl. Acad. Sci. USA
101, 13832?13837 (2004).
5. Agrawal, N. et al. Bacteriolytic therapy can generate a potent
immune response against experimental tumors. Proc. Natl. Acad. Sci. USA
101, 15172?15177 (2004).
Blueprint for making the L. Lacti IL-2 pumpers,
http://aem.asm.org/cgi/reprint/61/4/1627
Wow! And I thought that a IL-10 bug would be the end all for P
salvations.
Have a really nice Father's Day and or a great weekend.
randall
heuri...@gmail.com
randall
Not much in p news today, yet.
This looks sorta interesting,
New Inflammation GENE for autoimmune diseases
http://info.anu.edu.au/mac/Media/Media_Releases/_2005/_May/_260505_roquin.asp
Or
http://www.news-medical.net/?id=10568
Or
http://www.sciencedaily.com/releases/2005/06/050611154440.htm
Or
http://www.jdrf.org/index.cfm?page_id=103607
(...)
According to Professor Christopher Goodnow, the Head of the
Immunogenomics Laboratory at JCSMR and Director of the Australian
Phenomics Facility, the discovery hinged upon identifying a single
letter change in the DNA code of Roquin.
"It's one very small part of the genome that has proven a very big
breakthrough. That single nucleotide change reduces the function of an
autoimmunity gene and protein that was hithertoentirely unknown.
According to Professor Goodnow, the characteristics of the Roquin
protein suggest that it might repress immune cells by silencing the
communication channel between genes and cell functions.
"Roquin stops T-cells from displaying a stimulatory receptor, ICOS,
that may cause the cells to attack normal body tissues. Therefore this
gene seems critical in protecting us from autoimmunity -- but it only
takes the mutation of one letter in that gene to cripple its function
and lead to autoimmune disease.
"This finding immediately opens up research into testing the function
of Roquin, examining variants that may explain autoimmune disease and
working towards discovering drugs that might increase or decrease the
activity of the newly-realised process."
(...)
H'mmmm h'mm?!?!
Well? What do you think this time?
I hate to Pin my hoPe on it. But what the heck!
Go you downunder wonders! Now. Where do we go to
get our ICOS checked out?
Is Psoriasis a disease of to much ICOS?
Finally! We can tell peoPle the truth when they say, "YUCK"
Whats that muck on you?
"Elementary my good lad, it's some sucky stuff caused be ICOS".
"And you my little butterball may have a gene or three outa order
as well".
http://seattletimes.nwsource.com/html/health/2002341733_obesitygenes20.html
randall..... have a dePressed ICOS day.
randall
randall wrote:
> Hi,
>
> Not much in p news today, yet.
>
Yeah right. But what about the possible earthquake in the autoimmune
world? This is a nine on the P fault lines, no doubt and we may
owe it all to those australian scientists down under.
> This looks sorta interesting,
>
> New Inflammation GENE for autoimmune diseases
> http://info.anu.edu.au/mac/Media/Media_Releases/_2005/_May/_260505_roquin.asp
(...)
"Before this study, the existence and function of Roquin was not
known. However, we now know that in the immune system of mammals, the
protein Roquin usually suppresses the activity of forbidden T-cells
that bind to parts of the body.
"We found that a single mutation in Roquin causes these T-cells to be
abnormally activated, and results in autoimmunity affecting many
different parts of the body," Dr Vinuesa said.
Autoimmune disease occurs when the immune system is activated to mount
a response against normal tissue in the body, treating it as if it were
a germ and damaging and destroying the tissue. For example, in type 1
diabetes, an immune response is mounted against the insulin-secreting
cells of the pancreas; in lupus, virtually any part of the body can be
attacked by the immune system.
(...)
<sniP>
After re-reading this post from this morning (my time anyway).
I'm inducibly costimulated to figure out this ICOS (INDUCIBLE
COSTIMULATOR) and Roquin gene links to autoimmunity and psoriasis.
Is this the Big One i'm now buzzing in my little grey cells?
First stop Pubmed, (96 hits for keywords::: ICOS gene)
Here is the first one (chronological, from most recent backwards)
ICos and Immunity next,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15956289&query_hl=1
Absence of inducible costimulator on alloreactive T cells reduces
graft-versus-host disease and induces Th2 deviation.
Hubbard VM, Eng JM, Ramirez-Montagut T, Tjoe KH, Muriglan SJ, Kochman
AA, Terwey TH, Willis LM, Schiro R, Heller G, Murphy GF, Liu C,
Alpdogan O, van den Brink MR.
Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer
Center, NY, NY, USA.
Inducible costimulator (ICOS) is expressed on activated and memory T
cells, and is involved in the regulation of cytokine production. We
studied the role of ICOS on alloreactive T cells in graft-versus-host
disease (GVHD), and determined that ICOS expression was upregulated on
alloreactive T cells in recipients of an allogeneic hematopoietic stem
cell transplantation (allo-HSCT) with GVHD. We compared ICOS-/- T cells
to wild type (WT) T cells in two GVHD models. In both models,
recipients of ICOS-/- T cells exhibited significantly less GVHD
morbidity and mortality, which was associated with less intestinal and
hepatic GVHD, but increased cutaneous GVHD. In addition, recipients of
ICOS-/- donor T cells displayed a slight decrease in
graft-versus-leukemia (GVL) activity. Further analysis of alloreactive
ICOS-/- T cells showed no defect in activation, proliferation,
cytotoxicity, and target organ infiltration. Recipients of ICOS-/- T
cells had decreased serum levels of IFN-gamma, while IL-4 and IL-10
levels were increased, suggesting that alloreactive ICOS-/- T cells are
skewed towards Th2 differentiation. These data suggest a novel role for
ICOS in the regulation of Th1/Th2 development of activated T cells. In
conclusion, alloreactive ICOS-/- donor T cells induce less GVHD due to
a Th2 immune deviation while GVL activity is slightly diminished.
PMID: 15956289
If these pubmed links break. Just enter that PMID # in the empty search
box.
****
And since IL-10 levels for psoriatics is sub par, most, if not all of
the time, that would mean we have to much ICOS?
We, being psoriatic, are Th1 skewed and alloreactive ICOS-/- T cells
are skewed to Th2 differentiation according to the abstract right
above.
This next article is taken from a p news post in October of 2004.
http://www.sciencedaily.com/releases/2004/10/041006080939.htm
(...)
The researchers also found that the two adaptive Tregs share certain
characteristics. Both appear to communicate their peacekeeping message
using the same language: they produce a chemical called IL-10 and
signal their desires through the same pipeline, known as the ICOS-ICOSL
regulatory pathway.
But the two types of Tregs exhibit intriguing differences. Umetsu said
each appears to be associated with a different helper T cell (Th cell).
Each Treg has a gene turned on that is also turned on in the
corresponding Th cell, and each Treg appears to be produced in greater
numbers when its corresponding Th cell responds to an intruder.
Although an excess of one of the Th cells is associated with autoimmune
diseases such as multiple sclerosis and type 1-diabetes, and an excess
of the other is linked to allergies and asthma, both Th cells cause
inflammation. In turn, the two Treg cells have the opposite effect.
"Both can help reduce airway inflammation," said Umetsu.
(...)
*********
Lets do a ICOS search with keyword ::: IL-10,
http://groups-beta.google.com/groups?q=icos+il-10&qt_s=Search
Big BingO!!
Gotta thank Billie Goldberg for her tireless HIV work!
Back to pumbed,
PMID: 15950746
Wow! Dexa/mexa, tacro/macro- i'm in blue heaven already. There is a
rhyme to
this rhythm.. We may have the long lost P gene link here.
We just had that factor 5A drug (enbrel + dexamethasone) link recently
and now this. But this has the TLR link as #2 and I put my money on LPS
and TLR-4? Am i off?
Oh my!
Lions, tigers and bears, Oh my!
We have strong uP regulation of TNF and IL-6 but not IL-10. So why not?
Ok. Time to get serious. A web search,
http://www.google.com/search?q=icos%20gene%20cells&qt_s=Search&lr=&sa=N&tab=gw
More BingO. Pasteur's of plenty. A cornucoPia of ICOS.
Wow! I only checked the first two sanger hits and the entrez/ncbi hit
and i'm imPressed.
This ICOS is key. It's key to IL-10 and thats what i've been hooked on
uPregulating for a few years now....
I'm gonna need to sPend a long time on ICOS genes...
Lets do a group IL-6, P TNF search,
http://groups-beta.google.com/groups?q=tnf+il-6+psoriasis&qt_s=Search
H'mmm. Hypermethylation? Could be. Save that one for later searches.
I'm really really really stoked this time!
Back to entrez, but first we'll check the mad cow diseased gene
page,
http://www.mad-cow.org/00/genbrow_table_col.html
(Nope no where near anything there. But it is CTLA connected big time
and that rings true for psoriasis like crazy. I'll search it for the
group now.)
CTLA and Psoriasis on Entrez, but first lets get more data off that
third
hit on the web search, this one,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=29851
(...)
1: ICOS inducible T-cell co-stimulator [Homo sapiens] MGC cDNA
clone, Links
GeneID: 29851 Locus tag: HGNC:5351; MIM: 604558 updated
04-Jun-2005
Official Symbol: ICOS and Name: inducible T-cell co-stimulator provided
by HUGO Gene Nomenclature Committee
Transcripts and products:
(...)
Gene aliases: AILIM; CD278; MGC39850
Summary: The protein encoded by this gene belongs to the CD28 and
CTLA-4 cell-surface receptor family. It forms homodimers and plays an
important role in cell-cell signaling, immune responses, and regulation
of cell proliferation.
(...)
OK. Lets do CD28 and CTLA-4 in the P newsgroup.
First CD28,
http://groups-beta.google.com/group/alt.support.skin-diseases.psoriasis/search?group=alt.support.skin-diseases.psoriasis&q=cd28&qt_g=1&searchnow=Search+this+group
And next CTLA-4,
http://groups-beta.google.com/group/alt.support.skin-diseases.psoriasis/search?group=alt.support.skin-diseases.psoriasis&q=ctla-4&qt_g=1&searchnow=Search+this+group
This is like that lost jigsaw puzzle piece that makes the picture
clear.
And that clearing is GONNA BE US. HIP HIP HOORAY.
Sorry, i'm getting excited already.
*****
Ok we've got data. Now go lets here and enter ICOS,
http://www.ncbi.nlm.nih.gov/gquery/gquery.fcgi
Lets open OMIN for this,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM&cmd=search&term=Icos
Then click # 10 (Roquin)
http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=609424
*609424
ROQUIN
Alternative titles; symbols
RC3H1
KIAA2025
TEXT DESCRIPTION
Roquin encodes a highly conserved member of the RING type ubiquitin
ligase protein family (Vinuesa et al., 2005). The roquin protein is
distinguished by the presence of a CCCH zinc finger found in
RNA-binding proteins, and localization to cytosolic RNA granules
implicated in regulating mRNA translation and stability. 30 MEDLINE
Neighbors
CLONING
Vinuesa et al. (2005) developed a systematic strategy to identify
mechanisms for repressing anti-self immune responses by treating male
C57BL/6 mice with ethylnitrosurea to generate single-base substitutions
in the germline, breeding the variant genome sequences to homozygosity,
and screening for autoimmunity with the standard clinical test for
antinuclear autoantibodies. The first pedigree identified was named
sanroque because of accompanying lymphadenopathy. The sanroque mice
were found to have an autoimmune disorder inherited as a simple
recessive trait that linked to a single locus on distal chromosome 1.
In that region the authors identified a previously uncharacterized
gene, which they designated roquin, that carried a nonconservative
missense substitution in sanroque mice. Roquin mRNA transcripts were
found ubiquitously. The roquin protein is predicted to be a
1,130-residue intracellular protein highly conserved across its full
length in mammals to invertebrates. The protein has an amino-terminal
RING-1 zinc finger at residues 14-53 that conforms perfectly to the
consensus for the E3 ubiquitin ligase family of proteins.
Carboxy-terminal to the RING finger (residues 131-360) is a highly
conserved novel protein domain (ROQ domain). A zinc finger domain of
the C-X8-C-X5-C-X3-H type (CCCH type) occurs in the middle of roquin
(residues 419-438). The CCCH domain sequence conforms exactly to the
RNA-binding zinc finger domains found in a range of proteins.
C-terminal to the CCCH domain is a proline-rich region, representing
potential sites for binding SH3 domains of interacting proteins, and 2
coiled-coil domains that could mediate homomultimerization or
heteromultimerization. On the basis of the unique combination of RING
and CCCH domains, the gene encoding the roquin protein has been
assigned the symbol RC3H1.
(...)
Wow, back to zinc fingers. It figures to go along with
hypermethylation.
(I'll do that search tomorrow or later to-night. I'm jazzed already.)
And in the reference section of the above we've gone full circle back
downunder, The OZ study that the P news article tied into... yeah,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=15917799
A RING-type ubiquitin ligase family member required to repress
follicular helper T cells and autoimmunity.
Vinuesa CG, Cook MC, Angelucci C, Athanasopoulos V, Rui L, Hill KM, Yu
D, Domaschenz H, Whittle B, Lambe T, Roberts IS, Copley RR, Bell JI,
Cornall RJ, Goodnow CC.
Division of Immunology and Genetics, John Curtin School of Medical
Research, The _____Australian____ National University, Canberra, ACT
2601, Australia. carola....@anu.edu.au
Despite the sequencing of the human and mouse genomes, few genetic
mechanisms for protecting against autoimmune disease are currently
known. Here we systematically screen the mouse genome for autoimmune
regulators to isolate a mouse strain, sanroque, with severe autoimmune
disease resulting from a single recessive defect in a previously
unknown mechanism for repressing antibody responses to self. The
sanroque mutation acts within mature T cells to cause formation of
excessive numbers of follicular helper T cells and germinal centres.
The mutation disrupts a repressor of ICOS, an essential co-stimulatory
receptor for follicular T cells, and results in excessive production of
the cytokine interleukin-21. sanroque mice fail to repress
diabetes-causing T cells, and develop high titres of autoantibodies and
a pattern of pathology consistent with lupus. The causative mutation is
in a gene of previously unknown function, roquin (Rc3h1), which encodes
a highly conserved member of the RING-type ubiquitin ligase protein
family. The Roquin protein is distinguished by the presence of a CCCH
zinc-finger found in RNA-binding proteins, and localization to
cytosolic RNA granules implicated in regulating messenger RNA
translation and stability.
PMID: 15917799
*******
Now lets go back and open up # 9 on the IL-10 connects.
http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=124092
INTERLEUKIN 10; IL10
Alternative titles; symbols
CYTOKINE SYNTHESIS INHIBITORY FACTOR; CSIF
Gene map locus 1q31-q32
TEXT
CLONING
Immune responses are specific for both the antigen against which they
are mounted and the class of response that is induced. For example,
humoral (antibody-mediated) and delayed-type hypersensitivity (DTH)
responses can be mutually exclusive. Tuberculoid leprosy is accompanied
by a strong DTH response that ultimately kills and clears the bacilli,
while in lepromatous leprosy, with weak cell-mediated immunity, the
organisms multiply and the disease persists. In mice there is a
cytokine synthesis inhibitory factor suggested by studies of helper
T-cell clones that differ in their effector functions and cytokine
secretion patterns. Vieira et al. (1991) demonstrated the existence of
human cytokine synthesis inhibitory factor, which is also called
interleukin-10. By study of cDNA clones encoding human IL10 isolated
from a tetanus toxin-specific human T-cell clone, they found that, like
mouse IL10, the human homolog exhibits strong DNA and amino acid
sequence homology to an open reading frame in the Epstein-Barr virus.
(...)
Wow wow wow.
Go half way down the page and you'll find the HIV links to, to much
IL-10.
I noticed that in the group search of ICOS and IL-10 as well!!!
**************
This may be the big one....
We love you down under BIG BRAINED scientists!!
randall... whats next? My grey cells are swimming! I don't know!
randall
Trying to continue somewhat the ICOS and Roquin theme from a few days
ago and what they may or not mean for psoriasis. Here are a few more
abstracts that may link to P.
A RING-type ubiquitin ligase family member required to repress
follicular helper T cells and autoimmunity.
Vinuesa CG, Cook MC, Angelucci C, Athanasopoulos V, Rui L, Hill KM, Yu
D, Domaschenz H, Whittle B, Lambe T, Roberts IS, Copley RR, Bell JI,
Cornall RJ, Goodnow CC.
Division of Immunology and Genetics, John Curtin School of Medical
Research, The Australian National University, Canberra, ACT 2601,
Australia. carola....@anu.edu.au
Despite the sequencing of the human and mouse genomes, few genetic
mechanisms for protecting against autoimmune disease are currently
known. Here we systematically screen the mouse genome for autoimmune
regulators to isolate a mouse strain, sanroque, with severe autoimmune
disease resulting from a single recessive defect in a previously
unknown mechanism for repressing antibody responses to self. The
sanroque mutation acts within mature T cells to cause formation of
excessive numbers of follicular helper T cells and germinal centres.
The mutation disrupts a repressor of ICOS, an essential co-stimulatory
receptor for follicular T cells, and results in excessive production of
the cytokine interleukin-21. sanroque mice fail to repress
diabetes-causing T cells, and develop high titres of autoantibodies and
a pattern of pathology consistent with lupus. The causative mutation is
in a gene of previously unknown function, roquin (Rc3h1), which encodes
a highly conserved member of the RING-type ubiquitin ligase protein
family. The Roquin protein is distinguished by the presence of a CCCH
zinc-finger found in RNA-binding proteins, and localization to
cytosolic RNA granules implicated in regulating messenger RNA
translation and stability.
PMID: 15917799
Roquins? Where does this come from?
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=7571865&query_hl=2
[Spelt wheat and celiac disease]
[Article in German]
Forssell F, Wieser H.
Deutsche Forschungsanstalt fur Lebensmittelchemie, Garching, Germany.
Spelt wheat (Triticum spelta L.) has not been investigated for the
toxicity on coeliac disease patients until now. Because clinical
studies are out of considerations for ethical reasons, spelt wheat and
coeliac-active bread wheat (Triticum aestivum L.) were compared by the
analysis of N-terminal sequences of alpha-gliadins, which have been
proposed to be responsible for the toxic effect. The gliadin fractions
of the spelt wheats 'Roquin' and 'Schwabenkorn' and of the bread wheat
'Rektor' were preparatively separated by RP-HPLC and major
alpha-gliadin components were then compared by N-terminal sequence
analysis. The results did not reveal any significant difference between
spelt and bread wheats within the first 25 positions. For the
determination of sequences further from the N-terminus, the gliadin
fractions of the spelt wheats were hydrolyzed with pepsin and trypsin.
The resulting peptides were successively separated by gel permeation
chromatography and RP-HPLC. Those peptides derived from the N-terminal
part of alpha-gliadins were identified by reference peptides isolated
previously from bread wheat [this journal 194: 229 (1992)]. Retention
times upon RP-HPLC and amino acid compositions of corresponding
peptides confirmed the identity of spelt and bread wheat concerning the
N-terminal sequences of alpha-gliadins from position 3 to 56. For these
reasons, it can be concluded that spelt wheat is a coeliac-toxic cereal
and has to be avoided by coeliac patients.
PMID: 7571865
A definite percentage of us have the wheat issue. Around 16% according
to
past studies. Is there something with it thats genetic thats been
missed?
******
Is there a wheat and LPS thing in the gut? May be an area to look into.
As to LPS itself, there are always new things turning up.
IL-12 turned on by LPS is the signal for stat here,
http://bio.ifom-firc.it/biobase/transpath/4.1/doc/doc/maps/IL12_STAT4.html
Same basic thing from biocarta,
http://www.biocarta.com/pathfiles/h_IL12Pathway.asp
http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=609424
(...)
ANIMAL MODEL
In an effort to identify autoimmune regulators in the mouse genome,
Vinuesa et al. (2005) isolated the sanroque strain, which exhibits
severe autoimmune disease with accompanying lymphadenopathy.
Sanroque-homozygous (san/san) females developed antinuclear
autoantibodies by 6 to 7 weeks of age and males by 8 to 16 weeks.
Additional testing revealed that sanroque mice had the following
features typical of systemic lupus erythematosus (SLE; 152700):
high-affinity antibodies against double-stranded DNA; focal
proliferative glomerulonephritis with deposition of IgG (see
147100)-containing immune complexes; necrotizing hepatitis; anemia; and
autoimmune thrombocytopenia in CBA sanroque mice. By 7 weeks of age,
all san/san mice developed an enlarged spleen and lymph nodes. In
sanroque mice, the roquin gene carries a T-to-G substitution resulting
in a nonconservative methionine-to-arginine codon change at position
199. The sanroque mutation acts within mature T cells to cause
formation of excessive numbers of follicular helper T cells and
germinal centers. The mutation disrupts a repressor of ICOS (604558),
an essential costimulatory receptor for follicular T cells, and results
in excessive production of the cytokine IL21 (605384). Sanroque mice
failed to repress diabetes-causing T cells.
(...)
And once again LPS rears its ugly mug again.
http://www.jem.org/cgi/content/abstract/201/12/1899
Interleukin (IL)-4 inhibits IL-10 to promote IL-12 production by
dendritic cells
Yongxue Yao1,2, Wei Li1,2, Mark H. Kaplan1,2, and Cheong-Hee Chang1,2
1 Department of Microbiology and Immunology, Indiana University School
of Medicine, Indianapolis, IN 46202
2 Walther Oncology Center, Indiana University School of Medicine,
Indianapolis, IN 46202
CORRESPONDENCE Cheong-Hee Chang: chec...@iupui.edu
Interleukin (IL)-4 is known to be the most potent cytokine that can
initiate Th2 cell differentiation. Paradoxically, IL-4 instructs
dendritic cells (DCs) to promote Th1 cell differentiation. We
investigated the mechanisms by which IL-4 directs CD4 T cells toward
the Th1 cell lineage. Our study demonstrates that the IL-4?mediated
induction of Th1 cell differentiation requires IL-10 production by DCs.
IL-4 treatment of DCs in the presence of lipopolysaccharide or CpG
resulted in decreased production of IL-10, which was accompanied by
enhanced IL-12 production. In IL-10?deficient DCs, the level of IL-12
was greatly elevated and, more importantly, the ability of IL-4 to
up-regulate IL-12 was abrogated. Interestingly, IL-4 inhibited IL-10
production by DCs but not by B cells. The down-regulation of IL-10 gene
expression by IL-4 depended on Stat6 and was at least partly caused by
decreased histone acetylation of the IL-10 promoter. These data
indicate that IL-4 plays a key role in inducing Th1 cell
differentiation by instructing DCs to produce less IL-10.
INDUCIBLE COSTIMULATOR
Good site for understanding immune and biological terms etc
http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=eurekah.section.26293
http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=604558
The ever present LPS reveals more about its structure,
http://jdr.iadrjournals.org/cgi/content/abstract/84/7/584
Lipopolysaccharide Heterogeneity: Innate Host Responses to Bacterial
Modification of Lipid A Structure
D.R. Dixon1,2, and R.P. Darveau1,*
1 Department of Periodontics, University of Washington, Health Sciences
Center, Box 357444, Seattle, WA 98195, USA; and
2 The United States Army Dental Corps;
* corresponding author,rdar...@u.washington.edu
The innate host response system is composed of various mechanisms
designed to detect and facilitate host responses to microbial
components, such as lipopolysaccharides (LPS). To enable this to occur,
innate systems contain multiple pattern recognition receptors (i.e.,
LBP, CD14, and TLRs), which identify certain features within bacterial
LPS that are foreign to the host, as well as essential and uniquely
specific for bacteria. Innate host identification of unique bacterial
components or patterns, therefore, relies on the inability of bacteria
to alter these essential or critical components dramatically.
Historically, LPS have been viewed as essential outer-membrane
molecules containing both a highly variable outer region (O-segment) as
well as a relatively conserved inner region (lipid A). However, over
the last decade, new evidence has emerged, revealing that increased
natural diversity or heterogeneity within specific components of LPS,
such as lipid A-resulting in minor to moderate changes in lipid A
structure-can produce dramatic host responses. Therefore, examples of
natural lipid A heterogeneity, and the mechanisms that control it,
represent a novel approach in which bacteria modulate host responses
and may thereby confer specific advantages to certain bacterial species
under changing environmental host conditions.
IL-4 sometimes works in reverse! While its supposed to balance out Th1,
it may not. As psoriasis needs to go back towards Th0 this next one
may explain P pathways in regards to Th1/Th2 rebalancing.
http://www.jem.org/cgi/content/full/201/12/1867
Indecisive interleukin-4? A study on page 1899 may explain the
seemingly fickle ways of the cytokine interleukin (IL)-4. Yao and
colleagues show how this quintessential T helper (Th) 2 cytokine can
sometimes promote the opposite Th1 response.
IL-4 is known as the key cytokine for polarizing naive T cells toward a
Th2 phenotype, which is important for antibody production and
protection against parasitic infections. Under some conditions,
however, IL-4 has been shown to instead induce a Th1 response. Indeed,
a recent study showed that mice treated with IL-4 during initial
infection with Leishmania major had increased Th1 responses and were
protected. If given later, IL-4 increased Th2 responses and exacerbated
disease.
Yao et al. now suggest that the regulation of another
cytokine?IL-10?may explain these perplexing observations. They show
that dendritic cells (DCs) stimulated in the presence of IL-4 made less
IL-10 than those stimulated without IL-4. As a result, the IL-4?treated
DCs produced more of the Th1-polarizing cytokine IL-12?known to be
inhibited by IL-10?and polarized naive T cells toward a Th1 phenotype
more effectively. IL-10 was critical for the increased Th1 response, as
IL-4 did not increase IL-12 production or T cell polarization by
IL-10?deficient DCs.
IL-4 had the opposite effect on B cells, provoking increased IL-10
production. The authors suggest that the differential effect of IL-4 at
different times during infection may reflect a switch from DCs to B
cells as the predominant cell type that is presenting antigen
(The study from page 1899): (also above)
http://www.jem.org/cgi/content/abstract/201/12/1899?ijkey=d528223fe46bac9a715f03f95fed08a51753ba0d&keytype2=tf_ipsecsha
And please recall that people are making bugs to pump out the IL-10
right now,
http://www.nature.com/drugdisc/news/articles/nbt0605-645.html
Will we be able to unskew ourselves? Going from Th1 to Th0?
Not without knowing the exact pathway and what damage to other
homeostatic pathways we may be inadvertently thwarting.
Raise the Tregs for Th2/ cancer. But what about tregs and psoriasis?
Since we are Th1 do we need to lower the Tregs? And how do we do
that?
http://www.genengnews.com/news/bnitem.aspx?name=555199XSL_NEWSML_TO_NEWSML_WEB.xml
(...)
NeuroVax(TM), stimulated a significant increase in FOXP3, a gene marker
recently shown to track regulatory T-cells (Treg cells). The new data,
presented yesterday at the European Neurological Society (ENS) in
Vienna, demonstrated that monthly NeuroVax(TM) injections during a
one-year period increased the FOXP3 marker and Treg cell functional
activity in MS patients to a level equivalent to that seen in healthy
controls. Recently published research indicates that FOXP3, known to be
associated with maintaining immune tolerance and regulation of
autoimmune diseases, is significantly reduced in patients with MS
compared to healthy controls.
(...)
http://www.sciencedaily.com/releases/2004/10/041006080939.htm
(...)
But Umetsu and his colleagues found that both the adaptive and natural
Tregs depend on a gene called Foxp3. When this gene doesn't function
properly in humans, they lack natural Tregs and develop an autoimmune
disorder called IPEX Syndrome, which includes severe allergies among
its symptoms. By identifying this gene in the adaptive Tregs, the
researchers add credence to the idea that nonfunctional or inadequate
Tregs lead to allergies.
The researchers also found that the two adaptive Tregs share certain
characteristics. Both appear to communicate their peacekeeping message
using the same language: they produce a chemical called IL-10 and
signal their desires through the same pipeline, known as the ICOS-ICOSL
regulatory pathway.
But the two types of Tregs exhibit intriguing differences. Umetsu said
each appears to be associated with a different helper T cell (Th cell).
Each Treg has a gene turned on that is also turned on in the
corresponding Th cell, and each Treg appears to be produced in greater
numbers when its corresponding Th cell responds to an intruder.
Although an excess of one of the Th cells is associated with autoimmune
diseases such as multiple sclerosis and type 1-diabetes, and an excess
of the other is linked to allergies and asthma, both Th cells cause
inflammation. In turn, the two Treg cells have the opposite effect.
"Both can help reduce airway inflammation," said Umetsu.
"We have now found several subtypes of regulatory T cells," he added,
"and we are proposing how these are all interrelated. We believe this
study provides a scaffold for future studies of regulatory T cells."
****
FoxP3 is high for psoriasis?
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15611238&query_hl=4
Dysfunctional blood and target tissue CD4+CD25high regulatory T cells
in psoriasis: mechanism underlying unrestrained pathogenic effector T
cell proliferation.
Sugiyama H, Gyulai R, Toichi E, Garaczi E, Shimada S, Stevens SR,
McCormick TS, Cooper KD.
Department of Dermatology, University Hospitals of Cleveland and Case
Western Reserve University, 11100 Euclid Avenue, Cleveland, OH 44106,
USA.
The balance between regulatory and effector functions is important for
maintaining efficient immune responses, while avoiding autoimmunity.
The inflammatory skin disease psoriasis is sustained by the ongoing
activation of pathogenic effector T cells. We found that a CD4(+) T
lymphocyte subpopulation in peripheral blood, phenotypically
CD25(high), CTLA-4(+), Foxp3(high) (regulatory T (Treg) cells), is
deficient in its suppressor activity in psoriasis. This was associated
with accelerated proliferation of CD4(+) responder T cells in
psoriasis, the majority of which expressed CXCR3. Nevertheless,
criss-cross experiments isolated the defect to psoriatic Treg cells. To
examine Treg cells in a nonlymphoid tissue of a human T cell-mediated
disease, Treg cells were also analyzed and isolated from the site of
inflammation, psoriatic lesional skin. At the regulatory vs effector T
cells ratios calculated to be present in skin, however, the psoriatic
Treg cell population demonstrated decreased suppression of effector T
cells. Thus, dysfunctional blood and target tissue CD4(+)CD25(high)
Treg cell activity may lead to reduced restraint and consequent
hyperproliferation of psoriatic pathogenic T cells in vivo. These
findings represent a critical component of human organ-specific
autoimmune disease and may have important implications with regard to
the possible therapeutic manipulation of Treg cells in vivo.
PMID: 15611238
Lipopolysaccharide induces CD25-positive, IL-10-producing lymphocytes
without secretion of proinflammatory cytokines in the human colon: low
MD-2 mRNA expression in colonic macrophages.
Shirai Y, Hashimoto M, Kato R, Kawamura YI, Kirikae T, Yano H,
Takashima J, Kirihara Y, Saito Y, Fujino MA, Dohi T.
Department of Gastroenterology, Research Institute, International
Medical Center of Japan, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655,
Japan.
Despite the huge number of colonized Gram-negative bacteria in the
colon, the normal colon maintains its homeostasis without any excessive
immune response. To investigate the potential mechanisms involved,
human colonic lamina propria mononuclear cells (LPMCs) obtained from
uninflamed mucosa were cultured with lipopolysaccharide (LPS) prepared
from Bacteroides vulgatus (BV-LPS) or Bacteroides fragilis (BF-LPS), as
representatives of indigenous flora, or pathogenic Salmonella minnesota
(SM-LPS). Colonic LPMCs failed to produce inflammatory cytokines in
response to any type of LPS. Colonic macrophages barely expressed mRNA
for MD-2, an essential association molecule for LPS signaling via
Toll-like receptor 4. Further, BV-LPS induced CD25 and Foxp3 expression
in lymphocytes and CD4(+)CD25(+) cells expressed IL-10 mRNA. Thus, the
low expression of functioning LPS receptor molecules and induction of
IL-10-producing CD4(+)CD25(+) lymphocytes by indigenous LPS may play a
central role in the maintenance of colonic immunological homeostasis.
PMID: 14997033
Well OK. But this is curious. Where is that IL-10 for psoriatics? Isn't
it lacking?
Is it something with our T cells?
http://www.stresstips.com/tcells.htm
As they pumP out to much of the wrong cytokines?
http://pim.medicine.dal.ca/cytok.htm
The grand-daddy of immune drugs, (Cyclosporin)
http://www.world-of-fungi.org/Mostly_Medical/Harriet_Upton/Harriet_Upton.htm
And more current areas and pathways to tweak,
Ctla-4
http://www.wellcome.ac.uk/en/genome/genesandbody/hg06n004.html
(...)
?CTLA-4, or the genes on the same pathway, are potential targets for
therapy, as the gene variant is found in a majority of those who are
susceptible to autoimmune disease.?
(...)
On the groups for CTLA-4 & P,
http://groups-beta.google.com/groups?q=ctla-4+psoriasis&qt_s=Search
Taking out the triggers? Is this next one a likely P helper?
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15944258&query_hl=2
Tetrahydro-4-aminobiopterin attenuates dendritic cell-induced T cell
priming independently from inducible nitric oxide synthase.
Thoeni G, Stoitzner P, Brandacher G, Romani N, Heufler C,
Werner-Felmayer G, Werner ER.
Biocenter, Division of Biological Chemistry, Department of Dermatology
and Venerology, and Division of General and Transplant Surgery,
Department of Surgery, Innsbruck Medical University, Innsbruck,
Austria.
Formation of NO by NO synthases (NOSs) strictly depends on
tetrahydrobiopterin. Its structural analog,
tetrahydro-4-aminobiopterin, is an inhibitor of all NOS isoenzymes,
which prolongs allograft survival in acute murine cardiac rejection and
prevents septic shock in the rat. In this study, we show that murine
bone marrow-derived dendritic cells treated with
tetrahydro-4-aminobiopterin had a reduced capacity to prime
alloreactive murine T cells in oxidative mitogenesis. Checking for a
possible influence on LPS-induced dendritic cell maturation, we found
that tetrahydro-4-aminobiopterin down-regulated MHC class II expression
and counteracted LPS-induced down-regulation of ICOS ligand, while
expression of CD40, CD86, CD80, B7-H1, and B7-DC remained unchanged.
Tetrahydro-4-aminobiopterin also reduced activation of CD4(+) T cells
isolated from mice overexpressing an OVA-specific TCR by OVA-loaded
murine bone marrow-derived dendritic cells, thus indicating that its
effect on MHC class II expression is involved in attenuating T cell
activation. In line with affecting dendritic cell function and T cell
activation, tetrahydro-4-aminobiopterin impaired production of
proinflammatory cytokines and the Th1 response. With regard to cell
survival, tetrahydro-4-aminobiopterin induced efficient apoptosis of
murine T cells but not of murine dendritic cells. Experiments with
cells from inducible NOS (iNOS) knockout mice and with
N(6)-(1-iminoethyl)-l-lysine, a specific inhibitor of iNOS, ruled out
participation of iNOS in any of the observed effects. These findings
characterize attenuation of T cell stimulatory capacity of murine bone
marrow-derived dendritic cells as an immunosuppressive mechanism of
tetrahydro-4-aminobiopterin that is not related to its iNOS-inhibiting
properties.
PMID: 15944258
What is tetrahydro-4-aminobiopterin? and how does it stop NOS? Lets
check the RA (related articles on this one).
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Display&dopt=pubmed_pubmed&from_uid=15944258&tool=ExternalSearch
How do i get some into my gut, i'm now wondering. And will it kill me.
lol
Lets find it,
http://www.biochemj.org/bj/320/0193/bj3200193.htm
http://www.jbc.org/cgi/reprint/M302238200v1
This is a full test article of this next pubmed citation,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=retrieve&db=pubmed&list_uids=12740377&dopt=Abstract
At this point. Since it's back to the gut. One way to stop the bugs in
the gut
that make their living and influence your genetic activations is to
take away
their fuel. And that is easy. Take IP-6 to block the iron. You can also
get
other foods and supplements to further this theme. But the IP-6 is and
has
been a good ally in this bad bug gut battle. It doesn't win the war and
Cure you!
But in the continuing P battles its a tank or wart hog. Doing great
damage to
the enemy within.
And that does unskew the Th1 leaning gut somewhat. And lower the
flares of P.
Its nice to know whats actually going on down there.
*************************
One of my buds from this group is testing melatonin. So I thought
he would like these links to think over.
Why might thrill-seeking be more of a modern phenomenon?
There's some evidence dopamine receptor levels are linked to insulin
resistance and overeating. Eating activates the brain's reward pathways
and increases levels of dopamine. Obese individuals have fewer dopamine
receptors in the brain. I don't know if it's been determined that these
individuals lost these receptors due to overeating or they overate
because they were low to begin with.
I also don't know if non-obese individuals with insulin resistance are
similarly affected. They might be because there are connections between
the two. GSK-3b is activated with insulin resistance. Antipsychotics
like clozapine act to inhibit GSK-3b [OMID 15737699]. Variations in the
D2 receptor of psychotics can make them hypersensitive to dopamine.
There are age-dependent drops in D2 receptors which adversely affect
cognitive skill learn but can be reversed by D2/D3 agonist piribedil
[PMID 15138753]. Anti-addictive medicines like bupropion also act on
dopamine receptors.
And of course antioxidants like melatonin protect neurons from dopamine
depletion during toxic exposure.
*********
<http://www.nytimes.com/2005/06/20/health/menshealth/20friedma.html>
(you need to register with this site)
What's the Lure of the Edge?
By RICHARD A. FRIEDMAN, M.D.
Published: June 20, 2005
The root of the thrill-seeking experience lies in an ancient neural
circuit buried deep inside the brain that is intimately involved in
pleasure, reward and novelty seeking. This system, which connects our
thinking cortex with our more primitive limbic emotional center, runs
on
dopamine, a neurotransmitter. Many of life's greatest pleasures feel
good because, in the end, they cause the release of dopamine from the
brain's reward pathway. Sex, food and recreational drugs all flood the
brain with dopamine - and so does thrill seeking.
Like just about every other human attribute, there is great variation
in
individual taste for novelty and thrill seeking, much of it rooted in
the brain. For example, Dr. Nora Volkow at the National Institute on
Drug Abuse has shown that response to euphoria-producing drugs is
related to the levels of brain dopamine receptors.
In one experiment, she gave normal male controls intravenous Ritalin,
which releases dopamine, and found that those who experienced the drug
as pleasant had significantly fewer dopamine receptors than
participants
who reported unpleasant effects. Those with more dopamine receptors at
baseline are probably less likely to abuse drugs or seek any thrill
because their brains already have more dopamine activity to start with.
In fact, these guys are likely to be thrill-averse, like that fellow I
met on the zip line.
For the chronically underaroused, a simple bike ride or jog in the park
doesn't do the trick; it would take something more intense like diving
50 feet into a gorge or snorting cocaine to provide them with enough
dopamine for them to feel excited.
...
But what about thrill-averse guys? Can they learn to enjoy a little
more
excitement? If so, would thrilling activity itself change their neural
circuitry to make them more like thrill lovers?
Probably not, judging from studies of Dr. Jerome Kagan at Harvard, who
has shown that certain temperamental traits you are born with are
pretty
stable. Using M.R.I. brain scanning, Dr. Carl Schwartz at Harvard
recently found that these anxious adults showed greater responses in
the
amygdala, a brain region that processes fearful and threatening
stimuli,
to faces of strangers than to familiar faces. In other words, people
who
like novelty have biologically different brains than cautious folks,
and
no one knows if experience changes this.
Of course, the surge of dopamine that thrill seekers search out can
literally be addicting. The reason is that anything that activates our
reward system, whether it's a natural reinforcer like sex, food or a
thrilling act, is seen by the brain as something that should be
repeated
- over and over. And despite how smart we think we are, our brain can't
really distinguish among the activating effects of drugs, thrill or
useful behaviors. Even worse, for some people, drugs and thrill are
more
powerfully self-reinforcing than even food and sex. So the very design
of our brain that promotes survival also makes us vulnerable.
...
But few forms of thrill are as insidiously destructive as gambling.
Recently, scientists have peered into the brain while people are
playing
a game that simulates gambling. Dr. Hans Breiter at Harvard had
subjects
play a computer game of chance in which they either won or lost money,
and monitored their brain activity. He found that the prospect of
winning money activates the same dopamine reward pathway in the brain
as
recreational drugs like cocaine do. No wonder gambling is so
compelling.
This also helps explain why gamblers, like drug addicts, often seem
helpless to resist an impulse that brings intense pleasure but can ruin
their lives.
Curiously, winning the prize is not what seems to make gambling so
thrilling and addictive. Dr. David Zald at Vanderbilt University
measured dopamine release in a group of subjects who played a computer
game in two different conditions. In the first, subjects selected one
of
four cards and knew they might win a $1 reward, but didn't know when it
might occur. In the second, subjects knew ahead that they were
guaranteed to win $1 with every fourth card.
Dr. Zald found a large increase in dopamine activity when winning was
unpredictable, but not when the subjects knew what was coming. The
implication is that gambling is powerfully addictive precisely because
the outcome is uncertain.
Believe it or not, thrill seeking is pretty much a modern phenomenon.
Our hominid ancestors did not bungee jump or do any of the silly things
that we do these days for thrill. Life back on the savannah was
exciting
enough on its own, with ferocious predators and an overall lack of
amenities.
Nowadays, where the basics like food or a sexual partner are a mouse
click away, we don't really need our reward circuit for survival; we
are
free to use it just for pleasure. (To determine your risk comfort
level,
you can try a test adapted from the Zuckerman-Kuhlman Personality
Questionnaire at nytimes.com/menshealth.)
With few exceptions, like 9/11, modern life has become so safe and
controlled that you have to work at finding a little excitement. In
fact, one might predict that as life becomes more predictable, riskier
forms of excitement will emerge. Hang gliding off Mount Everest?
Antarctic triathlon? There's no telling what's next.
*******
How about a herb to toP this post off?
Bacopa monniera, a reputed nootropic plant: an overview.
Russo A, Borrelli F.
Department of Biological Chemistry, Medical Chemistry and Molecular
Biology, University of Catania, Catania, Italy. alr...@unict.it
Bacopa monniera (BM), a traditional Ayurvedic medicine, used for
centuries as a memory enhancing, anti-inflammatory, analgesic,
antipyretic, sedative and antiepileptic agent. The plant, plant extract
and isolated bacosides (the major active principles) have been
extensively investigated in several laboratories for their
neuropharmacological effects and a number of reports are available
confirming their nootropic action. In addition, researchers have
evaluated the anti-inflammatory, cardiotonic and other pharmacological
effects of BM preparations/extracts. Therefore, in view of the
important activities performed by this plant, investigation must be
continued in the recently observed actions described in this paper.
Moreover, other clinical studies have to be encouraged, also to
evidence any side effects and possible interactions between this herbal
medicine and synthetic drugs.
Publication Types:
* Review
* Review, Tutorial
PMID: 15898709
http://www.motherherbs.com/bacopa-monniera.html
Picture of flower and plant,
http://jerrycott.com/user/Bacopa-A-Flower.jpg
>From this site,
http://jerrycott.com/IntegrativePsychiatry.html
Looks like a good plant database for Integrative pyschiatry links.
I like the page for the dr. James Duke (duke of herbs page) link,
http://www.ars-grin.gov/duke/
Phytochemical and Ethnobotanical Databases
Dr. Duke is the duke of herbs,
http://abcasiapacific.com/englishbites/stories/s692079.htm
Buy his books on amazon,
http://www.amazon.com/exec/obidos/tg/detail/-/1579541836/104-7066353-2468708?v=glance
SuPPort the herbal cause,
http://www.healthactioncenter.org/action/index.asp?step=2&item=18077
Found 60% of the way down the next page,
http://jerrycott.com/IntegrativePsychiatry.html
Other Psychotherapeutic Plants:
* Ashwaganda (Withania somnifera)
* Passion flower (Passiflora incarnata) Clinical trials: PDF PDF2
* Lavender (Lavandula sp.)
* Skullcap (Scutellaria lateriflora)
* Bacopa monniera (Brahmi) Clinical trials: PDF PDF2
* Rauwolfia serpentina (the first antipsychotic)
* Evening Primrose (Oenothera biennis, seed oil)
* Flax (Linum usitatissimum, seed oil)
* Ginseng (Panax quinquefolius)
* Galanthus nivalis (galanthamine) Abstract
* Vinpocetine (Vinca minor) Info: PDF PDF2
* Cognitive Enhancers?
Keyword web search:: [ icos gene cells lps myd88 hypermethylation ]
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?/cmd=Search&db=OMIM&doptcmdl=Detailed&term=?161561
(...)
The observed Th1 deficiency did not appear to be a result of a defect
in the IL12 receptor, as both subunits of the receptor were expressed
normally in activated T cells, and the cells proliferated in response
to IL12 stimulation. Chen et al. (2000) proposed that TCCR and its
potential ligand are candidate targets for intervention in Th1-mediated
autoimmune disease and allograft rejection.
(...)
The Eurekah.com section of NCBi,
http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=eurekah.section.26293
Psoriasis requires more IL-10,
http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=eurekah.section.22627
IS the P fix gonna be a TEN. Like in IL-10 (Interleukin 10)?
http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=eurekah.section.22630
This bookshelf section of ncbi is pretty cool. I did the P search and
here it is,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Books&cmd=Search&term=psoriasis+AND+eurekah%5Bbook%5D&doptcmdl=DocSum
What about IL-12 then? Lets do the group on it again,
http://groups-beta.google.com/groups?q=IL-12+stat++psoriasis&qt_s=Search
****
Sorry. Starting to go in circles. Just like the inflammation in side of
us.
randall
randall
>
> Is there a wheat and LPS thing in the gut? May be an area to look into.
>
So. We venture off on a new area of inquiry. Yee ha!
I did the pubmed search not expecting to find much. Using keywords::
LPS + wheat, seems rather odd and not much like a match.
Well.
You be the judge.
Wheat gluten causes dendritic cell maturation and chemokine secretion.
Nikulina M, Habich C, Flohe SB, Scott FW, Kolb H.
German Diabetes Research Institute at the Heinrich-Heine-University of
Dusseldorf, Duesseldorf, Germany.
Wheat gluten causes gut inflammation in genetically predisposed
individuals. We tested the hypothesis that wheat gluten is not only a
target of adaptive immunity, but also modulates the function of APC.
Dendritic cells (DC) derived from the bone marrow of BALB/c mice were
exposed to chymotrypsin-treated wheat gluten. This induced DC
maturation as estimated by all surface markers tested (MHC class II,
CD40, CD54, and CD86). The effect was dose dependent, and, at 100
microg/ml gluten matched that caused by 10 ng/ml LPS. A role of
endotoxin contamination was ruled out by demonstrating the resistance
of wheat gluten effects to LPS antagonist polymyxin B. DC from LPS
nonresponder strain C3H/HeJ were affected by wheat gluten, but not by
LPS. Proteinase K-digested wheat gluten was unable to stimulate DC
maturation. Wheat gluten induced a unique secretion pattern of selected
cytokines and chemokines in DC. Classic pro- or anti-inflammatory
mediators were not produced, in contrast to LPS. Rather, chemokines
MIP-2 and ___keratinocyte-derived___(*) cytokine were secreted in large
amounts. We conclude that wheat gluten lowers the threshold for immune
responses by causing maturation of APC, by attracting leukocytes and
increasing their reactivity state. In the presence of an appropriate
genetic predisposition, this is expected to increase the risk of
adverse immune reactions to wheat gluten or to other Ags presented.
PMID: 15265926
(*)
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=7615975
Keratinocyte-derived vascular permeability factor (vascular endothelial
growth factor) is a potent mitogen for dermal microvascular endothelial
cells.
<sniP>
UNREAL!
Wheat bumps up the DC's to pump out their cytokines and MIP2
chemokines.
So? Is their where the broken P gene hangs its hat?
MIP2 could be a chlamydia and P thing,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15368304&query_hl=9
I'll need to look at this search later,
http://www.google.com/search?hl=en&lr=&biw=1182&q=chemokine+KC+gro-alpha+mip&btnG=Search
This is to easy. How about the RA (related articles) on the wheat
abstract.
One click away and right here,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Display&dopt=pubmed_pubmed&from_uid=15265926
Yep! And all fitting right into the known triggers and making more
sense of Th1 and LPS. Indirectly or not, all P genes don't have to do
much more then
add to inflammation one way or the other.
And all we need to do is find the weak link and break it.
And I'm still hanging my hat on making more IL-10 in the guts,
to do just that. :)
And if i had more time i'd make this post longer then the last.
randall... aren't you lucky!
Pi
>> Is there a wheat and LPS thing in the gut? May be an area to look into.
>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15265926&query_hl=3
>Wheat gluten causes dendritic cell maturation and chemokine secretion.
So eat no more bread? And no pasta? What would that do for P?
Pieter
randall
The last two P news posts mainly dealt with the roquin gene, till I
found a
type of spelt wheat called roquin. I falsely assumed they had more in
common
then just name.
http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=609424
&
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=7571865&query_hl=2
When one doesn't have enough time to adequately research this
stuff it's easy to jumP to conclusions. And when there false, it simply
goes over the grouP head. ;-0
"Wake uP head!" lol
Oh well! Yet it was ironic to find that noncongruous link. As Psoriasis
and gliadin (13 hits) and gluten (24 hits), on pubmed, do act as
triggers for a modest
amount of psoriatics. A figure of 16% is mentioned around here-- now
and then,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14690336&query_hl=4
&
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10651693&query_hl=4
&
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8286249&query_hl=4
And you can see where that comes from. <g>
While i'm more or less aware of my gliadin trigger, other lectins are
less well understood. There are 175 hits for a pumbed search of
[ psoriasis + lectin ] ,
And the most recent,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15914319&query_hl=2
And ironic again is the fact that we've had 100 less hits in our own
group on
this toPic,
http://groups-beta.google.com/group/alt.support.skin-diseases.psoriasis/search?group=alt.support.skin-diseases.psoriasis&q=lectins&qt_g=1&searchnow=Search+this+group
Not to get hung up on these items.
Other current items in the P news?
Lets take IL-10 and LPS for instance. In pubmed there are two abstracts
for P and IL-10/LPS. Yet over 106 abstracts for IL-10 and Psoriasis.
A few current abstracts,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15180472&query_hl=4
(...)
In conclusion IL-10 seems to have major importance in psoriasis.
Further investigations, in particular multicenter, placebo-controlled,
double blind trials are required to fully determine whether IL-10
application will become a successful antipsoriatic therapy.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15667561&query_hl=4
Interleukin-24 and its receptors.
Wang M, Liang P.
Department of Cancer Biology, Vanderbilt University School of Medicine,
Nashville, TN 37232, USA.
Interleukin 24 (IL-24) is a new member of the IL-10 family of cytokines
and it signals through two heterodimeric receptors: IL-20R1/IL-20R2 and
IL-22R1/IL-20R2. Upon binding to its receptors, IL-24 induces rapid
activation of Stat-1 and Stat-3 transcription factors, which appear to
play a role in cell survival and proliferation. Under physiological
conditions, the major sources of IL-24 are the activated monocytes and
T helper 2 cells, whereas the major IL-24 target tissues, based on the
receptor expression pattern, are non-haematopoietic in origin, and
include skin, lung and reproductive tissues. Structurally and
functionally, IL-24 is highly conserved across species. This review
highlights our current knowledge of IL-24 as a cytokine, with much less
emphasis placed on the non-receptor-mediated functions (a subject of
several reviews) focused on in much of the earlier literature on IL-24.
The potential roles of IL-24 as part of a complex cytokine network in
wound healing, psoriasis and cancer are discussed.
PMID: 15667561
While there is good IL-10 and IL-24 info out there,
http://www.rndsystems.com/mini_review_detail_objectname_MR03_Interleukin-10.aspx
I'm not finding it for psoriasis. And if you knew 20 different ways to
make more
IL-10 naturally, wouldn't you be doing a few more out of curiosity if
not anything
else?
Just hanging out in the sunshince makes more IL-10.
So your doing it already! But, do you do it enough?
Well, when the uvb is getting thru along with the normal rays, you are,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15889264&query_hl=5
For all we know. Eating some sesame oil may help out,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15626481&query_hl=7
Then again, one should do some due deligence in the newsgroups as well
as
the web before coming to any conclusions on anything,
Sesame oil could be evil devil stuff like soy bean oil (n-6). For all
you know.
How do you make uP your mind? To oPen sesame or not?
You ask and ye shall find. Ask google!
And the wider search of all groups. (The first hit on pagano is very
interesting!)
http://groups-beta.google.com/groups?q=sesame+psoriasis&qt_s=Search
There you go.
You choose the lectins/gliadins you consume or not.
The amount of Vitamin D rich sunshine that finds your naked skin.
The stress in and on your body.
etc.
But no one is telling you how to stoP your guts from leaking endotoxins
made by the gut flora in your colon right now...
Wait.
There is one person.
And he even told you how to alter the ratio of good to bad gut bugs. So
as to slow
that leak .
And that is for another post.
randall... Oh wait! That other post has been done! A zillion X's.
randall
This is from a series of emails and replys recently from a fellow
psoriatic and his trials and travails with (p). He will be known
as [x] and i will play (R).
Hi Randall:
It's now been 2 1/2 months since I've been back from my 1 month sun
experiment. The psoriasis is slowly returning, as I expected, but not
nearly as fast as it has in the past and so far, it's only come back as
very small dry spots except on my ankle where it's a bit more patchy.
[my reply:(R)] I've always wondered about gravity and P ankles? And if
so, then why aren't the feet worse off? Mine spot and the spots never
patch up. So, its like a guttate spot that warns of current
inflammation that is attempting
to spread, but then doesn't. Must be mechanical at that point. Not
enough angiogenic factors. But then why are knees and elbows conducive
to producing nice life long plaques? Is it an oxygen thing from outside
sources?
[X said} I've been keeping my tanning up once or twice a week to stay
darkish and I'm still eating lots of fish and also adding fish oil to
my regime. The sun thing keeps bringing me back to the Pineal gland
that produces the melatonin and seratonin in our bodies. If the sun
stimulates the Pineal gland to produce more melatonin, then doesn't it
make some sense that the key might have something to do with that gland
not functioning properly in some of us???
(R) > I've done my experiments with melatonin. and that led to leptin
experiments and from there to so many things its not funny any more.
Right now i'm doing high fiber, supplements and not worrying about the
current levels which are a little higher then i'd like. So, i need to
take time to go to the beach. Get in the water now and then and i'll
clear all the way for sure. :)
[x] This is an interesting article on melatonin and free radicals and
I'm wondering if that's why the tanning booth works for some us as
well, as long as we go often enough. Just wondering what you think.
http://members.aol.com/profchm/kreska.html
(R)> Thanks for the link. I scanned it and will ponder it once again. I
do love the stuff (melatonin) and have 2 and one third bottles of
Schiff's 1 mg. size of 300 tablets each hanging around and i did take
it the last two nights. My oldest son is using it now
as well occasionally. Which looking back, I wish i had had access to at
his age. To many nights spent reading all night.
(R)> Hope all else is well with you. Have you tried IP-6 yet? I'm about
to add it back into my program for the n-th time. It really helps. Take
about a half gram in the AM one hour before any food ... Goes back to
iron issues. Which may be looming even larger then the calcium ones. As
iron feeds the bad gut flora and i stick by my good/bad
gut bug ratio theory for living life as a mild psoriatic. :)
As in skewing yourself towards a positive level of gut flora will keep
your
p in the mild regions. And with tanning during the summers will take
one to
nearly clear. If your gonna be psoriatic you may as well be a mild one.
******
[x] in his next email said:
"I wrote back to you saying that I'm trying to keep my regimen as
simple as possible but here's my question.
I'm not at all disagreeing that the gut is involved in psoriasis, but
this is what I can't understand. I told you when I was away for a month
down South, the psoriasis almost completely disappeared even though I
was eating and drinking like a pig and gained 10 pounds over the month
period. I was eating bacon, eggs, french toast, desserts, ice cream,
and tropical drinks and wine. Now I know I was over indulging in the
food and drink department, but I think I was also trying to find out
just how much in my case is gut related and how much is sun/heat
related. I also became constipated for a few days now and then due to
the crappy food, pardon the pun, but like I say still cleared
significantly.
Do you have any explanation as to why I could torture my body like that
but still experience clearing at the same time if our problem stems
from our gut? I can't seem to put it all together.
Thanks,
XXXXXXX"
*****
To which I replied,
"How many times do to I have to say that the sun trumPs all other P
pathways?
With the possible exceptions of a few Jokers now and then.
I even said it today. In my last P news post.
And gave the reason why.
The sun via UVB causes more IL-10 in the body.
And that slows down the Th1 skew. No more huge TNF spew. All because of
IL-10.
Don't worry. You'll forget this as its intangible, right after your
done reading this. lol
******
And his reply,
Thanks for your reply Randall. Don't get me wrong, I do understand the
IL-10 relationship but if that's the case then why do I have to go so
far down south to get the benefit. In my case it's been Cuba, Costa
Rica and Puerto Vallarta Mexico. I travelled to Arizona in 2000 staying
for close to 3 weeks, getting quite a bit of sun but seeing almost 0%
improvement??? So is it all to do with the intensity of the sun?
As I say, I can understand how IL-10 can slow down the bad guys in our
situation and thanks for answering that, but what's up with only
clearing significantly in more Caribbean sun regions? Less stress and
more of a chance to let the body heal properly? Oh how I wish the
answer could be a simple one.
Anyway, thanks for your time once again."
******
(R)
My _simPle_ reply,
Sorry Dude,
There isn't a simple answer yet.
The sun mostly works till it doesn't.
And the why is still an unknown.
I only wished i knew.
How do you like XXXXX? was it worth going there?
********
That was my last email. His next one was travel talk.
********
(R)
So what are the answers?
we've had many folks who cleared in the troPics or the
big hole in the ground, called the Dead Sea.
Seems rather exPensive to go travel half way around the
world to get clear for a few months or so.
When you can go get some NB-uvb at your derms office, down the street.
Or in your light booth at home or anywhere the sun shines
on your skin.
Yet sometimes the light doesn't shine the way its supposed
to. You know... clear you the way you expected. Or it didn't
seem to last long enough once you returned home from that vacation
or course of treatment at your derms office.
So why does it lose its clearing effects? Heck, why do the
retinoids (vitamin D drugs) lose their effects as well?
And why do they all have side effects?
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15968262&query_hl=2
Are we really trumPing the inflammatory P pathways? Or are
we holding back the inevitable till some future date?
And why am I asking why?
randall... why not?
randall
There seems to be a dearth of P news that aPPeals to me this weekend.
I'll try pubmed.
And,
About the same over there.
This is the only thing that looked interesting.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15973592&query_hl=1
CBP-1011 (InKine Pharmaceutical Co).
Gionchetti P, Rizzello F.
Department of Internal Medicine and Gastroenterology, 59 Via S Vitale,
University of Bologna, Italy. pa...@med.unibo.it.
CBP-1011 (medroxyprogesterone acetate) is an immunosuppressant
corticosteroid under development by InKine Pharmaceuticals (formerly
CorBec Pharmaceuticals) for the potential treatment of a number of
inflammatory conditions. Phase III trials are underway in the US for
the treatment of idiopathic thrombocytopenic purpura [234943]. By
December 2000, it had completed phase II trials for the treatment of
inflammatory bowel disease (IBD) including Crohn's disease (CD) and
ulcerative colitis (UC) [393219]. In March 2001, the FDA designated
CBP-1011 an Orphan Drug for the treatment of thrombocytopenic pupura
[400935]. In June 2000, InKine reported that a US patent (subsequently
identified as US-06068983, entitled 'Methods of stimulating
phagocytosis' and assigned to University of Pennsylvania) had been
issued to Alan D Schreiber MD, Chairman of InKine's Scientific Advisory
Board. The patent describes methods of increasing Fc receptors on white
blood cells or macrophages, as well as inducing Fc receptors in cells
that do not normally possess them, such as lung and liver cells
[370990]. In April 2001, the University of Pennsylvania (inventor again
Alan D Schreiber) claimed the use of medroxyprogesterone acetate for
treating IBD, CD, UC, food allergies, hemorrhoids and psoriasis in
WO-00122959, entitled 'Method of treating inflammatory conditions with
progesterone or progesterone analogs'.
PMID: 15973592
What the heck is WO-00122959?
Nothing about it on google.
I'll pull out the BIG search engine,
http://pinch.com/skin/
Ed's site really is without equal for the serious inquiry of all things
P!
But,
I'm not finding it there either. Oh well. I won't worry about it for
now.
Lets see what this stuff can do for P.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12848589&query_hl=1
(...)
CBP 1011 or medroxyprogesterone, is a progesterone agonist and inhibits
pro-inflammatory mediators such as interleukin-6 and tumour necrosis
factor (TNF).
(...)
OK so it blocks some TNF-alpha and thats what all the biologicals do
more
or less.
Lets see what this stuff is,
http://groups-beta.google.com/groups?hl=en&q=medroxyprogesterone+acetate&qt_s=Search
Check out the thread called "fetishistic behavior" on the first page,
towards the bottom.
You'd be trading loss of libidio for clear skin?
OH FINE!
Your skin looks foxy and you don't feel like it! Now that is a trade
off
that most would eschew. You LOOK hot but aren't HOT.
I better check this for sure,
http://groups-beta.google.com/groups?hl=en&q=medroxyprogesterone+acetate+sex+drive&qt_s=Search
Lets see what else this stuff is called,
http://groups-beta.google.com/groups?hl=en&q=+Depo-Provera+medroxyprogesterone&qt_s=Search
And some more info,
http://groups-beta.google.com/groups?hl=en&q=+Depo-Provera&qt_s=Search
Looks like a mine field of beware stuff for male and females.
I wonder what some low dose Depo-provera ( medroxyprogesterone acetate)
would
do to a slightly higher then normal sex drive and a mild case of
psoriasis?
I'll most likely continue to wonder!
I don't want increased sized boobs any time soon. lol
http://groups-beta.google.com/groups?hl=en&q=+Depo-Provera+boobs&qt_s=Search
Maybe they can get the bugs out before they lose their OrPhan drug
status,
http://www.fda.gov/cder/handbook/orphan.htm
randall...Hey! Its not that interesting NOW!
randall
P News.
Today:: enbrel and "Psoriasis Cure NOW" and whats at stake
http://www.medadnews.com/News/Index.cfm?articleid=251655
Amgen/Wyeth's Enbrel Leads the Market for Biologic Therapies to Treat
Rheumatoid Arthritis and Psoriasis
Pharmacy/Medical Directors Continue to Use Several Measures to Contain
Cost of Biologics, According to a New Report from Decision Resources
WALTHAM, Mass., June 27, 2005 /PRNewswire/ -- Decision Resources, Inc.,
one of the world's leading research and advisory firms for
pharmaceutical and health care issues, finds that Amgen/Wyeth's Enbrel
leads the market for biologic therapies to treat rheumatoid arthritis
and psoriasis. Rheumatologists and dermatologists both prefer Enbrel
over all other biologic agents because the drug has been marketed for a
sufficient period of time to provide assurance of the durability of its
efficacy and safety.
"Prescriptions for Enbrel will increase modestly as a result of
continued uptake and the impact of Medicare reform," said Cynthia
Mundy, Ph.D., analyst at Decision Resources, Inc. "Among
rheumatologists, Enbrel already enjoys widespread use. Rheumatologists
also expect to move some of their patients currently treated with
Centocor's Remicade to Enbrel when Medicare reform takes effect in 2006
and changes the reimbursement landscape for self- administered drugs.
Enbrel is also the biologic agent most widely prescribed by
dermatologists."
(...)
(But, I can't get any low dose enbrel can I? For a mild case of P. )
*****************
Here's a guy thats working directly with goverment to helP us.
Please suPPort Michael and Psoriasis cure now. He seems to be
an effective advocate for us to get the gov to work on the scientific
cure of psoriasis.
http://i-newswire.com/pr27200.html
"Psoriasis Cure Now," a patient advocacy group based in our
nation's capital, today applauded the U.S. House of Representatives for
including its strongest language ever in support of increased federal
research on psoriasis and psoriatic arthritis. The Report language,
released today by the House Committee on Appropriations, was crafted by
a bipartisan group of Members of Congress working in close consultation
with Psoriasis Cure Now, and followed April testimony by Psoriasis Cure
Now's President before the Committee's Subcommittee on Labor, Health
and Human Services, Education and Related Agencies.
i-Newswire, - "This is a great day for every American with
psoriasis," said Michael Paranzino, president of Psoriasis Cure Now.
"The House Appropriations Committee has expressed its strong support
for increasing research on psoriasis and psoriatic arthritis, painful
and often debilitating diseases that affect as many as 7.5 million
Americans. We are grateful that the House Appropriations Committee has
included this historic language in its Report."
Psoriasis is an incurable, recurring disease of the immune system that
can first strike at any age, causing dry, painful skin lesions that can
crack, bleed and itch. Many people with psoriasis also have psoriatic
arthritis, a chronic, progressive and debilitating inflammatory disease
that often causes joint pain, stiffness and swelling, as well as bone
damage. The Report, issued by Subcommittee Chairman Ralph Regula to
accompany the annual Labor-HHS Appropriations bill, includes separate
language urging the Office of the Director of the National Institutes
of Health ( NIH ), as well as its National Institute of Allergy and
Infectious Diseases, its National Institute of Arthritis and
Musculoskeletal and Skin Diseases ( NIAMS ), and its National Center on
Minority Health and Health Disparities ( NCMHD ) all to undertake or
increase research on psoriasis and psoriatic arthritis. While NIAMS has
been conducting excellent psoriasis research for years, this new
language encourages other Institutes and Centers within NIH to join the
battle against this complex and costly disease, while urging NIAMS to
increase its focus on psoriasis.
"Chairman Regula's close questioning of me at the Congressional
Hearing was an encouraging sign that the Committee would support us,"
Paranzino added. "He said at that Hearing that his Subcommittee could
be called the 'Hope Committee,' and he is right. Today, millions of
Americans have renewed hope for themselves and their loved ones that we
will someday cure psoriasis. On behalf of all psoriasis patients and
their families, we thank Chairman Regula, Ranking Member Dave Obey, and
all the members who worked on this bipartisan effort to help people
with psoriasis. We look forward to working with NIH and the world's
leading psoriasis researchers to implement this Congressional language.
Finally, we look forward to continuing our close work with Senators
from both parties to see that the same strong language appears in the
Senate Report later this summer."
The psoriasis Report language is available here:
psorcurenow.org/house.php and the April testimony is available here:
psorcurenow.org/congress.php
Michael Paranzino
Psoriasis Cure Now
202-253-4863
mic...@psorcurenow.org
http://www.psorcurenow.org
******
So what does the NIH do? There suPPosed to protech OUR health.
(National Institute of Health: NIH)
Lets find an abstract from the this month on pubmed sponsored by the
NIH.
Here's one on a toPic that I deem extremely imPortant to us psoriatics.
Do we digest fats OK or do we goof up in our guts somewhere when it
comes
to omega-6 fats and the eventual arachidonic acids?
The NIH should be all over this for us. Instead of P all over us!
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15933212&query_hl=1
Human CYP2C8 is Transcriptionally Regulated by the Nuclear Receptors
CAR, PXR, GR, and HNF4{alpha}
Ferguson SS, Chen Y, Lecluyse EL, Negishi M, Goldstein JA.
NIEHS, NIH.
Abstract Cytochrome P450 (CYP) enzymes play important roles in the
metabolism of endogenous and xenobiotic substrates in humans. CYP2C8 is
an important member of the CYP2C subfamily which metabolizes both
endogenous compounds (i.e. arachidonic acids and retinoic acid) and
xenobiotics (e.g. paclitaxel). Induction of CYP enzymes by drugs can
result in tolerance as well as drug-drug interactions. CYP2C8 is the
most strongly inducible member of the CYP2C subfamily in human
hepatocytes, but the mechanism of induction by xenobiotics has not been
delineated. To determine the mechanisms controlling the regulation of
this important CYP, we cloned the 5'-flanking region of CYP2C8 and
investigated its transcriptional regulation by nuclear factors such as
the pregnane X receptor (PXR), constitutive androstane receptor (CAR),
glucocorticoid receptor (GR) and hepatic nuclear factor 4 (HNF4alpha)
that are known to be involved in the induction of other CYP enzymes
using both cell lines and primary hepatocyte models. First, we
identified a distal PXR/CAR binding site in the CYP2C8 promoter that
confers inducibility of CYP2C8 via the PXR agonist/ligand rifampicin,
and the CAR agonist/ligand CITCO. A glucocorticoid responsive element
was identified that mediates dexamethasone induction via the GR.
Finally, we identify an HNF4alpha binding site within the CYP2C8 basal
promoter region that is cis-activated by cotransfected HNF4alpha. In
summary, the present studies show that CAR, PXR, GR, and HNF4alpha can
regulate CYP2C8 expression and identify specific cis-elements within
the promoter that control these regulatory pathways.
PMID: 15933212
This study is reported in JUne of 2005.
(I wonder now what the NIEHS is? Can someone google that up? J?)
So what does this CYP450 stuff mean?
Only how severe you are!
Look here,
Hepatic cytochrome P450 CYP2C activity in psoriasis: studies using
proguanil as a probe compound.
Helsby NA, Ward SA, Parslew RA, Friedmann PS, Rhodes LE.
Department of Pharmacology and Therapeutics, University of Liverpool,
U.K.
Retinol and proguanil are metabolised by the same family of hepatic
cytochrome P450, i.e. CYP2C. We used proguanil as a probe to study
CYP2C activity, and by implication retinol metabolism, in psoriasis. In
vitro studies showed that retinol competitively inhibited the hepatic
metabolism of proguanil to cycloguanil. Proguanil metabolism was
assessed in 82 patients with chronic plaque psoriasis. Following
proguanil orally (200 mg), urine was analysed for proguanil and
cycloguanil. A proguanil to cycloguanil ratio < 1 signified extensive
metabolism and a ratio > 10 poor metabolism. A wider range of ratios
was observed in psoriasis than previously reported for normal subjects.
The proguanil to cycloguanil ratio was assessed in 10 cases each of
know severe and mild psoriasis. Low CYP2C activity was associated with
severe psoriasis, poor metaboliser status occurring in 50% of the
severe group, but in none of the mild cases, p < 0.01. These findings
may indicate differences in retinoid metabolism in psoriasis.
PMID: 9534880
This study is from March of 1998. How come we don't have follow up on
why we can't
digest these lipids correctly?
This goes to the question of HETE (group google me: randall hete) also.
I've known about the need to correct the ratio of omega-6 to omega-3's
, since the mid 90's. It was the first time I found that I could
control some of the severity by watching
what I ate or didn't eat.
Lets see whats on pubmed for this pathway thats more current now.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15304077&query_hl=3
Cytochrome p450: a target for drug development for skin diseases.
Ahmad N, Mukhtar H.
Department of Dermatology, University of Wisconsin, 1300 University
Avenue, Madison, WI 53706, USA.
Enzymes of the cytochrome P450 (P450 or CYP) super family are the most
versatile and important class of drug-metabolizing enzymes that are
induced in mammalian skin in response to xenobiotic exposure. At the
same time, CYP have numerous important roles in endogenous and
exogenous substrate metabolism in the skin. For example, they
participate in the metabolism of therapeutic drugs, fatty acids,
eicosonoids, sterols, steroids, vitamin A, and vitamin D, to name a
few. In addition, in some skin diseases, for example in psoriasis, many
CYP are elevated. CYP are the target of special interest in the
development of drugs for skin diseases because most, if not all, drugs
available in the armamentarium of the dermatologists are either
substrate, inducer, or inhibitor of this enzyme family. The functional
significance of drug metabolism in skin and the implication of CYP in
skin pathology and therapy is an area for future investigation. A
detailed insight into the mechanism of action of various cutaneous CYP,
being capable of modulating the drug bioavailability, will be helpful
in the development of better strategies for novel therapy against
constantly increasing skin disorders. This brief review discusses some
of these perspectives and suggests additional work in this research
area with regard to the expression and modulation of CYP in mammalian
skin as well as their implication in dermatological disorders and the
therapy of skin diseases.
PMID: 15304077
Well you do get 57 hits for a search of keywords [ P450 + psoriasis ]
on pubmed.
Yet I don't see the creative pursuit of exPloiting this pathway to our
benefit.
Yes it comes up for those drugs that we have now other then the
biologicals.
But do you really think that the ENBREL folks give a rats rear end
about this pathway?
We need the goverment money, our money btw, to protect us against the
money hungry
pharma's. And their agenda to charge $10,000.00 plus a year for a
therapy that doesn't cure us.
If i can simply exploit this n:6/n:3 ratio to stay in the mild zone P
wise by avoiding the n:6's
and suPPLementing the n:3's with flax seed oil, anyone can.
But whose telling you besides me?
CheaP, free advice easily testable in your own body. Bear witness to
your skin.
Its your hide on the line.
randall.... :)
randall
Don't you love it when the big C word gets tossed around!
As in CURE & P! Not! the infamous C word of course.
YeP! Today in the P news from all around the World.
Brought to you by me and my google news searches.
Your welcome and lets see IT now.
http://news.scotsman.com/scitech.cfm?id=709312005
New ointment is 'cure' for psoriasis
ROD MINCHIN
SCIENTISTS have claimed a breakthrough in treating the distressing skin
condition psoriasis, it was revealed today.
They say that an ointment used in treating the painful disease actually
kills off the cells that cause the problem.
The scientists at Newcastle University believe the discovery represents
a major step towards enabling the design of better treatments for
psoriasis, which affects up to a million people in the UK alone.
It is a genetic condition that causes the over-production of skin
cells, which causes a thickening of the skin, resulting in the raised,
red, scaly patches.
Professor Nick Reynolds and Dr Mark Birch-Machin studied the effects of
dithranol, an ointment applied to the surface of the skin.
The ointment is derived from the araroba tree found in the rainforests
of the Amazon. In India, the same substance is known as Goa powder.
Prof Reynolds said: "Dithranol is a very effective treatment for
episodes of psoriasis and it has been around for a long time, since the
early 1900s. By studying the action of the drug, we wanted to gain a
better understanding of how it works."
Laboratory studies showed that dithranol targets skin cells'
mitochondria - the part of a cell from which it draws its energy -
causing the cells to die within 48 hours of the application of the
ointment.
****
The longer version of same thing,
http://www.innovations-report.de/html/berichte/medizin_gesundheit/bericht-45869.html
Kim and Ed frequently mentioned Goa and the chrysarobin compound
derived from it in this group and its curative properties.
http://groups-beta.google.com/group/alt.support.skin-diseases.psoriasis/search?hl=en&group=alt.support.skin-diseases.psoriasis&q=+Chrysarobin&qt_g=1&searchnow=Search+this+group
http://groups-beta.google.com/group/alt.support.skin-diseases.psoriasis/search?hl=en&group=alt.support.skin-diseases.psoriasis&q=goa&qt_g=1&searchnow=Search+this+group
Wow! Go Goa! Go Goa! Squash that psoriasis!
But cure it?!?!
CURE IT? No wonder big ED left us i'm thinking now?!?!
Did he goa away due to goa goo? Oh well, he won't tell!
Give me that old time religion and medicines!?
The goa is 100's of years old. Thanks Ed.
But?
How about a nice placebo? Instead!
http://www.post-gazette.com/pg/05179/529689.stm
(...)
"We're trying to get the same drug effect with less drug." says James
W. Bodfish, professor of psychiatry at the University of North Carolina
at Chapel Hill. "Medications work, but the question is whether we
always need to use them at the highest dose."
At the University of Rochester in Rochester, N.Y., and Stanford
University researchers are studying whether the placebo conditioning
principle can help psoriasis patients use fewer corticosteroid
medications, which can have serious side effects with frequent use.
Patients in the study are sometimes given corticosteroid creams and
sometimes an inactive placebo cream. The goal is to find out whether
using the placebo will make it possible to control the condition with
lower doses of active medication.
(...)
*******
And once i come back to my senses. Praise the Lord!
I suppose another biological is warranted on the war against our
T-cells.
It may bring the price down in a biological war. We hoPe!
http://www.medadnews.com/News/Index.cfm?articleid=252020
DREIEICH, Germany, June 28, 2005--Biotest AG and Boehringer Ingelheim
have concluded an agreement in June 2005 for a joint research effort to
investigate the efficacy of the monoclonal antibody BT-061 in animal
models of asthma.
BT-061 is directed against a target on T-cells mediating a unique,
immunoregulatory mode of action. Previous studies conducted in the
collaborative partnership between Biotest and Boehringer have confirmed
the special properties of BT-061 compared to 15 other monoclonal
antibodies. The candidate is Biotest's most advanced monoclonal
antibody and has shown promising results in early clinical trials in
patients with rheumatoid arthritis and psoriasis. Biotest develops the
antibody in these autoimmune diseases and currently produces material
to continue clinical development.
The immunomodulatory properties of BT-061 provide the scientific
rationale to use this candidate in autoimmune diseases, asthma and
allergic diseases. Due to its TNF-independent mode of action, BT-061 is
not limited to diseases such as rheumatoid arthritis and psoriasis in
which the cytokine TNF plays a major role.
<sniP>
************
On the lighter side of flaky.
Rice dream turns nightmare on elm street!
Veggetarian parents (think June and Ward Cleaver) kill their offsPring!
You suPPose something like this next story haPPened to the Beaver?
(*~*)
http://www.duluthsuperior.com/mld/duluthsuperior/news/nation/12003735.htm
PHILADELPHIA - (KRT) - It's sold as Rice Dream, but doctors at
Children's Hospital of Philadelphia call it "rice nightmare."
That's because they've seen two youngsters in two years with
kwashiorkor, a potentially fatal form of malnutrition rarely
encountered outside the Third World. Doctors blamed Rice Dream, a
nondairy rice drink that millions of people buy instead of milk.
Rice Dream's makers insist it should never be used as infant formula,
and their Web site and packages say that. But both children - a
7-month-old Caucasian boy and a 14-month-old Latina - were fed Rice
Dream almost exclusively after they had problems with baby formula.
Soon their bodies were swollen and covered by a rash and what doctors
dubbed "flaky paint" or "crazy pavement" scales. The children seemed to
have stopped growing.
(...)
Epidemiologist Bradley Woodruff, a specialist in maternal/child
nutrition for the federal Centers for Disease Control and Prevention,
offers some perspective. "The average nutritional status of children in
this country is substantially better now than 50 years ago," he said,
"with the exception of cases like these."
They were pivotal for Matt Mahlberg, a University of Pennsylvania
medical student who saw one of the children on his pediatrics rotation.
He has since decided to become a dermatologist.
"This is a side of dermatology that nobody sees," he said. "People
think of acne and psoriasis and cosmetic procedures, but this is like a
public-health concern."
As for Katz, the son, nephew and cousin of dermatologists, kwashiorkor
is "definitely up there" on his list of most unusual cases. He cites
the old medical school chestnut that when you hear hooves, think horses
- but remember it could always be a zebra.
"This," he said, "was a zebra."
As to the beaver and his P (*~*),
http://www.dallasobserver.com/issues/2003-04-10/news/fullfrontal.html
*************
Sounded like a flaky zebra to me. You still gotta love the Beav. For
his
psoriasis work for the NPF and helping to bring in fresh $$$$.
Speaking of cash $$$$'s.
Lets play a game.
Follow the biological $$$$'s
http://www.boston.com/business/technology/biotechnology/articles/2005/06/28/drug_firm_mgh_fight_over_royalties/
Drug firm, MGH fight over royalties
By Christopher Rowland, Globe Staff | June 28, 2005
A dispute over royalties between Massachusetts General Hospital and the
manufacturer of the drug Enbrel could cut into the millions of dollars
in royalties received by the hospital and one of its star scientists.
Amgen Inc. last year sold nearly $2 billion worth of Enbrel, which
doctors prescribe to treat rheumatoid arthritis and psoriasis. Under
terms of a licensing agreement, the company paid Mass. General
approximately $41 million for its role in helping invent the drug --
about two-thirds of the $63 million in licensing payments the hospital
received from all sources last year. The money supports a major
genetics laboratory run by Brian Seed, a Harvard University
biophysicist who made key discoveries that led to Enbrel's development.
But now Amgen wants to reduce its payments to Mass. General.
Amgen, which is based in Thousand Oaks, Calif., inherited the Enbrel
pact with the hospital in 2001 when it bought Immunex Corp., a Seattle
company that developed the drug in the 1990s. Amgen's lawyers later
discovered language in the licensing agreement that ''allowed for a
certain amount of interpretation," said Frances Toneguzzo, director of
licensing deals at Mass General. The company's lawyers believe the
wording may allow Amgen to pay the hospital less, Toneguzzo said. Mass
General disagrees.
''When there are big dollars on the table, you tend to scrutinize every
piece of your contracts, and that's what happened here," Toneguzzo
said. She declined to say how much of its Enbrel royalties might be in
jeopardy.
<sniP>
****
We can hope and pray that there will be dozens of bilogicals one day.
And they all work at least as well as the current crop.
Then prices would droP.
How about some low dose naltrexone with low dose enbrel, and FAE (low
dose)
and randall's gut treatment?
Sounds good to me.
randall...i'll max the endorPhins first and then Goa the P away!
randall
If you missed the GOA P AWAY story yesterday. Here it is again.
Its still running in British news reports today.
Will this be a cheap simple method to treat your P? And over the
counter as well.
This saPPy stuff kills the activated cells that prime the process.
Is it saPPy or Barky?
And you can see the activated cells right here,
http://ard.bmjjournals.com/content/vol64/suppl_2/images/large/ar31120.f1.jpeg
So i'm guessing that its the CD68 + cell that GOA dead?
We can thank those scientist working in the UK. But how come this
wasn't on the table the last 50 years?
Did the biological/mtx/steroids/et al folks stoP the Goa goo from being
available to YOU?
I don't buy conspiracy theories very often,
http://www.physik.uni-frankfurt.de/~jr/gif/cartoon/chast.gif
And once the bad cells (CD68+) are knocked back, how long till
the whole thing ramPs back uP again?
I'm ready for it now. My knees and elbows, yes please! And I know
cruiser's nails would be a good test BED! Cruiser kill those bad boy
cells stat!
After thinking this one over since yesterday i'm kinda
excited about it. Stuff from the jungle (rainforest) that kills P
cells,
OK, here it is. Herbal tree gooP. Or Barky P cell killer stuff?
Barky P gooP make the P gone!
For how long?
http://www.cosmeticsdesign.com/news/news-ng.asp?n=60905-dermatologists-hone-psoriasis
6/29/2005 - A UK dermatological study into the affects of a compound
extracted from Araroba trees claim they have improved the treatment for
psoriasis. Simon Pitman reports on what could prove to be a
break-through for a condition that affects as many as one in six
people.
Scientists at the University of Newcastle upon Tyne, studying the
effects of the compound found that it actually kills off the cells
which are the cause of the problem. The team believe the discovery
represents a major step towards enabling the design of better
treatments for psoriasis, which affects up to a million people in the
UK alone, according the Psoriasis Association.
The study considered the compound, dithranol, which is widely used in
the treatment of psoriasis, and is derived from a natural compound,
called chrysarobin. Chrysarobin is prepared from the araroba tree found
in the rain forests of the Amazon. In India, the same substance is
known as Goa powder.
(...)
Professor Reynolds believes that his team's findings could lead to a
far more effective and manageable treatment of psoriasis - one that
could be conveniently home-administered in both over-the-counter and
prescription products.
"These findings represent an important step towards the development
of better-designed treatments for psoriasis sufferers," he said.
************************
This Girl in Malaysia needs some GOA fast. She may never leave her
room. But i only ranked the story a one. If you use the link you can
rank
it as well.
http://www.nst.com.my/Current_News/NST/Wednesday/National/20050629084304/Article/indexb_html
Home has been a prison for Nor Ermilia Abdullah since last May, when
she broke out in red blotches during her National Service (NS) training
in Merbok.
Treatment at the Universiti Teknologi Mara pharmacy saw her being
prescribed tablets and ointments which did little to relieve her
condition. Thinking it was chicken pox, the camp commandant gave her
two days of medical leave.
It was only about a month later that doctors at the Alor Star Hospital
identified the source of her problems: psoriasis.
Today, a year later, Nor Ermilia, 19, is familiar with the disease -
and the pain and emotional trauma that accompanies it.
(Psoriasis is a skin disease that may appear as raised, red patches or
lesions covered with a silvery white build-up of dead skin cells called
scales.)
IT HURTS: Siti Salmiah rubbing ointment on Nor Ermilia's back to
alleviate the symptoms of her disease.
"I am so sad that this has happened to me. I was healthy before
National Service," she said at her Kampung Hilir home near Kepala
Batas.
The former Sekolah Menengah Teknik 2 Sungai Petani student has hardly
left her room since then, except for monthly treatments at the
hospital.
The fourth of seven siblings, the once-active student is embarrassed by
the lesions on her body.
She does not know if she will pursue plans to study food catering at a
private college in Ipoh.
Nor Ermilia's mother, Siti Salmiah Mat Said, 40, said her
daughter's condition was stable but she required continuous medical
treatment. "I am very sad as my daughter's future appears bleak."
Siti Salmiah said she decided to make her daughter's condition public
after reading about NS trainee Noraini Abu Bakar, who suffers from
systemic lupus erythematosus. The disease flared up during her NS
training in Cherating, Pahang
*****
Why did the mom out her daughter from that room she's hiding in?
I'll send the writer this GOA post. Doesn't it grow there?
STAT! NOR needs the GOA!
That will out her from her room stat.
And give her some low dose naltrexone to brighten up her dePressed
brain cells.
OK ok.
randall.... home grown doctor.. heal thyself! Timber!
Pi
>http://www.cosmeticsdesign.com/news/news-ng.asp?n=60905-dermatologists-hone-psoriasis
>The study considered the compound, dithranol, which is widely used in
>the treatment of psoriasis, and is derived from a natural compound,
>called chrysarobin. Chrysarobin is prepared from the araroba tree found
>in the rain forests of the Amazon. In India, the same substance is
>known as Goa powder.
>Professor Reynolds believes that his team's findings could lead to a
>far more effective and manageable treatment of psoriasis - one that
>could be conveniently home-administered in both over-the-counter and
>prescription products.
So whats new about it? Dithranol already exists for years:
http://www.drugs.com/cons/Dithranol.html
Revised: 06/30/1998
Dithranol is also known as anthralin.
Side effects?:
> Anthralin has been shown to cause tumors in animals.
> However, there have been no reports of anthralin causing tumors in humans.
What is new about this? Other ways of treatment? The fact that you can
buy it everywhere instead of through your doctor? I miss the "news"
here.
I tanslated some pieces of the German website for you, showing that
this exists since 1916!!!:
http://www.psoriasis-forum-berlin.de/dithranol.html
Since 1916 it is known that with Dithranol Psoriasis can be treated
without sideeffects. (...) At first Dithranol was won from the
Araroba- or Goa-Bäume in Brasil. (...) Dithranol mainly works in the
ill skin. There it slows down the cell division. It influences the
energysupply in the cells. Because of this the flaking of the skin is
suppressed. (...) The most common side effect is skin irritation,
getting red of the skin. The most annoying side effect is the
coloration of the healthy skin: it quickly gets brown. How long
depends on the type of the skin. Usually the brown spots disappear
after a couple of weeks, but some patiets reported brown sopts that
lasted years. The advantage of Ditranol is that no long-term
sideeffects are known.
Pieter
Pieter
Pi
wrote:
>So whats new about it? Dithranol already exists for years:
I'll answer myself here...maybe I should read the articles better: The
difference is that they found that the Psoriasis was not suppressed,
but that certain cells were actually killed.
Makes me wonder what those cells were for. Especially causing cancer
in animals is something that makes me concered. Another case of
TH1/TH3?
Pieter
randall
I'm not sure about anthralin or dithranol and cancer side effects.
As with any real med you must find a good derm to keep
an eye open for YOU.
If I intended to use the stuff i'd be sure to know all about it.
Like DaveW i'd want to be fully loaded going into that meeting.
At this point I was really only trying to find an actual picture of the
tree and part used to make the stuff. It seems like a huge secret.
Chrysarobin is or seems to be the active compound.
http://www.prn2.usm.my/mainsite/plant/images/cassia3.jpg
Chrysarobin (m.w 240.258), C15H12O3
Here are a few more names I found since yesterdays search.
Geoffroea Inermis Bwa-Palmis', Bois-Olive, Angelin
http://www.vodou.org/images/herbs/angelin_a_grappes.jpg
http://www.ibiblio.org/herbmed/eclectic/kings/andira-arar.html
http://www.ibiblio.org/herbmed/eclectic/kings/chrysarobin.html
I'm not sure that the plant jpg is the right one, even. But do you
want to cry TIMBER for a really old cool tree? Or just cry for it?
When those british scientists can tell us which activated cell (cd68+
or ?)
is killed by which compound in/of Chrysarobin we will have a way to
treat part of the pathway that hopefully won't have any dire side
effects.
This abstract which looks good is from 1994.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8201600
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8201600&query_hl=6
And yes it can be used to promote skin cancer,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8187717
And I'm well aware of the history of P,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=1401327
And the history of ME and P! And the mystory of P.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=1765492&query_hl=6
So, if and when those scientists can kill just the bad boy cells right
in the patch without making a huge mess or skewing some other
pathway leading to cancer etc etc.
Then i will be looking at their non frankenstein meds for this rash
situation.
But lets not get to rash and jumP at some P news rePort that comes out
with
the "CURE" word attached to it.
I see it as a way to test facts involved in the p pathways. And that
may lead to better understanding of P genomics and proteomics.
And what the heck. I've never much been into toPicals till the
wheatgrass
spray came around.
But for those that want and need them.
Getting ToPical with ToPicals!
http://abcnews.go.com/Health/Healthology/story?id=893456&CMP=OTC-RSSFeeds0312
Topical treatments applied to the skin are the most commonly-used
therapy for psoriasis. In fact, about 70 to 80 percent of patients will
experience good results with creams, lotions, gels and other formulas.
For those who treat their psoriasis with pills or light treatments,
topical therapies may continue to be used on stubborn areas.
Here is a list of recommended treatments for psoriasis:
Topical Corticosteroids
Topical corticosteroids are typically a first-line treatment strategy
for
psoriasis. They range in strength from over-the-counter preparations
like hydrocortisone to prescription-strength drugs such as clobetasol,
halobetasol, betamethasone and diflorasone.
Topical corticosteroids are available in several different formulas.
Ointments are the most effective, but many people use them only at
night because they tend to have a greasy feel. Creams are a more
pleasant option for daytime use, while foams and gels work well on the
scalp and other areas with lots of hair.
Possible side effects associated with chronic and prolonged use of
topical corticosteroids include skin atrophy, stretch marks and red
spots. Rarely, heavy long-term use can cause a suppression of the
adrenal glands. Additionally, resistance can develop if steroids are
used over an extended period of time. In an effort to reduce the risk
of side effects and resistance, your doctor may recommend that you take
periodic breaks from the drug. A safe dose should not exceed more than
50 or 60 grams a week.
Vitamin D Compounds
Though topical corticosteroids are typically first line therapy for
psoriasis, research has shown comparable success with other topical
therapies such as vitamin D compounds. However, there is an increased
risk of side effects. Calcipotriene, a synthetic form of vitamin D,
reduces the excess production of skin cells associated with psoriasis.
It is available as an ointment, cream or solution and is effective in
about two-thirds of those who use it.
The main side effect of calcipotriene is skin irritation, so it should
not be used in combination with corticosteroids. A safe dose is less
than 120 grams a week. If used in conjunction with light therapy for
psoriasis, this treatment should be applied afterwards, as light
therapy inactivates vitamin D compounds.
Retinoids
Topical retinoids are vitamin A derivatives and have been used to treat
mild to moderate psoriasis. Despite the proven clinical efficacy of
these agents in the treatment of psoriasis, it remains unknown how they
work. Like vitamin D, research has also shown that they, too, are just
as effective as topical corticosteroids but with slightly increased
side effects. The most common side effects are local irritation and
increased sun sensitivity, which is fairly mild and can be prevented by
proper use and application. There are three FDA-approved topical
retinoids available in the United States: tretinoin, adapalene and
tazarotene. Topical corticosteroids are often prescribed with retinoids
because they may reverse some of the skin thinning corticosteroids can
cause. Conversely, corticosteroids can help with skin irritation caused
by tazarotene.
Coal Tar and Anthralin
Coal tar and anthralin are safer than corticosteroids, but are not used
as often because they have limited effectiveness, irritate the skin,
have an unpleasant odor and can stain skin and clothing. Coal tar is
available in medicated shampoos and bath preparations, while anthralin
is usually applied for 15 to 30 minutes and then thoroughly rinsed off
with lukewarm water to reduce staining. Coal tar ointment is sometimes
combined with ultraviolet B light therapy in a three-week regimen
called Goeckerman treatment.
Salicylic Acid
Salicylic acid is sometimes added to psoriasis creams because it
removes scales from the skin. It can be used with corticosteroids, coal
tar or anthralin. However, it has been shown to inactivate
calcipotriene.
Letting It Sink In
If you are currently using a topical treatment for psoriasis, be sure
to follow your doctor's instructions explicitly. If not, be sure to
talk with your doctor to find out if any of these options will help you
look and feel your best.
randall...knowing more lets you make better decisions i suPPose.
randall
Herbs like the stuff from araroba are cool but what about the gut bugs
living in us?
If you can work with the flora in your gut you can change or turn on
pathways to lower psoriasis. New info on these pathways are being
discovered
every day it seems like.
Here's the current news in this vein.
Once again the P Bells are Toll-ing for Us in pubmed and on the net.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt«stract&list_uids 982296
The Role of Toll-like Receptors in the Pathogenesis and Treatment of
Dermatological Disease.
McInturff JE, Modlin RL, Kim J.
Division of Dermatology, CHS David Geffen School of Medicine at UCLA,
Los Angeles, California, USA.
Toll-like receptors (TLR) are crucial players in the innate immune
response to microbial invaders. These receptors are expressed on immune
cells, such as monocytes, macrophages, dendritic cells, and
granulocytes. Importantly, TLR are not only expressed by peripheral
blood cells, but their expression has been demonstrated in airway
epithelium and skin, important sites of host-pathogen interaction. Host
cells expressing TLR are capable of recognizing conserved
pathogen-associated molecular patterns, such as lipopolysaccharide and
CpG DNA, and their activation triggers signaling pathways that result
in the expression of immune response genes and cytokine production. As
TLR are instrumental in both launching innate immune responses and
influencing adaptive immunity, regulation of TLR expression at sites of
disease such as in leprosy, acne, and psoriasis may be important in the
pathophysiology of these diseases. Furthermore, since TLR are vital
players in infectious and inflammatory diseases, they have been
identified as potential therapeutic targets. Indeed, synthetic TLR
agonists such as imiquimod have already established utility in treating
viral pathogens and skin cancers. In the future, it seems possible
there may also be drugs capable of blocking TLR activation and thus
TLR-dependent inflammatory responses, providing new treatment options
for inflammatory diseases.
PMID: 15982296
Imiquimod cream is rubbed onto the skin cancer and it causes a Th1
cascade to stop the cancer. Like you body should do naturally. But when
your
skewed to the Th2 side you are vulnerable to cancer.
But psoriasis is a Th1 condition to start with. So imiqimod is not what
we
want. Rubbing it onto P would simply make more P.
We want a cream that induces Th2 cytokines. Like IL-10 for instance.
Lets see whats up in easy to read (sorta) news reports.
http://www.news-medical.net/?id 345
And/or
http://www.sciencedaily.com/releases/2005/06/050623005022.htm
Scripps Research Scientists Solve Structure Of A Critical Innate Immune
System Protein
La Jolla, CA, June 20, 2005 -- Scientists at The Scripps Research
Institute have solved the structure of a crucial human immune system
molecule called TLR3, an acronym for Toll-like receptor three. In an
upcoming issue of the journal Science, the protein is described as a
large horseshoe-shaped coil composed of 23 leucine-rich repeats (LRRs).
The structure reveals details of TLR3 that have never been seen before,
an essential step toward fully understanding the critical role this
protein-and other TLRs-play in the human innate immune system to
rapidly detect invading pathogens.
"We don't know functionally how TLR proteins work," says Professor Ian
Wilson, D.Phil., who is a professor in the Department of Molecular
Biology at The Scripps Research Institute and a member of The Skaggs
Institute for Chemical Biology. "But the structure has given us great
insights into experiments we can design to explore their function. In
advance, we wouldn't have known where to look."
In addition to helping scientists better understand how TLRs work, the
structure may also help scientists take steps toward improving human
health, since TLRs are implicated in a number of diseases and, hence,
constitute potential therapeutic targets.
Innate Immunity and Toll-Like Receptors
Humans, like all other organisms, are constantly challenged in a world
filled with microbial pathogens. We are bathed in bacteria, confronted
with fungi, pilloried with parasites, and invaded by viruses. And yet,
most of the time, we survive.
We survive because we possess an ancient and crucial defense mechanism
known as innate immune system, which is active in eukaryotic organisms
as diverse as humans and fruit flies. Broadly speaking, the innate
immune system works something like this. Certain cells have the ability
to recognize foreign molecules such as components of membrane like LPS
or other protein molecules unique to microorganisms. The presence of
these pathogen-specific molecules activates the immune system, which
responds with a multi-stage biochemical defense starting with the
unleashing of an army of white blood cells, like macrophages, which
engulf and destroy pathogens. The macrophages also fight the pathogens
by producing large amounts of chemicals that induce inflammation and
help the body clear the infection.
One of the components of the innate immune system that scientists have
been studying for the last several years is a family of receptor
proteins called the Toll-like receptors (TLR)-a name that comes from
their resemblance to a fruit fly receptor called "Toll." In the fly,
Toll is important for both embryonic development and for immune
functions of the adult organism. In adult fruit flies, the protein is
an essential receptor molecule that defends against fungal infections.
In humans, TLRs play a critical role in the immune system because they
are the molecules responsible for detecting some of the antigens
produced by pathogens. For this reason, Toll-like receptors have been
called the eyes of the innate immune system. Normally, when human or
mouse cells encounter bacteria or viruses, they recognize proteins,
lipids, or other molecular components of these foreign invaders through
a family of TLR proteins, and then trigger the immune system's
multi-stage biochemical attack on the pathogens.
Humans have at least 10 different TLRs, each of which recognizes a
specific subset of antigens. For instance, TLR4 recognizes
lipopolysaccharide, a chemical component of the cell walls of certain
bacteria like Neisseria meningitides-one of the leading causes of
bacterial meningitis. TLR9 recognizes bacterial DNA that contains
distinguishing CpG dinucleotides motifs.
TLR3 in Detail
Likewise, TLR3 recognizes double-stranded RNA, which is the form of
genetic information carried by many viruses. The structure that Wilson
and his colleagues have solved shows how the repeating leucine-rich
repeat motifs assembled in TLR3 in never-before-seen detail. The
portion of TLR3 the scientists solved lies on the outside of the
membrane and reveals the potential binding site for its ligand,
double-stranded RNA.
TLR3 forms a large horseshoe shape that contacts with a neighboring
horseshoe, forming a "dimer" of two horseshoes. Much of the TLR3
protein surface is covered with sugar molecules, but on one face that
includes the interface between these two horseshoes, there is a large
surface that is sugar-free, suggesting that this is where the TLR3
might bind to its target molecule. This surface also contains two
distinct patches that are rich in positively-charged residues,
suggesting it as a possible binding site for negatively-charged
double-stranded RNA
"It's a sensational piece of work," says Scripps Research Professor
Bruce Beutler, M.D., who studies TLR signaling together with his group
in the TSRI Department of Immunology. "All of us in the TLR field have
been dying to see the structure of a TLR ectodomain since the innate
immune function of TLRs was discovered seven years ago. This will open
the way to a great many other studies that will allow us to understand
exactly how signaling occurs."
Significantly, says Wilson, the structure is also another milestone of
sorts. These membrane-spanning proteins are rich in repeats that
contain a high percentage of the amino acid leucine. This fact was
important to Wilson and his colleagues because the leucine-rich
proteins are often decorated with sugars (glycans), and fall into the
class of biological molecules known as "glycoproteins."
"Amazingly there is still this prevalent idea [many scientists have]
that glycoproteins don't crystallize," says Wilson. Crystallization of
a protein is a crucial initial step in solving its structure via x-ray
crystallography, the technique that Wilson and his colleagues employ.
Because glycoproteins are covered with sugars, they are heterogenous
due to the multiple glycoforms that make it harder, but not impossible,
to form good crystals. A number of leucine-rich repeat proteins have
been determined, but never one with this many leucine-rich repeats or
so many carbohydrates.
The article, "Crystal structure of human Toll-like receptor 3 (TLR3)
ectodomain" is authored by Jungwoo Choe, Matthew S. Kelker, and Ian A.
Wilson and is being published in SCIENCE EXPRESS, the early online
publication site of the journal Science. See:
http://www.sciencemag.org. The article will also appear in print in an
upcoming issue of Science. This work was supported by the National
Institutes of Health and The Skaggs Institute for Research.
(...)
Here's a stained _red/blue_ bad endotoxin called LPS and its recePtor
is TLR4
http://www.emsl.pnl.gov/docs/mssg/images/p_lpsesp.gif
See.
http://www-ermm.cbcu.cam.ac.uk/04007410h.htm
This says it binds to CD14.
So how do we get to CD68+ from there? Good question.
The scientist are working on that function of the immune system now.
Lets pretend that the good gut bugs are blue and the bad ones are red.
And they live in your gut. Well they do, whether you like it or not
chuck.
http://photos1.blogger.com/img/191/1429/640/2004countymap3.jpg
When you have a preponderance of the bad bugs your in dysbiosis.
In this case to much red causing inflammation and a Th1 skew.
But if it gets bad enough surely you will know due to changes in
your bowel movements. And it doesn't take much to know that something
is wrong.
And its your responsibility to clean it up. But what happens with
crohn's, colitis & IBD and other autoimmune (imid's) conditions
including psoriasis in your gut?
Psoriasis doesn't have to have those obvious symptoms in the gut. But
is it manifesting
on the skin instead?
Is plaque like skin, colitis on the outside some how.
Its my theory that some pernicious red or blue bugs (LPS) are leaking
into you and
keeping the immune system tilted in the Th1 mode (T helper cell 1's).
I don't expect Chuck to be reading this as he would point out that
republicans are red on that map and democrats are blue. Since this is a
metaphor for you to deduce a mind construct of whats going on in the
colon, which is which, isn't really any big deal.
The fact of the matter is what TOLL like recePtors are at work here and
whats
skewing us to far to the Th1 mode. I tend to go with the LPS still..
How do we stop or block it in the gut? Well we know that the scientist
are only
now figuring out the structures, which is key to knowing how to block
them.
What tack can we take now?
We know that bifidobacterium are part of the good gut flora.
http://groups-beta.google.com/group/alt.support.skin-diseases.psoriasis/search?hl=en&group=alt.support.skin-diseases.psoriasis&q=bifidobacteria&qt_g=1&searchnow=Search+this+group
The good guys block the bad dudes in the gut some how?
http://www.yakult.co.jp/institute/english/effort/img/eft_img03.gif
How do we get our guts to make more of it? And less of the clostridium
(red) bad guys?
We want good (blue) gut bug guys for health,
http://www.humannutrition.com/Probiotics/image003.gif
Ok ok you say. But were are the facts?
Try this,
http://www.humannutrition.com/Probiotics/Dysbiosis.php
So what good is this for psoriasis? If there is a link to the gut and
psoriasis and many abstracts at pubmed say there is. Then a better gut
will slow down TNF and that helps psoriasis. And LPS whiPs TNF into
action. So we want blue bugs stopping the
LPS from leaking into us.
Lets look at this,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt«stract&list_uids 735433&query_hl=4
Preventative effects of lactulose in the trinitrobenzenesulphonic acid
model of rat colitis.
Camuesco D, Peran L, Comalada M, Nieto A, Di Stasi LC,
Rodriguez-Cabezas ME, Concha A, Zarzuelo A, Galvez J.
Department of Pharmacology, School of Pharmacy, University of Granada,
Granada, Spain.
AIMS: Lactulose is a drug used as a laxative that has been shown to
promote the growth of lactobacilli and bifidobacteria, acting as a
prebiotic and with a potential beneficial effect in inflammatory bowel
disease. The present study describes the preventive antiinflammatory
activity of lactulose in the trinitrobenzenesulphonic acid (TNBS) model
of rat colitis. METHODS: Rats were rendered colitic by a colonic
instillation of 10 mg of TNBS dissolved in 0.25 mL of 50% ethanol. One
group of colitic rats received lactulose, which was incorporated in the
drinking water (2.5% wt/vol) for 2 weeks before TNBS instillation, and
colonic damage was evaluated 1 week after colitis induction. Different
biochemical markers of colonic inflammation were assayed:
myeloperoxidase activity, glutathione content, tumor necrosis factor
alpha, leukotriene B4 levels, and colonic inducible nitric oxide
synthase expression. In addition, bacterial counts (for lactobacilli
and bifidobacteria) were performed in colonic contents from colitic
rats. RESULTS: The results show that lactulose exerted a preventive
antiinflammatory effect in this model of rat colitis, as evidenced by a
significant reduction of myeloperoxidase activity and by a decrease of
both colonic tumor necrosis factor alpha and leukotriene B4 production.
This effect was also characterized by an inhibition of colonic
inducible nitric oxide synthase expression, which is unregulated as a
consequence of the inflammatory status. This beneficial effect was
associated with increased levels of lactobacilli and bifidobacteria
species in colonic contents in comparison with untreated colitic rats.
CONCLUSION: In conclusion, the intestinal antiinflammatory effect of
lactulose could be related to its prebiotic properties, supporting its
potential use in human inflammatory bowel disease.
PMID: 15735433
So ok. TAking something that will lets the good stuff grow in us is
good.
More good blue bugs crowding out the red bad guys in my metaPhor.
What can I take, you ask,
http://www.food.rdg.ac.uk/people/afsrastl/intropre.htm
Fos seems to come up in the groups,
http://groups-beta.google.com/groups?hl=en&lr=&q=bifidobacteria+fos&qt_s=Search
Or you can try that chicory root inulin product mentioned in one of the
first searches up
above and right here,
http://groups-beta.google.com/groups?hl=en&lr=&q=bifidobacteria+chicory&qt_s=Search
Or take some lactulose,
http://www.answers.com/topic/lactulose
Or take the stuff used to make lactulose.
Like galactose for instance.
http://groups-beta.google.com/groups?hl=en&lr=&q=galactose+psoriasis+gut&qt_s=Search
Where can i get some of that?
>From thewholewhey.com site,
http://www.thewholewhey.com/contents/products_info/proflora.htm
(This is what I use.)
But this says its lactose?
Don't worry. The lactose breaks down to galactose in your body.
The enzyme lactase splits lactose into its constituent sugars. The
lactose
molecule is made up of one galactose molecule plus one glucose
molecule.
And then you will have a TRUE blue bunch of gut bugs in you.
And here is a study showing that new bugs (good ones) can be
implanted and grown for colitis.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt«stract&list_uids 975209&query_hl=2
Mucosal bacteria in ulcerative colitis.
Macfarlane S, Furrie E, Kennedy A, Cummings JH, Macfarlane GT.
Microbiology and Gut Biology Group, University of Dundee, Dundee DD1
9SY, UK.
Ulcerative colitis (UC) is an acute and chronic inflammatory bowel
disease of unknown aetiology, although bacterial species belonging to
the normal colonic microbiota are known to be involved in its
initiation and maintenance. Several organisms have been linked to the
disease; however, mucosa-associated bacteria are more likely to be
involved than their luminal counterparts, due to their close proximity
to the host epithelium. Comparative bacteriological analyses were done
on rectal biopsies to investigate differences in mucosal bacteria in
patients with UC and healthy controls. Complex bacterial communities
were found in both groups, with significant reductions in
bifidobacterial numbers in UC, which suggested that they might have a
protective role in the disease. Accordingly, a therapy for treating UC
was designed, with the aim of modifying the mucosal microbiota to
increase bifidobacterial colonisation and reduce inflammation. Ranges
of mucosal and faecal bifidobacteria were tested for their substrate
preferences and their abilities to survive under a variety of
environmental conditions. A synbiotic comprising a probiotic
(Bifidobacterium longum) isolated from healthy rectal mucosa combined
with a prebiotic (oligofructose-enriched inulin - Synergy 1trade mark)
was developed. The treatment was used in a randomised controlled trial
involving eighteen patients with active UC, for a period of 1 month.
Rectal biopsies were collected at the beginning and end of the study.
Bacteriological analysis and transcription levels of epithelium-related
immune markers were assessed. Results demonstrated that short-term
synbiotic treatment resulted in increased bifidobacterial colonisation
of the rectal mucosa and induced significant reductions in the
expression of molecules that control inflammation in active UC.
PMID: 15975209
******
This is one more link to the ScriPPs TLR article,
http://www.mydna.com/resources/news/200506/news_20050623_tlr3.html
They have a search engine. Lets try their search for psoriasis. OK
http://www.mydna.com/search.html?SearchableText=psoriasis&portal_type%3Alist
*******
So how about a 30 year old drug with a off label use for psoriasis?
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15986076&query_hl=2
Mycophenolate mofetil: a dermatologic perspective.
Mydlarski PR.
Division of Dermatology, Departments of Medicine and Medical Genetics,
University of Calgary, Calgary, AB, Canada.
Introduced in the 1970s as a treatment for psoriasis, mycophenolic acid
has since been reformulated as mycophenolate mofetil (MMF). With an
improved side-effect profile and enhanced bioavailability, MMF is a
promising drug for immune-mediated skin disease. Currently approved for
the prevention of organ rejection, its list of "off-label" dermatologic
indications continues to grow. As a noncompetitive inhibitor of inosine
monophosphate dehydrogenase (IMPDH), MMF inhibits de novo purine
synthesis. Its relative lack of hepatonephrotoxicity and seemingly low
risk of carcinogenicity offer important therapeutic advantages. While
case reports and case series dominate the dermatologic literature,
preliminary results are sufficiently promising to warrant larger,
randomized clinical trials with this emerging therapy.
PMID: 15986076
*****
randall...seems to be loads of emering things these days.
randall
Alert! Alert!
Forty minutes from right now.
News today from Canda regrading their Phase III psoriasis trials.
You may want to watch it own the web.
http://www.newswire.ca/en/releases/archive/June2005/30/c7779.html
Isotechnika Preliminary Phase III psoriasis data to be presented at the
Canadian Dermatology Conference
EDMONTON, June 30 /CNW/ - Isotechnika Inc. (TSX:ISA) announced today
that
Dr. Kim Papp, a principal investigator in the Canadian Phase III
psoriasis
trial will present preliminary data from the trial at the Canadian
Dermatology
Association's annual conference at 4:10 p.m. ET today. The meeting is
being
held at the Fairmont Le Château Frontenac in Québec City, Quebec.
Dr. Papp's presentation will be made available to all interested
parties
through the Company's Web site at www.isotechnika.com
(((((((((((((((((((((((((((((((((((((((((((00)))))))))))))))))))))))))))))))))))))))))))))))))))
~
More and More P studies! we need to bring down the cost with
competition.
http://www.pharmalive.com/News/index.cfm?articleid=252739&categoryid=21
Hitchin, UK, 30 June 2005 York Pharma plc, the AIM-listed (AIM:YRK)
strategic acquirer, developer and marketer of pharmaceutical products
in the field of dermatology, announces ethics committee approval for
the start of a Phase II study in Australia of YP003, the company's
patented product with potential in the treatment of psoriasis. Dosing
of patients will commence shortly, and the study is expected to
complete by the end of 2005. The psoriasis market is valued at
approximately $630m currently and projected to grow to $2bn by 20081.
The randomised, double-blind Phase II study will compare the activity
of topical YP003, which has a novel mechanism of action, to
calcipotriol or placebo on multiple test sites in each patient using a
microplaque technique. Calcipotriol (marketed by Bristol-Myers Squibb
and Leo as Dovonex™) is the gold standard therapy used to treat mild
to moderate psoriasis, which affects approximately 85% of patients.
Data generated to date indicates that YP003 may have a favourable
profile in terms of efficacy, irritancy and safety compared with the
gold standard treatments for psoriasis.
The product has shown a powerful and statistically significant
interruption of the cellular proliferation that is a hallmark of
psoriasis, the reversal of which is a principal objective for an
effective treatment. It inhibits an enzyme not previously targeted in
psoriasis therapy, that acts as a regulator of cellular proliferation
and which is overactive in psoriatic lesions compared with normal skin.
This unique mechanism of action means that YP003 has the potential for
maintaining efficacy during continued use, unlike some currently used
agents which lose efficacy over time.
Commenting on the announcement, Terry Sadler, Chief Executive of York
Pharma, said: "This important milestone is excellent news for the
company and its shareholders, demonstrating further progress with our
innovative product pipeline. As illustrated by our comprehensive and
accelerated clinical development plan for YP003, we believe that it has
the potential to be an important new treatment for psoriasis".
**************
Would you buy a female rat one to many drinks?
A study that starts to show the problem with gut/endotoxins/liver.
When it comes to P we may all have the female rat genes!
Leaky guts due to whatever trigger. StreP?, bad gut flora, Alcohol et
al are
always first and foremost on my radar...
And look at what this leads too.....
Ancient knowledge from Israel over 2000 years ago...
http://www.hepatitisneighborhood.com/content/in_the_news/archive_2403.aspx
Women may be more susceptible to alcohol-induced liver damage, say
researchers who base their hypothesis on a study involving rats. Female
rodents given alcohol and a special diet had more severe liver damage
at the end of the research than their male counterparts did, report
doctors at the University of Pittsburgh, whose findings were released
at a medical conference in May.1
"Our aim was to determine whether chronic alcohol ingestion in male and
female rats resulted in ... subsequent liver injury, using two diets
differing in carbohydrate and fatty acid composition and degree of
liver injury," wrote Patricia Eagon, PhD, in the university's
Department of Molecular Genetics and Biochemistry, and her colleagues.
(...)
It has been known that women face greater risks of severe liver damage
from consuming alcohol compared to men,3,4 Eagon and her fellow
researchers noted.
Previous studies have also shown that alcoholic liver damage is caused
chiefly by the escape of poisons known as endotoxins released by
bacteria that live in the intestinal tract. That underlying cause
"wasn't totally new to us," Eagon said, in a telephone interview.
However, the exact reasons why there were differences in the extent of
liver disease between males and females weren't well known.
The researchers used two groups of rats for their study. The first
group was given alcohol with either a high-carbohydrate or a high fat
diet. The second group was fed no alcohol with either diet. The study
lasted for two months. The high fat diet was based on fatty fish oils
that included highly unsaturated fats, whereas the high-carb diet
contained a mixture of vegetable oils that contained the same amount of
fat, but included monounsaturated and polyunsaturated fats. One of this
study's co-investigators, Amin Nanji, MD, in the department of
Pathology at Harvard Medical School, had previously shown that the fish
oil-based diet played a key part in accelerating liver injury in ALD.
Dietary Influence on Female Liver Damage
At the end of the study, Eagon's team measured the extent of liver
injury in all rats, including the amount of fatty liver and liver
inflammation, in either males or females. They also measured levels of
endotoxins. High levels of these substances in parts of the rat's
bodies other than the intestine would be an indicator that they were
involved in the liver injury found.
Much higher levels of endotoxins that had migrated from the intestine
to abdominal lymph nodes and the bloodstream were found in the female
rats given alcohol and the high fish oil diet as compared to the other
groups, Eagon's team reported. Liver enzymes, which had also been
measured, were significantly higher in all the animals, but more
pronounced in the female rats given alcohol and high fish oil diets.
Additionally, liver inflammation was found only in this group.
"So it's alcohol plus fish oil" that is the key to inducing this type
of injury in women, Eagon explained. "There's something about the
highly unsaturated fatty acids in the diet that cause the gut injury,
and only in the females," she said. "And why that it, I wish we knew
right now. That's the next experiment."
Further, all rats that had evidence of alcoholic liver disease after
consuming the high vegetable oil-based diet had no levels of endotoxins
in the abdominal lymph nodes or bloodstream. But liver injury was
"enhanced" in female animals fed the high fish oil-based diet that
included alcohol, Eagon and her colleagues stated.
^^^^^^^^^^
Wow now read about the 2000 plus year old connections. Its true...
^^^^^^^^^^
This goes back to what Josh has posted on the web regarding the wrong
combo's of fats and psoriasis... I should do a post on it. But not now.
You can see his stuff here and now,
http://groups-beta.google.com/groups?q=randall+josh+psoriasis+talmudic+law&qt_s=Search
Now think about jewish dietary rules influencing genes for a long time
anyway.
Does that give rise to a smarter race?
Read the second post in this thread by SBH
http://groups-beta.google.com/group/sci.med/browse_frm/thread/0c340629c4cb582f/a104752279b3ee7b?hl=en#a104752279b3ee7b
Now think some more.
Did Talmudic laws attempt to dietarily deal with not inducing TZARAAT
(which some scholars have linked with modern day psoriasis).
Oh Well. Lets jumP back into the 21st century and really cool things to
puff
ones Pride uP over.
These ancient things are really cool to sPeculate over anyway..
****************************
I'm gonna splice that gene right out of my life.
http://www.medadnews.com/News/Index.cfm?articleid=252861
(...)
Cytokines are small secreted proteins which mediate and regulate
immunity, inflammation, and hematopoiesis. Monoclonal antibodies
against the cytokine tumor necrosis factor alpha (TNF-alpha) are
currently approved for the treatment of inflammatory diseases such as
rheumatoid arthritis.
"These two gene families are important actors in major therapeutic
areas, including cancer and inflammatory disease. Splice events in
these families can have profound effects. For instance the one splice
form of the Bcl-x gene, Bcl-x-L provides an anti-apoptotic effect in
cancer cells while another splice form, bcl-x-S, has a pro-apoptotic
function," stated Bruno Tocque, CEO ExonHit Therapeutics. "We are very
pleased to be able to offer arrays focused on these molecules to bring
a better level of resolution to gene expression."
(,,,)
^^^^^
Cool ... I'm gonna keeP an eye on this one. Looks like a maybe stock
buy.
Next, another culPrit in inflammation to look at....
*********
http://www.innovations-report.com/html/reports/life_sciences/report-46004.html
(...)
One reason, Rosen and his colleagues have reported in an upcoming issue
of the journal Proceedings of the National Academy of Sciences, may be
because of the signaling of a small lipid called sphingosine
1-phosphate (S1P), that is produced at sites of inflammation. The
activation of S1P3 receptors in the lung by S1P may be what causes
pulmonary edema to arise by causing a breakdown of the epithelial
barrier.
Breakdown of the Tight Junctions
The work started as a collaboration between Rosen and his Scripps
Research colleague Professor Jerold Chun, M.D., Ph.D., both of whom
have spent several years studying various lipids and lipid receptor
systems in the body including sphingosine 1-phosphate and the
lysophosphatidic acid receptors. Sphingosine 1-phosphate is produced or
secreted throughout the body, including in the lungs, where it has been
found in the lung fluid taken from patients with asthma. The production
of sphingosine 1-phosphate is induced as a response to the presence of
pro-inflammatory chemicals such as type-1 interferons and tumor
necrosis factor, which are both produced during septic shock, one of
the exact conditions that lead to edema.
Wanting to know what effect sphingosine 1-phosphate has on edema, the
Rosen lab looked at the effect of the lipid on the cells lining the
lung and the blood vessels surrounding the lungs. Chun's group had
created mutant mice deficient for the S1P3 receptor, which allowed a
clean assessment of its role in the lung.
On the blood vessel side, the "endothelial" cells lining the
capillaries express a type of protein known as S1P1 receptors.
Activation of these S1P1 receptors with the sphingosine 1-phosphate
leads to the tightening of junctions between the endothelial cells and
the stoppage of potential leakage-the opposite of what happens in
edema.
However, the epithelial cells on the lung side express a slightly
different type of S1P receptor called the S1P3 receptor protein.
Yasuhiro Gon, M.D., Ph.D., found that when sphingosine 1-phosphate is
administered into lung sacs, it activates the S1P3 receptors on the
airway side of these epithelial cells and induces pulmonary edema.
Significantly, they found that a mouse model that has no receptors of
this type is protected against pulmonary edema when exposed to
sphingosine 1-phosphate.
(...)
^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^
Aging from China with LOVE...Pass the green tea.
http://www.rednova.com/news/health/159177/scientists_shed_new_light_on_aging_process/
HONG KONG -- Scientists in Hong Kong have shed new light on why cell
repair is less efficient in older people after a breakthrough discovery
on premature aging, a rare genetic disease that affects one in four
million babies.
Premature aging, or Hutchison-Gilford Progeria Syndrome (progeria), is
obvious in the appearance of a child before it is a year old. Although
their mental faculties are normal, they stop growing, lose body fat and
suffer from wrinkled skin and hair loss.
Like old people, they suffer stiff joints and a buildup of plaque in
arteries which can lead to heart disease and stroke. Most die of
cardiovascular diseases before they are 20.
In 2003, a team of scientists in the United States found that progeria
was caused by mutation in a protein called Lamin A, which lines the
nucleus in human cells.
A team at the University of Hong Kong, led by Zhou Zhongjun, took the
research a step further in 2004 and found that mutated Lamin A actually
disrupted the repair process in cells, thus resulting in accelerated
aging.
The study was published in the July issue of the Nature Medicine
journal.
Zhou said the team came by their findings after comparing skin cells
taken from two progeria sufferers, normal humans, progeria mice and
normal mice.
While damaged DNA was quickly repaired in the healthy human and mice
cell samples, the samples taken from the progeria humans and mice had
difficulty repairing damaged DNA.
"Mutation in this protein (Lamin A) can cause defects in repair and
thus lead to progeria," Zhou, a research assistant professor with the
biochemistry department at the University of Hong Kong, said in an
interview.
"DNA damage is not effectively repaired in cells with defective Lamin A
but very efficiently repaired in normal cells."
The study highlights the importance of Lamin A to the repair process,
and any mutation to Lamin A that disrupts repair will bring about
aging, Zhou said.
Having established the link between Lamin A and repair, Zhou is using
major findings from other research he did in 2002 to work on his next
project, a product which he hopes could kill cancer cells.
Zhou, Professor Karl Tryggvason in Sweden's Karolinska Institute and a
Spanish research group found in 2002 that the enzyme Zmpste 24 was
responsible in converting prelamin A to functional Lamin A.
Zhou's laboratory is now developing inhibitors to Zmpste 24, which he
hopes to apply to tumors. These inhibitors should theoretically disrupt
Lamin A production, thwart the repair function in cancer cells, and
bring on their premature aging and death.
"We're now trying to develop inhibitors to Zmpste 24 and apply it to
tumor cells," he said.
&&&&&&&&&&&&&&&&&&&&&&&&
I'd rather just fade away if I had that progeria stuff, gracefully.
Come on science
get a cure for these little old people.
It's just to sad.
But isn't all aging sad?
Do those genes hit the dimmer switch?
^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^
http://www.newswise.com/articles/view/512758/
A 'Dimmer Switch' for Genes
ewswise - A protein that was thought to simply turn genes on and off
now looks to be more like a cellular "dimmer switch," researchers
from Huntsman Cancer Institute at the University of Utah, report in the
July 1, 2005, issue of the journal Science.
The scientists showed for the first time that when certain parts of a
protein molecule are modified - flexible, randomly structured regions
believed to be only minor players in the protein world - they become
important in turning genes on and off, but in a way that resembles a
dimmer switch rather than an on-off switch.
Genes carry the code that produces proteins to carry out almost all
functions in a living organism. But some of these proteins also help
control when and where genes do their jobs. The new study deals with
how one such protein, named Ets-1, turns genes on or off.
Huntsman Cancer Institute scientists, led by Barbara Graves, Ph.D.,
professor and chair of the Department of Oncological Sciences at the
University of Utah School of Medicine, and doctoral student Miles
Pufall, studied Ets-1, a protein known as a transcription factor that
helps read genetic information. This factor serves as a cell's
librarian, helping find the right genetic instructions.
How much information the librarian provides, and how accurate that
information is, must be tightly controlled. Without the right
information, cells can't behave properly, and may, as in the case of
cancer, grow out of control. The connection between factors such as
Ets-1 and a number of cancers prompted the study of how it works.
One way proteins are controlled occurs after a cell creates a protein.
Graves illustrates this process by comparing protein structure with
beads on a string. "After the protein is made, it can acquire what we
call post-translational modifications, which are like decorations on a
beaded necklace. In this analogy, one person creates a necklace using
similar beads and then a committee comes along and decorates it,
putting a gold star here and a diamond there. These modifications give
the protein different properties."
The "decorations" that were studied were phosphate molecules, which
previously had been shown to build up on proteins until a certain
number accumulated. The result, according to the study, has been
described in the past as a sharp on-off switch of protein activity.
"What we found was that each time we added a phosphate to a
particular unstructured region of Ets-1, there was an effect on the
protein's ability to bind to a gene. Binding was weakened, but it was
a gradual weakening. That isn't typical," Graves says. "Instead
of acting like an on-off switch, it behaved the way a dimmer switch
does to regulate lighting in a gradual manner."
In studying how this fine-tuning worked, they also discovered that
conventional wisdom failed to fully describe how proteins function. It
was known that proteins have regions with parts that are fixed in
space, with a definite structure, and parts that are randomly
positioned in space, like spaghetti strands. It was thought that the
structured regions did most of the work, while the unstructured regions
served only minor roles, such as tethering parts together.
"Scientists understand how a molecule works in part because we
understand the shape or structure," Graves explains. "But what we
discovered takes us beyond knowing the structure. Our data were about
features that are not fixed in space, but that are flexible and
changing."
The team used a nuclear magnetic resonance, or NMR, which allows
scientists to observe how the atoms of a molecule behave inside a
magnetic field. The Graves team found that unstructured regions of the
Ets-1 protein were affecting the structured regions in the work of
controlling genes. "In fact," Graves reports, "the region's
unstructured nature appears to be an essential requirement." NMR
showed that phosphate addition to this unstructured region caused a
gradual decline in DNA binding, gradually turning a gene off.
"One thing we didn't get was why Ets-1 worked differently before
and after phosphorylation [the addition of phosphate]," says Pufall,
"because as far as we could tell, the overall shape of the molecule
didn't change."
"A protein molecule is not like a rock. It's more like Jell-O: it
has structure, it has shape, but it jiggles," explains Graves. "We
didn't discover jiggling, but we were able to determine that the
amount of internal motion within a protein corresponds to the ability
of a protein to do its work." Phosphorylation was found to decrease
the internal motion of Ets-1, reducing its activity.
According to Pufall, "Ets-1 provides a remarkable illustration of how
elegantly proteins are put together - forming a distinct shape, but
with the versatility to respond to the changing needs of the cell,
however subtle."
The findings have long-term implications for the study of all proteins,
because, according to Graves, any protein has the potential to be
organized this way, with structured and unstructured regions that work
together.
Graves and Pufall conducted the study with doctoral student Mary L.
Nelson, also of the Huntsman Cancer Institute; Gregory M. Lee, Hyun-Seo
Kang and Lawrence P. McIntosh at the University of British Columbia;
and Algirdas Velyvis and Lewis E. Kay at the University of Toronto. The
National Institutes of Health, U.S. Department of Energy and the
Huntsman Cancer Foundation funded the study.
(Thanks you science dudes! )
Now lets fix cancer!
Two Mules for Sister Sara.
If she has cancer she may need a herd of them!
***********************
http://www.newswise.com/articles/view/512850/
(...)
Newswise - Researchers at UT Southwestern Medical Center have found
an enzyme vital for controlling the early stages of cell death - a
beneficial and normal process when it works right, but malignant in a
variety of cancers when it malfunctions.
The researchers are now examining tissue from cancer patients to try to
determine how mutations in the enzyme's gene may relate to cancer.
"We think this gene will really be a hot spot in research," said
Dr. Qing Zhong, postdoctoral researcher in biochemistry at UT
Southwestern and lead author of a paper to be published in the July 1
issue of the journal Cell.
The life and death of cells is a complex avalanche of reactions,
controlled by a few molecules that sit atop a biochemical
"pyramid."
The newly discovered enzyme, which the researchers have named Mule,
destroys a key molecule at the top of the pyramid, thus leading to the
cascading disintegration of the cell. Their findings also suggest a new
drug target for controlling tumor formation.
Dr. Xiaodong Wang, professor of biochemistry at UT Southwestern and a
researcher with the Howard Hughes Medical Institute, said the discovery
of Mule will open up a whole field of research to study the enzyme's
role in normal cell death and cancer.
"We think these findings are very significant," said Dr. Wang,
senior author of the Cell study. "This is the first enzymatic step
that regulates the degradation of proteins that control cell death."
The beneficial side of cell death - known as apoptosis - occurs
when it kills cells at appropriate times, as is the case, for example,
when it removes the webbing from the fingers of an embryo or shapes a
developing brain. But the darker side of this complex process manifests
itself in cancers when cells don't die when they're supposed to.
The key to the researchers' finding was the interaction between the
Mule enzyme and a major player in cell death, the protein Mcl-1. Dr.
Wang said that while there are many possible routes a cell may take
toward apoptosis, this interaction serves as one of the "master
switches" controlling whether or not those other pathways are
triggered.
Normally, Mcl-1 keeps cells alive by protecting them against apoptosis.
For a cell to die, Mcl-1 has to be disabled. "It's just like a
guardian," Dr. Zhong said.
A healthy organism needs just the right amount of Mcl-1. Too little
Mcl-1 can lead to a damaged immune system or even death. Too much, and
cells stay alive when they shouldn't, leading to cancers such as
lymphomas.
Using human cell extracts, the researchers found that Mule caused a
protein called ubiquitin to bind to several sites on Mcl-1. When
ubiquitin binds to a molecule, it serves as a flag for that molecule to
be destroyed.
"If you have too much Mule in a cell, Mcl-1 will degrade
tremendously," Dr. Zhong said.
The search for Mule took more than two years, as the UT Southwestern
researchers specifically searched for an enzyme that controls Mcl-1.
The interaction between Mule and Mcl-1 might someday be manipulated to
help cancer patients, Dr. Wang said. For instance, a tumor may contain
cells with a deficit of Mule, making the tumor more likely to grow and
perhaps be resistant to chemotherapy. Treatment might then focus on the
biochemistry of Mule and Mcl-1, he said.
"We might be able to see if there's a problem with Mule, or perhaps
we could screen beforehand," Dr. Wang said.
Other UT Southwestern researchers involved in the study were Wenhua
Gao, student research assistant, and Dr. Fenghe Du, research
specialist.
The work was supported by the Howard Hughes Medical Institute, the
National Institutes of Health and The Welch Foundation.
&&&&&&&&&&&&&&&&&&&&&&
Thanks for making it this far.
You can see how far things have gone and what great prosPects
lie on the horizon.
randall .... Brave New World... with a twist..NO P!
randall
An herb from India sold in the UK.
Would I use it? Not likely. I'm sure I could buy it at the local
healthfood co-op.
Why do I need another anti-bacterial, when I have wheatgrass spray?
Then again its natural and if you are. Bingo!
Does it work? Neem products
(Filed: 01/07/2005)
Barbara Lantin takes a closer look at a natural product that
discourages insects from biting
The neem tree, a familiar sight all over India, is known as the village
pharmacy because of its medicinal properties. Scientists recognised its
potential when locusts left it alone. Today, its leaf and seed kernels
are used in a range of products.
"Neem is one of the most complex natural products around," says Dr
Alison Blackwell of Advanced Pest Solutions, based at Edinburgh
University. "It contains many compounds with different properties."
More than 140 constituents have been isolated.
Dr Mark Cole, product development manager for Bioforce, which
manufactures NeemCare products, says: "Neem has many modes of action,
making it anti-inflammatory, antibacterial, antifungal and
insecticidal." In the West it is used mainly to treat minor ailments.
Insect repellent
The scent of neem oil discourages insects from biting. It is also
active against mosquitoes. "Chemical products such as Deet outperform
natural products, but some people, especially those with young
children, prefer to use something natural," says Dr Blackwell.
Head lice
A natural alternative to chemical-based products, Neem inhibits the
growth, feeding and reproduction of the parasite. Laboratory trials at
the School of Hygiene and Tropical Medicine in London have shown that
neem seed extract is more effective than oil in killing the parasites.
Skin and hair problems
"In India, eczema and psoriasis are traditionally treated with
preparations of neem leaf," says Dr Cole. Neem-based creams can be used
for athlete's foot, acne, eczema and psoriasis while neem shampoo may
help dandruff.
# NeemCare products are available from health stores and at
www.neemco.co.uk
# barbara...@telegraph.co.uk
**************
SKIN CAMP
http://www.fortwayne.com/mld/newssentinel/living/12032574.htm
Posted on Fri, Jul. 01, 2005
California camp a wonder for children with rare skin conditions
BY SANDY KLEFFMAN
Knight Ridder Newspapers
LIVERMORE, Calif. - (KRT) - Natasha Starkey and Lizie Fernandez, best
buddies at camp, prepare to launch into a song they composed.
"One, two, three, let's hit it," they chant, breaking into "Olivia, the
Black-Nosed Bunny."
It's a scene that could be repeated at camps throughout the United
States: two girls, 9 and 10, sharing the joyous creation of a close
friendship.
Except that behind a curtain next to the girls, a young boy with a
serious skin disease screams in agony as adults change his bandages.
Natasha and Lizie undergo their own dressing changes while they sing.
With sores and blisters covering much of their bodies, they have become
pros at the painful procedure, accepting it with grace and good cheer.
Such are the incongruities of Camp Wonder, the only camp in the western
United States for children with chronic and often disfiguring skin
diseases.
(...)
Older children with skin diseases frequently return to the camp to
serve as counselors and role models.
Beyond the feel-good experience, the camp provides a learning
opportunity for the medical staff. The campers have a variety of
diseases, some common and some very rare, including psoriasis, eczema,
ichthyosis, vitiligo, nevoid basal cell carcinoma syndrome and
pemphigus.
"You don't see the whole picture of what skin disease is like when you
just see kids in your office," said Stanford dermatologist Dr. Anna
Bruckner. She treats Alex, Brandi and their older brother, Corey, who
also has EB.
"It's wonderful to be able to help out in some way and see another side
of their life."
Doctors rarely get to view the scope of an EB patient's sores because
it takes too long to remove and reapply bandages during a typical
visit.
<sniP>
*************
Skin camp! What a marvelous idea.
**************
Yesterdays P News had a mention of sphingosine 1-phosphate (S1P)
This,
http://www.innovations-report.com/html/reports/life_sciences/report-46004.html
So, today we go with it to see where it goes in relationship to P and
P things. Like TNF and ceramides.
Roles for C16-ceramide and sphingosine-1-phosphate in regulating
hepatocyte apoptosis in response to TNF-alpha.
Osawa Y, Uchinami H, Bielawski J, Schwabe RF, Hannun YA, Brenner DA.
Medicine Dept., Columbia University, College of Physicians and
Surgeons, New York, NY 10032.
Tumor necrosis factor (TNF)-alpha signals cell death and simultaneously
induces the generation of ceramide, which is metabolized to sphingosine
and sphingosine 1 phosphate (S1P) by ceramidase (CDase) and sphingosine
kinase (SphK). Because the dynamic balance between the intracellular
levels of ceramide and S1P (the "ceramide/S1P rheostat") may determine
cell survival, we investigated these sphingolipid signaling pathways in
TNF-alpha-induced apoptosis of primary hepatocytes. Endogenous
C16-ceramide was elevated during TNF-alpha-induced apoptosis in both
rat and mouse primary hepatocytes. The putative acid sphingomyelinase
(ASMase) inhibitor imipramine inhibited TNF-alpha-induced apoptosis and
C16-ceramide increase as did the knock out of ASMase. Overexpression of
neutral CDase (NCDase) inhibited the TNF-alpha-induced increase of
C16-ceramide and apoptosis in rat primary hepatocytes. Moreover, NCDase
inhibited liver injury and hepatocyte apoptosis in mice treated with
D-galactosamine plus TNF-alpha. This protective effect was abrogated by
the SphK inhibitor N,N-demethylsphingosine (DMS), suggesting that the
survival effect of NCDase is due to not only C16-ceramide reduction but
also S1P formation. Administration of S1P or overexpression of NCDase
activated the pro-survival kinase AKT, and overexpression of dominant
negative AKT blocked the survival effect of NCDase. In conclusion,
activation of ASMase and generation of C16-ceramide contribute to
TNF-alpha-induced hepatocyte apoptosis. NCDase prevents apoptosis both
by reducing C16-ceramide and by activation of AKT through S1P
formation. Therefore, the crosstalk between sphingolipids and AKT
pathway may determine hepatocyte apoptosis by TNF-alpha.
PMID: 15946935
Well this points out an imPortant fact about P. We have to know each
and
every turn, pathway, molecule etc, when it comes to this rube goldberg
P machine. But are plaques floating islands of Th1? That we can isloate
pathways in or do we need to think systemic, body wide at times? And
what time?
http://www.sciencedaily.com/releases/2003/09/030915072358.htm
(...)
This study, titled, "Discovery and evaluation of inhibitors of human
sphingosine kinase," appeared in the Sept. 15 issue of Cancer Research
and was recently presented at two international scientific meetings.
Smith's research team in the Department of Pharmacology included: Kevin
J. French, Ph.D., Randy Schrecengost, Brian D. Lee, Yan Zhuang, Ph.D.,
Staci N. Smith, Justin L. Eberly, and Jong K. Yun, Ph.D., of the Jake
Gittlen Cancer Research Institute.
Previous studies have shown that sphingosine kinase (SK) plays a
pivotal role in regulating cell growth. Cell membranes contain
sphingomyelin, a precursor of two lipids: ceramide, which causes
programmed cell death (apoptosis), and sphingosine 1-phosphate (S1P),
which causes cell proliferation. The balance of ceramide and S1P
determine whether cells multiply or die.
A chain reaction with other enzymes can turn ceramide into
sphingosine, which then reacts with SK to form S1P. This promotes cell
proliferation, and stops the programmed cell death that would otherwise
rid the body of the cancer cells. This study aimed to find a way to
stop that chain reaction and create an effective option to treat
cancer.
(...)
This S1P gene is looking like a hot ticket. Lets do it,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM&cmd=search&term=S1P+
Which one do i check first?
Psor 6 gene is on 19p13 so lets check *603751 at (19p13.3)
http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=603751
And *605110 is on 19p.12,
http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=605110
May as well do the rest tomorrow.... :(
And vitamin D3 forms sphingosine-1-phosphate and knocks out, well
something in
the skin,
And S1P blocks LPS via Tight Junctions,
Protective effects of sphingosine 1-phosphate in murine
endotoxin-induced inflammatory lung injury.
Peng X, Hassoun PM, Sammani S, McVerry BJ, Burne MJ, Rabb H, Pearse D,
Tuder RM, Garcia JG.
Department of Medicine, Division of Pulmonary and Critical Care
Medicine, Johns Hopkins University School of Medicine, Baltimore,
Maryland, USA.
Our prior in vitro studies indicate that sphingosine 1-phosphate
(S1P), a phospholipid angiogenic factor, produces endothelial cell
barrier enhancement through ligation of endothelial differentiation
gene family receptors. We hypothesized that S1P may reduce the vascular
leak associated with acute lung injury and found that S1P infusion
produced a rapid and significant reduction in lung weight gain (more
than 50%) in the isolated perfused murine lung. The effect of S1P was
next assessed in a murine model of LPS-mediated microvascular
permeability and inflammation with marked increases in parameters of
lung injury at both 6 and 24 hours after intratracheal LPS. Each
parameter assessed was significantly reduced by intravenous S1P (1
microM final) and in selected experiments by the S1P analogue FTY720
(0.1 mg/kg, intraperitoneally) delivered 1 hour after LPS. S1P produced
an approximately 40-50% reduction in LPS-mediated extravasation of
Evans blue dye albumin, bronchoalveolar lavage protein content, and
lung tissue myeloperoxidase activity (reflecting phagocyte
infiltration). Consistent with systemic barrier enhancement, S1P
significantly decreased Evans blue dye albumin extravasation and
myeloperoxidase content in renal tissues of LPS-treated mice. These
studies indicate that S1P significantly decreases pulmonary/renal
vascular leakage and inflammation in a murine model of LPS-mediated
acute lung injury and may represent a novel therapeutic strategy for
vascular barrier dysfunction.
PMID: 15020292
This is complex but interesting. Could it solve some of the secrets
between P and C?
Time will tell...
Time cleared up many misconceptions regarding P53 recently.... I was
in love
with resveratol for P53 and sirT/sir2 genes (sirtuin). Not anymore, or
not as
madly in like,
http://www.medicalnewstoday.com/medicalnews.php?newsid=26710
The cellular cascade of molecular signals that instructs cells with
fatally damaged DNA to self-destruct pivots on the p53 tumor suppressor
gene. If p53 is inactivated, as it is in over half of all human
cancers, checks and balances on cell growth fail to operate, and body
cells start to accumulate mutations, which ultimately may lead to
cancer. Not surprisingly, the regulation of this vital safeguard has
been studied in great detail for many years but mainly in tissue
culture, or in vitro, models
<sniP>
*******
Whats up with the HCR genes and P? Is there a there there?
PSORS1 is the major susceptibility locus for psoriasis vulgaris (PV)
and lies within an approximately 200 kb segment of the major
histocompatibility complex on chromosome 6p21.3. Alleles of candidate
genes in this region including human leukocyte antigen (HLA)-C,
alpha-helical coiled coil rod (HCR), and corneodesmosin (CDSN) show
association with early-onset PV. Late-onset psoriasis (LOP) is defined
as a disease with onset after 40 y of age and is typically sporadic. We
assessed the role of PSORS1 in genetic susceptibility to LOP.
hcr and psoriasis
http://www.ncbi.nlm.nih.gov/Structure/cdd/cddsrv.cgi?uid=pfam07111
I hated being a freaking type I psoriatic. I want to LOP that gene
outa my life.
What can we find on HCR,
Genetic susceptibility for psoriasis is regulated to the greatest
extent by the PSORS1 locus. Three psoriasis-associated susceptibility
alleles have been identified within it, namely, HLACw6, HCR*WWCC and
CDSN*5, but strong linkage disequilibrium between them has made it
difficult to distinguish their individual genetic effects, and animal
models to study their effects are not known. To study the function of
HCR, we engineered transgenic mice with either a non-risk allele of HCR
or the HCR*WWCC risk allele under the control of the cytokeratin-14
promoter. These choices were motivated by the apparently dominant
effect of PSORS1 on psoriasis susceptibility and the physiological
expression of HCR in basal keratinocytes. Transgenic mice appeared
phenotypically normal and histologically their skin was
indistinguishable from wild-type mice. Expression studies using
Affymetrix arrays suggested that the HCR risk allele has specific
functional consequences relevant to the pathogenesis of psoriasis.
Comparison of gene expression changes between non-risk and risk allele
mice revealed similarities to previous observations in human psoriatic
skin, including upregulation of cytokeratins 6, 16 and 17 in risk
allele mice. We also observed changes in the expression of genes
associated with terminal differentiation and formation of the cornified
cell envelope. Our results support the concept that HCR may constitute
an essential gene in the PSORS1 locus. These observations are also
compatible with a model that a susceptibility gene for psoriasis
induces changes that are contributory but not sufficient by itself to
produce the clinical phenotype.
PMID: 15190014
(...)
Based on the observations that HCR is detected in cancers of
epithelial origin in Ki67-negative areas and that interferon-gamma
downregulates its expression, we suggest it to have an
antiproliferative function.
PMID: 14675183
Well thats all very interesting.
Lets move on,
http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=605310
*605310 Links
ALPHA-HELIX COILED-COIL ROD HOMOLOG
Alternative titles; symbols
HCR
C6ORF18
Gene map locus 6p21.3
Linkage results from genomewide scans placed a major psoriasis
susceptibility locus (see 177900) on chromosome 6p21.3, near the HLA-C
locus (142840). Asumalahti et al. (2000) determined the structure of a
gene from this region known as PG8 for 'putative gene-8,' a suggested
tricohyalin homolog (Guillaudeux et al., 1998), or HCR for 'alpha-helix
coiled-coil rod homolog' (Oka et al., 1999).
<sniP>
Look at this,
http://www.ncbi.nlm.nih.gov/Omim/getmap.cgi?l605310
Right next to the Hemochromatosis gene and MHC on one side and all the
histones on the other.
Thats odd,
We need info hyperlinked over proteins,
http://www.pdg.cnb.uam.es/UniPub/iHOP/gs/99928.html
And a picture of hcr,
http://www.dsi.univ-paris5.fr/genatlas/fiche1.php?symbol=C6orf18
Yet they can't say its the one or one of the ones?
randall.... the matrix goes on and on and on..
randall
Enbrel ads pulled. You need to register for the link.
http://news.google.com/news?auth=DQAAAGgAAABCE5CcPkVt9K9YR7W9Vd28G_SXzyP4c1SH2h7RjVpDCMUmsTzORruDKWo49cRwswR7mEwd_a_rwr6UCrw4r2JtgIYn9fcH7KDI3fGW4pg5FVaM2ZCVQTfrJJEh3TlPpHJ744qDKX1mllKkb51f4QeB&lr=&tab=gn&ie=UTF-8&scoring=d&q=psoriasis+enbrel+amgen+ads&btnG=Search+News
****************
In yesterdays P news, the S1P pathway was examined.
An agonist to S1P is,
http://www.caymanchem.com/app/template/Product.vm/catalog/10006292
FTY720 is a derivative of ISP-1 (myriocin), a fungal metabolite of the
Chinese herb Iscaria sinclarii as well as a structural analog of
sphingosine.<sniP>
Looks tasty,
http://www.hiddenforest.co.nz/fungi/family/clavicipitaceae/clavi01.htm
Way to powerful to fool with,
http://www.google.com/search?q=Isaria%20sinclairii&svnum=10&hl=en&lr=&sa=N&tab=iw
A 100 times more poweful then cyclosporin? Wow, a fungal with a KICK.
And it only took them 11 years to make something out of it,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15951022
(...)
FTY720 displays a novel mechanism of action that has not been observed
with other immunosuppressive agents and shows a synergism with
cyclosporin A (CsA) and tacrolimus, it is presumed that FTY720 provides
a useful tool for the prevention of transplant rejection and a new
therapeutic approach for autoimmune diseases including multiple
sclerosis and rheumatoid arthritis.
PMID: 15951022
Looks like a possible low dose deal some how for P?!
As you can use these FUNgals to skew th1/th2,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15778126
We need just enough to knock down Th1 a tad for mild P and bigTIME for
severe P.
This fungus looks like a possible for P going beyond MtX and
cyclosporin.
******************
If it isn't LPS per se, what else is haPPening?
This abstract came uP yesterday on pubmed,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15987478
A monoclonal antibody against kininogen reduces inflammation in the
HLA-B27 transgenic rat.
Keith JC Jr, Sainz IM, Isordia-Salas I, Pixley RA, Leathurby Y, Albert
LM, Colman RW.
Department of Cardiovascular and Metabolic Diseases Research, Wyeth
Research, Cambridge, Massachusetts, USA. jke...@wyeth.com.
ABSTRACT : The human leukocyte antigen B27 (HLA-B27) transgenic rat is
a model of human inflammatory bowel disease, rheumatoid arthritis and
psoriasis. Studies of chronic inflammation in other rat models have
demonstrated activation of the kallikrein-kinin system as well as
modulation by a plasma kallikrein inhibitor initiated before the onset
of clinicopathologic changes or a deficiency in high-molecular-mass
kininogen. Here we study the effects of monoclonal antibody C11C1, an
antibody against high-molecular-mass kininogen that inhibits the
binding of high-molecular-mass kininogen to leukocytes and endothelial
cells in the HLA-B27 rat, which was administered after the onset of the
inflammatory changes. Thrice-weekly intraperitoneal injections of
monoclonal antibody C11C1 or isotype IgG1 were given to male
23-week-old rats for 16 days. Stool character as a measure of
intestinal inflammation, and the rear limbs for clinical signs of
arthritis (tarsal joint swelling and erythema) were scored daily. The
animals were killed and the histology sections were assigned a
numerical score for colonic inflammation, synovitis, and cartilage
damage. Administration of monoclonal C11C1 rapidly decreased the
clinical scores of pre-existing inflammatory bowel disease (P < 0.005)
and arthritis (P < 0.001). Histological analyses confirmed significant
reductions in colonic lesions (P = 0.004) and synovitis (P = 0.009).
Decreased concentrations of plasma prekallikrein and
high-molecular-mass kininogen were found, providing evidence of
activation of the kallikrein-kinin system. The levels of these
biomarkers were reversed by monoclonal antibody C11C1, which may have
therapeutic potential in human inflammatory bowel disease and
arthritis.
PMID: 15987478
P has high kininogen levels?
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6204492
(...)
Extensive chronic inflammatory skin disease correlates with elevated
total plasma kininogen.
PMID: 6204492
Kallikrein-kinin system activation in Crohn's disease: differences in
intestinal and systemic markers.
OBJECTIVES: Observations in experimental models and in human ulcerative
colitis suggest that activation of the kallikrein-kinin system plays a
role in the pathogenesis of inflammatory bowel disease. The aim of this
study was to assess activation of the plasma and tissue
kallikrein-kinin system in Crohn's disease.<sniP>
HLA-B27 modulates nuclear factor kappaB activation in human monocytic
cells exposed to lipopolysaccharide.
Penttinen MA, Holmberg CI, Sistonen L, Granfors K.
National Public Health Institute, Turku, and Turku Centre for
Biotechnology, University of Turku, Turku, Finland.
markus.p...@utu.fi
OBJECTIVE: To study whether HLA-B27 modifies some key factors
controlling inflammatory responses on lipopolysaccharide (LPS)
stimulation in human monocytic cells. METHODS: U937 human monocytic
cells were stably transfected with either HLA-B27 genomic DNA, HLA-B27
complementary DNA, HLA-A2 genomic DNA, or with the resistant vector
pSV2neo (mock) alone. The cells were stimulated with LPS.
Electrophoretic mobility shift assay was performed to determine nuclear
factor kappaB (NF-kappaB) and heat-shock factor 1 activities, Western
blotting was performed to detect the expressions of inhibitory
kappaBalpha (IkappaBalpha) and heat-shock proteins (HSPs), and
enzyme-linked immunosorbent assay was performed to measure tumor
necrosis factor alpha (TNFalpha) secretion. RESULTS: The expression of
HLA-B27 modulated the response to LPS in U937 human monocytic cells.
Stimulation with LPS led to faster degradation of IkappaBalpha
regulatory proteins, accompanied by faster and prolonged activation of
NF-kappaB in HLA-B27-expressing cells compared with HLA-A2 and mock
transfectants. The secretion of TNFalpha upon LPS stimulation
correlated well with the activation of NF-kappaB. No activation of the
heat-shock response was observed. CONCLUSION: Our data indicate that
HLA-B27 has effects on host responses to LPS that are unrelated to
antigen presentation. Two crucial events in the development of
arthritis, the activation of NF-kappaB and the secretion of TNFalpha,
were found to be enhanced in HLA-B27-expressing cells upon LPS
stimulation. Because LPS is known to be present in the inflamed joints
of patients with reactive arthritis (ReA), the enhanced inflammatory
response of HLA-B27-positive cells upon LPS stimulation offers an
attractive explanation for the role of HLA-B27 in the development of
ReA.
PMID: 12209522
Yet HLA-B27 marks for PA (psoriatic arthritis) more so then psoriasis
in general?
http://www.emedicine.com/OPH/topic721.htm
And i'm interested in LPS and anything else to understands its
workings.
So a test of C11C1 on psor mice may turn up a clue or two,
(The whole trial on c11c1 from top abstract)
http://arthritis-research.com/content/7/4/R769
What happens in wound healing versus chronic inflammation with
kallikrein and P,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15576327
>From Namazi-- drugs to use to slow tryptase--> kiniogens,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15037212
(...)
Cetirizine, supposed to inhibit DNA binding activity of NF-kappa B,
inhibits the expression of adhesion molecules on immunocytes and
endothelial cells and the production of IL-8 and LTB4, two potent
chemoattractants, by immune cells. It induces the release of PGE2, a
suppressor of antigen presentation and MHC class II expression, from
monocyte/macrophages and reduces the number of tryptase positive mast
cells in inflammation sites. Tryptase is a chemoattractant, generates
kinins from kininogen, activates mast cells, triggers maturation of
dendritic cells and stimulates the release of IL-8 from endothelial
cells and the production of Th1 lymphokines by mononuclear immunocytes.
<sniP>
This guy confuses me. Not that that isn't easy. lol
But if C11C1 stops or slows P in some psoriatics, it would prove a gut
connection.
Or link at the very least.
How hard would it be to find a 100 psoriatics with gut problems to test
?
And if they have PA (psoriatic arthritis) so much the better,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15331420
********
Randall.... mabs and fungi for P! Whats not to like?
randall
P News from around the world. With some added comments.
Ayurveda and P from Bahrain,
http://www.gulf-daily-news.com/Story.asp?Article=116066&Sn=BNEW&IssueID=28105
Ancient guide to healthy living...
By SOMAN BABY
MANAMA
AN ancient guide to healthy living could hold the answer to many of our
modern lifestyle ailments, say experts. Ayurveda, the ancient Indian
system of medicine, promotes a balance that many people lack.
For instance, unhealthy combinations of food in our diets can lead to
long-term health problems, says Bahrain Wellness Resort (BWR) chief
medical officer Dr Devidas Vellodi.
"Ayurveda, the science of life describes in details about the healthy
habits and the way to keep away from ailments and disorders," he told a
seminar at Novotel Al Dana Resort.
It was organised by the Bahrain Chapter of the Institute of Chartered
Accountants of India (BCICAI) and was attended by around 150 people.
According to Ayurveda, sea foods, especially prawns or shrimp, should
not be taken along with milk or milk products, said Dr Vellodi, a
graduate of India's renowned Kottackal Ayurveda College, with 22 years
experience in Ayurvedic practice. "Yoghurt should not be taken together
with chicken varieties," he noted.
"Honey, ghee and water should not be mixed in equal quantity and honey
should not be heated.
Such unhealthy combinations may not lead to any sudden problems or
changes in the body, said Dr Vellodi.
"However, it may become a root cause for skin ailments like Psoriasis
and scabies ," he continued.
"Ayurveda recommends two principle meals for a day for a healthy
person.
"We should eat food only to fill half of the stomach.
"We have to reserve one fourth of the stomach for water and the balance
should be kept for movements of air."
Therapies
BWR naturopathy physician Dr P R Renjana talked about the relevance of
natural food habits and lifestyle.
The first and most basic principle of natural cure is that all forms of
disease are due to the same cause, namely, the accumulation of waste
materials and bodily refuse in the system, she said.
The seminar was part of the medical education programmes conducted by
BWR, the first resort of its kind in the Gulf offering Ayurveda and
other alternative medicine therapies under one roof.
BCICAI chairman Rajeev Nanda chaired the seminar.
(You suPpose that air in the stomach provides for elimination of GAS?
;-)
*********
http://www.app.com/apps/pbcs.dll/article?AID=/20050702/COMMUNITY/507020313/1065
Longtime Monmouth County resident Robert Guzman's new home is a
godsend.
A former vice president of an insurance company, Guzman said his life
took a drastic turn back in 1994. After losing both his mother and his
wife within the same month, Guzman was diagnosed and hospitalized a
dozen times for psoriasis.
"I became addicted to a sleep medication," he explained. "I lost my job
and my home. But my wake-up call came in June 2003 when I was arrested
for substance abuse."
After finding himself homeless, Guzman turned to HABcore for help. He
became a tenant of its Coffey Residence, a boarding home in Red Bank.
Established in 1988, HABcore provides permanent and transitional
supportive housing to low-income individuals who are homeless, disabled
or unable to care for themselves. As Guzman continued to work on his
life, he became eligible for the nonprofit's new apartment program,
which began at the end of last year. Under the apartment program,
boarding home tenants can graduate to supervised independent living
facilities.
"I filled out the required applications," Guzman explained. "(I)
provided them with the mandatory personal financial information, and
they immediately started working on finding affordable housing on my
behalf.
"It seemed to me at times to be a very long wait," he said of the
process. "I now fully realize that it was not having a safe place to
call home that made the wait appear to be so long."
In March, Guzman moved into his very own sparingly furnished
two-bedroom apartment.
"I was one of the lucky ones," he said standing outside his Mount Zion
Way home in Ocean Grove. "I found myself in need of housing, with a
very limited budget and not much assistance available."
Through the program, Guzman is required to delegate 30 percent of his
income from his part-time job at a local shop toward rent and
utilities. HABcore then subsidizes the balance.
Guzman credits HABcore for not only finding him a safe and affordable
apartment but for also providing some startup furniture and
accessories.
"The project affords you the ability to get some of the things people
take for granted, such as cable or a computer," he said.
"It's not the Taj Mahal," he said. "But it's a great apartment for
someone who is just starting. A case manager comes in once a week to
make sure things are OK."
In Guzman's case, that manager is Janice Von Pater, who also works as
the residential coordinator at HABcore's Laurel House in Asbury Park.
"Many low-income housing facilities are not particularly positive
places to live," Von Pater said at her Laurel House office. "A nice
clean apartment can make a world of difference."
With most participants on general assistance or social security
programs, Von Pater said budgeting is crucial.
"Many of our residents are living on $120 to $130 per month," she said.
"To offset their financial limitations, many volunteers try to help
curb expenses. They'll do this through a variety of ways, such as
making a hot meal for the tenants to little things we take for granted
like giving them detergent so they can do their laundry."
Additionaly, many items, Von Pater said, come from volunteers and
donations from members of the community. They include vacuum cleaners,
microwaves, tables of various sizes, air conditioning units and fans,
dishes, pots and pans, sheet sets and window treatments.
HABcore's two boarding homes serve 49 people in their Red Bank and
Asbury Park facilities, said executive director Steve Heisman. To date,
the organization's independent living program sponsors apartments in
Asbury Park, Ocean Grove, Spring Lake Heights, Matawan and Keansburg.
For information, visit www.habcore.org or call (732) 544-1975.
^^^^^^^^^^^^^^
Ok so we don't eat milk and prawns in the same meal if we
are doing the ayurveda thing.
Or milk and meat in Israel.
Or milk and anything if thats your P trigger thing.
But the lactose sugars in milk feed the good bacteria in your
gut (colon) and that is a good thing.
If you have no other dietary problems with dairy why shouldn't
you consume yougurt and dairy products? And when?
What about Whey? Curds and sPiders? Or even worse.
Bad gut flora. Really bad gut flora in this next link.
Supplemental Dietary Whey Protein Concentrate Reduces Rotavirus-
Induced Disease Symptoms in Suckling Mice1
ABSTRACT
Rotavirus-induced diarrhea is a common infection that results in the
death of nearly 500,000 children annually. Currently, no large- scale
preventative treatments or vaccines exist. Because some whey protein
concentrates (WPC) were shown to contain bioactive ingredients that may
activate immune cells and/or prevent infection, the current study was
conducted to assess whether the proprietary WPC IMUCARE(TM) (WPC-IC)
could protect against rotavirus. Suckling BALB/c mice were treated by
gavage once daily with WPC-IC or with the control protein bovine serum
albumin from the age of 9 to 17 d, and were infected with murine
rotavirus at the age of 11 d. Disease symptoms were graded as mild,
moderate, or severe, and viral shedding was measured in fecal samples
during the postinfection period. Severe diarrhea occurred in 63% of
control mice; this was significantly reduced to 36% in WPC-IC-fed mice.
Severe diarrhea occurred for a 4-d period in the control group but only
for a 2-d period in the WPC-IC group. Although the mean viral load per
mouse did not differ between the groups, the proportion of mice
shedding high levels of the virus in the feces postinfection was
significantly lower in the WPC-IC group on d 13, 16, and 17, and
significantly higher on d 14. Rotavirus-specific antibody levels in
serum and gut fluid did not differ between groups. Thus, prophylactic
treatment with WPC-IC may reduce rotaviral disease by decreasing the
prevalence of severe diarrhea and by decreasing the time period during
which severe symptoms and high viral shedding occur. J. Nutr. 135:
1470-1474, 2005.
KEY WORDS: * rotavirus * mouse model * whey protein concentrate
Rotavirus infection is the most common cause of diarrhea in young
children (1,2) and nearly 500,000 children die each year as a result of
severe rotaviral disease (3). Unlike many enteric pathogens, rotavirus
causes symptomatic disease mainly in the young, although adults can be
infected and will shed virus in the feces. Currently, no antirotavirus
vaccines are available. There is therefore a great need to develop safe
and effective preventatives for reducing childhood rotaviral infection
as a means of improving pediatric health.
Both T- and B-lymphocytes play an important role in the control of
rotavirus infection and in the subsequent clearance of the virus (4-7);
probiotics, which enhance the immune response, were shown to be
partially effective against rotavirus in animal models (8-12) and in
humans (13). Lactadherin in human milk blocks rotavirus attachment or
replication as do intestinal mucins and some cytokines in vitro
(14-17). Oral administration of a sulfated sialyl lipid reduced
rotavirus-induced diarrheal disease in suckling mice, and
rotavirus-specific Ig was partially effective in oral daily doses of
3-10 g for 4 d in children with rotavirus infection (18-20). However,
oral rehydration therapy remains the standard treatment (21,22);
neither probiotics nor Ig are yet used in routine clinical practice
(23,24).
Bovine milk and whey protein concentrates (WPC)3 contain antiviral and
immunomodulatory components and were shown to enhance a variety of
immune functions (23,25-31). The current study evaluated the effects of
the proprietary whey protein concentrate IMUCARE(TM) (WPC-IC) on
rotaviral disease in neonatal mice (32-35).
MATERIALS AND METHODS
<sniP>
Leaky guts have been done. But here goes again.
Increased iNOS activity is essential for intestinal epithelial tight
junction dysfunction in endotoxemic mice.
Han X, Fink MP, Yang R, Delude RL.
Department of Critical Care Medicine, University of Pittsburgh School
of Medicine, Pittsburgh, Pennsylvania, 15261, USA.
We tested the hypothesis that increased production of nitric oxide
(NO.) associated with lipopolysaccharide (LPS)-induced systemic
inflammation leads to functionally significant alterations in the
expression and/or targeting of key tight junction (TJ) proteins in
ileal and colonic epithelium. Wild-type or inducible NO. synthase
(iNOS) knockout male C57B1/6J mice were injected intraperitoneally with
2 mg/kg Escherichia coli O111:B4 LPS. iNOS was inhibited using
intraperitoneal L-N(6)-(1-iminoethyl)lysine (L-NIL; 5 mg/kg).
Immunoblotting of total protein and NP-40 insoluble proteins revealed
decreased expression and decreased TJ localization, respectively, of
the TJ proteins, zonula occludens (ZO)-1, ZO-2, ZO-3, and/or occludin
in ileal mucosa and colonic mucosa (total protein only) after injection
of C57B1/6J mice with LPS. Immunohistochemistry showed deranged
distribution of ZO-1 and occludin in both tissues from endotoxemic
mice. Endotoxemia was associated with evidence of gut epithelial
barrier dysfunction evidenced by increased ileal mucosal permeability
to fluorescein isothiocyanate-dextran (Mr=4 kDa) and increased
bacterial translocation to mesenteric lymph nodes. Pharmacologic
inhibition of iNOS activity using L-NIL or genetic ablation of the iNOS
gene ameliorated LPS-induced changes in TJ protein expression and gut
mucosal barrier function. These results support the view that at least
one mechanism contributing to the pathogenesis of gastrointestinal
epithelial dysfunction secondary to systemic inflammation is increased
iNOS-dependent NO. production leading to altered expression and
localization of key TJ proteins.
PMID: 14770040
Ethyl pyruvate ameliorates intestinal epithelial barrier dysfunction in
endotoxemic mice and immunostimulated caco-2 enterocytic monolayers.
Sappington PL, Han X, Yang R, Delude RL, Fink MP.
Department of Critical Care Medicine, University of Pittsburgh Medical
School, Pittsburgh, Pennsylvania 15261, USA.
Ethyl pyruvate (EP) solution ameliorates ileal mucosal
hyperpermeability and decreases the expression of several
proinflammatory genes in ileal and/or colonic mucosa when it is used
instead of Ringer's lactate solution (RLS) to resuscitate mice from
hemorrhagic shock. To test the hypothesis that EP can ameliorate gut
barrier dysfunction induced by other forms of inflammation, we
incubated Caco-2 monolayers for 24 to 48 h with cytomix (a mixture of
interferon-gamma, tumor necrosis factor-alpha, and interleukin-1beta)
in the presence or absence of graded concentrations of EP or sodium
pyruvate. Cytomix increased the permeability of Caco-2 monolayers to
fluorescein isothiocyanate-labeled dextran (FD4; average molecular mass
4 kDa), but this effect was inhibited by adding 0.1 to 10 mM EP (but
not similar concentrations of sodium pyruvate) to the culture medium.
EP inhibited several other cytomix-induced phenomena, including nuclear
factor-kappaB activation, inducible nitric oxide synthase mRNA
expression, and nitric oxide production. Cytomix altered the expression
and localization of the tight junctional proteins, ZO-1 and occludin,
but this effect was prevented by EP. Delayed treatment with EP solution
instead of RLS ameliorated ileal mucosal hyperpermeability to FD4 and
bacterial translocation to mesenteric lymph nodes in mice challenged
with lipopolysaccharide (LPS). These data support the view that EP
ameliorates cytokine- and/or LPS-induced derangements in intestinal
epithelial barrier function.
PMID: 12490623
I don't find much on Ethyl pyruvate on the newsgroups. Like can i run
down to the local health food store and buy it? Tighten uP the
leaky gut and bingo. LESS P? Due to less LPS?
Ok and how about loose junctions in the lungs as a focal point for
a P trigger? WE have nasal passage endotoxins and craP hiding
in and around the tonsils. Do we have things adding to immune factors
from the lungs that may trigger psoriasis?
Inhaled LPS induces blood release of Clara cell specific protein (CC16)
in human beings.
Michel O, Murdoch R, Bernard A.
Clinics of Allergology and Respiratory Diseases, Saint-Pierre
University Hospital, Free University of Brussels, Rue Haute 322, B-1000
Brussels, Belgium. omi...@ulb.ac.be
BACKGROUND: Animal models of lung inflammation have validated the
plasma 16-kd Clara cell protein (CC16) as a peripheral marker of the
permeability of the alveolocapillary barrier. OBJECTIVE: We
investigated in human beings whether inhaled LPS induced a rise in
airways permeability measured by the plasma changes in CC16. METHODS:
The CC16 was measured in plasma from 15 subjects exposed to LPS by
inhalation, during which the kinetics and the dose-response
relationship of LPS-induced CC16 were evaluated. Because LPS-induced
response involves macrophages activation, the protective effect of oral
methylprednisolone was also evaluated. RESULTS: An inhalation of 50
microg LPS induced a significant ( P < .001) rise in CC16 after 6 hours
(from 7.24 [+/-0.68] microg/L to 10.69 [+/-0.99] microg/L) that
normalized at 24 hours (6.65 [+/-0.33] microg/L). The CC16 response was
dose-related, with the no-response threshold 0.5 microg LPS. A 6-day
treatment with 20 mg/d methylprednisolone inhibited significantly ( P <
.001) the CC16 response to 50 microg LPS. CONCLUSION: Exposure to LPS
by inhalation in healthy subjects induces an intravascular leakage of
CC16 that can be blocked by corticosteroids. These observations further
validate plasma CC16 as a noninvasive test of the alveolocapillary
barrier permeability.
PMID: 15940126
The web search begs the addition of keywords TNF, LPS,
http://www.google.com/search?hl=en&lr=&q=cc16+clara+cell+protein+lps+tnf&btnG=Search
I don't know. Going down the Git seems like more fertile ground for P.
Lets go back to the rednova people for their current page on the Gi
TRACT.
http://www.rednova.com/news/science/161113/comparative_gut_microflora_metabolic_challenges_and_potential_opportunities/
Comparative Gut Microflora, Metabolic Challenges, and Potential
Opportunities
Primary Audience: Researchers, Nutritionists, Veterinarians
SUMMARY
Bacteria colonize practically every habitat in the nature. Bacterial
community of the gastrointestinal tract (GIT) is one of the major
metabolic tissues of animals. Still, its species composition is not
known, because methods that have been previously used for bacterial
analysis do not capture the species present. The bacterial community
within the GIT not only has intracommunity interactions, but it also
interacts with the host tissues. For the host, it is essential to
tolerate commensal bacteria and to recognize and fight intestinal
pathogens. In addition to recognized pathogens, there are many
functional bacterial groups, which produce metabolites considered
harmful for the host. Such functional bacterial groups include
protein-fermenting bacteria that produce toxic end products in their
amino acid metabolism, which is why a high-protein diet is often
considered unhealthy. Carbohydrates are preferred substrates for
gastrointestinal bacteria, but in the distal colon, they may become
depleted, and putrefaction becomes the dominating type of fermentation.
This largely accounts for the health effects of slowly fermenting
dietary fibers.
Microbial communities in the GIT of different animals have developed
hand-in-hand with their digestion strategy. In monogastric animals,
bacterial fermentation has concentrated in the lower GIT, whereas in
ruminants bacteria are responsible for the initial digestion of the
diet. Rumen-like sites with intense bacterial fermentation are found in
most animals, but no other group of animals totally depends on
bacteria. The response of rumen bacteria to feed components can be
evaluated by an in vitro rumen simulation, which measures relevant
fermentation parameters, such as the yield of bacterial biomass
(protein) and volatile fatty acids (energy). In monogastric animals, it
is essential that the host has measures to prevent bacterial
competition for substrates in regions in which absorption takes place;
the use of prophylactic antibiotics for production animals has aided
this.
Availability of good methods for monitoring the total bacterial
communities and their metabolism is a prerequisite for informative
studies in the future.
Key words: intestinal bacteria, chicken, rumen, human, putrefaction,
bacterial metabolite, antimicrobial growth promoter
2005 J. Appl. Poult. Res. 14:444-453
DEVELOPMENT OF GASTROINTESTINAL MICROBIAL COMMUNITIES
Bacteria are spread everywhere in nature and readily colonize a new
habitat with available nutrients and energy for growth and maintenance.
Bacterial cells are carried by water, soil, dust, aerosols, or simply
by air. Indeed, there are few bacteria-free zones in our environment.
Consequently, newborn animals are exposed to bacteria from the very
moment of birth or hatching. The gastrointestinal tract (GIT) of
mammals receive the first inoculum of bacteria from feces and breast
milk of the mother [1, 2], whereas newly hatched chicks get bacteria
from the surface of the eggshells [3, 4]. Very little information is
available on the bacterial colonization of the fish gut, but it seems
logical that the original inoculum for the fry comes from the
surrounding water. In chickens the GIT becomes rapidly colonized by
bacteria, with the maximum bacterial densities being reached within the
first 5 d after hatching [5]. During the following weeks, the
composition of microflora changes markedly [6, 7].
The ingested bacteria from habitats other than GIT mainly just pass
through the intestine unable to colonize any compartment of the tract.
However, some bacteria thrive under the gut conditions and become
members of the resident microbial community. In such communities,
bacteria do not live independently of the other species but interact
and depend on each other and their host in many ways. Bacterial
communities are metabolically versatile mixtures of different bacteria
whose relative abundance is regulated by environmental factors, such as
substrate flows, antibacterial compounds, and the structure and
function of the host epithelium. As entities, bacterial communities are
energetically more efficient and metabolically more flexible than
representatives of any single bacterial species present or the host
itself, because natural selection inevitably forces out bacteria, which
do not have a unique role (ecological niche) in the community. In
addition, any strain becomes replaced if a more efficient one appears.
Following this general mechanism of bacterial community evolution,
site- and diet- specific bacterial communities evolve in the GIT
compartments of different animal species.
The GIT of an adult homeothermic animal maintains bacteria in
quantities exceeding the total number of host cells and the metabolic
activity of any host tissue. Yet, the composition and metabolic
function of this bacterial tissue is poorly known today, because most
methods used for bacterial analysis have been based on dilution and
cultivation; these methods separate the interdependent bacterial
species from each other and the host. Only a fraction of
gastrointestinal bacteria grows independently as pure cultures with the
practices applied in most laboratories today [8, 9, 10].
Intestinal lumen should be considered as a part of the external world
in which the animal is at its closest vicinity to the bacteria of the
surrounding environment but still clearly separated by the intestinal
epithelium. The bacterial community residing within the GIT not only
has intracommunity interactions, but it also interacts with the
intestinal tissue of the host. A difficult task of the defense
mechanism of the intestinal tissues is to allow close contact with the
friendly commensal bacterial community while recognizing and fighting
pathogenic bacteria. Indeed, well-directed immunological tolerance and
defense mechanisms are important determinants of intestinal health [11,
12]. While natural selection drives the development of the bacterial
community to the best possible fit for its habitat, a similar selection
drives the evolution of host animals to accommodate a beneficial
bacterial community. Failure to tolerate commensal bacteria may be as
detrimental as the failure to recognize and successfully fight
intestinal pathogens. Indeed, one of the challenges of today's animal
breeding is to select for animals, which show both good performance and
high resistance against incidental intestinal pathogens.
DISTRIBUTION OF MICROBES IS DETERMINED BY THE DIGESTIVE SYSTEM OF THE
HOST
Microbial communities in the GIT of different animal species have
developed hand-in-hand with their digestion strategy, because the
structure and function of the digestive machinery determines the sites
of intestine in which both physicochemical and nutritional requirements
for bacteria] growth are fulfilled. Still, there are no sites in the
GIT in which bacterial growth would be entirely missing. The overall
bacterial activity may be modest in compartments, such as an acidic
stomach, but specialized bacteria thrive under difficult conditions and
benefit from the reduced competition by other bacteria.
FIGURE 1. Relative intensity of bacterial fermentation in compartments
of the GIT of various animals. Intensity of bacterial metabolism in the
intestinal compartments is indicated by the fill intensity in
respective textboxes.
The nutritional diversity and digestion potential of bacterial
communities clearly exceed that of any host animals. Consequently, many
components in the diet cannot be attacked by the host digestive enzymes
but can be utilized by intestinal bacteria. Coevolution of animal
species and their intestinal microflora has led to a situation in which
hot spots of bacterial fermentation have been restricted to defined
parts of the GlT. In monogastric animals, bacterial fermentation has
concentrated in the cecum and colon (Figure 1). These parts of the GIT
receive dietary compounds that escape host digestion and absorption;
therefore, bacteria do not compete with the host when they ferment the
entering substrates. However, in the upper GIT competition occurs for
all the simple sugars and amino acids utilized by the host, which are
also available for the bacteria. In poults, equines, and rodents, the
site for intense bacterial fermentation is a well-developed appendix or
cecum. In other monogastric animals, such as humans and swine, the
cecal appendix is diminished, and the bacterial fermentation mainly
occurs in the colon (Figure 1).
In ruminants, bacteria are responsible for the primary digestion of the
diet. This strategy saves energy, since the costs for feed digestion
and fighting against bacterial overgrowth are clearly reduced. The
drawback is that the metabolism of the host depends on the end products
of bacterial metabolism, such as short-chain fatty acids, which have
only half of the energy content of the carbohydrates. However, since
the metabolic potential and nutritional diversity of the rumen
bacterial community is far beyond that of the host, ruminants can
benefit from dietary components, such as cellulose and hemicellulose,
which are not available for monogastric animals. Provided that feed
intake is adequate, the microbial community of an adult cow with more
than 10^sup 16^ fully adapted bacteria is a high-capacity fermenter
capable of providing enough energy for the h\ost.
All the homeothermic animals mentioned above have 1 compartment in the
intestinal tract with high fermentation intensity (Figure 1). Bacterial
density in the cecum, colon, and rumen exceeds 10^sup 11^/ g of
digesta, the habitats are anoxic, and their redox potential is in the
range of -200 to -400 mV [13, 14, 15, 16]. Typically, such bacterial
communities are methanogenic or sulfidogenic, and the major end
products of fermentation are highly reduced volatile fatty acids, such
as acetic, propionic, and butyric acids and gases, such as CO2 and
CH^sub 4^. Not all animals have such bacterial concentrates in their
intestine. The GIT of Atlantic salmon has a stomach, proximal intestine
with a number of pyloric ceca, and distal intestine. All these
compartments are characterized by flat bacterial densities lower than
those in the ileum of the homeothermic animals and modest bacterial
fermentation, producing lactic and acetic acids [17] (Figure 1). Such
low bacterial density and the lack of bacterial gradients are likely to
reflect the low body temperature and highly digestible,
carbohydrate-poor diet of these carnivorous species.
PROTEIN FERMENTATION IN THE GUT PRODUCES HARMFUL METABOLITES
In the GIT, we can name obvious pathogenic bacteria, which invade host
tissues and produce potent toxins. Well-known examples are some species
of the genera Salmonella, Campylobacter, and Clostridium, which lead to
acute diarrhea, intestinal inflammation, and sometimes lethal necrosis
of the intestinal tissue [18, 19, 20]. In addition to such indisputably
recognized pathogens, there are many functional bacterial groups, which
under certain conditions release metabolic products considered harmful
for the well-being of the host. Such functional bacterial groups
include putrefactive, protein- fermenting bacteria, which produce toxic
end products in their amino acid metabolism. The metabolism of all
amino acids produces, in addition to short-chain fatty acids, ammonia,
and amines, which tend to increase the pH of the intestinal contents
(Figure 2). Saccharolytic fermentation (fermentation of carbohydrates)
produces mainly organic acids, which tend to reduce luminal pH. The
general assumption is that a low intestinal pH is good for intestinal
health, because the growth of many known pathogens is inhibited under
such conditions [21, 22, 23, 24, 25]. Indeed, the relative intensity of
the fermentation types determines the effect of the bacteriological
activity on the acidity of the intestinal contents (Figure 2).
Products of putrefaction have several undesired effects on the host
health, which is why high-protein diets are often considered unhealthy
for humans. Firstly, amino acid assimilation always produces ammonia,
which may lead to neoplastic growth of colon epithelium and harmful
accumulation of ammonia in body fluids [26]. For risk groups, this can
be especially hazardous. Aromatic amino acids, such as tyrosine,
phenylalanine, and tryptophan are converted to phenols and indoles,
which have been shown to express hypertensiveness, schizophrenia, and
migraine, and phenols are, in addition, cocarcinogens [27, 28, 29].
Generally, bacteria favor carbohydrates, if those are available. In
practice, this means that saccharolytic fermentation is characteristic
of proximal colon, which is rich in carbohydrates. Carbohydrates in the
distal colon become depleted; thus, putrefaction becomes the dominating
type of fermentation. This largely accounts for the health effects of
prebiotics and dietary fibers; as slowly digestible structures, they
provide carbohydrates also to distal colon, thus suppressing
putrefaction [30]. An obvious alternative for the inclusion of
nonstarch polysaccharides in the diet is to limit the intake of poorly
digestible protein. If dietary protein became readily digested in the
upper GIT by the digestive system, there would be less substrate
available for the colonie putrefaction. Predatory animals have their
meals raw, which keeps the meat-derived proteins native and far more
susceptible to digestive enzymes. Little is known about the extent to
which the end products of putrefaction affect the performance of
production animals. It seems likely, however, that any protein escaping
digestion in the small intestine of chickens and pigs is a potential
risk for the health of the animal.
MICROBIAL GROWTH IN THE SMALL INTESTINE IS COSTLY FOR THE PRODUCTION
ANIMALS
Taking into account that small intestinal digesta is very rich in
nutrients, it is striking how efficiently animals can keep bacterial
numbers low in this critical part of the digestive tract. Monogastric
animals have several mechanisms that restrict bacterial growth in the
proximal GIT, including chemical inhibition (e.g., acid and bile),
highly competitive rate of nutrient absorption (large absorptive
surface and active transport), high passage rate of digesta (washout of
free bacteria), continuous sloughing of the epithelial cells and mucus
(washout of adhered bacteria), and the immunological defense mechanisms
(IgA production). Failure to prevent bacterial growth in the proximal
small intestine would, no doubt, lead to starvation of the host.
FIGURE 2. Schematic presentation of characteristic pathways and
potential health effects of saccharolytic and putrefactive
fermentations by intestinal bacteria.
Physiological functions, such as those mentioned above, prevent the
wild competition for substrates, and bacteria are restricted to densely
populated sites, such as rumen, cecum, or colon. In these compartments,
bacteria benefit the host by converting unavailable dietary compounds
to end products of fermentation, which can then be utilized by the
host. However, in spite of all the measures to limit bacterial growth
to described compartments, bacteria do grow throughout the GIT. Even
though the density of actively metabolizing bacteria in the low-density
regions rarely exceeds 1% of those in the most active sites, bacteria
can still capture a significant proportion of simple substrates that
could be readily absorbed and utilized by the host. In broiler
chickens, as much as 20% of the total absorptive surface in the small
intestine can be bacterial. If we assume that the respected absorptive
surfaces would be evenly distributed in the small intestine and the
rate of uptake through bacterial membranes would be comparable to that
of the epithelial membranes of the host, bacteria could capture up to
20% of the nutrients. The true figure is most likely somewhat lower
because of an increasing gradient of bacterial density and a decreasing
concentration of simple substrates towards the distal end of the small
intestine.
Animal production has been commonly using prophylactic antibiotics to
support the animals' inherited measures to fight bacteria in the
intestinal regions that are essential for the nutrient extraction and
absorption. The total bacterial numbers in the ileum of broiler
chickens are reduced by 90% with Avoparcin [13]. Possibly based on such
bacterial growth reduction, growth- promoting antibiotics improve
weight gain and feed conversion efficiency in pigs and broiler chickens
[31, 32]. Recently, the use of some prophylactic antibiotics has been
banned in many countries in an attempt to limit the spread of
antibiotic-resistant organisms. The trend will likely expand to
limitation of the remaining antimicrobial growth promoters and perhaps
even the coccidiostats. The consequence of the present development
varies and will continue to vary from country to country. In countries
in which the feed production and farm management practices follow high
standards, the situation is relatively well under control. However, in
many countries, abandoning the prophylactic antibiotics has led to
serious problems in animal health and performance. Figure 3 summarizes
the effect of a coccidiostat (monensin) alone and in combinations with
a growth promoter bacitracin methylene disalicylate (BMD) or a
therapeutic antibiotic (penicillin) on the growth of broiler chickens
[33]. At the age of 11 d, none of the antimicrobials had an effect on
the growth of the animals, whereas 1 wk later all the treatment groups
had gained significantly more weight than the control group. It was not
until after 4 wk from hatching that the antibiotics combined with
monensin started to affect the growth of the chicken (Figure 3). Even
though some antimicrobial compounds are called and registered as
coccidiostats instead of growth promoters, their effect on the growth
of total microflora may not differ significantly.
FIGURE 3. Effect of antibacterial agents on the growth of broiler
chickens. Birds were grown on a wheat-based diet amended with monensin,
bacitracin methylene disalicylate (BMD), and phenoxy methyl penicillin
as indicated in the figure. Bars in columns indicate SE between
replicate animals [33].
The presence of antibiotics in feed has been one of the major selective
factors affecting the composition of microflora in the GIT of animals.
For decades, microbe selection has favored those tolerating antibiotics
in comparison to those sensitive to antibiotics. This
antibiotic-tolerant microflora has become the normal intestinal
microflora as we know it, and indeed, most of our knowledge and
experience on animal management leans against this background.
Veterinarians have been able to recognize the microbe- mediated
disorders developing from this normal microflora base. Likewise, most
feed companies, animal breeders, and so on have developed their
products for conditions using growth-promoting antibiotics. Removing
antibiotics from feeds has changed the rules of competition (selection
pressure) in the intestinal microbial community from favoring
antibiotic-resistant microbes to the advantage of microbes growing
efficiently on feed residues in the absence of antibiotics. Since most
microbes in the GIT of animals have been and are still unknown, the new
selection c\riteria may lead to the outgrowth and establishment of
unforeseeable bacterial species.
FIGURE 4. Flow chart illustrating the role of rumen fermentation in
ruminant nutrition.
Following the recent ban of growth promoters, feed and feed ingredient
companies are actively seeking for alternative strategies to control
unwanted growth of small-intestinal microflora. As the tools for
microbial community analysis have become more accurate and independent
of bacterial culturability we have learned that bacteria in the GIT can
be modulated by numerous dietary vehicles, such as grain, feed types,
and feed enzymes [13, 34, 35].
RUMEN BACTERIA BUILD PROTEIN AND ENERGY FOR THE HOST
Gastrointestinal bacteria have a central role in the life of ruminants,
not only on the health of individual animals but also on the evolution
of a whole animal species. In a nutrient-poor environment, animals with
emerging characteristics of ruminants would benefit from diversified
selection of utilizable feed and retrieval of energy from cellulose and
hemicellulose. Rumen-like sites with intense bacterial fermentation are
found in most animal species, but no other group of animals depends on
bacterial fermentation to the same extent as the ruminants, which have
been estimated to derive 70% of their energy from the products of rumen
fermentation, mainly acetic, propionic, and butyric acids [36]. Not all
acids have the same value for the host. Different fatty acids are
preferred energy sources for different tissues; therefore, their
relative value for the host varies, depending on the physiological
status of the animal. Monogastric animals, such as swine and human, may
significantly gain from bacterial fermentation; they have been
estimated to achieve 10 to 20% of their energy requirements by
absorbing short-chain fatty acids produced by bacteria in the hindgut
[36, 37].
FIGURE 5. Yield of volatile fatty acids and microbial biomass in rumen
fermentation simulation. In vitro fermentation was carried out for 12
h, and then fermentation products were quantified. Volatile fatty acids
were analyzed by gas chromatography and bacteria by flow cytometry as
described previously [17, 38]. Bars in columns indicate SE between the
replicate fermentation vessels [33].
The bulk of dietary nitrogen is assimilated by the actively growing
rumen microflora. Subsequently, the majority of the protein assimilated
by the animal comes from the digestion of bacterial biomass in
abomasum, the true stomach of the ruminants.
Optimization of the diet for ruminants is challenging due to the
involvement of the complicated rumen parameters. How to optimize
dietary protein and energy when they cannot be readily analyzed from
the components of the ration? True protein and energy available for the
host are not in the diet but are being produced by rumen bacteria from
the components of the diet (Figure 4). Feed materials used for ruminant
rations are many, and their quality may vary. Quality of forages
depends on plant varieties, fertilization, and seasonal conditions,
such as light, temperature, and humidity. Quality of fermented silages
depends, in addition to the factors listed above, on the bacteria
present and the fermentation conditions. Also, farmers use many types
of byproducts, the specifications of which are difficult to control.
One way to evaluate the response of rumen bacteria to feed components
is to use an in vitro rumen simulation and to measure relevant
fermentation parameters, such as the yield of bacterial biomass
(protein) and volatile fatty acids (energy). As an example, we tested
fermentation characteristics of different fractions of corn silage,
using such an approach. Significant differences were observed in the
yield of bacterial biomass, volatile fatty acids, and gas production of
different fractions (Figure 5). The highest yields of both microbial
protein and volatile fatty acids were found with the grain fraction;
rumen fermentation produced 800 g of acids and bacteria from 1 kg (DM)
of ensiled grain [33]. The other fractions and the mixed silage
produced about 500 g of the fermentation products. It is noteworthy
that not only the total yield, but also the energy-to-protein ratio of
different fractions of corn silage varied significantly (Figure 5). The
approximate ratio of microbial biomass to volatile fatty acids was 1:4
in mixed corn silage but close to 1:2 in the leaf fraction of the corn
silage.
How accurately can protein and energy yields of different feed raw
materials be estimated from their chemical composition? Is it possible
that the production efficiency of dairy and beef cattle could be
significantly improved if we knew how to optimize the relative
production kinetics of the true protein and energy?
FUTURE POTENTIAL OF KNOWLEDGE-BASED MICROBIAL MANAGEMENT
The structure and function of gastrointestinal bacteria affect our
daily life and society. Gut bacteria may become recognized because of
the intestinal disorders caused by enteric pathogens or the high price
of farm products affected by the efficiency of rumen fermentation.
Obviously, we should regulate the growth of beneficial and harmful
bacteria and thus improve the quality of life. However, it is only
within the last decade that scientists have shown that there is an
undiscovered microbial world in the GIT of animals. This discovery has
emerged with the new tools for microbial community analysis. Earlier
methods were based on the cultivation of bacteria under artificial
laboratory conditions, whereas the new analytical tools are based on
direct extraction of bacterial DNA from intestinal samples and
subsequent sequencing of the taxonomically relevant genes. Such
approaches have revealed that we used to know only a fraction of the
total bacteria. Now we acknowledge the true diversity of bacteria, but
for most newly discovered species, we only know a partial DNA sequence.
In the present situation, microbial management based on true
understanding is challenging. Modulation of the intestinal bacterial
community to a beneficial direction by feeding of live bacteria
(probiotics) or specialty carbohydrates for the beneficial bacteria
(prebiotics) are currently under active research and development. Since
the growth requirements of bacteria differ, it should be possible to
shift the microbial community from harmful to nonharmful direction by
changing the gut dynamics through dietary modulations. Probiotic
bacteria are meant to improve the health of the GIT, but these are
likely to be effective only if the requirements for their growth are
fulfilled or if their physiological effect is independent of their
viability. If viability is a requirement, a synbiotic product that
contains both a probiotic strain and a prebiotic substance, favoring
the growth of that particular probiotic, might be a good solution.
CONCLUSIONS AND APPLICATIONS
1. Modem tools to detect each member of the microbial communities have
brought up new questions about the role of microflora. What are all the
bacterial species doing? Are they good or bad for the health of the
host?
2. Thorough epidemiological studies together with well-designed animal
trials, measuring parameters that reflect animal performance and health
should be carried out to improve our understanding of gastrointestinal
interactions and the role of individual bacteria in the
gastrointestinal microbial community.
3. When relevant indicator bacteria and their metabolites are known, it
is possible to design animal trials and laboratory simulations, which
can be effectively used for product evaluation and screening of novel
microbial modulators.
REFERENCES AND NOTE
<sniP>
Ok. Boring.
But not if we can slow P. Not so boring.
randall.... remember the gut flora. Grows where sprouted! How NOw
brown...
randall
Cuban skin camp for Chernobyl kids__some have P!
http://ca.today.reuters.com/news/newsArticle.aspx?type=oddlyEnoughNews&storyID=2005-07-04T124509Z_01_N29443941_RTRIDST_0_LIFESTYLE-CUBA-CHERNOBYL-COL.XML
"They live in bungalows built as beach houses by rich Cubans before
Fidel Castro's 1959 revolution."
Lets hope and pray that those rich people left some cigars behind for
the children. lol
After that placenta head pack their gonna need one.
I'll run a pubmed on this placenta thing for p. Just to see.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15990135
Stem cells are the magic words. But does it work?
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=2394297
Should have known it was socialist propaganda BS. I mean not even rich
women in
capitalist countries falls for this kind of expensive treatments? Do
they? lol
Lets face it. I know plenty of folks, well at least one psoriatic, that
loves the cuban
sunshine to clear their psoriasis. And they eat and drink and have a
good time
Showing that the sun's rays trump all other pathways to clear you.
And if you don't clear you need to be studied or go the biological
route.
Maybe we can get those rich cubans to pay for your airline tickets. You
can
take your DVD camera so they can see what a good socialist dictator
does
with their real estate.
Is there BAD socialism? ;-0
*********************
Who knew that P news could be so entertaining?
This next one has been a major bugaboo for me.
These guys are spending major bucks to sell galactose.
Dressed up as the wizard of OZ behind a curtain. Sic em
Toto!
Galactose/lactose is whats in my proflora whey powder. A carbohydrate
whey
powder high in lactose that breaks down to galactose.
And feeds the good gut bacteria.
So if your mild to moderate you stand a good chance of nearly
clearing by taking it.
Yet, while I don't have the $$ to run tests, apparently they do.
Whats the differences between this,
http://www.thewholewhey.com/contents/products_info/proflora.htm
And XP-828L? Other then PRICE?
Not much if theirs actually helps the psoriatic lower their psoriasis.
Yet, for a severe psoriatic by doing the witkit good bacteria gut
implant
and then staying on a very bland diet for one month.
YOu get a high ratio of good flora in your colon that will clear you.
Lets see them offer that.
Got that one out of my system for the zillion'th time.
Now read about the hooPLA over this mere galactose
sugar.
http://biz.yahoo.com/prnews/050704/mo191.html?.v=2
Press Release Source: ADVITECH INC.
Media and Market Advisory: Advitech to release the results of its
clinical study on XP-828L for psoriasis
Monday July 4, 10:05 am ET
TSX Venture ExchangE: AVI
QUEBEC CITY, July 4 /PRNewswire-FirstCall/ - Advitech Inc. (TSX-V: AVI
- News) a Canadian biotech company, will present tomorrow, July 5,
2005, the results of its recently completed multi-center, double-blind,
placebo-controlled clinical study for XP-828L, its new oral treatment
for mild-to-moderate psoriasis. The objective of the 112-day study,
which involved 84 psoriasis patients, was to confirm the safety and the
efficacy of this product. Advitech will report the results via news
release at approximately 8:00 a.m. (ET).
Conference Call and Live Webcast
A conference call has been scheduled for 10:00 a.m. (ET) on Tuesday,
July 5, 2005 to discuss the results. Renaud Beauchesne, President and
CEO of Advitech and Patrice E. Poubelle, M.D., Ds.C., Chairman of
Advitech's scientific advisory committee, will participate in this
conference call.
The dial-in numbers to participate in the conference call are
1-416-640-4127 or 1-800-814-4859. Please connect approximately fifteen
minutes prior to the beginning of the call to ensure participation. The
conference call will be archived for replay until Thursday, July 7,
2005 at midnight. To access the archived conference call, dial
1-416-640-1917 or 1-877-289-8525 and enter the password number
21128405(pound key) .
A live audio webcast of the conference call will be available at the
address below. The webcast will be archived at the same address for 90
days.
www.newswire.ca/en/webcast/viewEvent.cgi?eventID(equal sign)1161160
For the media, please note that Mr. Beauchesne and Dr. Poubelle will be
available for interviews immediately after the conference call. See
contact information below.
About Advitech
Advitech is a biotechnology company specializing in the development of
bioactive ingredients from dairy proteins. Its key focus areas are in
the fields of immunology and inflammation. Its main platform, XP-828L,
is a growth factor complex used as an oral product for mild-to-moderate
psoriasis and other immune-mediated chronic inflammatory diseases.
Advitech's common shares are listed on the TSX Venture Exchange under
the symbol AVI. The number of common shares outstanding is 54,799,818.
This press release contains forward-looking statements which reflect
the Company's current expectations regarding future events. The
forward-looking statements involve risks and uncertainties. Actual
results could differ materially from those projected herein. The reader
is cautioned not to rely on these forward-looking statements.
The TSX Venture Exchange does not accept responsibility for the
adequacy
or accuracy of this release.
******
I suppose I'll tell you tomorrow the boring news that it does help.
Then the fireworks will be over.
randall... For those in the US, have a haPPy 4th!!!
randall
To follow through with yesterdays P news post regarding the following.
Advitech announces positive results of XP-828L study in psoriasis
http://www.npicenter.com/anm/templates/newsATemp.aspx?articleid=12885&zoneid=28
(...)
Moreover, analysis of PGA values demonstrates that 21.4% of patients
treated with XP-828L experienced a reduction in the severity of their
condition by at least one level on the PGA scale. These results further
strengthen the Company's claim that XP-828L can be successfully used
as a viable option for mild-to-moderate psoriasis patients.
(...)
(Big deal! A mere 20% of mild to moderate psor heads clear a little.
With my
methods even the most severe could achieve levels similar to the
biologicals. )
*********
More skin camp from california (not cuba this time).
My apologies to those socialist that may have been offended
yesterday.
Seeing as how it was 4th of July and many have died to support
FREEDOM, a shot across the bow of a failed economic/political
system seemed appropriate.
http://www.ledger-enquirer.com/mld/ledgerenquirer/living/12043580.htm
(...)
Natasha and Lizie undergo their own dressing changes while they sing.
With sores and blisters covering much of their bodies, they have become
pros at the painful procedure, accepting it with grace and good cheer.
Such are the incongruities of Camp Wonder, a camp for children with
chronic and often disfiguring skin diseases.
Seventy-four boys and girls gathered at the Livermore, Calif., camp in
mid-June. Away from the stares of strangers, they swam, rode horses,
climbed a rock wall, slept in bunk beds and devised crazy skits.
As much as possible, for five days, they left their diseases behind.
"The main thing I wanted to do is give the kids a sense of self-respect
and let them know there are people who will accept them," said camp
founder Francesca Tenconi.
"Many of these kids are very ill, and there's always a question about
who will come back next year."
Tenconi, 21, can empathize with the campers. A decade ago, she became
one of the youngest people in the United States diagnosed with
pemphigus foliaceus, a rare autoimmune disease that blistered her body,
causing her skin to peel like tissue paper.
She shows few signs of the disease today, after discovering the best
medications to use. But Tenconi has continued her dedication to the
camp she founded after her 16th birthday.
Now in its fifth year, Camp Wonder is one of several weeklong events
for children with a variety of life-threatening illnesses and
disabilities held each summer at Camp Arroyo in Livermore.
(...)
************
Fresh today in pubmed.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15994876
Homozygous mutations in LPIN2 are responsible for the syndrome of
chronic recurrent multifocal osteomyelitis and congenital
dyserythropoietic anaemia (Majeed syndrome).
Ferguson PJ, Chen S, Tayeh MK, Ochoa L, Leal SM, Pelet A, Munnich A,
Lyonnet S, Majeed HA, El-Shanti H.
University of Iowa Hospital, 2615 JCP, 200 Hawkins Drive, Iowa City, IA
52242, USA. hatem-e...@uiowa.edu.
BACKGROUND: Majeed syndrome is an autosomal recessive, autoinflammatory
disorder characterised by chronic recurrent multifocal osteomyelitis
and congenital dyserythropoietic anaemia. The objectives of this study
were to map, identify, and characterise the Majeed syndrome causal gene
and to speculate on its function and role in skin and bone
inflammation. METHODS: Six individuals with Majeed syndrome from two
unrelated families were identified for this study. Homozygosity mapping
and parametric linkage analysis were employed for the localisation of
the gene responsible for Majeed syndrome. Direct sequencing was
utilised for the identification of mutations within the genes contained
in the region of linkage. Expression studies and in silico
characterisation of the identified causal gene and its protein were
carried out. RESULTS: The phenotype of Majeed syndrome includes
inflammation of the bone and skin, recurrent fevers, and
dyserythropoietic anaemia. The clinical picture of the six affected
individuals is briefly reviewed. The gene was mapped to a 5.5 cM
interval (1.8 Mb) on chromosome 18p. Examination of genes in this
interval led to the identification of homozygous mutations in LPIN2 in
affected individuals from the two families. LPIN2 was found to be
expressed in almost all tissues. The function of LPIN2 and its role in
inflammation remains unknown. CONCLUSIONS: We conclude that homozygous
mutations in LPIN2 result in Majeed syndrome. Understanding the
aberrant immune response in this condition will shed light on the
aetiology of other inflammatory disorders of multifactorial aetiology
including isolated chronic recurrent multifocal osteomyelitis, Sweet
syndrome, and psoriasis.
PMID: 15994876
Yeah! Another gene to add to the list. But is it connected to P
somehow?
Lets run it now,
http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=605519
&
http://www.ncbi.nlm.nih.gov/mapview/maps.cgi?ORG=hum&CHR=18&maps=loc-r,morbid,gene&R1=on&query=LPIN2&VERBOSE=ON&ZOOM=3
If there is a there there. I'm not there. lol
Animal models for Psoriasis wanted! Sign uP now!
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15992087
With good models the GENEs will fall.
No no not the rat models. Ours!
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15992159
ISIS 2302, an antisense inhibitor of intercellular adhesion molecule 1.
Shanahan Jr WR.
Isis Pharmaceuticals, Inc., 2292 Faraday Avenue, Carlsbad, California
92008-7208, USA. wsha...@isisph.com.
ISIS 2302 is a 20 base phosphorothioate oligodeoxynucleotide (ODN) that
inhibits intercellular adhesion molecule 1 (ICAM-1) expression through
an antisense mechanism. Murine and rat analogues have been effective at
doses of 0.06 - 10 mg/kg in a spectrum of models of human inflammatory
diseases and allograft transplantation, and ISIS 2302 inhibits the
upregulation of ICAM-1 expression in a variety of human cells in vitro.
In animals, including primates, plasma distribution half-life ranges
from 30 - 60 min, but tissue elimination half-lives range from 1 - 5
days, and the compound is metabolised as other nucleic acids. In a
Phase I iv. study, the pharmacokinetic behaviour of ISIS 2302 was
similar to that in other primates, and single and multiple every other
day doses from 0.06 - 2 mg/kg infused over 2 h were well-tolerated.
Phase IIa studies have been completed in Crohn's disease, rheumatoid
arthritis, and psoriasis, and a combined Phase I/II renal allograft
acute rejection prophylaxis study has just completed enrolment. In
these studies, ISIS 2302, 0.5 - 2 mg/kg, or placebo was administered
iv. every 2 - 3 days over 14 - 26 days (7 - 13 infusions) to 17 - 52
patients, with follow up for 6 months. In the Crohn's study, evidence
of highly durable (5+ month) remission-inducing and steroid-sparing
properties were demonstrated, without clinically important adverse
events. A 300-patient, pivotal quality trial investigating the
steroid-sparing and remission-inducing qualities of ISIS 2302 in
patients with steroid-dependent Crohn's disease is completely enrolled,
with results expected in the first half of 2000. Modest efficacy and
excellent tolerability were demonstrated in the psoriasis and
rheumatoid arthritis trials. A Phase IIa trial of a topical formulation
in patients with psoriasis is expected to commence in late 1999, as is
a trial of an enema formulation in distal ulcerative colitis.
Administration by nebulisation for asthma is undergoing preclinical
evaluation. Execution of future plans in organ transplantation will
await the results of the ongoing Phase I/II trial.
PMID: 15992159
This next one is for JX and ALL the P- Js waiting out there.
Will the long awaited FAEs be better once they debut in the US?
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15991882
BG 12: BG 00012, BG 12/Oral Fumarate, FAG-201, Second-Generation
Fumarate Derivative - Fumapharm/Biogen Idec.
.
Fumapharm AG has developed a second-generation fumarate (fumaric acid)
derivative, BG 12 [BG 00012, FAG-201, BG 12/Oral Fumarate], for the
oral treatment of psoriasis. Biogen Idec is currently evaluating the
product in clinical trials as an oral treatment for multiple sclerosis
(phase II) and psoriasis (phase III) trials.BG 12 has an
immunomodulatory mechanism of action. It seems that this product has
been developed to reduce the adverse effects associated with a
first-generation product containing fumaric acid esters (mixed
dimethylfumarate and monoethylfumarate salts), Fumaderm((R)).
Fumaderm((R)) was approved in Germany in August 1994 and is currently
the leading oral systemic therapy for moderate-to-severe psoriasis in
Germany. One of the problems associated with Fumaderm((R)) capsules has
been its gastrointestinal adverse effects (including diarrhoea and
nausea).In September 2003, Biogen (now Biogen Idec) licensed exclusive
worldwide rights (excluding Germany) from Fumapharm to develop and
market BG 12. Biogen plans to collaborate with Fumapharm to accelerate
phase III development for psoriasis and the registration programme
worldwide. Financial terms of the agreement were not disclosed.
Development plans for BG 12 include other autoimmune and inflammatory
disorders, such as multiple sclerosis.In November 2003, Biogen and IDEC
Pharmaceuticals merged to form Biogen Idec. Fumapharm completed phase
II trials of this second-generation fumarate derivative for psoriasis
prior to licensing of the product to Biogen, also with positive
results.
PMID: 15991882
&&&&&&&&&&&&&&&&&&&
randall .... still awaiting the FAEs... Low dose of course.
Mathias Mildenberger
> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15991882
> BG 12: BG 00012, BG 12/Oral Fumarate, FAG-201, Second-Generation
> Fumarate Derivative - Fumapharm/Biogen Idec.
> ..
> Fumapharm AG has developed a second-generation fumarate (fumaric acid)
> derivative, BG 12 [BG 00012, FAG-201, BG 12/Oral Fumarate], for the
> oral treatment of psoriasis. Biogen Idec is currently evaluating the
> product in clinical trials as an oral treatment for multiple sclerosis
> (phase II) and psoriasis (phase III) trials.BG 12 has an
> immunomodulatory mechanism of action. It seems that this product has
> been developed to reduce the adverse effects associated with a
> first-generation product containing fumaric acid esters (mixed
> dimethylfumarate and monoethylfumarate salts), Fumaderm((R)).
> Fumaderm((R)) was approved in Germany in August 1994 and is currently
> the leading oral systemic therapy for moderate-to-severe psoriasis in
> Germany. One of the problems associated with Fumaderm((R)) capsules has
> been its gastrointestinal adverse effects (including diarrhoea and
> nausea).In September 2003, Biogen (now Biogen Idec) licensed exclusive
> worldwide rights (excluding Germany) from Fumapharm to develop and
> market BG 12. Biogen plans to collaborate with Fumapharm to accelerate
> phase III development for psoriasis and the registration programme
> worldwide. Financial terms of the agreement were not disclosed.
> Development plans for BG 12 include other autoimmune and inflammatory
> disorders, such as multiple sclerosis.In November 2003, Biogen and IDEC
> Pharmaceuticals merged to form Biogen Idec. Fumapharm completed phase
> II trials of this second-generation fumarate derivative for psoriasis
> prior to licensing of the product to Biogen, also with positive
> results.
>
> &&&&&&&&&&&&&&&&&&&
>
> randall .... still awaiting the FAEs... Low dose of course.
You can avoid most of the side effects by taking it with your meals and
increasing your milk intake. The "classic" Fumaderm usually is taken
with increasing dosage. First 1 tablet daily of "Fumaderm initial"
containing 30mg of FAE, once a week one more up to 3 (= 90mg). Then the
normal "Fumaderm", increasing from 1 (= 120mg) to 6 (=720mg) per day
once a week. Usually you stop the process of increasing the dosage when
seeing a therapeutic effect. Blood checks at last once a month are required.
Fumaderm is licensed here in Germany for Psoriasis treatment only, no
other inflammatory or autoimmune diseases. The big advantages of FAE are
their very good 'impact' on Pso and the usually minimal side effects.
The package insert is much shorter than the one for Ciclosporin
(Immunosporin/Sandimmun optoral/Neoral). Believe me, I 've seen both of
them. ;)
While taking Fumaderm I had no special troubles with side effects except
the need to see a toilet a little quicker some times. I only discovered
one "no-no" - Fumaderm and onion soup. ;))
My problem was that there was no effect with my skin, even with the
maximum dose. I seem to be one of the few Fumaderm shows no effects in
therapy at. Now I am getting Raptiva. The funny thing is that my brother
takes a low dose of Fumaderm with very, very good effect.
I think it's time to see this fine stuff being introduced in the US
market. Perhaps Fumapharm just did not have the bucks for the pre-sale
checks, as they're not one of the big players here.
Best regards from Weimar, Germany -
Mathias
randall
P News to follow this critical info for psor heads
all around the world wanting to try/use FAE's (fumaderm)..
Finally! Someone has reported an adverse side effect from onions
related to P and a P treatment.
I'd give uP some onions for a trial of FAEs.
> My problem was that there was no effect with my skin, even with the
> maximum dose. I seem to be one of the few Fumaderm shows no effects in
> therapy at. Now I am getting Raptiva. The funny thing is that my brother
> takes a low dose of Fumaderm with very, very good effect.
>
> I think it's time to see this fine stuff being introduced in the US
> market. Perhaps Fumapharm just did not have the bucks for the pre-sale
> checks, as they're not one of the big players here.
>
> Best regards from Weimar, Germany -
>
> Mathias
Thanks Mathias,
YOur information is very helpful.
And the process to allow us to take fumaderm is very slow.
I sure hope i'm like you brother and a low dose has positive
effects.
*********************************************************
*********************************************************
P News for today July 6th, 2005
New P site in the UK,
http://www.webuser.co.uk/sites/site_review.php?rev_id=2570
Talk Psoriasis
Rating:
www.talkpsoriasis.com
Reviewed By: Web User
Psoriasis sufferers will find this support and information site
soothing. The chronic skin condition characterised by patches of red,
raised skin often flares up under stress.
Having somewhere to go for an A-Z of available products and treatments
will hopefully alleviate any worries. The site's creator Talk Health is
an ond hand at health websites and runs a free service, although the
homepage is covered with adverts. Features written by specialists offer
authoritative advice, but the site's best features are its forum for
sharing stories and Find a Friend, which aims to help sufferers who
feel isolated. A Message Board is planned soon.
******
I wonder how this site will fare comPared to the really PoPular PHO?
******
The P ridden Shinning Path Guzman enlists Dancer
http://www.alertnet.org/thenews/newsdesk/N05159543.htm
Dancer on trial for hiding Peru rebel chief
06 Jul 2005 00:39:42 GMT
Source: Reuters
LIMA, Peru, July 5 (Reuters) - A court ruled on Tuesday that the
imprisoned leader of Peru's Shining Path rebel movement could testify
in the retrial of the ballet dancer accused of hiding him for years
above her dance studio.
Prosecutors are seeking a life sentence for Maritza Garrido Lecca, who
does not deny links with Shining Path.
Peruvian special forces captured Abimael Guzman, a former philosophy
professor, in September 1992 after staking out Garrido Lecca's building
on a tip that he was hiding there.
Garrido Lecca won a request to have Guzman, 70, who is serving a life
term, testify in her trial.
The prosecution is asking for a life sentence for Garrido Lecca and
accuses her of being a leader of Shining Path, which she denies.
Garrido Lecca was given a life sentence by a military court in her
first trial in 1992 under then-President Alberto Fujimori's Draconian
anti-terror laws. She was granted a new trial in 2003 and the retrial
is being held in a civilian court.
Police posing as trash collectors, meter readers and a pair of lovers
spent months searching the garbage taken out of Garrido Lecca's dance
studio building in their pursuit of Guzman. Agents found discarded
tubes of cream for the treatment of psoriasis, an ailment that Guzman
was known to have.
Shining Path remains on the official U.S. list of terrorist groups. A
government truth commission in 2003 blamed Shining Path for 54 percent
of an estimated 69,280 deaths by rebel groups and the military in Peru
in the 1980s and 1990s.
Today, Shining Path counts several hundred die-hards holed up in Andean
and jungle areas whose biggest recent actions were a 2002 car bomb in
Lima and a 2003 kidnapping.
********
PDC alert in Vancouver
http://www.jem.org/cgi/content/abstract/202/1/5
A pathogenic role for pDCs and IFN (15) in human psoriasis was
suggested by Michel Gilliet (Houston, TX).
(...) up-regulation of TLR3 and TLR4 expression, which enabled
responsiveness to LPS (a property of ... it is becoming possible to
witness how DC and T cells interact in <snip> production was dependent
on MyD88
(...)a combination of TLR agonists that mobilize both MyD88 and TRIF
adaptors for TLR signal transduction-such as the TLR4 ligand
lipopolysaccharide (LPS)
(...)
(Doesn't that just say it all! ) ;-)
&
http://www.jem.org/cgi/content/abstract/202/1/135
Plasmacytoid predendritic cells initiate psoriasis through
interferon-{alpha} production
Frank O. Nestle1, Curdin Conrad1, Adrian Tun-Kyi1, Bernhard Homey2,
Michael Gombert2, Onur Boyman1, Günter Burg1, Yong-Jun Liu3, and
Michel Gilliet1
1 Department of Dermatology, University Hospital of Zurich, 8091
Zurich, Switzerland
2 Department of Dermatology, Heinrich-Heine-University, 40225
Düsseldorf, Germany
3 Department of Immunology, M.D. Anderson Cancer Center, Houston, TX
77030
CORRESPONDENCE Michel Gilliet: mgil...@mdanderson.org OR Frank O.
Nestle: nes...@derm.unizh.ch
Psoriasis is one of the most common T cell-mediated autoimmune
diseases in humans. Although a role for the innate immune system in
driving the autoimmune T cell cascade has been proposed, its nature
remains elusive. We show that plasmacytoid predendritic cells (PDCs),
the natural interferon (IFN)-{alpha}-producing cells, infiltrate the
skin of psoriatic patients and become activated to produce IFN-{alpha}
early during disease formation. In a xenograft model of human
psoriasis, we demonstrate that blocking IFN-{alpha} signaling or
inhibiting the ability of PDCs to produce IFN-{alpha} prevented the T
cell-dependent development of psoriasis. Furthermore, IFN-{alpha}
reconstitution experiments demonstrated that PDC-derived IFN-{alpha} is
essential to drive the development of psoriasis in vivo. These findings
uncover a novel innate immune pathway for triggering a common human
autoimmune disease and suggest that PDCs and PDC-derived IFN-{alpha}
represent potential early targets for the treatment of psoriasis.
Abbreviations used: CLSM, confocal laser scanning microscopy; IDDM,
insulin- dependent diabetes mellitus; IRF, IFN regulatory factor; PDC,
plasmacytoid pre-DC; SLE, systemic lupus erythematosus; TLR, toll-like
receptor. M. Gilliet's present address is Dept. of Immunology, M.D.
Anderson Cancer Center, Houston, TX 77030
*******
Greek fish oil study-- taking one gram a day or .6 gr/day even, is A OK
http://news.google.com/news?lr=&tab=gn&ie=UTF-8&scoring=d&q=fish+oil+greek+3%2C000&btnG=Search+News
*******
OK, now how does fumaric acid esters stop PDC's in the skin?
Obviously its blocking something in the gut...
randall... painfully obvious once again...
JXStern
On 6 Jul 2005 08:52:07 -0700, "randall" <ranh...@aol.com> wrote:
>Psoriasis is one of the most common T cell-mediated autoimmune
>diseases in humans.
That's me!
J.
randall
randall wrote:
>
> PDC alert in Vancouver
Maybe a PDC alert in you! Oh my!
Is that like a great white shark thing?
NoPe. Its worse. A P thing.
> http://www.jem.org/cgi/content/abstract/202/1/5
> A pathogenic role for pDCs and IFN (15) in human psoriasis was
> suggested by Michel Gilliet (Houston, TX).
> (...) up-regulation of TLR3 and TLR4 expression, which enabled
> responsiveness to LPS (a property of ... it is becoming possible to
> witness how DC and T cells interact in <snip> production was dependent
> on MyD88
> (...)a combination of TLR agonists that mobilize both MyD88 and TRIF
> adaptors for TLR signal transduction-such as the TLR4 ligand
> lipopolysaccharide (LPS)
>
> (...)
> (Doesn't that just say it all! ) ;-)
>
No. Not enough actually. What was i thinking? lol
> &
> http://www.jem.org/cgi/content/abstract/202/1/135
> Plasmacytoid predendritic cells initiate psoriasis through
> interferon-{alpha} production
>
> Frank O. Nestle1, Curdin Conrad1, Adrian Tun-Kyi1, Bernhard Homey2,
> Michael Gombert2, Onur Boyman1, Günter Burg1, Yong-Jun Liu3, and
> Michel Gilliet1
>
> 1 Department of Dermatology, University Hospital of Zurich, 8091
> Zurich, Switzerland
> 2 Department of Dermatology, Heinrich-Heine-University, 40225
> Düsseldorf, Germany
> 3 Department of Immunology, M.D. Anderson Cancer Center, Houston, TX
> 77030
>
> CORRESPONDENCE Michel Gilliet: mgil...@mdanderson.org OR Frank O.
> Nestle: nes...@derm.unizh.ch
>
> Psoriasis is one of the most common T cell-mediated autoimmune
> diseases in humans. Although a role for the innate immune system in
> driving the autoimmune T cell cascade has been proposed, its nature
> remains ___elusive__. We show that plasmacytoid predendritic cells (PDCs),
> the natural interferon (IFN)-{alpha}-producing cells, infiltrate the
> skin of psoriatic patients and become activated to produce IFN-{alpha}
> early during disease formation. In a xenograft model of human
> psoriasis, we demonstrate that blocking IFN-{alpha} signaling or
> inhibiting the ability of PDCs to produce IFN-{alpha} prevented the T
> cell-dependent development of psoriasis. Furthermore, IFN-{alpha}
> reconstitution experiments demonstrated that PDC-derived IFN-{alpha} is
> essential to drive the development of psoriasis in vivo. These findings
> uncover a novel innate immune pathway for triggering a common human
> autoimmune disease and suggest that PDCs and PDC-derived IFN-{alpha}
> represent potential early targets for the treatment of psoriasis.
>
>
The elusive white ghost? ;-)
P or orchid?
Not O,
http://www.sptimes.com/2003/05/15/photos/wk-art-ORCHID.jpg
P, stuPid!
Oh!
**********************
This looks serious. But all the studies (pDcs) seem to implicate a
virus.
Could a P virus be a mimic? Or a common one? And unlike the Th2 HIV we
continue to skew towards the Th1 side somehow?
But how?
Lets start with DC's and immunity.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15984324
The role of dendritic cells in shaping the immune response.
Howard CJ, Charleston B, Stephens SA, Sopp P, Hope JC.
Institute for Animal Health, Compton, Newbury, Berkshire RG20 7NN, UK.
Chris....@BBSRC.ac.uk
Dendritic cells are central to the initiation of primary immune
responses. They are the only antigen-presenting cell capable of
stimulating naive T cells, and hence they are pivotal in the generation
of adaptive immunity. Dendritic cells also interact with and influence
the response of cells of the innate immune system. The manner in which
dendritic cells influence the responses in cells of both the innate and
adaptive immune systems has consequences for the bias of the adaptive
response that mediates immunity to infection after vaccination or
infection. It also provides an opportunity to intervene and to
influence the response, allowing ways of developing appropriate
vaccination strategies. Mouse and human studies have identified
myeloid, lymphoid and plasmacytoid dendritic cells. Studies in
domesticated animals with agents of specific infectious diseases have
confirmed the applicability of certain of the generic models developed
from mice or from in vitro studies on human cells. In vivo and ex vivo
studies in cattle have demonstrated the existence of a number of
subpopulations of myeloid dendritic cells. These cells differ in their
ability to stimulate T cells and in the cytokines that they produce,
observations clearly having important implications for the bias of the
T-cell response. Dendritic cells also interact with the innate immune
system, inducing responses that potentially bias the subsequent
adaptive response.
PMID: 15984324
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15990333
Plasmacytoid dendritic cells-virus experts of innate immunity.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15997468
Activation of human NK cells by plasmacytoid dendritic cells and its
modulation by CD4(+) T helper cells and CD4(+) CD25(hi) T regulatory
cells.
Romagnani C, Della Chiesa M, Kohler S, Moewes B, Radbruch A, Moretta L,
Moretta A, Thiel A.
German Rheumatism Research Centre, Clinical Immunology, Berlin,
Germany.
Plasmacytoid dendritic cells (pDC) represent a specialized cell
population that produce type I interferon (IFN) in response to virus.
Although type I IFN is a natural killer (NK) cell modulator, a direct
role for pDC in coordinating NK cell functions has not yet been
elucidated in detail, especially in humans. Here we report that human
pDC, following engagement of Toll-like receptor (TLR) 9, not only
activate autologous NK cells, as indicated by the induction of CD69
expression, but also enhance their effector functions, especially
cytotoxicity. Moreover, they can induce selective proliferation of
CD56(bright) CD16(-) NK cells. This activity can be strongly augmented
by the addition of autologous CD4(+) CD25(-) T helper cells in an
IL-2-dependent fashion. Strikingly, CD4(+) CD25(hi )T regulatory (Treg)
cells completely abrogate this IL-2-dependent proliferation of NK
cells, while they are not able to influence NK cell activation or
proliferation solely induced by pDC. Our data show that TLR9-engaged
pDC represent a critical stimulus for human NK cells and that CD4(+) Th
cells and CD4(+) CD25(hi )Treg cells play an important role in
modulating human NK cell responses.
PMID: 15997468
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15987599
The host type I interferon response to viral and bacterial infections.
Perry AK, Chen G, Zheng DH, Tang H, Cheng GH.
Department of Microbiology, Immunology and Molecular Genetics,
University of California Los Angeles, Los Angeles, CA 90095, USA;
Center for Infection and Immunity, Institute of Biophysics, Chinese
Academy of Sciences, Beijing 100101, China; Email:
genh...@microbio.ucla.edu.
Type I interferons (IFN) are well studied cytokines with anti-viral and
immune-modulating functions. Type I IFNs are produced following viral
infections, but until recently, the mechanisms of viral recognition
leading to IFN production were largely unknown. Toll like receptors
(TLRs) have emerged as key transducers of type I IFN during viral
infections by recognizing various viral components. Furthermore, much
progress has been made in defining the signaling pathways downstream of
TLRs for type I IFN production. TLR7 and TLR9 have become apparent as
universally important in inducing type I IFN during infection with most
viruses, particularly by plasmacytoid dendritic cells. New
intracellular viral pattern recognition receptors leading to type I IFN
production have been identified. Many bacteria can also induce the
up-regulation of these cytokines. Interestingly, recent studies have
found a detrimental effect on host cells if type I IFN is produced
during infection with the intracellular gram-positive bacterial
pathogen, Listeria monocytogenes. This review will discuss the recent
advances made in defining the signaling pathways leading to type I IFN
production.
PMID: 15987599
OK, ok alright already.
Its PDC somehow bugging out IFN in the skin?
We could test LPS according to this next abstract with MG132 or
pyrrolidinedithiocarbamate.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15265881
Regulation of IFN regulatory factor-7 and IFN-alpha production by
enveloped virus and lipopolysaccharide in human plasmacytoid dendritic
cells.
Dai J, Megjugorac NJ, Amrute SB, Fitzgerald-Bocarsly P.
University of Medicine and Dentistry of New Jersey-New Jersey Medical
School, Newark, NJ 07103, USA.
Human plasmacytoid dendritic cells (PDC) are a major source of
IFN-alpha upon exposure to enveloped viruses and TLR-7 and TLR-9
ligands. Although IFN regulatory factor-7 (IRF-7) is known to play an
essential role in virus-activated transcription of IFN-alpha genes, the
molecular mechanisms of IFN-alpha production in human PDC remain poorly
understood. We and others have recently reported high constitutive
levels of IRF-7 expression in PDC as compared with other PBMC. In this
study, we demonstrate that both LPS and HSV up-regulate the expression
of IRF-7 in PDC, and that this enhancement of IRF-7 is dependent on
NF-kappa B activation. The NF-kappa B inhibitors MG132 and
pyrrolidinedithiocarbamate efficiently inhibited the induction of IRF-7
by HSV or LPS, and also down-regulated the constitutive expression of
IRF-7 in PDC and blocked the HSV-induced production of IFN-alpha. In
addition, we found that nuclear translocation of IRF-7 occurred rapidly
in response to HSV stimulation, but not in response to LPS, which is
consistent with the stimulation of IFN-alpha production by virus and
not by LPS. Although LPS by itself was not able to induce IFN-alpha
production, it led to rapid up-regulation of TLR-4 on PDC and increased
the magnitude and accelerated the kinetics of HSV-induced IFN-alpha
production in PDC, providing a mechanism that might be operative in a
scenario of mixed infection. In contrast to the current concept of
IFN-alpha regulation established in cell lines, this study strongly
supports the immediate availability of high constitutive levels of
IRF-7 expression in PDC, and suggests an activation required for IRF-7
that contributes to IFN-alpha production in virus-stimulated PDC.
PMID: 15265881
So there should be a test. But every one of these abstracts are
pointing at a virus. Ghost virus?
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14991609
Viral infection and Toll-like receptor agonists induce a differential
expression of type I and lambda interferons in human plasmacytoid and
monocyte-derived dendritic cells.
Coccia EM, Severa M, Giacomini E, Monneron D, Remoli ME, Julkunen I,
Cella M, Lande R, Uze G.
Laboratory of Immunology, Department of Infectious, Parasitic and
Immune-mediated Diseases, Istituto Superiore di Sanita, Rome, Italy.
In humans, the type I interferon (IFN) family consists of 13 IFN-alpha
subtypes, IFN-beta and IFN-omicron the newly discovered IFN-like family
consists of IFN-lambda1, -lambda2 and -lambda3. We have investigated
the expression of type I and lambda IFN genes following virus
infections or Toll-like receptor (TLR) triggering in monocyte-derived
DC (MDDC) and plasmacytoid DC (pDC). We found that all IFN-alpha,
-beta, -omicron and -lambda subtypes are expressed in
influenza-virus-infected MDDC or pDC. Conversely, differential type I
IFN gene transcription was induced in MDDC and pDC stimulated by
specific TLR agonists. TLR-9 stimulation by CpG DNA induced the
expression of all IFN-alpha, -beta, -omicron and -lambda subtypes in
pDC, whereas TLR-4 stimulation by LPS, or TLR-3 stimulation by poly
I:C, induced only IFN-beta and IFN-lambda gene expression in MDDC. The
expression pattern of IFN regulatory factor (IRF)-5 and IRF-7 in MDDC
and pDC was also determined. IRF-5 was constitutively expressed in the
two DC subsets whereas IRF-7 was constitutive in pDC but its expression
was induced along MDDC maturation. Overall, our data indicate that the
coordinated expression of IFN-lambda with IFN-beta would be of crucial
importance for the maturation of DC.
PMID: 14991609
And going back to October of 2001
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11592079
Toll-like receptor expression reveals CpG DNA as a unique microbial
stimulus for plasmacytoid dendritic cells which synergizes with CD40
ligand to induce high amounts of IL-12.
Krug A, Towarowski A, Britsch S, Rothenfusser S, Hornung V, Bals R,
Giese T, Engelmann H, Endres S, Krieg AM, Hartmann G.
Department of Internal Medicine and Division of Clinical Pharmacology,
University of Munich, Munich, Germany.
Human plasmacytoid dendritic cells (DC) (PDC, CD123+) and myeloid DC
(MDC, CD11c+) may be able to discriminate between distinct classes of
microbial molecules based on a different pattern of Toll-like receptor
(TLR) expression. TLR1-TLR9 were examined in purified PDC and MDC.
TLR9, which is critically involved in the recognition of CpG motifs in
mice, was present in PDC but not in MDC. TLR4, which is required for
the response to LPS, was selectively expressed on MDC. Consistent with
TLR expression, PDC were susceptible to stimulation by CpG
oligodeoxynucleotide (ODN) but not by LPS, while MDC responded to LPS
but not to CpG ODN. In PDC, CpG ODN supported survival, activation
(CD80, CD86, CD40, MHC class II), chemokine production (IL-8, IP-10)
and maturation (CD83). CD40 ligand (CD40L) and CpG ODN synergized to
activate PDC and to stimulate the production of IFN-alpha and IL-12
including bioactive IL-12 p70. Previous incubation of PDC with IL-3
decreased the amount of CpG-induced IFN-alpha and shifted the cytokine
response in favor of IL-12. CpG ODN-activated PDC showed an increased
ability to stimulate proliferation of naive allogeneic CD4 T cells,
butTh1 polarization of developing T cells required simultaneous
activation of PDC by CD40 ligation and CpG ODN. CpG ODN-stimulated PDC
expressed CCR7, which mediates homing to lymph nodes. In conclusion,
our studies reveal that IL-12 p70 production by PDC is under strict
control of two signals, an adequate exogenous microbial stimulus such
as CpG ODN, and CD40L provided endogenously by activated T cells. Thus,
CpG ODN acts as an enhancer of T cell help, while T cell-controlled
restriction to foreign antigens is maintained.
PMID: 11592079
Viral or a LPS malfunction going into the skin?
randall... whatever hapPened to cliP?
WhooPs, better not end it here.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15817706
HLA-DO transduced in human monocyte-derived dendritic cells modulates
MHC class II antigen processing.
Bellemare-Pelletier A, Tremblay J, Beaulieu S, Boulassel MR, Routy JP,
Massie B, Lapointe R, Thibodeau J.
Departement de Microbiologie et Immunologie, Universite de Montreal, CP
6128, Succursale Centre-Ville, Montreal, Quebec, Canada, H3C 3J7.
Jacques....@umontreal.ca.
Through the regulation of human leukocyte antigen (HLA)-DM (DM) in B
cells, HLA-DO (DO) modulates positively or negatively the presentation
of specific peptides. Transduction of DO into human blood
monocyte-derived dendritic cells (MoDC) has been proposed as a mean of
modifying the peptide repertoire of major histocompatibility complex
class II molecules. However, maturation of DC induced by inflammatory
stimuli or possibly the adenoviral vector itself triggers acidification
of vesicles and shuts down transcription of the class II transactivator
gene as well as de novo biosynthesis of class II-related molecules and
DM activity. In these conditions, it is unclear that transduced DO
could alter the peptide repertoire. Our Western blot and reverse
transcriptase-polymerase chain reaction analyses revealed that human DC
derived from blood monocytes express small amounts of DOalpha.
Transduction of DObeta alone resulted in the accumulation of a small
pool of DO in DM(+) CD63(+) vesicles and at the plasma membrane of
mature DC. The cell-surface increase in class II-associated invariant
chain peptide (CLIP)/class II complexes is in line with an inhibitory
role of DO on DM. Cotransduction of DOalpha and DObeta only slightly
increased CLIP and DO levels at the cell surface. Together with the
fact that a large fraction of transduced DO remains in the endoplasmic
reticulum, this suggests that DM is limiting in these conditions. DO
expression did not affect a mixed lymphocyte reaction but reduced
presentation of the exogenous gp100 antigen to a specific T cell clone.
These results show that transduced DO modulates antigen presentation in
human mature MoDC, evoking the possible use of this chaperone for
immunotherapy.
PMID: 15817706
And this next one has IFN producing skew from a tumor protein (NEU
peptide).
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15721842
Functionally divergent T lymphocyte responses induced by modification
of a self-peptide from a tumor-associated antigen.
Hess AD, Thoburn CJ, Miura Y, Bright EC.
The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins
University, 1650 Orleans Street, Room 489, Baltimore, MD 21231, USA.
adh...@jhmi.edu
The N- and C-terminal flanking domains of the invariant chain peptide,
CLIP, have remarkable immunological properties. Addition of these
flanking domains to a foreign peptide antigen increases its immunologic
potency. The present studies evaluated whether altering a peptide
ligand from the tumor-associated antigen c-neu with the flanking
domains of CLIP could modify the systemic immune response. The results
indicate that the immunogenicity of an MHC class II restricted peptide
(NEU) derived from c-neu was significantly altered by addition of the
flanking domains from CLIP. Interestingly, selective modification of
the peptide with either the N- or the C-terminal flanking domains
resulted in functionally divergent systemic immune responses.
Immunization of normal F344 rats with the NEU peptide modified with the
N-terminal domain of CLIP (N-NEU) resulted in an immune response
primarily consisting of type 1 (IL-2, IFNgamma) cytokine producing T
cells. On the other hand, type 2 (IL-4) cytokine responses were largely
predominant following immunization with the self-peptide modified with
the C-terminal flanking domain (NEU-C). The functionally divergent
responses elicited by the modified self-peptides were accompanied by
significant changes in the expression of the CD28/CTLA4/B7 family of
co-stimulatory molecules. Immunization with the N-NEU peptide led to
enhanced expression of CD28 in the antigen-specific, CD4+ T cell
compartment while expression of B7.1 was dramatically reduced in
antigen-specific CD8+ T cells. Comparatively, expression of CTLA4 was
down-regulated in the antigen-specific CD4+ T cell compartment
following immunization with NEU-C peptide. The N-NEU peptide also had a
direct effect on dendritic cells leading to the up-regulation of B7.1
expression. Taken together, functionally divergent systemic immune
responses can be elicited by strategically altering a self-peptide
ligand with the N- and C-terminal flanking domains of CLIP. Moreover,
changes in expression of co-stimulatory molecules that are required for
T cell activation and T cell-T cell communication may account for the
polarization of the immune response elicited by the chimeric peptides.
PMID: 15721842
The question du jour for psoriasis.
Whats uPregulating the IFN in the skin????
randall... is today a good day? Feels like it!
randall
But, don't you want to be common like the 98 outa 100?
Instead of the 2 outa 100? Yet if we take all the 2% 'ers.
For Th1 I.M.I.Ds i suPPose we are common. We are common
in a large subset of skewed autoimmune people.
Certainly more common then real rare genetic diseases,
http://www.ntsad.org/pages/modes.htm
Since they garner more nobel prizes. They could figure
out the genes for P and Tay-Sachs, you'd think?
http://www.ntsad.org/pages/t-sachs.htm
Or maybe tzaraat is karma?
randall... i'll wait for the geneticist to exPlain it. :)
Mathias Mildenberger
> Mathias Mildenberger wrote:
>>While taking Fumaderm I had no special troubles with side effects except
>>the need to see a toilet a little quicker some times. I only discovered
>>one "no-no" - Fumaderm and onion soup. ;))
> Finally! Someone has reported an adverse side effect from onions
> related to P and a P treatment.
Experimentally proven. ;) Fumaderm may make you search for a restroom a
little quicker sometimes. As onions may do. Together, this may prove a
much more time-critical combination. Believe me. ;))
> I'd give uP some onions for a trial of FAEs.
Come over here for a medical holiday trip. Most of the docs at the
University of Jena dermatologic hospital have an excellent knowledge of
English. ;)) The price tags: Fumaderm initial, box of 40 tablets á 30mg
= 101.50- €. Fumaderm, box of 100 tab. á 120mg = 264,99- €. Both
available only on prescription. Prices from www.docmorris.com
> And the process to allow us to take fumaderm is very slow.
As usual with the introduction of really interesting medicaments... :(
> I sure hope i'm like you brother and a low dose has positive
> effects.
We 'll see.
Best Regards from Germany,
Mathias
randall
Not much in P news. Very quiet so far today.
For sPinning the Good work of Whey, hey i'm haPPy,
http://www.nutraingredients-usa.com/news/news-ng.asp?n=61159-psoriasis-trial-brings
Psoriasis trial brings Advitech's XP-828L launch closer
7/7/2005 - Canadian biotech company Advitech has come a step closer to
launching whey-derived XP-828L as an oral alternative to conventional
drugs for psoriasis sufferers with the announcement of positive results
in a clinical trial to test its safety and efficacy, reports Jess
Halliday
(...)
How did this product come about? Here are the old news posts regarding
it and
the Canadian Goverments $ support.
http://www.nutraingredients-usa.com/news/news-ng.asp?n=60115-advitech-seeks-new
&
http://www.nutraingredients-usa.com/news/news-ng.asp?n=25205-advitech-gains-rights
randall
Fizziwig2
"JXStern" <JXSternC...@gte.net> wrote in message
news:al2oc1d8648sr9j40...@4ax.com...
I'm not common!
Skeats
Fizziwig2
"randall" <ranh...@aol.com> wrote in message
news:1120754420....@f14g2000cwb.googlegroups.com...
That looks hopeful for the type I suffer from.
btw- I found a pdf poster of an evaluation of safety and efficacy of XP-828L
by the Centre de Recherche Dermatologique du Quebec Metropolitain (in
English)! that people might like to see.
Easier to understand than most reports.
http://www.advitech.com/pdf/Poster_ParisF.pdf
Skeats
randall
Thanks for the advitech pdf. The facts remain as they are using
sweet whey for their products.
And that is whats in the proflora whey product from
thewholewhey.com
I know their trying to get scientific with it. But a
peach is a peach regardless of what's in the pit.
And its not the controversial scamish Laetrile from aPricot
pits this time...
And if they knew how to implant the right gut seeds and
use the sweetwhey with a diet essential to regrowing
the new colon flora, they could report clearing severe psoriatics
with their products.
Seeing as how i've proven it for me. Its only a matter of
time till randall's whey is used by severe autoimmune patients
from A to Z and including P!
Thanks again.
Any light in this area is needed. As most folk haven't figured out
the simPle truths in regards to rebuilding intestinal fortitude from
the bug uP.
Yet they groPe for the truths,
http://news.google.com/news?q=probiotics&svnum=10&hl=en&lr=&tab=in&ie=UTF-8&scoring=d
***************
P News today: July 9, 2005...
This next may be confusing to some of you.
Recently we've reported on the LPIN2 gene as a possible
inflammatory gene in the P pathways.
And Lupin is a company from Goa India in this next
article.
And last week I looked for a picture
of the goa tree in Brazil for at least a few days with no
luck.
So its LPIN2 the gene and Lupin the P company in Goa the
place and NOT the P tree which makes the orignal anthralin
goa gooP, which seems to work really well for Ed A.
And he isn't here to say anything about his personal use of it.
Go google!
And back to the confusing news,
http://www.telegraphindia.com/1050709/asp/business/story_4967939.asp
US tonic helps Lupin dream big
OUR SPECIAL CORRESPONDENT
Mumbai, July 8: Lupin Ltd is on course to enhance its product offering
in the US and European markets to include non-cephalosporin oral dosage
forms. The company today announced that its non-cephalosporin oral
dosage facility at Goa has passed the US Food and Drug Administration
(USFDA) test.
The Goa facility, commissioned in March 2004, was set up to facilitate
Lupin's foray into advanced markets with non-cephalosporin oral dosage
forms.
The Goa facility will be the company's eleventh plant to receive USFDA
approval. Earlier, the USFDA had approved its non-cephalosporin API
(active pharmaceutical ingredients) plant at Tarapur in Maharashtra.
Lupin?s managing director Kamal K. Sharma said, ?The clearance by the
US authority will enable Lupin to significantly enhance its product
offering in the US, the European Union and other advanced markets.?
Meanwhile, Lupin had posted net sales of Rs 1,161 crore for the year
ended March 31. While its revenues from the advanced markets of North
America and Europe, in both APIs and finished dosages, during the year
was Rs 202 crore, it was Rs 951.9 crore from the developing markets
(including India).
Over the last fiscal, the company had spent 6.9 per cent of its net
sales on research and development and filed 14 abbreviated new drug
applications (ANDAs). Lupin had already got the approval for five ANDAs
and four drug molecules are in the clinical trial stage.
The company had received the approval of the Drug Controller General of
India (DCGI) last December for conducting phase I clinical trials for
two of its new drug molecules, LL 4858 and LL 4218.
LL 4858 is an anti-TB drug and pre-clinical studies show that the
ailment can be treated faster with it with low adverse effects than the
existing anti-TB therapy. LL 4218 is for the treatment of a chronic
skin condition, known as psoriasis.
Apart from these, the company is also focussing on NCE research for
inflammatory disorders, respiratory diseases and anti-bacterials.
Last fiscal, Lupin's wholly owned subsidiary, Lupin Pharmaceuticals Inc
(LPI), had entered into a promotional tie-up with Cornerstone BioPharma
Inc for the US market for its Suprax (cefixime) anti-infective drug.
According to the agreement, Cornerstone's sales force will co-promote
Suprax with a focus on primary care physicians.
Lupin also entered into an in-licensing agreement with Cornerstone for
clinical development of a novel drug delivery system (NDDS) for an
anti-infective product.
On the Bombay Stock Exchange today, the Lupin scrip closed at Rs 704.05
after opening at Rs 698 and rising to an intra-day high of Rs 709.90.
*****
randall... OK? time to GOA away.
randall
Sunday P News.... Lets start with head P and work
our way down.
A new site dedicated to your HEAD. I didn't open it.
Please be my guest and rePort back should you get
the urge,.
http://www.emediawire.com/releases/2005/7/emw259667.htm
Launch of Directory of Dandruff and Other Scalp Disorder Sites
DandruffDirectory.com is a niche directory which provides the relevant
websites for people who are looking for information or to buy products
related to Scalp Disorders, such as Dandruff or Psoriasis.
(PRWEB) July 10, 2005 -- http://www.DandruffDirectory.com, the first
niche directory of scalp disorder websites, has gone live.
The objective of DandruffDirectory.com is to provide the visitor
seeking information or products related to Dandruff, Psoriasis, Itchy
Scalp, Scalp Acne, Scalp Fungus or other Scalp related disorders, with
a central place where they can quickly and easily find what they are
looking for.
Jim Tyron, one of DandruffDirectory.com's moderators said: "We are
happy that we can provide a website which tries to clear through all
the clutter on the Internet, and allows our visitors to find what they
are looking for, quicker and easier. We have already had a number of
dandruff and psoriasis websites apply for a free listing, and as long
as the quality and relevancy of the sites are at our required level,
we'll add them for free to DandruffDirectory.com".
DandruffDirectory.com has entered into a marketing agreement with
http://www.no-more-dandruff.com, a site which sells the top selling
AntiDandruff eBook "How to overcome Dandruff and other Scalp
Disorders", to generate traffic for DandruffDirectory. No-More-Dandruff
currently gets around 20 000 highly targetted visitors per month
seeking information on Dandruff and other Scalp Disorders.
As part of the agreement, No-more-Dandruff will place a link to
DandruffDirectory.com at the top of every page of their website.
****************
I love this rednova site. A short tutorial on skin and TF. And you can
skiP it if you like.
http://www.rednova.com/news/health/169454/tissue_factor_as_a_link_between_wounding_and_tissue_repair/
Tissue Factor As a Link Between Wounding and Tissue Repair
The initial phase of wound repair involves inflammation, induction of
tissue factor (TF), formation of a fibrin matrix, and growth of new
smooth muscle actin (α-SMA)-positive vessels. In diabetes, TF
induction in response to cutaneous wounding, which ordinarily precedes
increased expression of vascular endothelial growth factor (VEGF) and
α-SMA transcription, is diminished, though not to a degree causing
excessive local bleeding. Enhanced TF expression in wounds of diabetic
mice caused by somatic TF gene transfer increased VEGF transcription
and translation and, subsequently, enhanced formation of new blood
vessels and elevated blood flow. Furthermore, increased levels of TF in
wounds of diabetic mice enhanced wound healing; the time to achieve 50%
wound closure was reduced from 5.5 days in untreated diabetic mice to
4.1 days in animals undergoing TF gene transfer (this was not
statistically different from wound closure in nondiabetic mice). Thus,
cutaneous wounds in diabetic mice display a relative deficiency of TF
compared with nondiabetic controls, and this contributes to delayed
wound repair. These data establish TF expression as an important link
between the early inflammatory response to cutaneous wounding and
reparative processes. Diabetes 54:2143-2154, 2005
Physiologic wound healing involves a complex interaction between cells,
mediators, growth factors, and cytokines. The cascade of events starts
with activation of the procoagulant pathway and recruitment of
inflammatory cells and is followed by a phase of cellular proliferation
and tissue repair/resolution of the injury. Recent studies (1-3)
indicate that tissue factor (TF), the major initiator of the extrinsic
coagulation cascade, is involved in all phases of the host response to
wounding, implying a likely central role for TF in wound healing.
TF is an immediate early gene. TF transcription, which is upregulated
when cells start to divide (4,5), is controlled by a variety of
transcription factors associated with the inflammatory response such as
SP-1, activator protein-1 (AP-1), and nuclear factor-κB (NF-κB)
(6-11). As might be expected, TF expression is also closely linked to
inflammation (6,7,9) and hypoxia (10), both conditions also associated
with wounding. The physiologic function of rapid induction of TF, a
member of the class II cytokine receptor family, in response to a range
of stimuli has been less clear. The major function of TF is believed to
be related to initiation of the procoagulant pathway (11-14). In fact,
as TF is plentiful in the subendothelial and, especially, subcutaneous
spaces, contact of blood with these tissue surfaces, a part of the
hemostatic process, rapidly results in clot formation. Thus, hemostasis
does not require de novo TF synthesis, implying that immediate early
upregulation of TF is important in processes other than hemostasis
(1,11-15).
Consistent with this view, recent studies have pointed to functions of
TF that are quite distinct from its role in coagulation. Depending on
the genetic background, TF^sup -/-^ mice not only display severe
defects in hemostasis but also die at an early embryonic stage for
reasons other than bleeding (16-18). Defective vitello-embryonic
vasculature (16) in TF^sup -/-^ mice suggests a link between TF and
angiogenesis (19). Recent studies (20- 22) have shown that TF, either
directly or indirectly (via binding of factor VIIa and activation of
the coagulation cascade) (23,24), triggers a number of cellular
responses. The latter include de novo synthesis of vascular endothelial
growth factor (VEGF) (24-26); recruitment of signal transduction
pathways, in part through changes in cytosolic calcium (27); transient
tyrosine phosphorylation (28); mitogen-activated protein kinase
activation (29); and gene transcription (24).
While most of these data were obtained using cells stably transfected
to overexpress TF, fewer studies have addressed the importance of
TF-dependent gene regulation. In this context, one example is the
positive correlation between TF and VEGF (1,25,26), consistent with the
concept that low levels of TF might be associated with diminished VEGF
expression. These observations led us to explore pathophysiologically
relevant situations in which decreased cell proliferation and
angiogenesis might be explained by a relative impairment in local TF
induction.
Delayed healing of cutaneous wounds in diabetes is associated with
reduced VEGF expression (30) and impaired recruitment of smooth muscle
cells (31). Thus, such wounds in diabetic mice might provide an ideal
setting to determine whether local induction of TF might be linked to
the subsequent proliferative and angiogenic response. Furthermore, the
inflammatory response, characterized by cytokine expression and
recruitment of immunocompetent inflammatory cells (32) and critical for
initiating wound healing, has been shown to be impaired in diabetes
(33,34). We reasoned that reduced expression of inflammatory cytokines
after cutaneous wounding of diabetic animals might result in reduced
cytokine-dependent induction of TF (8,9,35- 37). If this proved to be
true, then reduced TF in diabetic wounds might, in turn, be followed by
decreased angiogenesis, diminished recruitment of smooth muscle cells,
and delayed wound healing in diabetes. We have tested these concepts in
a murine model of diabetes using somatic cell transfer of the TF gene
to drive local upregulation of TF.
(...)
REFERENCES
<snip>
6. Mackman N, Brand K, Edgington TS: Lipopolysaccharide-mediated
transcriptional activation of the human tissue factor gene in THP-1
monocytic cells requires both activator protein 1 and nuclear factor
kappa B binding sites. J Exp Med 174:1517-1526, 1999
*************************
What haPPens with the Fox3P gene in P and other autoimmune conditions?
http://www.sciencedaily.com/releases/2005/06/050627061854.htm
(...)
In a study published in the July issue of the Journal of Neuroscience
Research, OHSU scientists, in collaboration with The Immune Response
Corp. of Carlsbad, Calif., found that MS patients have lower expression
of the FOXP3 gene found in a subset of T-cells that may regulate
defense
against MS and other autoimmune diseases, such as diabetes and
arthritis (and P?). They say that when FOXP3 is reduced due to
abnormalities in
its expression, the suppressive activity of regulatory T-cells, or
T-regs, also plummets.
(...)
NeuroVax, a T-cell
receptor peptide vaccine co-discovered by Vandenbark and colleagues at
The Immune Response Corp., was shown in a separate study to increase
FOXP3 expression levels among MS patients receiving injections of the
drug for a year.
"When we vaccinate with the T-cell receptor peptides -- the NeuroVax --
we can restore the FOXP3 levels,"
(...)
"What
we think NeuroVax is doing is stimulating regulatory T-cells that then
down-regulate proliferation of the pathogenic T-cells. The link between
FOXP3 and T-regs is quite important to our program."
T-cells are white blood cells produced by the human body to defend
against infection. Scientists believe a sub-group of "pathogenic"
T-cells cause MS by attacking myelin, the fatty sheath insulating nerve
fibers in the brain and spinal cord.
(...)
The CD4+ and CD25+ T-regs isolated from
the MS patients were found to contain abnormalities in FOXP3 mRNA and
protein expression as well as reductions in suppressive activity.
(...)
The interesting thing about
T-reg cells is that they're not very specific. They will, for example,
inhibit through cell-cell contact any CD4-positive cell that's in the
process of being activated to attack self tissue. Thus, the T-reg cells
may also be important in regulating inflammatory T-cells that
contribute
to other autoimmune diseases besides MS."
********
Looks like MS and P aren't so different as far as FOX3P and CD(25)+ are
concerned.
High FOX3P for P?,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15611238
Dysfunctional blood and target tissue CD4+CD25high regulatory T cells
in psoriasis: mechanism underlying unrestrained pathogenic effector T
cell proliferation.
Sugiyama H, Gyulai R, Toichi E, Garaczi E, Shimada S, Stevens SR,
McCormick TS, Cooper KD.
Department of Dermatology, University Hospitals of Cleveland and Case
Western Reserve University, 11100 Euclid Avenue, Cleveland, OH 44106,
USA.
The balance between regulatory and effector functions is important for
maintaining efficient immune responses, while avoiding autoimmunity.
The inflammatory skin disease psoriasis is sustained by the ongoing
activation of pathogenic effector T cells. We found that a CD4(+) T
lymphocyte subpopulation in peripheral blood, phenotypically
CD25(high), CTLA-4(+), Foxp3(high) (regulatory T (Treg) cells), is
deficient in its suppressor activity in psoriasis. This was associated
with accelerated proliferation of CD4(+) responder T cells in
psoriasis, the majority of which expressed CXCR3. Nevertheless,
criss-cross experiments isolated the defect to psoriatic Treg cells. To
examine Treg cells in a nonlymphoid tissue of a human T cell-mediated
disease, Treg cells were also analyzed and isolated from the site of
inflammation, psoriatic lesional skin. At the regulatory vs effector T
cells ratios calculated to be present in skin, however, the psoriatic
Treg cell population demonstrated decreased suppression of effector T
cells. Thus, dysfunctional blood and target tissue CD4(+)CD25(high)
Treg cell activity may lead to reduced restraint and consequent
hyperproliferation of psoriatic pathogenic T cells in vivo. These
findings represent a critical component of human organ-specific
autoimmune disease and may have important implications with regard to
the possible therapeutic manipulation of Treg cells in vivo.
PMID: 15611238
Here's a NICKEL for your P asPirations,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14634084
Now recall that LOMA LUX under the guise of being a homeopathic has a
nickel compound for P.
I'm not saying chew on your nickels or run out for loma lux. They do
have a zit formula in the drug stores that is most likely similar to
their P drug.
So how do we stoP the Treg cells from becoming TREG cells? We don't. We
need them. We just need to find a way to balance them out.
All the PDCs stuff recently seems to be working in this arena.
http://groups-beta.google.com/groups?q=pdc+pdcs+ifn+alert+dendritic+cells&qt_s=Search
And to get to cd(25)+ you have to go thru IL-2 first,
http://groups-beta.google.com/groups?hl=en&q=il-2+psoriasis+cd%2825%29&qt_s=Search
And that is regulated by IL-15,
http://www.bloodjournal.org/cgi/content/abstract/105/2/697
Dendritic cell-derived IL-2 production is regulated by IL-15 in humans
and in mice
Dendritic cells (DCs) are involved in the initiation and regulation of
innate and adaptive immune responses. Several molecular mechanisms
regulate these diverse DC functions, and we have previously reported
that mouse dendritic cells (mDCs) can produce interleukin-2 (IL-2) in
vitro and in vivo, in response to microbial activation and
T-cell-mediated stimuli. This property is shared by different DC
subtypes, including Langerhans cells. Here we show that, on appropriate
stimulation, human DCs, both plasmacytoid and myeloid subtypes, also
express IL-2. Interestingly, the production of IL-2 by myeloid DCs is
induced by T-cell-mediated stimuli and depends on the presence of
IL-15. The key role of this cytokine in regulating IL-2 production was
also confirmed in the mouse system. In particular, we could show that
DCs from IL-15-deficient mice were strongly impaired in the ability to
produce IL-2 after interactions with different microbial stimuli. Our
results indicate that DC-produced IL-2 is tightly coregulated with the
expression of IL-15.
*******
So? How about Stem cells? When they figure them out we could
grow a new immune system from the ground uP.
But understanding the process will give us a shot at correcting
the key players in the P pathways.
http://www.sciencedaily.com/releases/2005/06/050623000101.htm
Researchers Grow Stem Cells From Human Skin
WINSTON-SALEM, N.C. -- Researchers at Wake Forest University School of
Medicine have successfully isolated stem cells from human skin,
expanded them in the laboratory and coaxed them into becoming fat,
muscle and bone cells. The study, one of the first studies to show the
ability of a single adult stem cell to become multiple tissue types, is
reported today in Stem Cells and Development.
"These cells should provide a valuable resource for tissue repair and
for organs as well," said Anthony Atala, M.D., director of the Wake
Forest Institute for Regenerative Medicine and senior researcher on the
project. "Because these cells are taken from a patient's own skin,
there would not be problems with organ or tissue rejection."
<sniP)>
Yeah unless you have an autoimmune disease to begin with.
*****
To get a good idea about DCs and their pathways this may helP,
http://www.uni-regensburg.de/Fakultaeten/Medizin/HaemOnko/Forschung/Englisch/Mackensen/Cellular%20Therapy.htm
So how do those PDCs come about,
http://www.jem.org/cgi/content/abstract/201/3/373
(...) facilitating cells (FCs) <sniP> we have identified the main
subpopulation of FCs as plasmacytoid precursor dendritic cells
(p-preDCs). FCs and p-preDCs share many phenotypic, morphological, and
functional features: both produce IFN-{alpha} and TNF-{alpha}, both are
activated by toll-like receptor (TLR)-9 ligand (CpG ODN) stimulation,
and both expand and mature after Flt3 ligand (FL) treatment. <sniP>
Flt3 ligand regulates dendritic cell development from Flt3+ lymphoid
and myeloid-committed progenitors to Flt3+ dendritic cells in vivo.
Karsunky H, Merad M, Cozzio A, Weissman IL, Manz MG.
Institute for Research in Biomedicine (IRB), Via Vincenzo Vela 6,
CH-6500 Bellinzona, Switzerland. karu...@stanford.edu
Stimulation of Flt3 receptor tyrosine kinase through its cognate ligand
expands early hematopoietic progenitor and dendritic cells (DCs) in
humans and mice. The exact developmental stages at which hematopoietic
progenitors express Flt3, are responsive to its ligand, and
subsequently develop to DCs, are not known. Here we show that common
lymphoid and common myeloid progenitors, as well as steady state DCs in
thymus, spleen, and epidermis, express Flt3. The receptor is
down-regulated once definitive B cell, T cell, and
megakaryocyte/erythrocyte commitment occurs, and Flt3 is not detectable
on other steady state hematopoietic cell populations. Upon in vivo Flt3
ligand (Flt3L) administration, Flt3+ progenitor cells and their progeny
DCs are expanded, whereas Flt3- downstream progenitors are not, or are
only slightly increased. Transplantation of common lymphoid and common
myeloid progenitors and subsequent Flt3L injection increases progeny
DCs of both precursor populations. These findings provide a definitive
map of Flt3 expression in the hematopoietic hierarchy and directly
demonstrate that Flt3L can drive DC development along both the lymphoid
and myeloid developmental pathways from Flt3+ progenitors to Flt3+ DCs.
PMID: 12874263
BDCA-2, a novel plasmacytoid dendritic cell-specific type II C-type
lectin, mediates antigen capture and is a potent inhibitor of
interferon alpha/beta induction.
Dzionek A, Sohma Y, Nagafune J, Cella M, Colonna M, Facchetti F,
Gunther G, Johnston I, Lanzavecchia A, Nagasaka T, Okada T, Vermi W,
Winkels G, Yamamoto T, Zysk M, Yamaguchi Y, Schmitz J.
Miltenyi Biotec GmbH, D-51429 Bergisch Gladbach, Germany.
Plasmacytoid dendritic cells are present in lymphoid and nonlymphoid
tissue and contribute substantially to both innate and adaptive
immunity. Recently, we have described several monoclonal antibodies
that recognize a plasmacytoid dendritic cell-specific antigen, which we
have termed BDCA-2. Molecular cloning of BDCA-2 revealed that BDCA-2 is
a novel type II C-type lectin, which shows 50.7% sequence identity at
the amino acid level to its putative murine ortholog, the murine
dendritic cell-associated C-type lectin 2. Anti-BDCA-2 monoclonal
antibodies are rapidly internalized and efficiently presented to T
cells, indicating that BDCA-2 could play a role in ligand
internalization and presentation. Furthermore, ligation of BDCA-2
potently suppresses induction of interferon alpha/beta production in
plasmacytoid dendritic cells, presumably by a mechanism dependent on
calcium mobilization and protein-tyrosine phosphorylation by src-family
protein-tyrosine kinases. Inasmuch as production of interferon
alpha/beta by plasmacytoid dendritic cells is considered to be a major
pathophysiological factor in systemic lupus erythematosus, triggering
of BDCA-2 should be evaluated as therapeutic strategy for blocking
production of interferon alpha/beta in systemic lupus erythematosus
patients.
PMID: 11748283
Well this next one is on lupus skin, but close enough to
have most of these current terms to help understand the
pathways of pdc's,
http://depts.washington.edu/rheum/JC%20article%206-3.pdf
So, while a evil P virus to guard against would be nice. We
may have to settle for a lectin according to the second link
back.
http://www.google.com/search?hl=en&lr=&q=bdca-2+lectin&btnG=Search
Giving us plenty of links,
http://www.expasy.org/uniprot/Q8WTT0
Lets make it more specific,
http://www.google.com/search?hl=en&lr=&q=bdca-2+lectin+psoriasis&btnG=Search
Got to go. To be continued... One of the PDC authors sent me the full
pdf file.
And one of the regulars here sent me the other one. I have got homework
on
PDCs! Oh Boy!
Time to watch "This Week" with George SteppingonanOctapoopalos. And
he has Michael Turttleoff as his first guest.
Politics being almost as much fun as this. Whats not to like?
You can do this,
http://groups-beta.google.com/groups?hl=en&q=lectins+psoriasis&qt_s=Search
And listen to it.
randall...
randall
One of our sister conditions gives up her secrets.
Seeing as how the pathways overlaP. The P Genes are
coming down next.
Yesterday we did this comparison of MS and P from a
cytokine and gene standPoint.
Also mentioned was the need to balance T-regs and effector
cells.
The fact that scientist now know the pathways/genes to MS is big.
Look. Once they know, they can FIX.
And for MS it's the FOXp3 gene that was key.
When the keys to the P genes are nailed, then we
too will have a definite plan of action.
randall wrote:
> http://www.sciencedaily.com/releases/2005/06/050627061854.htm
> NeuroVax, a T-cell
> receptor peptide vaccine co-discovered by Vandenbark and colleagues at
> The Immune Response Corp., was shown in a separate study to increase
> FOXP3 expression levels among MS patients receiving injections of the
> drug for a year.
> "When we vaccinate with the T-cell receptor peptides -- the NeuroVax --
> we can restore the FOXP3 levels,"
> (...)
> "What
> we think NeuroVax is doing is stimulating regulatory T-cells that then
> down-regulate proliferation of the pathogenic T-cells. The link between
> FOXP3 and T-regs is quite important to our program."
> T-cells are white blood cells produced by the human body to defend
> against infection. Scientists believe a sub-group of "pathogenic"
> T-cells cause MS by attacking myelin, the fatty sheath insulating nerve
> fibers in the brain and spinal cord.
> (...)
> The interesting thing about
> T-reg cells is that they're not very specific. They will, for example,
> inhibit through cell-cell contact any CD4-positive cell that's in the
> process of being activated to attack self tissue. Thus, the T-reg cells
> may also be important in regulating inflammatory T-cells that
> contribute
> to other autoimmune diseases besides MS."
>
http://www.news-medical.net/?id=11599
News-Medical.Net
Research explains one of the fundamental mysteries of multiple
sclerosis
Medical Research News
Published: Monday, 11-Jul-2005
Scientists have pinpointed a chemical messenger that frees some white
blood cells from the body's normal constraints, allowing the cells to
act like renegades that could damage nerves in the central nervous
system. The work, to be published in the July 15 issue of the Journal
of Immunology and just published on-line, helps explain one of the
fundamental mysteries of multiple sclerosis (MS).
The scientists discovered that a chemical messenger found at high
levels in MS patients allows some immune cells known as T- effector
cells to evade normal regulation. Instead, the cells bypass their usual
gatekeepers and could become active in the body's tissues, including
the brain and spinal cord. Scientists believe that during MS, renegade
T-effector cells damage the myelin coating that covers nerve cells,
causing the disease's symptoms. While another subset of white blood
cells called T-regulatory cells normally control the activation of
T-effector cells, investigators found that the chemical messenger
interleukin-12 or IL12 allows some cells to sidestep that regulation
and run amok.
"Normally effector T cells are under strict control as they circulate
through the blood stream in order to prevent unnecessary inflammation
that could be harmful to otherwise healthy tissues," says Benjamin
Segal, M.D., the neurologist who led the University of Rochester study.
"However, occasionally they escape the body's suppression system. We're
learning how they do that."
In the 1990s, while working in the laboratory of Ethan Shevach, M.D.,
at the National Institute of Allergy and Infectious Diseases, Segal was
one of the first scientists to show that IL12 could be important in
autoimmune diseases like MS. He showed that the molecule empowers CD4+
T cells to enter the central nervous system, where they don't belong,
and attack myelin. He has also shown that mice without the IL12 gene
are completely protected against an MS-like disease, and that ordinary
mice can be protected from developing MS-like symptoms if their IL12 is
knocked out. In contrast, exposure of normally harmless T-effector
cells to IL-12 appears to unmask a latent ability to induce MS-like
disease in mice.
Building on this and the work of others, Segal and other doctors around
the world are now testing in MS patients an experimental drug produced
by Centocor that is designed to inhibit IL12 and hopefully suppress
attacks.
In the latest paper, published in the journal's "Cutting Edge" section,
Segal and neuroscience graduate student Irah L. King use funding from
the National Institutes of Health and the National Multiple Sclerosis
Society to show that IL12's effects are unexpectedly far-reaching and
affect some of the immune system's most powerful cells. The team found
that IL12 confers upon CD4+ T-effector cells the ability to overcome
suppression by T-regulatory cells, whose job it is to keep the body
from attacking itself. Without the order imposed by T-regulatory cells,
scientists have shown that animals are more prone to develop autoimmune
diseases like MS.
A drug that inhibits IL12, like the one under development by Centocor,
could restore the function of the T-regulatory cells, allowing them to
be more effective in clamping down on rogue T-effector cells. Such a
medication might also be useful in other autoimmune diseases like
Crohn's disease, psoriasis, and arthritis, where scientists suspect
IL12 also plays a role.
"There are a variety of treatments for MS, but most are only modestly
effective," says Segal, associate professor of Neurology and director
of Neuroimmunology Research. "We are always looking for better
treatments that are more convenient for our patients, with fewer side
effects. Inhibiting IL12 offers one potential option."
Segal's work helps explain why MS patients are more likely to suffer a
relapse of the disease when they get an infection like the flu. When a
person is infected, IL12 levels rise to allow the person to fight off
the infection. Segal's work showing that IL12 helps usher harmful white
blood cells into the central nervous system clarifies why MS patients
sometimes worsen when they get an infection.
http://www.urmc.rochester.edu/
****
So, lets look at P and MS from the Th1/Th2 paradigm.
>From the groups,
http://groups-beta.google.com/groups?q=ms+th2+th1&qt_s=Search
>From pubmed, [ ms + Th1/Th2 ] 294 hits [ MS + Th1] 514 hits
pubmed [ P + th1/th2] 72 hits [ p + Th1] 123 hits
MS has the hits and P is lagging behind.
******
There you have it. MS beats us to the GRAIL gene. She must of
had more money and dad always gave her the keys to the car on
firday night.
Poor little P is still waiting to go to the dance in hand me downs. lol
randall... our Gene will come!
randall
Hey, in my last post on MS and P (two hrs back) a couple of MS genes
came up. FOXp3 and this next one called TIM. And it has its own family.
How sweet! Or is it?
That th1/th2 + MS search had this next abstract,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?holding=npg&cmd=Retrieve&db=PubMed&list_uids=12776205&dopt=Abstract
The TIM gene family: emerging roles in immunity and disease.
Kuchroo VK, Umetsu DT, DeKruyff RH, Freeman GJ.
Center for Neurologic Diseases, Brigham and Women's Hospital,
Dana-Farber Cancer Institute, Harvard Medical School, 77 Avenue Louis
Pasteur, Boston, Massachusetts 02115, USA.
vkuc...@rics.bwh.harvard.edu
The search for cell-surface markers that can distinguish T helper 1
(T(H)1) cells from T(H)2 cells has led to the identification of a new
gene family, encoding the T-cell immunoglobulin mucin (TIM) proteins,
some of which are differentially expressed by T(H)1 and T(H)2 cells.
The role of the TIM-family proteins in immune regulation is just
beginning to emerge. Here, we describe the various TIM-family members
in mice and humans, and discuss the genetic and functional evidence for
their role in regulating autoimmune and allergic diseases.
PMID: 12776205
While foxP3 is key for MS, will TIM be a dream team member of the P
genes?
What is TIM?
Timmy? Timmmmmmiiii! ?
hint,
http://www.sptimmy.com/pics/sp414_timmyfire.gif
Nope, (for a laymans article from eurekaalert go towards the end of
this post).(**)
Will the real tim please express your genes. Or is that ours?
http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=606652
http://www.ncbi.nlm.nih.gov/Omim/getmap.cgi?l606652
& moving uP,
http://www.ncbi.nlm.nih.gov/Omim/getmap.cgi?d2656
Look at HA right next to it. Now that's a clue or two.
Let's look at it,
http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=600936
(...)
Hardwick et al. (1992) cloned a hyaluronan receptor cDNA from mouse 3T3
cells. The 2.9-kb cDNA codes for a predicted 477-amino acid protein,
which they designated RHAMM. Antibodies directed against the protein
blocked locomotion of cells induced by expression of a mutant H-ras
(190020). Savani et al. (1995) showed that RHAMM is upregulated in
response to wound healing
(...)
Now that is a real clue!
But why does hep A 2 receptor come up for TIM?
http://www.ncbi.nlm.nih.gov/mapview/maps.cgi?ORG=hum&CHR=5&maps=loc-r,morbid,gene&R1=on&query=HAVCR2&VERBOSE=ON&ZOOM=3
Oh,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=retrieve&dopt=default&list_uids=84868
It's an alias and
I see TIM4 right above it,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=retrieve&dopt=default&list_uids=91937
And TIM does and is this,
DESCRIPTION
CD4 (186940)-positive T helper lymphocytes can be divided into types 1
(Th1) and 2 (Th2) on the basis of their cytokine secretion patterns.
Th1 cells and their associated cytokines are involved in cell-mediated
immunity to intracellular pathogens and delayed-type hypersensitivity
reactions, whereas Th2 cells are involved in the control of
extracellular helminthic infections and the promotion of atopic and
allergic diseases. The 2 types of cells also cross-regulate the
functions of the other. TIM3 is a Th1-specific cell surface protein
that regulates macrophage activation and enhances the severity of
experimental autoimmune encephalomyelitis in mice. 30 MEDLINE Neighbors
CLONING
By immunoscreening Th1 and Th2 cells with monoclonal antibodies derived
from mouse Th1 cell-immunized rats, followed by gene-expression
cloning, Monney et al. (2002) obtained a cDNA encoding mouse Tim3. By
genomic database searching and RT-PCR, the authors isolated a cDNA
encoding human TIM3. The deduced 301-amino acid type I membrane
protein, 63% identical overall and 77% identical in the cytoplasmic
domain, has an Ig variable-like domain, a mucin-like domain consisting
of 31% serine and threonine residues, and a cytoplasmic domain with a
tyrosine phosphorylation motif. Monney et al. (2002) noted that TIM3 is
related to the hepatitis A virus cellular receptor (HAVCR1; 606518),
also known as the kidney injury molecule (Kim1). 30 MEDLINE Neighbors
Sabatos et al. (2003) identified an 800-bp cDNA encoding a soluble
isoform of mouse Tim3 lacking the mucin and transmembrane domains. The
truncated form contains only exons 1, 2, 6, and 7, while the
full-length protein contains all 7 exons.
GENE FUNCTION
Using flow cytometric and RT-PCR analysis, Monney et al. (2002)
detected Tim3 only on activated Th1 cells and CD11b+ (ITGAM; 120980)
macrophages. Cells expressing Tim3 predominate in the central nervous
system of mice at the onset of experimental autoimmune
encephalomyelitis (EAE), a Th1-mediated autoimmune disease. Anti-Tim3
treatment enhanced the clinical and pathologic severity of EAE and
increased the number and activation level of macrophages. Monney et al.
(2002) proposed that anti-Tim3 may trigger the production of
proinflammatory cytokines in vivo and induce macrophage activation
possibly by enhancing the migration of Th1 cells into the brain or by
blocking an interaction between Tim3 and an inhibitory ligand. 30
MEDLINE Neighbors
By flow cytometric analysis using full-length and soluble mouse Tim3
fusion proteins, Sanchez-Fueyo et al. (2003) demonstrated that a
putative ligand for Tim3 exists on resting CD4-positive T cells, but
not on CD8 (see 186910)-positive T cells, B cells, or CD11b-positive
leukocytes. Some expression was detected on splenic CD11c (ITGAX;
151510)-positive dendritic cells. Expression of the ligand was
downregulated on activated CD4-positive/CD25 (147730)-negative effector
T cells but persisted on CD4-positive/CD25-positive regulatory T cells.
30 MEDLINE Neighbors
Independently, Sabatos et al. (2003) also demonstrated the lack of
expression of a mouse Tim3 ligand on non-CD4-positive T cells and B
cells. Limited expression was detected on CD11c-positive dendritic
cells and CD11b-positive macrophages. Treatment with a Tim3-Ig fusion
protein induced hyperproliferation of CD3 (see 186740)-positive T
cells, but not other leukocyte types, and induced expression of
Th1-type cytokines. 30 MEDLINE Neighbors
GENE STRUCTURE
The mouse Tim3 gene contains 7 exons (Sabatos et al., 2003).
MAPPING
By screening congenic mouse T-cell lines for reduced Th2
responsiveness, McIntire et al. (2001) identified a segment of
chromosome 11 homologous to human chromosome 5q23-q35 that they termed
the 'T-cell and airway hyperreactivity phenotype regulator' (Tapr)
locus. They mapped the mouse Tims, including Tim3, to the Tapr locus on
chromosome 11 and the human homologs to chromosome 5q33.2. 30 MEDLINE
Neighbors
ANIMAL MODEL
Sanchez-Fueyo et al. (2003) found that blockade of Tim3 by anti-Tim3 or
a full-length Tim3 fusion protein appeared to enhance the capacity of
Th1 cells to mediate tissue damage after induction of diabetes in a
nonobese diabetic-severe combined immunodeficiency mouse model (see
222100). Anti-Tim3 also prevented the acquisition of transplantation
tolerance induced by blockade of costimulatory molecules by dampening
the antigen-specific immunosuppressive function of
CD4-positive/CD25-positive regulatory T cells. 30 MEDLINE Neighbors
Sabatos et al. (2003) found that Tim3-deficient mice were refractory to
the induction of high-dose immunologic tolerance.
****************
So, this next abstract makes sense now,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15889130
Evidence for natural selection in the HAVCR1 gene: high degree of
amino-acid variability in the mucin domain of human HAVCR1 protein.
Nakajima T, Wooding S, Satta Y, Jinnai N, Goto S, Hayasaka I, Saitou N,
Guan-Jun J, Tokunaga K, Jorde LB, Emi M, Inoue I.
[1] 1Division of Genetic Diagnosis, The Institute of Medical Science,
The University of Tokyo, Tokyo, Japan [2] 2Department of Molecular
Biology, Institute of Gerontology, Nippon Medical School, Kawasaki,
Japan.
The family of genes encoding T-cell immunoglobulin and mucin-domain
containing proteins (Tim), which are cell-surface molecules expressed
in CD4(+) T helper cells, has important roles in the immune system.
Here, we report three unusual patterns of genetic variation in the
human hepatitis A virus cellular receptor 1 gene (HAVCR1) that are
similar to patterns observed in major histocompatibility complex loci.
First, levels of polymorphism in exon 4 of HAVCR1 were exceptionally
high in humans (nucleotide diversity (pi)=45.45 x 10(-4)). Second,
nonsynonymous substitutions and insertion/deletion variants were more
frequent than synonymous substitutions in that exon (10 out of 12
variants). The rate of the mean number of nucleotide substitutions at
nonsynonymous sites to synonymous sites at HAVCR1-exon 4 is >1
(P(A)/P(S)=1.92 and pi(A)/pi(S)=2.23). Third, levels of divergence
among human, chimp, and gorilla sequences were unusually high in
HAVCR1-exon 4 sequences. These features suggest that patterns of
variation in HAVCR1 have been shaped by both positive and balancing
natural selection in the course of primate evolution. Evidence that the
effects of natural selection are largely restricted to the mucin domain
of HAVCR1 suggests that this region may be of particular evolutionary
and epidemiological interest.Genes and Immunity advance online
publication, 12 May 2005; doi:10.1038/sj.gene.6364215.
PMID: 15889130
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15876308
Polarization of Th1/Th2 in human CD4 T cells separated by CD62L:
analysis by transcription factors.
Matsuzaki S, Shinozaki K, Kobayashi N, Agematsu K.
Department of Pediatrics, Graduate School of Medicine, Shinshu
University, Matsumoto, Japan.
BACKGROUND: T-cell surface antigens that differentiate clearly between
Th1 and Th2 have not been identified. Discrimination of Th1/Th2
subpopulations by CD62L expression has been reported. We investigated
the expression of transcription factors that regulate Th1/Th2 cytokine
synthesis in human CD4+ T-cell subpopulations separated by CD45RO and
CD62L, and compared the ratio of CD62L+ to CD62L- cells between healthy
individuals and patients with allergic diseases. METHODS: Human
peripheral blood samples were obtained from healthy volunteers and
patients. CD4+ T cells were isolated by negative selection. Three CD4+
T-cell subpopulations separated by CD45RO and CD62L were isolated using
three-color fluorescence. Sorted cells were stimulated with anti-CD3
monoclonal antibody, and the cytokine levels were measured using a
Cytometric Bead Array Kit. Transcription factor expression was examined
by reverse transcriptase polymerase chain reaction (RT-PCR) and
real-time RT-PCR. RESULTS: Interleukin (IL)-4 and IL-5 production
levels by CD45RO+CD62L+CD4+ T cells were higher than those of
CD45RO+CD62L-CD4+ T cells (P < 0.05), whereas interferon-gamma and
tumor necrosis factor-alpha production were lower levels (P < 0.05).
T-cell immunoglobulin mucin-3 and T-bet expression were detected in
CD45RO-CD62L+ and CD45RO+CD62L- cells following stimulation, but not in
CD45RO+CD62L+ cells. However, the ratio of CD62L+ to CD62L- cells was
the same in both healthy individuals and patients (P = 0.54). There was
no difference in Th1/Th2 cytokine synthesis by CD4+ T cells.
CONCLUSION: Analyses of cytokine syntheses and transcription factor
expression demonstrated that CD62-negative and -positive subpopulations
of human CD45RO+CD4+ T cells represent characteristics of Th1 and Th2,
respectively.
PMID: 15876308
******
So lets do a [ cd62l + psoriasis ] search on pubmed and get 9 hits.
And those all look like a selectin, lectin, integrin, sugar thingy.
******
I should go and look a little closer at the MS support group for TIM.
Bingo and in laymans terms, (**)
http://www.eurekalert.org/pub_releases/2003-10/bidm-sst103003.php
And that was all I found in the groups.
Lets try the web,
http://www.google.com/search?hl=en&q=T-cell%20immunoglobulin%20mucin%20tim-3&qt_s=Search&lr=&sa=N&tab=gw
And now we wait for science to take up the slack and reveal how TIM
functions with P.
And we need more $$$$$$.
Support NPF and psorcure now and call your legal reps in washington.
We want to be clear. Biological clear and all the time.
randall... But, does TIM work on activated T cells and P?
randall
Looks like the big break through in MS has a payoff for P after
all.
http://www.mydna.com/resources/news/200507/news_20050711_msre.html
(...)
A drug that inhibits IL12, like the one under development by Centocor,
could restore the function of the T-regulatory cells, allowing them to
be more effective in clamping down on rogue T-effector cells. Such a
medication might also be useful in other autoimmune diseases like
Crohn's disease, psoriasis, and arthritis, where scientists suspect
IL12 also plays a role.
(...)
Segal's work helps explain why MS patients are more likely to suffer a
relapse of the disease when they get an infection like the flu. When a
person is infected, IL12 levels rise to allow the person to fight off
the infection. Segal's work showing that IL12 helps usher harmful white
blood cells into the central nervous system clarifies why MS patients
sometimes worsen when they get an infection.
****
Then again, who knows? When ever i got sick and it was mostly pretty
rare, I never cleared much.
Even when I got really sick, I hoped to clear more then I did.
randall... you can't ever trust P! lol It always is screwing with you.
randall
If your on biologics. Look forward to a cocktail with retinoids in the
future.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16004016
A review of the chemopreventive and chemotherapeutic effects of topical
and oral retinoids for both cutaneous and internal neoplasms.
Khera P, Koo JY.
University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
pooja...@gmail.com
Retinoids, a group of compounds encompassing Vitamin A and its analogs,
have been shown to inhibit tumor growth in laboratory studies. Based on
these findings, a number of clinical trials have been conducted to
investigate the chemoprotective and chemotherapeutic effects of
retinoids. This paper reviews the current database regarding the use of
oral and topical retinoids in the prevention and treatment of cutaneous
and internal malignancies. Clinical studies have shown that retinoids
have beneficial effects in the prevention and treatment of certain
neoplasms. In view of the heightened __concern of malignancy__
associated with the use of biologic agents in the treatment of
psoriasis, retinoids may be an attractive option for combination
therapy with the biologic agents. Future clinical investigations are
needed to precisely define how this combination will fit into the
treatment algorithm for moderate-to-severe psoriasis.
PMID: 16004016
*********
Ok. So if we all of a sudden have a cancer risk, whats the reason?
Our skewed Th1 cytokines that contribute to psoriasis (TNF, IFN etc)
are taken from
the equation by the biologic blockers. Whats left in that could cause
the cancer?
How about AA? Its still an unCLEAR area in psoriasis.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16000313
15(S)-lipoxygenase-2 mediates Arachidonic acid-stimulated adhesion of
human breast carcinoma cells through the activation of TAK1, MKK6, and
p38 MAPK.
Nony PA, Kennett SB, Glasgow WC, Olden K, Roberts JD.
Laboratory of Molecular Carcinogenesis, National Institute of
Environmental Health Sciences, Research Triangle Park, NC 27709.
The dietary cis-polyunsaturated fatty acid, arachidonic acid,
stimulates adhesion of metastatic human breast carcinoma cells
(MDA-MB-435) to the extracellular matrix, but the molecular mechanisms
by which fatty acids modify the behavior of these cells are unclear.
Exposure to arachidonic acid activates multiple signaling pathways.
Activation of p38 mitogen-activated protein kinase (p38 MAPK) is
required for increased cell adhesion to type IV collagen, and this
activation is sensitive to inhibitors of lipoxygenases, suggesting a
requirement for arachidonic acid metabolism. The goals of the current
study were to identify the key metabolite(s) of arachidonic acid that
is responsible for activation of p38 MAPK and to elucidate the upstream
kinases that lead to p38 MAPK activation. HPLC analysis revealed that
MDA-MB-435 cells metabolize exogenous arachidonic acid predominantly to
15(S)-hydroxyeicosatetraenoic acid [15(S)-HETE]. Immunoblot analysis
with antibodies specific to 15(S)-lipoxygenase-1 (15-LOX-1) and
15(S)-lipoxygenase-2 (15-LOX-2) demonstrated the expression of
15-LOX-2, but not 15-LOX-1, in these tumor cells. A LOX inhibitor,
nordihydroguaiaretic acid, attenuated production of 15(S)-HETE and
inhibited the phosphorylation of p38 MAPK following exposure to
arachidonic acid. Addition of exogenous 15(S)-HETE to MDA-MB-435 cells
stimulated cell adhesion to type IV collagen and activated the p38 MAPK
pathway, including the upstream kinases TGF-(beta){sub1)-activated
protein kinase-1 (TAK1) and MAPK kinase 6. Transfection of these cells
with a dominant negative form of TAK1 blocked arachidonic
acid-stimulated p38 MAPK phosphorylation. These data demonstrate that
15-LOX-2 generation of 15(S)-HETE activates specific growth factor
receptor-related signaling pathways, thereby initiating signal
transduction events leading to increased cell adhesion to the
extracellular matrix.
PMID: 16000313
Is the stereo fat like 12R-hete that psoriatics get somehow protective,
like The TNF and
IFN of cancer develoPement?
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12432924
&
http://www.pnas.org/cgi/content/abstract/95/12/6744
Or is it just in the unSKEWing of the Th1 cytokines that leave us
vulnerable?
Is it worth it to live clear for X amount of years and then die
10-20-30-40 years
premature?
Only time and good P demograPhics will tell...
Working closer with your derm in the future may save your life
as well as keep your skin clear.
*********
Other Fats in the news today,
Vindication for 'Lorenzo's oil'
Doctors find that mix of olive and rapeseed oils can help prevent a
severe form of a rare disease affecting boys
http://www.newsday.com/news/health/ny-hsoil124340182jul12,0,6928307.story?coll=ny-health-headlines
(...)
ALD affects one in 17,000 people. In the U.S., there are about 12,000
to 16,000 patients with ALD. Half have the severe form, like Lorenzo.
There is also an adult form of the illness that is less severe but
quite disabling. It is often mistaken for multiple sclerosis. Both men
and women can have this adult form of ALD.
(I thought this was the greatest story when it first broke as I was
sure
I had found the P Grail at the same time. By ending my consumPtion
of omega-6 vegetable oils, like soy bean oil, my P went into a steep
decline for a few months. The feeling then were awe inspiring. So much
so that I stayed on the trek to finding the good gut flora implant and
diet.)
*****
P and terror?
Skin Treatment offers hope to bomb victims
http://www.dailymail.co.uk/pages/live/articles/health/healthmain.html?in_article_id=355504&in_page_id=1774&in_a_source=
A remarkable new treatment that can tackle burns scars - as well as
treat acne scars, psoriasis and eczema - is being offered to survivors
of last week's London bombings.
The treatment is based on growing new skin cells from a sample taken
from the patient, then injecting them into the damaged area of skin to
improve its appearance and elasticity.
One of the problems with natural wound healing is that the reaction of
the body is to seal the wound as quickly as possible.
While that stops infection and other complications setting in, the
downside is that in the rush to heal, the skin quality is not as good
as healthy skin.
Scar tissue is thin, taut, and lacks the elasticity, flexibility, bulk
and softness of healthy skin. Its appearance is also different.
A key ingredient in skin is collagen, a naturally occurring protein
that forms a network of fibres that gives skin structure and support.
The skin cells responsible for forming collagen are fibroblasts, and
the new treatment developed by Isolagen, a US bio-technology film, is
based on growing millions of these fibroblast cells from a tiny biopsy
of skin taken from the patient.
In the laboratory, the patient's skin sample is deliberately and
extensively cut, which triggers the release of fibroblasts.
These cells are then encouraged to divide and multiply, and after about
six weeks, they are injected into the patient around the sites of the
scars.
Multiple injections can be carried out if the treatment area is quite
large as in the case of the injured bomb victims.
<sniP>
******
http://www.clarionledger.com/apps/pbcs.dll/article?AID=/20050712/FEAT07/507120388/1242
Some herbal remedies may cause serious side-effects
Q: I started taking turmeric to help my psoriasis. Then I developed a
severe rash and stopped the turmeric.
My biggest concern is that I take Coumadin. When I went in for a
routine blood test, my doctor told me that my blood was extremely thin.
I was told to come in immediately for a vitamin-K shot to reverse this
effect.
A: Thanks for alerting us to a potentially life-threatening interaction
between Coumadin (warfarin) and turmeric. Another reader reported
liver-enzyme elevation with this spice. These cases demonstrate that
herbal remedies can have serious side-effects or interactions and are
not appropriate for everyone.
(When you play doctor with yourself, be sure to check with your real
doctor first.)
Oh and my two a day curcumin sessions seems like a little helPful.
Do Mumbai residents die from to much curry? Or just the ones
on the heart drugs?
******
This one is for B hunt,
A real nano drug to inject into the skin.
http://newark.dbusinessnews.com/shownews.php?newsid=34858&type_news=past
(...) IGI has licensed Novasome(R) nano-vesicular delivery technology
to leading global dermatological and skin care companies including
Johnson & Johnson Consumer Products, Inc., Estee Lauder Corporation,
Chattem Inc., Genesis Pharmaceutical, Inc. and Apollo Pharmaceutical,
Inc., and recently sub-licensed the rights to obtain FDA approval for
and market IGI's PTH (1-34) compound using Novasome(R) nano-vesicular
delivery technology for psoriasis, which is slated for Phase II
clinical trials, to Manhattan Pharmaceuticals, Inc.<sniP>
*******
More on that MS gene that may have some bearings on P pathways.
FoxP3,
http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=300292
(...)
GENE FUNCTION
Due to similarities between the autoimmunity and inflammation produced
by manipulation of CD25 (147730)-positive/CD4 (186940)-positive
regulatory T (Tr) cells and those induced by genetic defects in the
FOXP3 gene, Hori et al. (2003) investigated the contribution of Foxp3
to the development and/or function of Tr cells in mice. RT-PCR analysis
of normal mice showed stable, constitutive expression of Foxp3 that was
high in Tr cells, low in CD4-positive/CD25-negative cells, and absent
in CD4-negative/CD8-positive T cells. Transduced expression of Foxp3 in
CD4-positive/CD25-negative cells imparted a Tr phenotype in these
cells, with low levels of cytokine expression, compared with
nontransduced or vector-only transduced cells, and high levels of CD103
(604682), GITR (TNFRSF18; 603905), and CTLA4 (123890). Transduced cells
also showed cell-cell contact suppressive activity in vitro, as well as
suppression of autoimmunity and inflammation in vivo. Hori et al.
(2003) proposed that FOXP3 may be a master regulatory gene and a more
specific marker of Tr cells than other cell surface molecules. They
also suggested that FOXP3 transduction could be a therapeutic mode for
the treatment of inflammatory diseases.
(...)
To get back on track with foxP3,
http://groups-beta.google.com/groups?q=foxp3+psoriasis&qt_s=Search
It was funny how we had three days of ms and foxp3 and then yesterday
a story included the word psoriasis with them.
http://news.google.com/news?qt_s=Search&lr=&tab=gn&ie=UTF-8&q=ms+psoriasis+il-12&btnG=Search+News
You want to sex something uP or down and P is the clown word.
&&&&&&&&&&&&&&&&&&&&&&&&&&&
While I awaited the GREAT debate of the bug versus the terrain. It
never
haPPened.
Lets let this stand instead,
http://www.rednova.com/news/health/160855/letter_diseases_are_not_due_to_germs_alone/
Letter: Diseases Are Not Due to Germs Alone
Sir: Acquiring an infection equals infective agent plus level of
immunity ('Superbug hits 15 hospitals', 30 June). Louis Pasteur
favoured the germ theory whereby the infective agent was the direct
cause of disease. Claude Bernard, on the other hand, believed that the
internal 'terrain', or health of the immune system, was more important.
It is well established that our immune systems are compromised by poor
diet, stress, pollution and inappropriate use of antibiotics.
Antibiotics can cause microbial resistance and therefore more virulent
microbes: they also kill off beneficial bacteria leaving the intestines
open to invasion by pathogens which can become harmful to the host,
causing diarrhoea and septicaemia. The diarrhoea causes loss of vital
nutrients, further compromising the immune system. Therefore doctors
should be prescribing probiotics, nutritional supplements and improving
diets for vulnerable patients and not oversubscribing antibiotics.
On his deathbed Pasteur said: 'Bernard was right, the pathogen is
nothing, the terrain is everything.' Unfortunately Pasteur's legacy is
the obsession with the pathogen. Modern medicine has largely forgotten
the importance of the terrain.
HELEN MURRAY
CARDIAC PHYSIOLOGIST BRIGHTON
Source: Independent, The; London (UK)
**************
What does the terrain mean for P?
It means making a colony of good flora in your gut to unSKEW
yourself naturally.
"Il faut cultiver notre jardin." Voltaire, (Candide)
randall... or maybe you like those funky gut bugs to prevent cancer?
randall
Yesterday's P news was so good I read it again just
now.
Now I don't know how to toP it. I'll try. But first,
Lets pick at advitech! Their in the google news for the X consecutive
day.
http://news.google.com/news?lr=&tab=gn&ie=UTF-8&scoring=d&q=psoriasis+advitech&btnG=Search+News
They sure are sPending a lot of money on their sweetwhey P product,
that got a ~20% clearance for mild to moderate psoriatics.
Read to the end of this page for what it is,
http://www.advitech.com/en/produits_xp_828.php
And don't you feel like their selling you your own psoriasis there?
Yet, not explaining fully how their product works?
What makes that product better then this?
http://www.thewholewhey.com/contents/products_info/proflora.htm
Did you read about the terrain versus the bug in the end of
yesterday's p news?
The good flora certainly comes into play in our Th1 skew.
But P is more then a Th1 skew. Its genes.
And with a trigger those genes fire uP!
&&&&&&&&&&&&&&&&
These (2) emails I had with a P friend the last two days sorta go along
with the above.
*****
Hi Randall:
<sniP> Personal stuff.
Ya ya ya, I know the th1/th2 thing has been talked about zillions of
times, but I just wanted to know if this article basically sums it all
up in a nice, kind of coherent way.
Balancing Th1 and Th2
(These notes were taken from the Healthline radio show with Dr. Alan
Pressman. This show first aired on Jan 26th, 2000 and was rebroadcast
on April 28th, 2000.)
(R) Number one, its really old now and concepts of th (T helper cells)
has changed with the times and become much more complicated day by day.
White blood cells secrete them. They're secreted by T-cells, by
epithelial cells.
(R) And from FAT cells. Adipose tissue is the largest organ of immunity
in the body its now known.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15749839
&
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14732844
(R) So as you can see with the influence of Leptin, Th1 skews are due
to more then we know still. The very T helper pathways are mediated by
unknown factors. Which means
we don't have a rudder on that shiP of dreams to go launching any
schemes.
These cytokines release interleukins and interferons and a whole bunch
of other things and that deals with the immune system and that deals
with whatever illness is coming on. The problem occurs when Th1 and Th2
are not in correct balance. Th1 is what we call cell-mediated immunity.
These are the killer T-cells, the CD8 cytotoxic lymphocytes. This is
driven by immunoglobulins and inflammation and DHEA, a very important
area of the body.
(R) I took DHEA till it came out my ears. Didn't seem to make a
difference one way or the other for psoriasis.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15613680
DHEA/LePtin are still unclear as to pathways like Th1 and fat. So,
while you take their good advice for these things you still don't get
much bang for your efforts or $$$'s.
Th2, these cytokines are what we call humoral immunity. These assist
the production of antibodies and the goal is a balance between Th1 and
Th2.
If they're balanced, you are immunologically sound.
(R) Sorta like a teeter totter with Th0 at the fulcrum point. Or is
that the focal point. ;-)
(R) Changing that point is the point isn't it?
The problem occurs when they fall out of balance and we never knew this
before.
(R) bingo! And the more we know, the more it brings uP that we don't
know. As to
psoriasis we're sure we don't know these pathways yet.
The fact is that in most illnesses, most chronic illnesses, starting
with AIDS, Chronic Fatigue Syndrome, candida, multiple allergies, food
sensitivities, multiple chemical sensitivities, hepatitis, even Gulf
War Syndrome and cancer, there's a dramatic imbalance and what happens
is that they're a failure of
Th1 and an overactive Th2 and that combination, underactive Th1,
overactive Th2, is where you are if you've got Chronic Fatigue
Syndrome, if you've got
multiple chemical sensitivities, if you've got a wide variety of
illnesses including multiple sclerosis, psoriasis, rheumatoid
arthritis, inflammatory bowel disease. These are all problems where Th1
is underfunctioning and you
want to have Th1 functioning better. You want to have it stimulated.
(R) NOPe ,,, P is a strong Th1 skew without a virus/bug to blame it on
yet. A mimic or bug poop could be suspect. But no one knows how
to show this pathways from the vague incipient point. And the pDC
abstracts recently in the p group show a lectin/selectin of some sort
could be in there.
Once again its not the food. Its the genes. Your either making a
protein or not making it due to genes. Sure foods could support a
skew, but thats a far cry from causing P.
And what about my head? My funky head responds to head and shoulders
fairly well.
So is it Th1 or Th2? Does P float on our skin to compensate for
Well, what we looked at was what are the nutrients that support Th1
cytokines?
(R) Who are we? Pressman has a lab where he does real science? Whats
the name of it? DE pressed man clinic? lol
Has he taken plenty of dhea? lol
So if you have any of those illnesses and you want to boost Th1
cytokines, how would you do that? What are the nutrients to boost
immune function, especially Th1? Well, number one our list was the
Omega 3 fatty acids, EPA at 500 to 1000 mg a day, and DHA between 1500
to 2500 mg a day.
Also, olive oil, which contains oleic acid: 4 tbs a day of fresh olive
oil that's been refrigerated is very supportive of Th1 cytokines.
Vitamin A at 25,000 international units and we want you to not only
just take Vitamin A at 25,000 units, we want to you to eat a lot of
carotenoids, a lot of vegetables, carrots and things like that. In
addition to that, l-glutamine: 10 to 20 grams a day will strengthen
Th1.
(R) Nonsense. L-glutamine will cause you to flare if you have P....
sorry but true. I looked at the pathway for a long time as it was so
counter-intuitive. As to omega-3's go ahead and try to get clear with
them. You'll be trying forever. And yes you may feel great, but one day
your going to realize that n-3's only go so far. And for someone
greater then moderate it may not be enough in all cases.
Lactobacillus, two or three different kinds. Even bifidobactrim,
magnesium, silica. That's right. One serving of cooked oatmeal or
millet a day is crucial if you want to boost Th1. Glutathione-we talked
about the fact that in Th1 depression where you body is not having this
proper balance, glutathione gets depleted so you want to add
glutathione. You might even want to add, after careful testing, DHEA,
because the higher the levels of DHEA within normal the better Th1
performs. Vitamin E, Vitamin B complex, panax ginseng, garlic,
digestive
enzymes, even something called arabanogalactins. These are the
important nutrients that support Th1 cytokines.
(R) The above while a worthwhile idea is still off track. Its the genes
that are turned on and off that cause the skew at this point.
You can take, and i do, tons of NAC and still not have enough effects
to make you happy P wise. As to taking good bacteria, you have to know
how to do that as well.
Simply eating it does nearly nothing P wise unless you've gone on a
diet to allow
an implant of good flora to thrive. NAC being the active form of
glutathione in the body is good for P somehat. I don't see much point
in taking more then one gram a day.
And as to taking flax seed oil, i don't see taking more then one
tablespoon a day as being optimal. P or not withstanding.
Now the Th2 cytokines, again if they're in balance, they're fine. How
do they get elevated that causes the depression of Th1? Well, faulty
digestion would elevate these Th2 cytokines. A leaky gut syndrome will
elevate Th2 cytokines, white sugar, over consumption of glucose and
processed foods, that weakens systemic resistance to infection.
(R) A Leaky gut is leaking LPS from the endogenous bad gut flora.
Nothing else much makes it thru or you become sePtic and die.
Most alts just don't get this point and its crucial. That alone skews
their understanding of Th/Th2 with Th0 being the goal....it is the
point.
And that fulcrum point is mediated by the good and bad gut flora before
any absoprtion takes place. You want to maximize your lever by doing
what it takes to regrow
a good terrain of gut bacteria.
Trans-fatty acids, these are heated, processed, vegetable oils, a diet
high in the omega 6 fatty acids like linoleic acid, all of these
promote over functioning of Th2.
(R) See what i mean? This is wrong for someone skewed towards the Th1
side like a psoriatic. If n-6 oils skewed me
towards th2 then i would make IL-10 and clear up and the reverse is
true. Good gut flora will balance il-10 and
unskew the psoriatic. I've proved it via my own guts.
This makes the membranes pourous and very vulnerable to infection. We
also said that adrenal exhaustion may promote a cytokine shift from Th1
to Th2. That's not good. Any kind of lack of glutathione. So, this is a
very important area and in fact, there was an article that came down on
asthma that says, "More clues found to molecules role in asthma. A new
study has found additional evidence that a chemical involved in
inflammation may play a role in asthma. The study found more of the
chemical found known as
interleukin 9, IL-9." Interleukin 9 is one of those Th2 substances that
gets overactive, suppresses Th1, and you wind up with asthma. This was
a study printed in the Journal of Allergy and Clinical Immunology at
McGill
University and the Institute Pasteur in France. They believe that if
you can control, if you can lower IL-9 this is going to help treat and
even prevent asthma. It goes on to say that "Interleukins have been
known to play a role in regulating the immune system and in particular
to be
responsible for causing the early stages of inflammation." They found
that if you can lower the potency of Th2, especially these
interleukins, and boost Th1 with all the things we've been speaking
about, all those nutrients, they're going to help dramatically in the
management of a wide variety of illnesses, including multiple
sclerosis, psoriasis, rheumatoid arthritis, inflammatory bowel disease,
AIDS, Chronic Fatigue, candida, multiple allergies, multiple chemical
sensitivities, hepatitis, Gulf War Syndrome and cancer.
(R) Once again wrong on asthma. Its the LPS (airborne endotoxins-poop-
from big bugs like cockroaches) that kids breathe and triggers their
asthma. And i'm fairly sure about that. Under privileged kids taken out
of their enviroment will start to clear fast.
Airborne LPS could be a trigger for psoriactics as well during the
spring after rain has pooled. Or even in water in and around the base
of your house plants.
All I wanted to know is if that would be a good article to show to
someone with inflammatory problems that you're trying to explain why
certain supplements might be worth trying and at the same time why to
avoid certain things.
(R) Well i don't know. While you should eat nutrient dense foods loaded
with vitamins to live long, the skewing
of Th1/Th2 should be looked at from the level of the good gut flora.
You have it you have health. Its the focus and for P a fulcrum to
lever better results.
(R) Its all that simple. The problem we have with P is once the
trigger has fired off the condition the maintenance of that dis-ease is
easily accomplished due to the genes. Your fighting an uP hill battle.
(R) Aids/Hiv is Th2. But you have a real virus in that condition that
will eventually deplete the immune factors and you
die. You die due to Th2 and its skew from a REAL bug/virus. It doesn't
become Th1, the hiv prevents the Th1 from becoming active as it attacks
those cells
(R) With P and our th1skew, there isn't an exact cause beyond a mimic
or lectin/selectin.
If there was then we'd know and we'd have a target beyond the ability
of the body to react at the drop of a pin. If their was a real virus
we'd know. The only thing left is the gut immunity and the flora of the
gut at some point in this equation.
Thanks for your feedback. If there's any other article you'd recommend
instead, that would be much appreciated.
(R) I'll try to look around for one. I like the diagram showing th1 th2
and th0,
http://www.iir.suite.dk/IIR/03Th/Th.htm
You need th1 & th2. But are better off maintaining balance. But eating
what you want is fun and makes the teeter totter more fun with highs
and lows and thats life.
&
If you can nutritionally live with only a slight skew of Th1 your less
likely to get cancer IMO.
And that is why the mediterranean diet makes sense. The one glass a day
of wine will cause
a slight leakage of the gut and just a bit of LPS will get thru and
keep the immune system alert.
Sorta like making sure your police force is alert but not out shooting
the bad guys 24/7 and exhausting the adrenals/immune system. Not
because of a mimic but because of real culprits like in aids.
OTOH its alright to cry wolf once a day to bring the immune system to
an alert status but not all day long either.
As far as this nutrition stuff above is concerned. I look at it like a
failed attempt to correlate the two with the abitilty of the body to
stay healthy.
If their is a mimic for p its sure not showing itself and its sister,
LPS maybe the only one left standing.
And she has a curious affair with the P genes.
And we have new ones this week. FOXP3, LPIN and i can't remember the
other one or two.
randall
*********
The response to the above,
Subject: Much better explanation
Sorry for the first email Randall.
(R) and sorry i spent an hour on that reply? lol
This webpage is much longer, but appears to sum things up quite nicely,
in detail.
http://www.drkaslow.com/html/immune_restoration.html
You're 100% correct on the gut issue,
(R) of course i am and thats the point. the fulcrum thingy is made
easier my whey.
http://www.fi.edu/time/Journey/Time/Escapements/lever.gif
no doubt about that, but my problem is that I can't get the Proflora
whey up here in Canada.
(R) I'll give you a link at the end of this thing.
I'd like to ad in a good flora supplement on a regular basis but don't
know which one to go with.
(R) Since DavidWebster doesn't ship outa the USofA. Buy his directions
and then go out and buy what he uses in his witkit and duplicate his
process.
I know he usually doesn't sell the directions in the US, but maybe
he'll sell them
to someone in Canada?
Any suggestions on another product that might give similar results???
Thanks again,
XXXX
Your welcome,
As to your Dr. Kaslow.
His home page is good,
http://www.drkaslow.com/home.html
This looks a little flaky,
http://www.drkaslow.com/html/bioresonance_feedback.html
And it mentions Voll towards the end of the page.
I looked at and have used the old BRFT machines called the Interro.
They were late voll machines from germany. Or copies made in Las
Vegas, iirc.
http://www.globalserve.net/~redpaw/faq.htm
When chiro's were caught with them they were arrested. So i wonder
how this doc gets away with this machine? To much time for me to look
now.
You could help me out and take a look and let me know what you find,
http://www.google.com/search?hl=en&lr=&q=+interro++electrodermal+&btnG=Search
I like his page here,
http://drkaslow.com/html/pyroluria.html
And i like his diet page and he has bielers broth as a way to de-acidfy
the body. A great old doctor who had a neat little book called " Food
is your best medicine" Henry Bieler md
Hey is Kaslow an ALT? Or are his credentials real?
http://www.drkaslow.com/html/leaky_gut.html
(,,,)
When the integrity of the intestinal barrier has been compromised,
intestinal toxins are not the only pathogens to be absorbed.
(...)
Look XXX when tight junctions fail in the small intestines we have a
hard time proving more then a genetic pathway has been fired off.
If your really leaking your simply gonna die. In that instance
antibiotics start to look pretty good.
And for psoriasis a complete vegetarian diet may take you to clear. But
its still the flora
that prevents the LPS from skewing you Towards A TH1 profile that is
important.
And even if you do this to the letter,
http://www.drkaslow.com/html/our_management_approach.html
You will not stop P much unless you also do a vegetarian diet.
But if you want to turbo that diet. Then do the witkit implant first
and then do the diet
and see how fast you clear up.
Its like deciding to go to new york from london. Your not gonna start
out on a skate board.
You want to go first class in a 747. Or at least in coach and sleep.
The same is true
for your colon. You want good flora you have to implant live viable
lacti bugs and then
do the diet that will grow them out.
Or you never get to the destination.
**************************************
And if you can't get sweetwhey in canada then find some lactose and try
that.
http://www.google.com/search?q=lactose%20sweet%20whey&svnum=10&hl=en&lr=&sa=N&tab=iw
Let me know how you do.
Poor Dr, Kaslow is looking like he made it to the 99 yard line and fell
down or fumbled. lol
He sure has a nearly great site and pages.
But no cigar for him today. These alt like doctors through out all the
goodies, but
don't know how to implant flora and grow it ot and thats what it's all
ABOUT.
One day they may catch on. Like some of you will. I'm waiting!
randall... when good doc's go bad? Or is that ALT? Nearly Good!
randall
A serotonin antagonist drug for psoriasis?
http://www.bioworld.com/servlet/com.accumedia.web.Dispatcher?next=bioWorldHeadlines_article&forceid=35793
(...)
Immune Control's human trials are expected to begin with a study in
patients with multiple myeloma, a cancer that affects B cells. A second
clinical study is expected to test a serotonin antagonist in psoriasis,
a T-cell disease.
<sniP>
*****************
Oleander has been used to treat psoriasis? Thats a new one to me.
http://www.cyprus-mail.com/news/main.php?id=20871&cat_id=1
Woman dies after eating oleander.
(...)
"Thevetia has also been used before to treat skin ailments,
particularly psoriasis and is also an effective rat poison, when
burrows are stuffed with its leaves, as the rodents eat their way
through it."
<sniP>
******
Taxanes for P and C,
http://press.arrivenet.com/pro/article.php/668435.html
(...)
Bioxel Pharma Inc. is an emerging leader in biopharmaceuticals, focused
on developing, manufacturing and marketing taxane pharmaceutical
ingredients. Taxanes are used in drug products for the treatment of
cancer and other diseases, including psoriasis, rheumatoid arthritis,
Alzheimer's disease and cardiovascular disease. The Corporation sells
cGMP paclitaxel and develops a portfolio of other generic taxane API's
and taxane-based proprietary products for improved cancer therap
<sniP>
******
Finding turned on genes in a single human cell,
http://pubs.acs.org/cen/news/83/i29/8329escic1a.html
And besides kicking SOD into action it turns on the IFN Th1, T helper
cell DNA.
******
randall... Slow news day so far.
randall
Lets get political,
http://press.arrivenet.com/pol/article.php/669238.html
Psoriasis Cure Now Applauds U.S. Senate for its Strong Commitment to
Psoriasis Research
Distribution Source : U.S. Newswire
Date : Friday, July 15, 2005
To: National Desk
Contact: Michael Paranzino of Psoriasis Cure Now, 202-253-4863 or
Mic...@psorcurenow.org
KENSINGTON, Md. July 15 /U.S. Newswire/ -- "Psoriasis Cure Now," a
patient advocacy group based in our nation's capital, today applauded
the U.S. Senate for including its strongest language ever in support of
increased federal research on psoriasis and psoriatic arthritis. The
psoriasis-related language is in a Report that accompanies the Fiscal
Year 2006 Labor-HHS Appropriations Bill, and mirrors historic language
included in the House Report last month that also strongly urged a
greater commitment to psoriasis and psoriatic arthritis research (more
on that is available here: http://www.psorcurenow.org/house062205.php).
"Both the House and Senate have now spoken, and have spoken with one
voice, that the National Institutes of Health should significantly
increase its commitment to research on psoriasis and psoriatic
arthritis," said Michael Paranzino, president of Psoriasis Cure Now.
"We are grateful that Senator Arlen Specter, chairman of the
Appropriations Committee's Labor-HHS Subcommittee, included this
language and stood firmly with the 6.5 million Americans living with
psoriasis."
<sniP>
*****
randall..
randall
P news from around the world.
First,
The man who shed light on Wisconsin and P.
Deluca the Vitamin D man,
http://www.madison.com/wsj/home/local/index.php?ntid=47166&ntpid=2
*******
http://www.timesonline.co.uk/article/0,,2099-1685395,00.html
July 17, 2005
Best of Times, Worst of Times
David Warner
Interview by Ann McFerran
In 1965, David Warner gave a legendary performance as Hamlet at the RSC
opposite Glenda Jackson's Ophelia. But psoriasis and stage fright
combined to keep him off the English stage for decades. Today, at 63,
he is playing King Lear at Chichester Festival Theatre, his first
leading role in Britain for 34 years
"I never thought I'd work in films, but that was always my dream. Then,
in the mid-1960s, I did Hamlet for the Royal Shakespeare Company, and
later the film Morgan: A Suitable Case for Treatment, so I was working
in film, TV and theatre. Though some critics liked my Hamlet, not
everyone thought I was the greatest thing since sliced bread. But on
the strength of it I did The Bofors Gun, The Sea Gull and Midsummer
Night's Dream.
But then I got this terrible skin problem, psoriasis. Think Michael
Gambon in The Singing Detective.
<sniP>
****the end.......
Well. That was rather thin.
Lets check pubmed for anything current.
PPARbeta/delta selectively induces differentiation and inhibits cell
proliferation.
Kim DJ, Bility MT, Billin AN, Willson TM, Gonzalez FJ, Peters JM.
[1] 1Department of Veterinary Science and The Center for Molecular
Toxicology and Carcinogenesis, The Pennsylvania State University,
University Park, PA 16802, USA [2] 2Graduate Program in Molecular
Toxicology, The Huck Institutes of the Life Sciences, The Pennsylvania
State University, University Park, PA 16802, USA.
Peroxisome proliferator-activated receptor (PPAR) beta-null mice
exhibit exacerbated epithelial cell proliferation and enhanced
sensitivity to skin carcinogenesis, suggesting that ligand activation
of PPARbeta will inhibit keratinocyte proliferation. By using of a
highly specific ligand (GW0742) and the PPARbeta-null mouse model,
activation of PPARbeta was found to selectively induce keratinocyte
terminal differentiation and inhibit keratinocyte proliferation.
Additionally, GW0742 was found to be anti-inflammatory due to
inhibition of myeloperoxidase activity, independent of PPARbeta. These
data suggest that ligand activation of PPARbeta could be a novel
approach to selectively induce differentiation and inhibit cell
proliferation, thus representing a new molecular target for the
treatment of skin disorders resulting from altered cell proliferation
such as psoriasis and cancer.Cell Death and Differentiation advance
online publication, 15 July 2005; doi:10.1038/sj.cdd.4401713.
PMID: 16021179
We've had more then a few PPAR threads about the P/PPar cures,
http://groups-beta.google.com/groups?hl=en&q=ppar+psoriasis&qt_s=Search
But this mpo angle may help us to understand it better.
http://www.chmeds.ac.nz/research/freerad/tony.htm
http://groups-beta.google.com/groups?q=myeloperoxidase+psoriasis&qt_s=Search
http://meds.queensu.ca/medicine/physiol/undergrad/3and4year/patho/baer/inflam.htm
GWO742 doesn't seem to have any clues,
http://www.google.com/search?q=GW0742&svnum=10&hl=en&lr=&sa=N&tab=iw
Lets find a way to block MPO,
http://www.google.com/search?q=benzoic%20acid%20hydrazide%20analog&svnum=10&hl=en&lr=&sa=N&tab=iw
Oh Well... this one is to deeP for me.
If I could control my P via the PPARs without having to quit eating
lipids/fats/meats/
eggs/dairy etc, then i'd take keen interest. Is that why mpo goes out
of the
equation when you go vegetarian? No need or less need for mpo? Thats
one
way to change a pathway, quit eating meat.
Yet if taking a PPAR agonist like MCC-555 did something positive in
multiple pathways without doing harm i'd certainly be interested,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16012905
Still, I am taking ALA (alpha lipoic acid) and not getting much bang
for my buck,
P wise,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15221328
So, ALA is better then the antidiabetic thiazolidinedione,
rosiglitazone and MCC-555 is three times stronger then rosiglitazone.
Will MCC-555 slow IL-2 any more effectively
and why?
Like I said. My body handles sugars fine for the time being and I don't
anticipate
diabetes problems till after my body has turned to dust. lol
In the meantime knowing what the lipids are doing may help the P skin.
So. Why's it so confusing?
*****
This next one isn't.
Antibiotics trigger really really nasty psoriasis (the kind you can die
from).
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16021293
Acute generalized exanthematous pustulosis (AGEP). case report.
Belda Junior W, Ferolla AC.
Department of Dermatology, Sao Paulo University, Sao Paulo, SP, Brazil.
Acute Generalized Exanthematous Pustulosis (AGEP) is a drug-induced
dermatosis characterized by an acute episode of sterile pustules over
erythematous-edematous skin. It is accompanied by an episode of fever,
which regresses a few days after discontinuation of the drug that
caused the condition or as a result of corticosteroid treatment. The
main triggering drugs are _____antibiotics____, mainly beta-lactam
ones. Other medications, such as antifungal agents, non steroid
anti-inflammatory drugs, analgesics, antiarrhythmic, anticonvulsant and
antidepressant drugs, may also be responsible. Histologically, it is
characterized by the existence of vasculitis, associated with
non-follicular subcorneal pustules. A case of a Caucasian female
outpatient unit of Dermatology with AGEP, who presented with
generalized pustulosis lesions after the use of __cephalosporin__ for
urinary infection is related. The diagnosis was confirmed by the
clinical and pathological correlations, the resolution of the
dermatosis after discontinuation of the drug and use of systemic
corticosteroid treatment, and the recurrence of the disorder after the
introduction of a similar drug. The importance of the recognition of
this ___drug-induced dermatosis__ is given by its main differential
clinical and histological diagnoses: generalized pustular psoriasis and
subcorneal pustulosis.
PMID: 16021293
So lets look at it,
http://images.google.com/images?svnum=10&hl=en&lr=&q=Acute+Generalized+Exanthematous+Pustulosis+&btnG=Search
http://images.google.com/images?svnum=10&hl=en&lr=&q=generalized+pustular+psoriasis&btnG=Search
http://www.psoriasisguide.ca/tf/content.asp?a=472
I guess anytime a dis-ease is triggered it looks pretty bad in the
acute phase.
And when it simmers down into the P (chronic) phase forever it isn't
cute either.
Now, whether you end uP with P forever is the question. In this last
abstract it
was antibiotics that got the ball rolling.
Using the randall whey technique to rebuild good gut (colon) flora is
suPPose
to undo the damage from antibiotics.
Still, even if you do it and the diet perfect your p comes back once
you go back to a normal diet.
So that brings into the question of whats normal. For us normal isn't
normal if you clear on a vegetarian diet to some degree.
Is that what mediates mpo then? Sure looks like it now.
And if we had a way to stop/slow/block the pathway set uP by strep,
would we be able to control it better? Like a vaccine for strep?
Yu'd think they already tried that angle. Guess i'll go look.
Oh well... so much for today.
randall... P news makes you think. When will it get better?
randall
How about getting involved in some P political action today?
Go for it!
http://www.webwire.com/ViewPressRel.asp?aId=3415
Psoriasis Cure Now Makes Final Push for Full Coverage of Psoriasis
Treatments in Medicare Prescription Plans
Psoriasis Cure Now
7/21/2005 10:36:30 AM
WASHINGTON, July 21 -- "Psoriasis Cure Now," a patient advocacy group
based in our nation's capital, today launched a final push to ensure
that the new Medicare Prescription Drug Benefit that takes effect
January 1 will include coverage for the full range of effective
psoriasis treatments. In September, lists of covered drugs will be
released by the Centers for Medicare & Medicaid Services (CMS). The
psoriasis group is urging interested Americans to write directly to CMS
using the group's special Medicare Alert, available on the web:
http://capwiz.com/psorcurenow/home
"Older Americans need access to the full range of effective treatments
for psoriasis and psoriatic arthritis," said Michael Paranzino,
president of Psoriasis Cure Now. "We think some last- minute, friendly
pressure on CMS can help ensure that psoriasis patients are not
short-changed by this promising new drug benefit."
Psoriasis is an incurable, recurring disease of the immune system that
can first strike at any age, causing dry, painful skin lesions that can
crack, bleed and itch. Many people with psoriasis also have psoriatic
arthritis, a chronic, progressive and debilitating inflammatory disease
that often causes joint pain, stiffness and swelling, as well as bone
damage. Private entities will offer Medicare prescription plans based
on guidelines established by CMS. If the guidelines are not crafted
properly, plans might only cover the less safe and/or less effective
psoriasis treatments. This could eventually also impact younger
Americans, as many experts believe the Medicare guidelines will come to
influence non-Medicare prescription plans.
"The Medicare Prescription Benefit must not force older Americans into
less safe or less effective treatments." Paranzino added. "If the new
Medicare Prescription Benefit is to prove successful, it must fully
cover Seniors with incurable, serious diseases like psoriasis and
psoriatic arthritis."
More information is available on the Psoriasis Cure Now website:
http://www.psorcurenow.org .
**********************
How does one find out about pathways for immunity and P?
http://www.the-scientist.com/2005/7/18/20/1
state-of-the-art implementation of flow technology
Its a color thing!
Connect the dots till they all turn red?
******
And I'm sure these scientists had that last one in mind when they did
this next study.
Transcriptional responses of human epidermal keratinocytes to
Oncostatin-M.
Finelt N, Gazel A, Gorelick S, Blumenberg M.
Department of Dermatology, NYU School of Medicine, 550 First Avenue,
New York, NY 10016, United States.
Oncostatin-M (OsM) plays an important role in inflammatory and
oncogenic processes in skin, including psoriasis and Kaposi sarcoma.
However, the molecular responses to OsM in keratinocytes have not been
explored in depth. Here we show the results of transcriptional
profiling in OsM-treated primary human epidermal keratinocytes, using
high-density DNA microarrays. We find that OsM strongly and
specifically affects the expression of many genes, in particular those
involved with innate immunity, angiogenesis, adhesion, motility, tissue
remodeling, cell cycle and transcription. The timing of the responses
to OsM comprises two waves, early at 1h, and late at 48h, with much
fewer genes regulated in the intervening time points. Secreted
cytokines and growth factors and their receptors, as well as nuclear
transcription factors, are primary targets of OsM regulation, and
these, in turn, effect the secondary changes.
PMID: 16023359
http://bio.ifom-firc.it/biobase/transpath/4.1/doc/doc/maps/OSM.html
This seems like it would add to the flare.
Untill you look deePer,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11890661
Oncostatin M in the anti-inflammatory response.
Wahl AF, Wallace PM.
Seattle Genetics, Inc, Bothell, WA 98021, USA. aw...@seagen.com
Oncostatin M (OM) is a pleiotropic cytokine of the interleukin 6
family, whose in vivo properties and physiological function remain in
dispute and poorly defined. These in vivo studies strongly suggest that
OM is anabolic, promoting wound healing and bone formation, and
anti-inflammatory. In models of inflammation OM is produced late in the
cytokine response and protects from lipopolysaccharide (LPS)-induced
toxicities, promoting the re-establishment of homoeostasis by
cooperating with proinflammatory cytokines and acute phase molecules to
alter and attenuate the inflammatory response. Administration of OM
inhibited bacterial LPS-induced production of tumour necrosis factor
alpha and septic lethality in a dose dependent manner. Consistent with
these findings, in animal models of chronic inflammatory disease OM
potently suppressed inflammation and tissue destruction in murine
models of rheumatoid arthritis and multiple sclerosis. T cell function
and antibody production were not impaired by OM treatment. Taken
together, these data indicate that the activities of this cytokine in
vivo are anti-inflammatory without concordant immunosuppression.
PMID: 11890661
So. It looks like fighting fire with fire. Your flaring anyway and you
toss OM on toP of it
and it hits/delivers the goods and some how slows the inflammation.
How?
I don't know. But it does figure into the LPS pathway, adding to that
mystery pathway for
P.
****
http://www.jem.org/cgi/content/full/202/1/5
(...)
. New insights into the molecular mechanisms of DC function and their
influence on immune regulation, their role in infectious and autoimmune
disease, and new clinical applications are highlighted.
DC maturation
DCs are "immunological sensors" that reside throughout the body in an
immature form. Immature DCs can capture invading microbes, which
provide a source of antigens and ligands for Toll-like receptors (TLRs)
that trigger a process of maturation and/or differentiation. The mature
DCs migrate to draining secondary lymphoid tissues, present the
captured antigen, and up-regulate costimulatory molecules and
cytokines. Mature DCs both initiate and direct T and B cell responses.
During the meeting, it was reported that a combination of TLR agonists
that mobilize both MyD88 and TRIF adaptors for TLR signal
transduction-such as the TLR4 ligand lipopolysaccharide (LPS) with
the synthetic viral RNA mimic and TLR7 ligand R848, or alternatively
the TLR3 ligand poly IC with R848-synergize to induce elevated and
sustained interleukin (IL)-12 production by human DCs, enhancing T
helper (Th) type 1 responses in vitro (Federica Sallusto, Bellinzona,
Switzerland) (1). TLR signals were also reported to alter the
expression of Notch family ligands on DCs, up-regulating Delta-4 and
down-regulating Jagged1, a finding that confirms earlier mouse data
(2). Delta-4-expressing DCs promoted Th1 responses, whereas Jagged
promoted Th2 responses. Thus, modulation of Notch ligands on DCs may be
an important mechanism by which TLR maturational signals push Th
responses in the Th1 or Th2 direction.
Another type of microbial recognition occurs via C-type lectin
receptors (CLRs), which primarily mediate the uptake of microbial
antigens. Carl Figdor (Nijmegen, Netherlands) demonstrated that DC-SIGN
binds numerous pathogens and is organized in well-defined membrane
microdomains (3). The CLR Dectin-1, which binds ß-glycans and zymosan
from fungi, induces TNF and IL-12 production (Siamon Gordon, Oxford,
UK). These fungal products are recognized by DCs through both TLR2 and
Dectin-1, and TNF production has been shown to be dependent on the TLR
signaling adaptor MyD88. Caetano Reis e Sousa (London, UK) showed that
zymosan binding to Dectin-1 on DCs additionally induced high levels of
IL-10 and IL-2, which required Syk kinase (4). In contrast, IL-12
production was dependent on MyD88 and independent of Syk. A fine
balance between these signaling pathways in response to fungal products
such as zymosan will undoubtedly determine the outcome of an immune
response to fungi.
Mechanisms of type I IFN production in DCs
Type I interferon (IFN) is especially important for antiviral immunity.
Although various kinds of cells including macrophages, fibroblasts, or
conventional DCs can also produce type I IFN, a unique DC subset, the
plasmacytoid dendritic cells (pDCs), is the most potent type I IFN
producer.
<sniP>
****
A flurry of pubmed abstracts today..
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16029332
A study of PSORS1C1 gene polymorphisms in Chinese patients with
psoriasis.
****
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16029331
A new endogenous retroviral sequence is expressed in skin of patients
with psoriasis.
Moles JP, Tesniere A, Guilhou JJ.
Laboratoire de Dermatologie Moleculaire, Institut Universitaire de
Recherche Clinique, 641 avenue du Doyen G. Giraud, 34093 Montpellier
cedex 5, France.
Summary Background The origin of psoriasis, a chronic inflammatory skin
disease involving keratinocyte proliferation, immune disturbances and
complex inheritance, remains unknown. Human endogenous retroviruses
(HERVs) are part of the normal human genome and their participation in
the pathogenesis of various human diseases with complex genetic traits
has been proposed. A possible role of HERVs in the induction of
psoriasis was suggested many years ago. However, to date no study has
searched for HERV expression in psoriasis. Objectives To determine
firstly, which HERV families are expressed in the psoriatic lesion and
secondly, whether specific variants can be detected. Methods HERV
expression was analysed at the mRNA level after degenerated reverse
transcription-polymerase chain reaction (RT-PCR) of retroviral pol
sequences followed by sequencing. Screening for a specific variant was
performed by RT-PCR on lesional and nonlesional psoriatic skin and
compared with normal and atopic dermatitis skin. Results We report the
expression of three HERV families in psoriatic lesions, namely HERV-W,
K and E. We then partially characterized a new endogenous retroviral
variant, which was related to the ERV-9/HERV-W family. This sequence
contains at least two open reading frames that could encode for a gag
protein and a retroviral protease. The expression of this sequence was
detected in 29 of 43 lesional psoriasis skin samples and rarely in
normal (two of 21) or atopic dermatitis (three of 14) skin samples.
Conclusions In psoriatic lesions, HERV sequences of the W, K and E
families are expressed and a new variant of the ERV-9/HERV-W family has
been characterized. The possible role of HERV-related sequences in the
pathogenesis of psoriasis is under investigation.
PMID: 16029331
Good one~! The bugs in us get bugs.
Go vegetarian and eliminate a class of bugs and their bugs?
Less E coli, LPS etc..
Just a thought.
*****
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16028009
(...) For the analysis, plasma efalizumab concentration was used as
the PK measurement, the percent of predose CD11a was used as the PD
measurement, and the psoriasis area and severity index was used as the
measure of efficacy. A receptor-mediated PK/PD model was developed that
describes the dynamic interaction of efalizumab binding with CD11a. In
the efficacy model, the rate of psoriasis skin production is directly
proportional to the amount of free surface CD11a on T cells, which is
offset by the rate of skin healing. (...)
Great! A simple blood test and we know how much P you should have or
do. This
should be a good tool in the labs. Can I have one?
*****
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16029324
CDK5 regulates cell-cell and cell-matrix adhesion in human
keratinocytes.
Nakano N, Nakao A, Ishidoh K, Tsuboi R, Kominami E, Okumura K, Ogawa H.
Atopy (Allergy) Research Center, Department of Biochemistry, Juntendo
University School of Medicine, Tokyo, Japan.
Summary Background CDK5 is a member of proline-directed serine/threonin
kinases. Although its cDNA was originally cloned as a homologue to
those for the other members of the cyclin-dependent kinase (CDK)
family, CDK5 has been shown to function differently from other CDKs.
CDK5 is activated by non-cyclin partners, p35 and p39, and important
during brain development by influencing adhesion, migration and
differentiation of neurones. Objectives We sought to investigate the
expression and functions of CDK5 in human keratinocytes. Methods
Expression of CDK5/p35, interaction of CDK5/p35 with adhesion
molecules, and its roles in cell-cell and cell-matrix adhesion were
studied by reverse transcriptase-polymerase chain reaction,
immunoblotting and aggregation/adhesion assays in primary cultured
normal human keratinocytes from infant foreskins and a human
keratinocyte HaCaT cell line. Localization of CDK5 and p35 in normal
human epidermis and psoriatic epidermis was studied by
immunohistochemistry. Results Both CDK5 and p35 were expressed in
primary cultured keratinocytes, HaCaT cells and normal human epidermis.
Roscovitine, an inhibitor of CDK5, enhanced Ca(2+)-dependent
(cadherin-dependent) aggregation of HaCaT cells whereas it inhibited
adhesion of HaCaT cells to fibronectin associated with reduced active
states of beta1 integrin. Interestingly, psoriatic skin showed reduced
CDK5 and p35 expression in the lower half of the epidermis, which might
be associated with decreased amount of activated beta1 integrin in the
epidermis of psoriatic skin. Conclusions CDK5/p35 may be involved in
cell-cell and cell-matrix adhesion in human keratinocytes by
differently regulating cadherins and integrins. Furthermore, reduced
expression of CDK5/p35 in the epidermis might be involved in the
pathogenesis of psoriasis.
PMID: 16029324
(click the RA on this one. for grins)
****
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16029329
Plaque psoriasis vs. atopic dermatitis and lichen planus: a comparison
for lesional T-cell subsets, epidermal proliferation and
differentiation.
****
Lithium P different from regular P,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16026493
Who didn't susPect that? Pass the lithium... its time...oh wait ..all
that fish oil has made
me cheeryO!
randall
randall
Nanobac-teria or NANO-Nonsense from the nanobac folks
http://www.medadnews.com/News/Index.cfm?articleid=258293
(...)
Nanobacteria, or CNPs, actually consist of a core phospholipid vesicle,
surrounded by a calcium phosphate layer that binds proteins from its
surroundings. These proteins involve blood clotting proteins,
inflammation promoters and regulators and many other proteins that are
implicated in many diseases.
"Nanobacteria or calcified nano-particles are like ticking time bombs,"
stated Dr. Kajander. "The particles carry many of the known proteins
implicated in coronary artery disease and many other diseases
associated with pathological calcification or plaque. Therefore, the
particles are capable of activating multiple disease pathways. This
leads us to believe that many diseases such as kidney stones,
atherosclerosis, prostatitis, arthritis and psoriasis are local
manifestations of a systemic disease," Dr. Kajander concluded.
<sniP.>
***********
*****
Botox helps a large group of people whose quality of life is rated
lower than psoriasis sufferers?
http://www.news24.com/News24/Backpage/HotGossip/0,,2-1343-1344_1741525,00.html
******
Since the gov doesn't like it when we kill ourselves to soon, they lean
towards making
more gov and rules to protect us from ourselves.
This next one is asking them to back off.
If some funky plant in Africa (following story) has anything in it to
maybe help
with P, you want to go native on it.
What if a weed is found that has three times the efficacy of goa?
Will the gov protech the pharma's under the guise of helping us?
And take away the gooP?
So, tell them to go fly a kite.
****************
Knowledge of Health, Inc.
457 West Allen Avenue #117, San Dimas, CA 91773 Bill Sardi, President
H.R. 3156 The Dietary Supplement Access & Awareness Act
Elected representatives Susan A. Davis (CALIF), John D. Dingell (MICH)
and Henry A. Waxman (CALIF) have introduced legislation [HR 3156]
before the House of Representatives, now in committee, that would
virtually destroy the dietary supplement industry.
The legislation is identified as the "Dietary Supplement Access &
Awareness Act," but it does not address free access and only creates a
negative awareness of these products.
Previous FDA Warning Eliminated One Dietary Supplement
Here is why HR 3156 poses such a threat to the availability of dietary
supplements. Not long ago the Food & Drug Administration (FDA) issued
just a similar warning, asking physicians to report adverse reactions
associated with kava kava supplements, an anti-anxiety herbal product.
The public was also warned to report any side effects and the FDA
warning was published in newspapers and on TV news reports. Later,
published studies cleared kava kava from any suspicion, but the damage
had been done. The public backed away from kava supplements based upon
the bulletin issued by the FDA, and today kava farmers in the South
Pacific have plowed up their fields. A $25 million product was
destroyed by FDA meddling. The same destruction could result from the
passage of HR 3156.
Guilt By Assumption
This legislation was written without adequate prior evidence that
vitamin, mineral or herbal products pose a mortal or serious risk to
humans. HR 3156 requires the public and their physicians to report to
federal health authorities within 15 days of the onset of any serious
adverse reaction. This legislation assumes the industry is hiding
product hazards that have escaped normal monitoring.
Guilt By Association
Every physician who treats a patient that has had a stroke, heart
attack, or experienced sudden death, will now be obligated to report
any dietary supplements after an adverse event. This is guilt by
association.
The Dietary Supplement Information Bureau reports that six in ten
Americans (59 percent) report taking dietary supplements on a regular
basis. Subsequent reports will read there is an association between
mortal and near-mortal events and dietary supplements. But there is
little if any evidence of cause and effect.
Imagine the government commissioned a study of hit-and-run
auto-pedestrian accidents and found that 95% of children hit by cars
were wearing tennis shoes. Would we then mistakenly conclude that the
tennis shoes caused the accidents? Such non-scientific association
would likely be aired in news reports to frighten the public away from
relatively safe products.
For example, this recently occurred when researchers at Harvard Medical
School published a report showing more lutein in fatty tissues of
people who have heart attacks. The researchers publicly suggested this
was a concern that required more investigation. But lutein accumulates
in fatty tissues to protect them from turning rancid, and individuals
with more body fat will exhibit higher concentrations of lutein in
these tissues. There is simply no evidence that lutein, provided in
spinach and from marigold extracts in dietary supplements, causes heart
attacks!
Dietary Supplements Relatively Safe
For many years running the American Association of Poison Control
Centers has reported the mortality and morbidity associated with
dietary supplements to be relatively low, with no mortality associated
with multivitamins for a period of more than 8 years running. Even
though dietary supplements are safer than food (food borne infection
strikes millions annually), safer than table salt, and safer than many
over-the-counter remedies such as aspirin, onerous reporting
requirements would be mandated by HR 3156. The dietary supplement
industry has nothing to hide. These reporting requirements are
unjustified.
Mandates Scare Tactics
HR 3156 would require that millions of dollars of public money be spent
to educate the public to report alleged side effects to their
physicians. HR 3156 will likely result in labeling that will say
"Report any serious adverse reactions to your physician." Or imagine
listening to the radio and a government sponsored ad says: "If you or a
loved one experience a serious side effect such as a stroke, heart
attack, or even death) that you believe may be related to a dietary
supplement, please notify your physician." Such efforts to label
products or educate the public in this manner only serves to create
doubt in the public's mind over the relative safety of these products
and assumes serious adverse reactions are a major but unreported
problem.
Timing of Legislation Questioned
HR 3156 appears misdirected. It comes at a time when the side effects
emanating from properly prescribed and ingested prescription drugs
result in the needless death of more than 100,000 Americans annually.
Where is legislation that would adequately protect the public from
unsafe over-the-counter or prescription drugs? Relatively troublesome
drugs like Vioxx and Bextra have been returned to pharmacy shelves with
black box warnings that put the burden on consumers to check for
potential side effects.
FDA Inaction Over Unsafe Drugs Has Prompted The Search for Safer
Alternatives
Furthermore, the public has become aware the FDA has approved drugs
that have not undergone adequate safety testing, and permitted
pharmaceutical companies to advertise these very same drugs on
television, making unsubstantiated claims of their effectiveness and
safety, which resulted in the demise of thousands of Americans. This
has prompted millions of Americans to search for safer alternatives to
unsafe drugs, namely dietary supplements, to allay symptoms posed by
arthritis, headaches, menopause and other conditions.
Dietary supplements are concentrated foods, just as table salt is
concentrated sodium. Will physicians be required to report strokes
induced by patients who ingest excessive amounts of salt?
Would Patients Be in a Position to Report Serious Side Effects?
Pray tell, how would a patient experiencing a serious side effect
(death, stroke, cardiac arrest, etc.) be in a position to even
ascertain their harmful health event was related to a dietary
supplement? The average older American takes 2.4 prescription drugs in
addition to dietary supplements. Why are the dietary supplements being
fingered for reporting and not the more hazardous drugs?
Drugs and Other Agents Would Be Unreported
For example, a patient taking aspirin therapy to prevent a heart
attack, and steroids to treat arthritis, estrogen replacement therapy
for menopause, along with vitamin E, and experiences a heart attack,
would have to disclose to their doctor they were taking vitamin E
pills. Aspirin, estrogen and steroids deplete the body of vitamin C
which weakens blood vessels, induces their collapse, and can result in
blockage of a coronary artery that produces a heart attack. But the
vitamin E might be unfairly blamed for inducing this event. The patient
may also be a smoker and/or alcohol drinker, which further depletes
vitamin C and increases the risk for a heart attack. But only the
vitamin E pills would be reported to the FDA!
No Demonstration Project
Virtually all patients and their physicians would be obligated under
HR3156 to report to the FDA such adverse events, at a cost of millions
of dollars, with no demonstration project that proves threats to public
health would be eliminated or the public welfare improved.
HR 3156
Sponsor: Rep Davis, Susan A. [CA-53] (introduced 6/30/2005)
Co-Sponsors: Rep Dingell, John D. [MI-15] - 6/30/2005
Rep Waxman, Henry A. [CA-30] - 6/30/2005
To find out the status of this bill go to:
http://thomas.loc.gov/cgi-bin/query/z?c109:H.R.3156.IH:
To read the bill: http://www.ahpa.org/05_0630_HR3156.pdf
To contact your elected representative: http://www.house.gov/writerep/
Bill Sardi, Knowledge of Health, Inc, San Dimas, CA. Website:
www.knowledgeofhealth.com
http://www.google.com/search?hl=en&lr=&scoring=d&q=h.r.+3156+supplement&btnG=Search
&&&&&&&&&&
The african weed and could it help P?
In vitro 12(S)-HETE inhibitory activities of naphthoquinones isolated
from the root bark of Euclea racemosa ssp. schimperi.
Wube AA, Streit B, Gibbons S, Asres K, Bucar F.
Department of Pharmacognosy, Institute of Pharmaceutical Sciences,
Karl-Franzens University Graz, Universitaetsplatz 4/1, A-8010 Graz,
Austria.
Platelet 12-lipoxygenase is believed to play a role in cancer and other
pathological conditions, such as psoriasis, atherosclerosis and
arthritis. The inhibition of 12-LOX is a potential therapeutic approach
in the treatment of tumor metastasis. The extracts of Euclea racemosa
Murr. ssp. schimperi (A. DC.) F. White (Ebenaceae) obtained by
maceration and naphthoquinones isolated from the dichloromethane
extract have been investigated for their 12(S)-HETE inhibitory activity
using human platelets. At 100mug/ml, the dichloromethane extract
inhibited the formation of 12(S)-HETE by 88.7% and compounds
7-methyljuglone (2), isodiospyrin (3), neodiospyrin (4) and
mamegakinone (5), isolated from this extract, exhibited significant
activities with IC(50) values ranging from 4 to 58mug/ml
(22.2-155.7muM). Of these the most abundant compound, 7-methyljuglone
displayed a potent inhibitory activity with an IC(50) value of
4.18mug/ml (22.2muM), which was comparable to the positive control
baicalein with an IC(50) value of 5mug/ml (18.5muM). In contrast,
4(S)-shinanolone (1), the reduced form of compound 2, did not show any
significant inhibitory activity even at a concentration of 60mug/ml.
PMID: 16019177
Cool weed. Lets look at RA (related articles),
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Display&dopt=pubmed_pubmed&from_uid=16019177&tool=ExternalSearch
****
http://www.desert-tropicals.com/Plants/Ebenaceae/Diospyros_discolor.html
Euclea racemosa subsp. schimperi are important weeds, especially in
tsetse?barrier clearings (Ivens, East African weeds and their control,
p. 56, 1967). When natural forest or thicket is cleared they often
become dominant because of their apparently inexhaustible capacity for
coppice and root sucker production. They also appear to invade existing
pasture. Fruits are normally produced in abundance, but, although they
are eaten by birds and mammals, including squirrels and man, they do
not seem to be much sought?after, and frequently remain on the plant or
on the ground beneath it for a year or more after ripening.
http://www.illustratedgarden.org/mobot/rarebooks/page.asp?relation=QK98J311809&identifier=0223
to
http://www.illustratedgarden.org/mobot/rarebooks/plantinfo.asp?relation=QK98J311809&identifier=0223
****
Do, i think this is it?
No...But i want the choice without the nanny state having say so!
randall....
randall
Half of us have funky nails,
http://www.medicalnewstoday.com/medicalnews.php?newsid=27958
You want to clear uP naturally? Get knocked uP.
http://www.macleans.ca/topstories/health/article.jsp?content=20050725_100606_5116
July 25, 2005
Psoriasis severity eases during pregnancy
Increased levels of the female hormone estrogen may improve the skin
condition
The increased levels of the hormone estrogen that occur during
pregnancy appear to be associated with improvements in psoriasis, a
chronic skin condition.
Psoriasis affects up to three per cent of the population. The most
common form -- plaque psoriasis -- features thickened patches of red
skin covered with silvery-white scales, most commonly on the scalp,
elbows, knees, hands, feet and genitals. It is thought to be caused by
the body's own immune system attacking the skin.
In both men and women, psoriasis appears to develop more frequently or
worsen after puberty. Women have often reported their sores improve or
disappear during pregnancy, only to reappear after childbirth. Another
smaller peak is reported at menopause.
Dr. Jenny Murase, of the University of California at Irvine, and
colleagues tracked the severity of psoriasis in 47 pregnant women and
27 non-pregnant menstruating women over the course of one year.
Non-pregnant women reported no change in their psoriasis throughout the
year. In contrast, 55 per cent of the pregnant women reported an
improvement in their psoriasis, while 21 per cent reported no change
and 23 per cent reported worsening of symptoms. The greatest
improvement was reported between 10 and 20 weeks of pregnancy.
After giving birth, nine per cent of the women reported improvement, 26
per cent reported no change in symptoms and 65 per cent said their
psoriasis worsened, with the condition returning to the state it was in
at the beginning of the study.
Symptom improvement was associated with increased levels of estrogen in
the blood. Murase notes estrogen is associated with changes in the
immune system, and these changes could explain the improvement in
psoriasis symptoms
************
P and DNA, (figuring out where it all starts-hopefully)
http://www.signonsandiego.com/news/science/20050722-9999-7m22evolve.html
If this link dies, try,
http://www.medicalnewstoday.com/medicalnews.php?newsid=27844
or
http://www.rednova.com/news/health/182705/comparative_chromosome_study_finds_breakage_trends_cancer_ties/
Lets look back on Pavel Pevzner and his math buddy,
http://www.signonsandiego.com/uniontrib/20041215/news_2m15genomes.html
These guys are busy,
http://ftp.informatik.uni-trier.de/~ley/db/indices/a-tree/p/Pevzner:Pavel_A=.html
Doesn't it seem like an answered is being aPProached from all angles
now?
randall
randall
XXX wrote:
> x-no-archive: yes
>
> randall wrote:
>
> > You want to clear uP naturally? Get knocked uP.
> > http://www.macleans.ca/topstories/health/article.jsp?content=20050725_100606_5116
> >
> > July 25, 2005
> >
> > Psoriasis severity eases during pregnancy
> >
> > Increased levels of the female hormone estrogen may improve the skin
> > condition
> > The increased levels of the hormone estrogen that occur during
> > pregnancy appear to be associated with improvements in psoriasis, a
> > chronic skin condition.
>
> I don't see how they reached the conclusion that estrogen is responsible.
>
> How about the immune modulation that takes place so that the mother's
> body doesn't reject fetal tissue?
Good question. I don't know.
Lets use LPS and estrogen as keywords and try to find out.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16013043
&
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15953991
&
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15796756
&
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15748951
>
> XXXX
Dear XXXX,
Certainly looks like somethings going on here. A last tango with butter
and
endotoxins? Er, hormones and butter? No, LPS and estrogens.
So the hormones in the butter that we eat are the problem. lol
randall... and i still don't know, but feel a little closer!
randall
I'm not buying this next one. If you do, let us know how it works.
http://press.arrivenet.com/hea/article.php/674145.html
More Ayurvedic medicine from Dr. S Dhawan
All of the plants that may help out with blocking AA (arachidonic
acid). We must have posted quite a few in this group. I wonder how
many Ayurvedic plants are on this list?
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16041764
Lipoxygenase inhibitors from natural plant sources. Part 2: medicinal
plants with inhibitory activity on arachidonate 12-lipoxygenase,
15-lipoxygenase and leukotriene receptor antagonists.
Schneider I, Bucar F.
Institute of Pharmaceutical Sciences, Department of Pharmacognosy,
Karl-Franzens-University, Graz, Austria.
The metabolism of arachidonic acid can be catalysed by either one of
two enzyme families: the cyclooxygenases or the lipoxygenases. The
lipoxygenase enzymes are classed into several subcategories including
5-, 12- and 15-lipoxygenases. The 5-lipoxygenase pathway has been the
major focus of study due to the pronounced pro-inflammatory role of
leukotrienes and the approval of 5-lipoxygenase inhibitors and
leukotriene receptor antagonists for the clinical treatment of asthma.
Although less well characterized, the 12-lipoxygenase as well as the
15-lipoxygenase pathway may also play an important role in the
progression of human diseases such as cancer, psoriasis and
atherosclerosis. The present review article summarizes the findings
from an extensive literature search on plants that have been assessed
for 12- and 15-lipoxygenase inhibitory activity as well as for
leukotriene receptor antagonistic properties. The results are presented
in a tabular format, and a discussion about promising plant species and
natural compounds as well as relevant in vitro assays are included in
this article. Copyright (c) 2005 John Wiley & Sons, Ltd.
PMID: 16041764
Using goats to solve autoimmundisease.
http://www.checkbiotech.org/root/index.cfm?fuseaction=news&doc_id=10860&start=1&control=218&page_start=1&page_nr=101&pg=1
Monday, July 26, 2005
By Katharina Schoebi, Checkbiotech
People suffering from autoimmune disorders, such as rheumatoid
arthritis, psoriasis or multiple sclerosis, may be aided in the future:
Merrimack Pharmaceuticals, Inc. is developing MM-093, a recombinant
version of human á-Fetoprotein (hAFP), which is believed to have a
beneficial impact on many autoimmune disorders. The twist is that
Merrimack's strategic manufacturing partner, GTC BIOTHERAPEUTICS,
INC, is producing MM-093 in the milk of transgenic goats.
The glycoprotein called human á-Fetoprotein (AFP) is constitutively
produced at low levels throughout life. In the fetus' blood, there
are about five microgram AFP per milliliter. Since fetal AFP enters the
maternal bloodstream, pregnant women have a maximal concentration of
300 - 500 nanogram per milliliter during the third trimester of
pregnancy. It is known that during pregnancy, especially during the
last three months, several autoimmune disorders, such as multiple
sclerosis, rheumatoid arthritis and psoriasis, go into remission.
Therefore, researchers have examined AFP for its immunomodulatory
properties. The effect of AFP on rheumatoid arthritis, multiple
sclerosis, myasthenia gravis and thyroiditis has been well documented
in animal experiments and provides a rationale for testing MM-093 in
humans. However, human clinical testing requires a great deal of
properly constructed and biologically active protein. Therefore, there
is need for a production system that can cost-effectively generate
large amounts of MM-093.
Several experiments have shown, that recombinant AFP produced in
systems such as Escherichia coli, baculovirus and yeast, has
immunomodulatory properties. However, the molecule is quite large and
complicated and recovery of a sufficient yield of properly folded
protein can be problematic in certain systems - for example, E. coli.
Thus, there was a need to investigate a novel production system and
Merrimack chose to investigate the transgenic goat system with GTC
Biotherapeutics (previously Genzyme Transgenics) of Framingham,
Massachusetts.
GTC Biotherapeutics has developed the transgenic goat technology as a
cost-effective alternative for the production of complex proteins on a
large scale. The goats produce the protein of interest in their milk
- the goats are maintained on a high-tech farm using state-of-the-art
animal husbandry techniques and procedures and milked using standard
processes that would be employed on a dairy farm.
Merrimack then developed a process to purify MM-093 out of the goat
milk and performed a battery of tests to demonstrate that it was highly
comparable to human AFP (M. H. Parker et al,. 2004. Purification and
characterization of recombinant human alpha-fetoprotein expressed in
the milk of genetically modified goats. Protein Expression and
Purification. 38:177-183.)
Once the goat milk is filtered to remove milk fat and milk proteins -
essentially creating "extreme" skim milk - the purification
process is very similar to purification of proteins from any other
production system. The process involves standard chromatography-based
purification steps that remove contaminants. The development team
demonstrated that MM-093 and hAFP were virtually identical using
several analytical techniques to evaluate primary, secondary and
tertiary structure. In addition, the biological activity of MM-093
produced in transgenic goats was tested using cell binding assays and
in animal models of disease and MM093 was determined to be biological
active.
Merrimack has tested MM-093 produced in transgenic goats in Phase 1
human clinical trials and is currently testing MM-093 in a large
clinical trial of rheumatoid arthritis patients who do not receive
adequate relief from current therapies. Like most other therapeutic
proteins, MM-093 is administered to these patients by a subcutaneous
injection.
While sometimes joked about, it is important to note that it is not
possible to use goat milk or goat cheese therapeutically, as the
management of the goats, and the goat products, are strictly regulated
by multiple government agencies. The goats are handled with the utmost
care and neither the goats nor their milk will ever end up in the food
chain.
****
Genes and P. Longevity gene SirT1 may help us to live longer.
http://www.sciencedaily.com/releases/2005/07/050720065228.htm
http://www.news-medical.net/?id=11855
or
http://www.betterhumans.com/News/News/tabid/61/News/977/Default.aspx
This next gentleman, Bruce Ames is smart, (ALCAR comes from him!)
http://www.nature.com/embor/journal/v6/n1s/full/7400426.html;jsessionid=F1893FD5C09BA4816867AB0F38376993
23 worm genes to live longer some how,
http://www.news-medical.net/?id=11967
http://www.sagecrossroads.net/Default.aspx?TabID=28&newsType=ArticleView&articleId=125
Monday, July 25, 2005
Can We Catch Diseases of Aging?
By Mitch Leslie
Categories: Age-related diseases
See user comments and add yours at the bottom of the page
A controversial notion holds that Alzheimer's disease, atherosclerosis,
and other chronic illnesses result from infections. If bugs are to
blame, we might be able to combat such diseases with antibiotics and
vaccines.
(...)
Amassing definitive data that C. pneumoniae and other bugs incite
chronic scourges won't be possible, says Ewald, because the microbes
are so much harder to study than, say, the bacterium that causes strep
throat. Unlike that germ, many of the suspects in chronic disease
resist being isolated in the lab or grown in culture. Even finding the
bugs can be difficult, he says, because our methods for flushing out
furtive pathogens such as C. pneumoniae, which takes refuge inside body
cells, are limited. Moreover, some pathogens might serve as "triggers"
for the disease, says Balin. The microbes could ignite illness,
possibly by unleashing inflammation, which can progress even if the
infections later disappear.
The price of waiting for stronger evidence is high, says Ewald. Chronic
illnesses "are the most important diseases--they are killing over half
of us." So he advocates loosening the stringent standards for
establishing microbial involvement in a disease. If we tentatively
accept that viruses and bacteria are culpable, we can deploy our
anti-infection arsenal to battle the bugs. Treating everybody with
antibiotics would be counterproductive because it would trigger
resistance to the drugs. But dosing young patients with lung infections
might squelch C. pneumoniae before it infiltrates the brain and blood
vessels, says Balin.
But antibiotics aren't going to be a panacea, as a Journal of the
American Medical Association report showed earlier this year.
<sniP>
******
How long has cruiser been trying to knock out the nanobac's and ???
that cause his nail psoriasis? He's used more then a few antibiotics
under
the direction of his doctor.
I would tend to think he'd only increase his P in the long run.
Maybe that's why we haven't heard back from him since his last
set of antibiotic tests.
randall.... change the terrain and bad bugs can't live in you.
randall
NPF 2005 National Conference, Aug. 5-7. Boston Park Plaza Hotel &
Towers
http://biz.yahoo.com/prnews/050729/sff027.html?.v=15
(...)
For registration and detailed conference information, visit
www.psoriasis.org, or call toll free 800-723-9166. After Aug. 1,
registration will only be available onsite at the conference hotel.
Cost is $95 for Psoriasis Foundation members; $115 for nonmembers.
(...)
https://psoriasis.org/securezone/2005_national_conference.php
I went last year. Well worth it.
*****
Quite interesting story about the Plague. Not plaque, plague.
http://www.innovations-report.com/html/reports/studies/report-47207.html
(...)
These cells make up what immunologists call the "innate" immune system.
They are the first to respond to a bacterial invasion. Their role is to
rush to the infection site, engulf the bacteria, chew them up into
smaller pieces and present those pieces to the T and B cells -- the
"adaptive" immune system -- which enter the fray more slowly but bring
powerful and very specific weapons targeted at those individual pieces.
"This is a very clever system for this particular kind of bacteria,"
said Schneewind. It can take eight to 10 days for the B and T cells to
multiply and fully engage. "By that time, with plague," he said, "the
host is dead."
The bacteria?s Achilles heel, however, may be a protein called LcrV,
which Y. pestis transports through the needle and uses to inject its
toxins. LcrV plays two roles. It helps the needle to penetrate the
membrane surrounding the target cell. It also suppresses the immune
response. LcrV causes affected cells to release 40 times the normal
levels of interleukin 10 (IL-10), which dampens down the immune
response. LcrV also prevents secretion of tumor necrosis factor (TNF),
which causes inflammation.
"LcrV is secreted in massive amounts via the type-III pathway during an
infection," Schneewind said. "Without it, the bacteria are relatively
harmless."
Consequently, researchers have tried to use LcrV alone as a vaccine.
Unfortunately, because it suppresses the immune system, immunization
with this molecule may be harmful.
Schneewind and colleagues, however, tested 11 truncated versions of
LcrV, snipping out, from different locales, 30 of the protein?s 326
amino acids in hopes of eliminating the elements that suppressed the
immune response but retaining enough of the normal protein?s structure
to generate protective antibodies.
Out of 11 altered versions they found one that met both criteria. In
mouse and human macrophages, version rV10, missing amino acids 271
through 300, triggered only small amounts of IL-10 and had little
effect on TNF secretion. Mice immunized twice over six weeks with rV10
developed antibodies that protected them from many times the lethal
dose of the bacteria.
"Our data, the authors conclude, "provide the first evidence of plague
vaccines that do not suppress innate immune responses ? and that may be
useful for plague vaccination in animals, and, perhaps, humans." The
next steps include testing in other animal models, said Schneewind.
The two papers combined, Schneewind suggested, are a good example of
how, in this era of heightened awareness, "we can use modern tools to
learn new things about an ancient scourge, and to prepare for the
possible re-emergence of diseases we would like to forget, but better
not."
*************
P abstracts as the regular news is to thin.
Detection of IL-20 and its receptors on psoriatic skin.
Wei CC, Chen WY, Wang YC, Chen PJ, Lee JY, Wong TW, Chen WC, Wu JC,
Chen GY, Chang MS, Lin YC.
Institute of Basic Medical Sciences, Medical College, National Cheng
Kung University, Tainan, Taiwan; Department of Medical Technology,
Chung Hwa College of Medical Technology, Tainan, Taiwan.
The aim of this study was to investigate the expression of
interleukin-20 (IL-20) and its receptors on psoriatic skin by
immunohistochemical analysis and to evaluate the correlation of
CD8-positive T lymphocytes with epidermal proliferation. Overexpression
of IL-20 and its receptors was detected in the keratinocytes of the
lesional skin of psoriasis and spongiotic dermatitis. The expression
pattern of IL-20 spreads throughout the whole layer of epidermis, while
IL-19 was expressed in up to three or four layers suprabasally. The
serum level of IL-20 in psoriatic patients was significantly lower than
that in healthy controls. IL-20 upregulated KGF transcripts on
CD8-positive T cells. We hypothesize that overexpression of IL-20 is
correlated with keratinocyte proliferation that acts through their
receptor complex expressed by keratinocytes themselves. Furthermore,
IL-20 can stimulate CD8-positive lymphocytes to produce KGF, which may
contribute to sustaining the hyperproliferative status of the
keratinocytes.
PMID: 16043414
http://www.pdg.cnb.uam.es/UniPub/iHOP/gs/98974.html
Expression and regulation of murine macrophage angiopoietin-2.
Hubbard NE, Lim D, Mukutmoni M, Cai A, Erickson KL.
Department of Cell Biology and Human Anatomy, University of
California, School of Medicine, Davis, CA 95616-8643, USA.
Our understanding of angiogenesis has increased significantly in the
past few years with the discovery of angiopoietins (Ang). Specifically,
Ang2 has been associated with pathologic as well as normal
vascularization. While previous studies have shown that a major source
of Ang2 has been endothelial cells and tumor cells, we reasoned that
macrophages would also have the ability to express angiopoietins,
specifically Ang2, due to that cell's role in wound healing, tumor
angiogenesis, and a number of non-oncological diseases, such as
rheumatoid arthritis and psoriasis. In this study, murine macrophages
constitutively expressed both transcripts and protein for Ang2 but not
Ang1 or Ang3. The secretion of Ang2 was enhanced by treatment with
lipopolysaccharide, interferon-gamma, prostaglandin E(2) and other
cyclic AMP-elevating agents, as well as vascular endothelial growth
factor (VEGF). Cyclic AMP-dependent protein kinase (PKA) played a major
role in this enhancement since the PKA inhibitor, H89, blocked
secretion of Ang2. Since stimulation of the PKA pathway can lead to
macrophage production of VEGF, it is possible that enhancement of Ang2
production by macrophages may be due to autocrine responsiveness to
VEGF. Adding anti-VEGF antibodies to the supernatants of stimulated
macrophages blocked secretion of Ang2. This study is the first to show
murine macrophage production of Ang2 and to provide evidence that it
can be regulated. Understanding the regulation of macrophage Ang2
production is especially important in an effort to target the
pathologic role of macrophages while preserving their role in immunity
and homeostasis.
PMID: 16045902
Besides H89, here are a few more PK inhibitors,
http://www.proteinkinase.de/html/protein_kinase_inhibitors.html
You may even recognize one or two on this list.
http://www.pdg.cnb.uam.es/UniPub/iHOP/gs/86414.html?IN=1
A new trigger for P. Anti-TNF biologicals used on rheumatoid arthritis
patients!
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16052599
Psoriasis induced by anti-tumor necrosis factor therapy: A paradoxical
adverse reaction.
Sfikakis PP, Iliopoulos A, Elezoglou A, Kittas C, Stratigos A.
Athens University Medical School, Athens, Greece.
Administration of anti-tumor necrosis factor (anti-TNF) agents is
beneficial in a variety of chronic inflammatory conditions, including
psoriasis. We describe 5 patients in whom psoriasiform skin lesions
developed 6-9 months after the initiation of anti-TNF therapy for
longstanding, seropositive rheumatoid arthritis (etanercept or
adalimumab), typical ankylosing spondylitis (infliximab), and
Adamantiades-Behcet's disease (infliximab). In all 5 patients, the
underlying disease had responded well to anti-TNF therapy. Four
patients developed a striking pustular eruption on the palms and/or
soles accompanied by plaque-type psoriasis at other skin sites, while 1
patient developed thick erythematous scaly plaques localized to the
scalp. In 3 patients there was nail involvement with onycholysis,
yellow discoloration, and subungual keratosis. Histologic findings from
skin biopsies were consistent with psoriasis. None of these patients
had a personal or family history of psoriasis. In all patients, skin
lesions subsided either with topical treatment alone, or after
discontinuation of the responsible anti-TNF agent. The interpretation
of this paradoxical side effect of anti-TNF therapy remains unclear but
may relate to altered immunity induced by the inhibition of TNF
activity in predisposed individuals.
PMID: 16052599
P Genes
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16048752
Gene expression profiling of peripheral blood mononuclear leukocytes
from psoriasis patients identifies new immune regulatory molecules.
Koczan D, Guthke R, Thiesen HJ, Ibrahim SM, Kundt G, Krentz H, Gross G,
Kunz M.
Institute of Immunology, University of Rostock, Schillingallee 70,
18055 Rostock, Germany.
In the present report gene expression profiling of peripheral blood
mononuclear cells (PBMC) from psoriasis patients suffering from severe
generalized disease was performed comparing diseased stage with cured
stage. By this means, 18 genes were identified which showed
differential expression. The most significant differences were found
for IL-8, annexin A3, cycloxygenase-2 (COX-2), cell cycle regulator
G0S2, and pre-B cell enhancing factor (PBEF), all of which showed
upregulation in the diseased stage. Microarray data were confirmed by
real-time RT-PCR. Further analyses using support vector machines
identified three pairs of genes (IL-8 - CDKN1C/p57, cyclooxygenase-2 -
NR1D2, and desmocollin-2 - CDKN1C/p57) which allowed an accuracy of
disease stage prediction of 86%, based on gene expression patterns.
Taken together, this is the first large-scale gene expression study of
psoriasis PBMC identifying candidate genes that might contribute to
psoriasis immunopathogenesis. The genes identified in the present
report and the molecular mechanisms underlying their regulation might
serve as future targets for therapeutic intervention in psoriasis.
PMID: 16048752
randall
randall
http://biz.yahoo.com/prnews/050801/sfm110.html?.v=16
Psoriasis Foundation Launches Local Lobby Week as Senate Declares
August 2005 Psoriasis Awareness Month
Monday August 1, 8:18 pm ET
PORTLAND, Ore., Aug. 1 /PRNewswire/ -- The U.S. Senate passed a
resolution Friday, July 29, recognizing August 2005 as Psoriasis
Awareness Month -- just as the National Psoriasis Foundation prepares
to launch its first-ever Local Lobby Week.
<sniP>
Go to www.psoriasis.org and give them some money.
How's that for being aware!
http://news.bbc.co.uk/1/hi/health/4738277.stm
(...)
Red clover is used as a herbal remedy for respiratory problems,
particularly whooping cough.
It is also marketed as a treatment for chronic skin conditions such as
eczema and psoriasis. <sniP>
******
And the p news craPs out again.
Talk about awareness. So what else is out there?
http://www.sciencedaily.com/releases/2005/07/050731233846.htm
Well-known Protein Helps Stem Cells Become Secretory Cells
Johns Hopkins researchers have discovered that a single protein
regulates secretion levels in the fruit fly's salivary gland and its
skin-like outer layer.
Described in the May 15 issue of Development, the finding improves
understanding of how cells become specialized for secretion, which is a
critical ability of certain glands and cell types in organisms from
insects to humans.
The researchers discovered that a protein called CrebA single-handedly
controls the entire set of events leading to secretion in the fruit
fly's salivary gland and epidermis, its skin-like outer layer.
^^^^^^^^^
http://www.jcb.org/cgi/content/abstract/170/3/477
Response to Staphylococcus aureus requires CD36-mediated phagocytosis
triggered by the COOH-terminal cytoplasmic domain
Lynda M. Stuart1,3, Jiusheng Deng2, Jessica M. Silver2, Kazue
Takahashi1, Anita A. Tseng2, Elizabeth J. Hennessy1, R. Alan B.
Ezekowitz1, and Kathryn J. Moore2
1 Laboratory of Developmental Immunology, Department of Pediatrics
2 Lipid Metabolism Unit, Massachusetts General Hospital, Harvard
Medical School, Boston, MA 02114
3 Medical Research Council Centre for Inflammation Research, University
of Edinburgh, Edinburgh EH8 9AG, Scotland, UK
Correspondence to Kathryn J. Moore: kmo...@molbio.mgh.harvard.edu
Phagocyte recognition and clearance of bacteria play essential roles in
the host response to infection. In an on-going forward genetic screen,
we identify the Drosophila melanogaster scavenger receptor Croquemort
as a receptor for Staphylococcus aureus, implicating for the first time
the CD36 family as phagocytic receptors for bacteria. In transfection
assays, the mammalian Croquemort paralogue CD36 confers binding and
internalization of Gram-positive and, to a lesser extent, Gram-negative
bacteria. By mutational analysis, we show that internalization of S.
aureus and its component lipoteichoic acid requires the COOH-terminal
cytoplasmic portion of CD36, specifically Y463 and C464, which
activates Toll-like receptor (TLR) 2/6 signaling. Macrophages lacking
CD36 demonstrate reduced internalization of S. aureus and its component
lipoteichoic acid, accompanied by a marked defect in tumor necrosis
factor-{alpha} and IL-12 production. As a result, Cd36?/? mice fail to
efficiently clear S. aureus in vivo resulting in profound bacteraemia.
Thus, response to S. aureus requires CD36-mediated phagocytosis
triggered by the COOH-terminal cytoplasmic domain, which initiates
TLR2/6 signaling.
Abbreviations used in this paper: HEK, human embryonic kidney; LPS,
lipopolysaccharide; LTA, lipoteichoic acid; RNAi, RNA interference; SR,
scavenger receptor; TLR, Toll-like receptor.
http://www.pnas.org/cgi/content/abstract/102/7/2340
or
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15701701
Nitrolinoleic acid: an endogenous peroxisome proliferator-activated
receptor gamma ligand.
Schopfer FJ, Lin Y, Baker PR, Cui T, Garcia-Barrio M, Zhang J, Chen K,
Chen YE, Freeman BA.
Department of Anesthesiology, University of Alabama at Birmingham,
Birmingham, AL 35294, USA.
Nitroalkene derivatives of linoleic acid (nitrolinoleic acid, LNO2) are
formed via nitric oxide-dependent oxidative inflammatory reactions and
are found at concentrations of approximately 500 nM in the blood of
healthy individuals. We report that LNO2 is a potent endogenous ligand
for peroxisome proliferator-activated receptor gamma (PPARgamma; Ki
approximately 133 nM) that acts within physiological concentration
ranges. This nuclear hormone receptor (PPARgamma) regulates glucose
homeostasis, lipid metabolism, and inflammation. PPARgamma ligand
activity is specific for LNO2)and not mediated by LNO2 decay products,
NO donors, linoleic acid (LA), or oxidized LA. LNO2 is a significantly
more robust PPARgamma ligand than other reported endogenous PPARgamma
ligands, including lysophosphatidic acid (16:0 and 18:1),
15-deoxy-Delta12,14-PGJ2, conjugated LA and azelaoyl-phosphocholine.
LNO2 activation of PPARgamma via CV-1 cell luciferase reporter gene
expression analysis revealed a ligand activity that rivals or exceeds
synthetic PPARgamma agonists such as rosiglitazone and ciglitazone, is
coactivated by 9 cis-retinoic acid and is inhibited by the PPARgamma
antagonist GW9662. LNO2 induces PPARgamma-dependent macrophage CD-36
expression, adipocyte differentiation, and glucose uptake also at a
potency rivaling thiazolidinediones. These observations reveal that
NO-mediated cell signaling reactions can be transduced by fatty acid
nitration products and PPAR-dependent gene expression.
PMID: 15701701
Coming to griPs with the process,
http://www.jbc.org/cgi/content/full/277/8/5832
And more reasons to use NAC,
Pathological Roles of Advanced Glycation End Product Receptors SR-A and
CD36.
Horiuchi S, Unno Y, Usui H, Shikata K, Takaki K, Koito W, Sakamoto Y,
Nagai R, Makino K, Sasao A, Wada J, Makino H.
Department of Medical Biochemistry, Kumamoto University Graduate School
of Medical and Pharmaceutical Sciences, Honjo 1-1-1, Kumamoto 860-8556,
Japan. hori...@gpo.kumamoto-u.ac.jp.
The pathological significance of advanced glycation end product
(AGE)-modified proteins deposited in several lesions is generally
accounted for by their cellular interaction via the AGE receptors and
subsequent acceleration of the inflammatory process. In this study, we
focused on two AGE receptors-specifically, the role of SR-A in
pathogenesis of diabetic nephropathy and the role of CD36 in
AGE-induced downregulation of leptin by adipocytes. In terms of SR-A,
diabetic wild-type mice exhibited increased urinary albumin excretion,
glomerular hypertrophy, and mesangial matrix expansion, whereas
SR-A-knockout mice showed reduced glomerular size and mesangial matrix
area. In these diabetic SR-A-knockout mice, the number of macrophages
that infiltrated into glomeruli was remarkably reduced (P < 0.05),
suggesting that SR-A-dependent glomerular migration of macrophages
plays an important role in the pathogenesis of diabetic nephropathy. In
terms of CD36, incubation of glycolaldehyde-modified bovine serum
albumin (GA-BSA) with 3T3-L1 adipocytes reduced leptin secretion by
these cells. The binding of GA-BSA to these cells and subsequent
endocytic degradation were effectively inhibited by a neutralizing
anti-CD36 antibody. AGE-induced downregulation of leptin was protected
by N-acetyl-cysteine, an antioxidant. These results indicate that the
interaction of AGE ligands with 3T3-L1 adipocytes via CD36 induces
oxidative stress and leads to inhibition of leptin expression by these
cells, suggesting a potential link of this phenomenon to exacerbation
of the insulin sensitivity in metabolic syndrome.
PMID: 16037291
CD36 and FA may have further roles with long chain fatty acid
transport,
http://www.pnb.sunysb.edu/faculty/abumrad/abumrad.htm
***
Anything out there that turns uP and on LPS?
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16045757
An antimicrobial peptide tachyplesin acts as a secondary secretagogue
and amplifies lipopolysaccharide-induced hemocyte exocytosis.
Ozaki A, Ariki S, Kawabata S.
Department of Biology, Faculty of Sciences, Kyushu University, Fukuoka,
Japan.
In the horseshoe crab, bacterial lipopolysaccharide (LPS) induces
exocytosis by granular hemocytes, resulting in the secretion of various
defense molecules, such as lectins and antimicrobial peptides, via a G
protein-mediating signaling pathway. This response is a key component
of the horseshoe crab innate immune response against infectious
microorganisms. Here, we report an endogenous amplification mechanism
for LPS-induced hemocytes exocytosis. The concentration of LPS required
for maximal secretion decreased in proportion to the density of
hemocytes, suggesting the presence of a positive feedback mechanism for
secretion via a mediator secreted from hemocytes. The exocytosed fluid
of hemocytes was found able to induce hemocyte exocytosis in the
absence of LPS. Furthermore, tachyplesin, a major antimicrobial peptide
of hemocytes, was able to trigger exocytosis in an LPS-independent
manner, which was inhibited by a phospholipase C inhibitor, U-73122,
and a G protein inhibitor, pertussis toxin. Surface plasmon resonance
analysis showed that tachyplesin directly interacts with bovine G
protein. These findings suggest that the tachyplesin-induced hemocyte
exocytosis also occurs via a G protein-mediating signaling pathway. We
concluded that tachyplesin functions not only as an antimicrobial
substance, but also as a secondary secretagogue of LPS-induced hemocyte
exocytosis, leading to the amplification of the innate immune reaction
at sites of injury.
PMID: 16045757
randall... whats turning on/uP our LPS? StreP/staPh/???
randall
http://biz.yahoo.com/prnews/050803/to047.html?.v=11
Isotechnika announces interim blinded phase III psoriasis results
Wednesday August 3, 7:00 am ET
EDMONTON, Aug. 3 /PRNewswire-FirstCall/ - Isotechnika Inc. announced
today that the Canadian Phase III psoriasis trial for its lead
immunosuppressive drug, ISA247, continues to demonstrate a promising
safety and efficacy profile.
<sniP>
http://www.medadnews.com/News/Index.cfm?articleid=261643
MARKHAM, Ontario, August 03, 2005 /PRNewswire/ - Cytochroma Inc. today
announced positive results from a Phase Ib clinical study for CTA018, a
novel vitamin D analog developed for the treatment of psoriasis. The
study, involving 28 subjects with plaque psoriasis, was designed to
characterize the local and systemic safety of CTA018. Results of the
study indicate that the drug is safe and unlikely to produce adverse
reactions.
(...)
About CTA018
CTA018 is a novel vitamin D analog with a dual mechanism of action. It
is a strong activator of the vitamin D signaling pathway and also a
potent inhibitor of CYP24 activity (the enzyme responsible for the
breakdown of vitamin D). CTA018 was designed by Prof. Gary H. Posner
and is protected under patents and patent applications exclusively
licensed to Cytochroma Inc. from the Johns Hopkins University.
^^^^^^^^^^
http://webwire.com/ViewPressRel.asp?SESSIONID=&aId=3569
Psoriasis Cure Now Taking Battle for Psoriasis Research Funding to
Local Congressional Offices
Psoriasis Cure Now
8/3/2005 9:34:47 AM
KENSINGTON, Md., Aug. 3 -- With Congress in recess and Members of
Congress in their home districts, "Psoriasis Cure Now," a patient
advocacy group based in our nation's capital, is bringing its battle
for more psoriasis research funding to local Congressional offices
around the nation.
"Psoriasis patients tell me again and again that the most important
issue to them is getting more research conducted on this incurable and
challenging disease," said Michael Paranzino, president of Psoriasis
Cure Now and a psoriasis patient himself. "Psoriasis research has been
severely shortchanged for over a decade, and this needs to be
reversed."
While federal medical research funding is up 99 percent since 1995,
even after inflation, psoriasis research funding is down 8 percent.
$6.5 million, or just one dollar per patient, is invested in psoriasis
research annually, out of a total research budget of roughly $29
billion. Psoriasis Cure Now has made a briefing memo on this issue
available here on its website for constituents to deliver to their
lawmakers: http://www.psorcurenow.org/august.php . This summer, both
the House and Senate Appropriations Committees have released strong
language urging the National Institutes of Health (NIH) to step up its
research on psoriasis and psoriatic arthritis, to correct this
shortfall.
"The first words a psoriasis patient should say when entering a
Congressional office this month are 'thank you,'" Paranzino added.
"Congress has made clear to NIH its deep interest in seeing psoriasis
research expanded. But the battle is not over. Psoriasis research
remains woefully underfunded, and every Member of Congress needs to be
enlisted in this ongoing campaign to help the as many as 7.5 million
Americans who have psoriasis."
<sniP>
*******
Abstract time.
Your skin needs more Ceramides!
Role of ceramides in barrier function of healthy and diseased skin.
Choi MJ, Maibach HI.
Department of Dermatology, School of Medicine, University of
California, San Francisco, California, USACharmzone Research and
Development Center, Won-Ju, Kangwon-do, Korea.
Stratum corneum intercellular lipids play an important role in the
regulation of skin water barrier homeostasis and water-holding
capacity. Modification of intercellular lipid organization and
composition may impair these properties. Patients with skin diseases
such as atopic dermatitis, psoriasis, contact dermatitis, and some
genetic disorders have diminished skin barrier function. Lipid
composition in diseased skin is characterized by decreased levels of
ceramide and altered ceramide profiles. To clarify mechanisms
underlying ceramides as a causative factor of skin disease,
investigators have examined the activity of enzymes in the stratum
corneum on ceramide production and degradation. The activities of
ceramidase, sphingomyelin deacylase, and glucosylceramide deacylase are
increased in epidermal atopic dermatitis. Investigators have also
compared the expression levels of sphingolipid activator protein in the
epidermis of normal and diseased skin. A decreased level of prosaposin
has been identified in both atopic dermatitis and psoriasis. These
results indicate that decreased ceramide level is a major etiologic
factor in skin diseases. Hence, topical skin lipid supplementation may
provide opportunities for controlling ceramide deficiency and improving
skin condition.
PMID: 16060709
Looks like you really need prosaposin. Or your dead.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15944902
Maybe we have a slight defect in the lipid storage prosaposin gene
also.
Another quirk with the stereo fat?
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12432924
(...) The human 12R-LOX product, 12R-HETE, appears to be involved in
the pathophysiology of psoriasis and other proliferative skin
diseases;<sniP>
Does it go back to NO?
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15679111
Nitric oxide regulates synthesis of gene products involved in
keratinocyte differentiation and ceramide metabolism.
Gallala H, Macheleidt O, Doering T, Schreiner V, Sandhoff K.
Kekule Institut fur Organische Chemie und Biochemie der Universitat
Bonn, Bonn, Germany.
During terminal differentiation of keratinocytes the expression of
various proteins, which are required for the formation of the epidermal
water barrier in the skin of land dwelling animals, is upregulated.
Using a cell culture model for the differentiation of human
keratinocytes and real-time PCR, we quantified the mRNA levels of
several proteins involved in differentiation and ceramide metabolism. A
calcium shift (1.1 mM CaCl2, 10 microM linoleic acid) for 8 days
triggered an increase in mRNA levels of keratin 10 (75-fold),
profilaggrin (55-fold), glucosylceramide synthase (40-fold),
beta-glucocerebrosidase (30-fold), prosaposin (15-fold), acid
sphingomyelinase (5-fold), and serine palmitoyltransferase (SPTLC2,
4-fold). However, mRNA levels of keratin 14 and acid ceramidase did not
change significantly. On the other hand nitric oxide added at
concentrations lower than 0.25mM stimulates proliferation of
keratinocytes (Krischel et al., J. Invest. Dermatol. 111, 286-291,
1998). Accordingly, the NO donor S-nitroso-N-acetyl-D,L-penicillamine
(SNAP, 0.2 mM) had no effect on the morphology of cultured
keratinocytes, whereas in cultured human fibroblasts apoptosis was
induced. The expression patterns obtained suggest that keratinocytes
remain in a basal proliferative state, with a 3-fold increase in
keratin 14 expression, a marked decrease in mRNA levels of
differentiation markers and of most ceramide-metabolizing enzymes to
negligible levels. The inhibitor of the NO synthase,
N(G)-nitro-L-arginine-methyl ester (L-NAME, 10 mM), induced a transient
increase in ceramide formation, followed by apoptosis in keratinocytes
but not in fibroblasts. Both, SNAP and L-NAME, decreased the mRNA
levels of all proteins involved in ceramide metabolism.
PMID: 15679111
We know arginine feeds the flare.
Yet it participates in compounds that are suPPose to inhibit
keratinocytes.
It's to much for me.
Unless it's a NO, prosaposin, ceramide, arginine, iNOS, eNOS, LPS,
12R-Hete thingy with a few funky genes lurking in the background.
Nah!
randall
randall
Severe Psoriatic goes on the LAM with Rush Limbaugh (Hill-Billy heroin)
drug Oxycontin.
http://www.rutlandherald.com/apps/pbcs.dll/article?AID=/20050806/NEWS/508060373/1002/NEWS01
(...)
"We've got people selling it on the street," Humphries said. "If you
can't get heroin, it's a good substitute."
Heck was described as 6 feet 1 inch tall, weighing 200 pounds with
brown eyes, black hair and a severe case of psoriasis.
<sniP>
*****
P call home!
http://southyorks.police.uk/news/details.php?id=1394
(...)
Steven attended Cambridge University. He is described as a white male,
6ft 2ins tall, slim build with mousey hair and blue eyes. He suffers
from asthma and psoriasis but was otherwise a healthy young man. <sniP>
****
So much for the tabloid P news.
Lets move on,
http://www.dddmag.com/ShowPR.aspx?PUBCODE=016&ACCT=1600000100&ISSUE=0508&RELTYPE=BIO&PRODCODE=00000000&PRODLETT=M
Cellular Imaging Widens View of Signal Transduction
******
Lets move backwards in time.
On 8/3/2005 I said:
http://groups-beta.google.com/group/alt.support.skin-diseases.psoriasis/browse_frm/thread/fd94fd93bd8e5ab3/69924a72cccc1910#69924a72cccc1910
Having had posted this on the same day.
So, i guess the quest is to link LPS with the P skin.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Display&dopt=pubmed_pubmed&from_uid 002999&tool=ExternalSearch
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt«stract&list_uids 823548
Acylation of lysophosphatidylcholine plays a key role in the response
of monocytes to lipopolysaccharide.
Schmid B, Finnen MJ, Harwood JL, Jackson SK.
School of Biosciences, Cardiff University, UK.
Mononuclear phagocytes play a pivotal role in the progression of septic
shock by producing tumor necrosis factor-alpha (TNF-alpha) and other
inflammatory mediators in response to lipopolysaccharide (LPS) from
Gram-negative bacteria. Our previous studies have shown monocyte and
macrophage activation correlate with changes in membrane phospholipid
composition, mediated by acyltransferases. Interferon-gamma
(IFN-gamma), which activates and primes these cells for enhanced
inflammatory responses to LPS, was found to selectively activate
lysophosphatidylcholine acyltransferase (LPCAT) (P < 0.05) but not
lysophosphatidic acid acyltransferase (LPAAT) activity. When used to
prime the human monocytic cell line MonoMac 6, the production of
TNF-alpha and interleukin-6 (IL-6) was approximately five times greater
in cells primed with IFN-gamma than unprimed cells. Two LPCAT
inhibitors SK&F 98625 (diethyl
7-(3,4,5-triphenyl-2-oxo2,3-dihydro-imidazole-1-yl)heptane phosphonate)
and YM 50201 (3-hydroxyethyl 5,3'-thiophenyl pyridine) strongly
inhibited (up to 90%) TNF-alpha and IL-6 production in response to LPS
in both unprimed MonoMac-6 cells and in cells primed with IFN-gamma. In
similar experiments, these inhibitors also substantially decreased the
response of both primed and unprimed peripheral blood mononuclear cells
to LPS. Sequence-based amplification methods showed that SK&F 98625
inhibited TNF-alpha production by decreasing TNF-alpha mRNA levels in
MonoMac-6 cells. Taken together, the data from these studies suggest
that LPCAT is a key enzyme in both the pathways of activation (priming)
and the inflammatory response to LPS in monocytes.
PMID: 12823548
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt«stract&list_uids 570723
Unfolding the pathophysiological role of bioactive lysophospholipids.
Xu Y, Xiao YJ, Zhu K, Baudhuin LM, Lu J, Hong G, Kim KS, Cristina KL,
Song L, S Williams F, Elson P, Markman M, Belinson J.
Department of Cancer Biology, The Lerner Research Institute, Cleveland
Clinic Foundation, 9500 Euclid Avenue, OH 44195, USA. x...@ccf.org
Lysophospholipids (LPLs), including glycerol- and sphingoid-based
lipids, stimulate cell signaling and play important pathophysiological
roles in humans and other animals. These LPLs include lysophosphatidic
acid (LPA), lysophosphatidylinositol (LPI), lysophosphatidylcholine
(LPC), lysophosphatidylserine (LPS), sphingosine-1-phosphate (S1P), and
sphingosylphosphorylcholine (SPC). Analyses of LPLs in human body
fluids from subjects with different pathophysiological conditions
reveal not only the relevance of LPLs in human diseases, but also their
potential application as biomarkers and/or therapeutic targets. In
recent years, the identification and/or characterization of the plasma
membrane receptors for LPLs and enzymes regulating the metabolism of
LPLs have greatly facilitated our understanding of their role and
signaling properties. In vitro and in vivo functional and signaling
studies have revealed the broad and potent biological effects of LPLs
and the mechanisms of LPL actions in different cellular systems.
Development of specific antagonists for each of the LPL receptors will
provide powerful tools for dissecting signaling pathways mediated by
receptor subtypes. More importantly, these antagonists may serve as
therapeutics for relevant diseases. Genetic depletion of LPL receptors
in mice has provided and will continue to provide critical information
on the pathophysiological roles of LPL receptors. It is important to
further evaluate the significance of targeting these bioactive LPL
receptors, their downstream signaling molecules, and/or metabolic
enzymes in the treatment of cancers and other diseases.
PMID: 12570723
A new understanding of triggers and pathways?
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt«stract&list_uids 014326
Proton-sensing and lysolipid-sensitive G-protein-coupled receptors: A
novel type of multi-functional receptors.
Tomura H, Mogi C, Sato K, Okajima F.
Laboratory of Signal Transduction, Institute for Molecular and Cellular
Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi 371-8512,
Japan.
OGR1, GPR4, G2A, and TDAG8 share 40% to 50% homology with each other
and seem to form a family of GPCRs. They have been described as
receptors for lipid molecules such as sphingosylphosphorylcholine,
lysophosphatidylcholine, and psychosine. Recent studies, however, have
revealed that these receptors also sense extracellular protons or pH
through histidine residues of receptors and stimulate a variety of
intracellular signaling pathways through several species of
hetero-trimeric G-proteins, including G(s), G(i), G(q), and G(12/13).
Thus, this family of GPCR seems to recognize both lipid molecules and
protons as ligands. Although our knowledge of proton-sensing and
lysolipid-sensitive GPCRs is preliminary, the receptor levels and
ligand levels especially protons are both sensitively modulated in
response to a variety of microenvironmental changes. These results
suggest a multiple role of proton-sensing GPCRs in a variety of
physiological and pathophysiological states.
PMID: 16014326
Lysophosphatidylcholine (LPC) are involved in the pathogenesis of
inflammatory diseases.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt«stract&list_uids 043165
The phosphatidylcholine/lysophosphatidylcholine ratio in human plasma
is an indicator of the severity of rheumatoid arthritis: Investigations
by (31)P NMR and MALDI-TOF MS.
Fuchs B, Schiller J, Wagner U, Hantzschel H, Arnold K.
Institute of Medical Physics and Biophysics, Medical Department,
University of Leipzig, Hartelstr. 16/18, D-04107 Leipzig, Germany.
OBJECTIVES:: Lipid second messengers, e.g. lysophosphatidylcholines
(LPC) are involved in the pathogenesis of inflammatory diseases, for
instance, rheumatoid arthritis (RA). Unfortunately, the analysis of LPC
in complex mixtures as present in body fluids is still challenging.
DESIGN AND METHODS:: Matrix-assisted laser desorption and ionization
time-of-flight mass spectrometry (MALDI-TOF MS) was applied for
phospholipid (PL) analysis of organic extracts of synovial fluids from
patients with RA as well as the corresponding plasma. These data were
compared with results obtained by high resolution (31)P NMR
spectroscopy. RESULTS:: Synovial fluids may be replaced by plasma since
the analysis of both body fluids gives very similar results. Patients
undergoing treatment with TNF-alpha inhibitors (ADALIMUMAB (HUMIRA(R)))
were examined in order to investigate whether the
clinically-significant attenuation of disease activity is accompanied
by changes of the PL composition of plasma. It will be shown that
especially the PC/LPC ratios of plasma represent a reliable measure of
inflammation and increase upon therapy. CONCLUSIONS:: Since plasma
samples are readily available, our approach might be useful to draw
conclusions before puncture of the affected joints is necessary and the
PC/LPC ratio detected in plasma may serve as an indicator of RA in
early stages.
PMID: 16043165
This next one is shocking,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt«stract&list_uids 144218
Iso[7]LGD2-protein adducts are abundant in vivo and free
radical-induced oxidation of an arachidonyl phospholipid generates this
D series isolevuglandin in vitro.
Poliakov E, Meer SG, Roy SC, Mesaros C, Salomon RG.
Department of Chemistry, Case Western Reserve University, Cleveland,
Ohio 44106-7078, USA.
Isolevuglandins (isoLGs) are a family of gamma-ketoaldehydes, aka
isoketals or neuroketals, that are generated by free radical-induced
oxidation of polyunsaturated fatty acid-containing lipids. Because of
their high reactivity toward epsilon-amino groups of lysyl residues,
isoLGs are found as protein adducts in vivo. Plasma levels of
isoLG-derived protein modifications are orders of magnitude higher than
levels of the corresponding isoprostane. This suggests that while
isoprostanes are rapidly cleared from the circulation, isoLG-protein
adducts accumulate over the lifetime of the protein, which can be
weeks, and this may provide a dosimeter for oxidant stress. We now
confirm the postulated formation of the first D series isoLG,
iso[7]LGD(2), by free radical-induced oxidation of
1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphocholine in vitro. We also
show that iso[7]LGD(2)-protein adduct levels in blood are the highest
known for an isoLG-derived epitope. They average 30-fold higher than
isoLGE(2)-protein and 3-fold higher than iso[4]LGE(2)-protein levels.
Similarly, iso[7]LGD(2)-derived epitope levels in oxidized low density
lipoprotein are 20 times higher than isoLGE(2)-protein and five times
higher than iso[4]LGE(2)-protein levels. Previous studies showed that
plasma levels of protein-bound E series isoLGs, i.e., isoLGE(2) and
iso[4]LGE(2), are elevated in individuals with atherosclerosis as
compared with age-matched controls. Plasma iso[7]LGD(2)-protein
immunoreactivity in individuals with atherosclerosis averages 8.5 +/-
3.1 nmol/mL, significantly higher (P = 0.01) than the 3.5 +/- 0.1
nmol/mL in healthy controls. Plasma levels of iso[7]LGD(2)-protein
adducts are strongly correlated with iso[4]LGE(2)- (r = 0.933) and
isoLGE(2)-protein adducts (r = 0.877). This supports the hypothesis
that isoLGs are generated in vivo by parallel competing radical-induced
pathways.
PMID: 15144218
And these isoLGs are involved in more serious things as well,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt«stract&list_uids 037255
Ceramides and LPS in your brain cells,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15800925
I'm lost, i need to go back already and try to figure out whats posted.
Was this what i wanted?
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14764599
Hyaluronan fragments stimulate endothelial recognition of injury
through TLR4.
Taylor KR, Trowbridge JM, Rudisill JA, Termeer CC, Simon JC, Gallo RL.
Department of Dermatology, University of California, San Diego and
Veterans Affairs Medical Center, San Diego, California 92161, USA.
Tissues must quickly recognize injury to respond to the rapid pace of
microbial growth. In skin, dermal microvascular endothelial cells must
also react to danger signals from the surrounding tissue and
immediately participate by initiating the wound repair process.
Components of the extracellular matrix such as hyaluronan are rapidly
broken down into smaller molecular weight oligosaccharides in a wound,
and these can activate a variety of biological processes. This study
set out to determine if hyaluronan fragments released following injury
can stimulate endothelial cells and what mechanism is responsible for
this response. Using genechip microarray analysis, a response to
hyaluronan fragments was detected in endothelial cells with the most
significant increase observed for the chemokine IL-8. This observation
was verified with qualitative reverse transcriptase-PCR and ELISA in
human endothelial cell culture, and in a mouse model by observing serum
levels of MIP-2 and KC following hyaluronan fragment administration in
vivo. Activation was TLR4-dependent, as shown by use of TLR4 blocking
antibody and TLR4-deficient mice, but not due to the presence of
undetected contaminants as shown by inactivation following digestion
with the hyaluronan-degrading enzyme chondroitinase ABC or incubation
with the hyaluronan-specific blocking peptide Pep-1. Inactivation of
LPS activity failed to diminish the action of hyaluronan fragments.
These observations suggest that endogenous components of the
extracellular matrix can stimulate endothelia to trigger recognition of
injury in the initial stages of the wound defense and repair response.
PMID: 14764599
That will take even more glial work.
randall.. one again. Not a HAppy gliass
hamza...@gmail.com
Many people with acne find it cosmetically disfiguring and use cosmetics and dekkremer. This application can itself provoke pimples. Cosmetics Acne is a separate diagnosis, due acne provoked by the use of cosmetics. There have been numerous studies on acne and food intake. This was summarized in a recent review article. There is no evidence that chocolate, fat intake or salt causes pimple problems. The American Association for dermatologists have found that there is evidence to recommend the few changes in diet for those with acne. There is some evidence that the risk of acne can be somewhat increased in those who drink a lot of milk. There are however no evidence that by quitting drinking milk one's acne problems be "cured". This is unlikely and can not be recommended. Medications like steroids, lithium and certain epilepsy medications can also cause acne. You do not get pimples poor hygiene !
See more at:-> http://cosmedica.no/a-g-artikler-akne.html
http://cosmedica.no/
sundayval...@gmail.com
RHgam because i or the fetus had negative conflicting blood types and that was supposed to help with preventing that in future pregnancies. Its now February 2016 and about a month or two ago i started getting a red spotted rash on body then on scalp. I looked up every possible thing and so far i've come up with guttate psorosis or rosacea psorosis. It just happened out of nowhere. I Thought it might be hair dye, only other thingi thought of was to much of a vitamin. I was taking biotin, vitamin B and c and probiotics. Also i wandered about flea bites aswell. I was curious if the shot i received could have caused a reaction? Isn't it essentially a human plasma? And does it have anything to do with strep? I really appreciate your time, i know this is long but i don't want this psorosis to get worse and I'm worried that there isn't enough info to trust medications. I've taken notes on your remidies and ideas they have been very helpful. Your opinion or feedback Would be greatly appreciated. Thank you