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P NEWs 2007

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randall

unread,

Jan 2, 2007, 2:16:22 PM1/2/07

Hi,

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17197238&query_hl=1&itool=pubmed_docsum
The pathogenic role of tissue-resident immune cells in psoriasis.

* Boyman O,
* Conrad C,
* Tonel G,
* Gilliet M,
* Nestle FO.

Division of Immunology and Allergy, University Hospital of Lausanne
(CHUV), CH-1011 Lausanne, Switzerland.

Psoriasis is a common chronic inflammatory skin disease, the study of
which might also be of considerable value to the understanding of other
inflammatory and autoimmune-type diseases, such as rheumatoid
arthritis, inflammatory bowel disease, multiple sclerosis and diabetes
mellitus. There is clear evidence that T cells and dendritic cells have
a central role in psoriasis. Based on recent data from humans and
animal models, we propose that a psoriasis lesion can be triggered and
sustained by the local network of skin-resident immune cells. This
concept focuses attention on local, rather than systemic, components of
the immune system for rationalized therapeutic approaches of psoriasis
and possibly also other chronic inflammatory diseases.

PMID: 17197238

Geez, we look at all the IMIDs around this neck of the woods. We
already know the amount of
money spent to cure P is way behind more serious and deadly conditions.

So, we take the clues with the P blues. Big deal! Yet we are informed.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17198155&query_hl=1&itool=pubmed_docsum
New heartbreak from psoriasis.

[No authors listed]

PMID: 17198155

---------------------

This abstract above came from a nurse study of some sort.

----------------------------------

Here's a term thats never been seen before in this group.

MePrin!

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17195012&query_hl=1&itool=pubmed_docsum
The alpha and beta Subunits of the Metalloprotease Meprin Are Expressed
in Separate Layers of Human Epidermis, Revealing Different Functions in
Keratinocyte Proliferation and Differentiation.

* Becker-Pauly C,
* Howel M,
* Walker T,
* Vlad A,
* Aufenvenne K,
* Oji V,
* Lottaz D,
* Sterchi EE,
* Debela M,
* Magdolen V,
* Traupe H,
* Stocker W.

1Institute of Zoology, Johannes Gutenberg University, Johannes von
Muller-Weg 6, Mainz, Germany.

The zinc endopeptidase meprin (EC 3.4.24.18) is expressed in brush
border membranes of intestine and kidney tubules, intestinal
leukocytes, and certain cancer cells, suggesting a role in epithelial
differentiation and cell migration. Here we show by RT-PCR and
immunoblotting that meprin is also expressed in human skin. As
visualized by immunohistochemistry, the two meprin subunits are
localized in separate cell layers of the human epidermis. Meprin alpha
is expressed in the stratum basale, whereas meprin beta is found in
cells of the stratum granulosum just beneath the stratum corneum. In
hyperproliferative epidermis such as in psoriasis vulgaris, meprin
alpha showed a marked shift of expression from the basal to the
uppermost layers of the epidermis. The expression patterns suggest
distinct functions for the two subunits in skin. This assumption is
supported by diverse effects of recombinant meprin alpha and beta on
human adult low-calcium high-temperature keratinocytes. Here, beta
induced a dramatic change in cell morphology and reduced the cell
number, indicating a function in terminal differentiation, whereas
meprin alpha did not affect cell viability, and may play a role in
basal keratinocyte proliferation.Journal of Investigative Dermatology
advance online publication, 28 December 2006;
doi:10.1038/sj.jid.5700675.

PMID: 17195012

I'll do a short study of meprin tomorrow.

---------------------

Are gut hookworms the low tech way to tune down the immune system?

http://www.medicalnewstoday.com/medicalnews.php?newsid=58994&nfid=nl

Do hookworms turn up tregs? (T regulatory cells like IL-10)

Sort of like a gut worm vaccination? I'd do it for clear skin I
suppose.

I'll have to get in to the mood by watching that Eating Fried worms
movie.

Is it out in dvd now?

---------------

If the skin isn't the site of P initiation then the thymus is running a
close second.

Nailing the exact mechanism would be nice.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17190001&query_hl=7&itool=pubmed_docsum
Early events in the thymus affect the balance of effector and
regulatory T cells. (T-regs)

* Pennington DJ,
* Silva-Santos B,
* Silberzahn T,
* Escorcio-Correia M,
* Woodward MJ,
* Roberts SJ,
* Smith AL,
* Dyson PJ,
* Hayday AC.

Peter Gorer Department of Immunobiology, King's College London School
of Medicine, Guy's Hospital, London SE1 9RT, UK.
d.penn...@qmul.ac.uk

In cellular immunology the critical balance between effector and
regulatory mechanisms is highlighted by serious immunopathologies
attributable to mutations in Foxp3, a transcription factor required for
a major subset of regulatory T (Tr) cells. Thus, many studies have
focused on the developmental origin of Tr cells, with the prevailing
view that they emerge in the thymus from late-stage T-cell progenitors
whose T-cell receptors (TCRs) engage high affinity (agonist) ligands.
This study questions the completeness of that interpretation. Here we
show that without any obvious effect on TCR-mediated selection, the
normal differentiation of mouse gammabeta T cells into potent cytolytic
and interferon-gamma-secreting effector cells is switched towards an
aggregate regulatory phenotype by limiting the capacity of CD4+CD8+
T-cell progenitors to influence in trans early gammabeta cell
progenitors. Unexpectedly, we found that the propensity of early
TCR-alphabeta+ progenitors to differentiate into Foxp3+ Tr cells is
also regulated in trans by CD4+CD8+ T-cell progenitor cells, before
agonist selection.

PMID: 17190001

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17185041&query_hl=7&itool=pubmed_docsum
Transient regulatory T-cells: A state attained by all activated human
T-cells.

* Pillai V,
* Ortega SB,
* Wang CK,
* Karandikar NJ.

Department of Pathology, The University of Texas Southwestern Medical
Center, 6000 Harry Hines Blvd., Dallas, TX 75390-9072, USA.

CD4(+)CD25(+)FOXP3(+) regulatory T-cells (T(regs)) form an important
arm of the immune system responsible for suppressing untoward immune
responses. T(regs) can be thymically derived or peripherally induced,
even from CD4(+)CD25(-)FOXP3(-) T-cells. FOXP3 expression and in vitro
suppressive activity are considered unique hallmarks of this dedicated
and stable lineage of regulatory cells. Here we show that virtually all
human CD4(+)CD25(-)FOXP3(-) T-cells and CD8(+)CD25(-)FOXP3(-) T-cells
attain a transient FOXP3(+)CD25(+) state during activation. In this
state of activation, these cells possess the classic phenotype of
T(regs), in that they express similar markers and inhibit in vitro
proliferation of autologous CD4(+)CD25(-) T-cells. This state is
characterized by suppressed IFN-gamma production and robust TNF-alpha
and IL-10 production. Interestingly, the great majority of the
activated cells eventually downregulate FOXP3 expression, with a
concomitant drop in suppressive ability. Our results show that, in
humans, FOXP3 expression and T(reg) functionality are not exclusive
features of a stable or unique lineage of T-cells but may also be a
transient state attained by almost all T-cells. These results warrant
caution in interpreting human studies using FOXP3 and suppressive
activity as readouts and suggest that attempts to induce "T(regs)" may
paradoxically result in induction of effector T-cells, unless stability
is confirmed.

PMID: 17185041

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17183612&query_hl=7&itool=pubmed_docsum
FOXP3: Not just for regulatory T cells anymore.

* Ziegler SF.

Immunology Program, Benaroya Research Institute, Seattle WA 98101 USA.
The forkhead family transcription factor FOXP3 has been shown to be
critical for the development and function of CD4(+)CD25(+) regulatory T
cells. Recently, FOXP3 expression has been shown to be induced upon
activation of human CD4(+) T cells. A new report in this issue of the
European Journal of Immunology shows that expression of FOXP3 in
activated T cell leads to hyporesponsiveness, but not necessarily to
acquisition of suppressor function. This finding suggests a new role
for FOXP3 in human CD4(+) T cells: down-modulating responses to
TCR-mediated stimulation.See accompanying article
http://dx.doi.org/10.1002/eji.200636435.

PMID: 17183612

This forkhead gene is a big one for P! Damn broken forked uP forkhead
thingy.

OK, mini rant over. Feel good. Get on UP! Like a DEX machine. <w>

--------------

Can Th1 conditions like psoriasis and Th2 cancer diseases both,
at some junction uPstream in the immune system, be stoPPed?

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17185984&query_hl=1&itool=pubmed_docsum
A Human mAb Specific to Oncofetal Fibronectin Selectively Targets
Chronic Skin Inflammation in vivo.

* Trachsel E,
* Kaspar M,
* Bootz F,
* Detmar M,
* Neri D.

1Department of Chemistry and Applied Biosciences, Institute of
Pharmaceutical Sciences, ETH Zurich, Zurich, Switzerland.

The antibody-based targeted delivery of bioactive agents to sites of
angiogenesis is an attractive therapeutic strategy for cancer
treatment, but is largely unexplored for chronic inflammatory diseases.
In this article, we show that the extra domain B (EDB) domain of
fibronectin, a marker of angiogenesis, is expressed in psoriatic
lesions, and that the anti-EDB human antibody L19 can selectively
localize to chronically inflamed skin in vivo. The L19-based delivery
of the cytokines IL10 and IL12 did not improve or worsen inflammation
in a mouse model of chronic skin inflammation, which overexpressed
vascular endothelial growth factor under the control of the keratin-14
promoter. By contrast, the L19-based targeted delivery of the
proinflammatory cytokine IL2 or of the photosensitizer Sn(IV) chlorin
e6 resulted in an increased swelling and reddening of inflamed skin.
These results indicate that antibodies specific to components of the
modified extracellular matrix can selectively accumulate at chronically
inflamed sites in vivo. This observation now stimulates the search for
bioactive molecules which can be fused to antibodies and which may
confer a therapeutic benefit as a result of their preferential
accumulation in psoriatic lesions and other sites of
inflammation.Journal of Investigative Dermatology advance online
publication, 21 December 2006; doi:10.1038/sj.jid.5700653.

PMID: 17185984

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=15304094&query_hl=5&itool=pubmed_docsum
Proliferating keratinocytes are putative sources of the psoriasis
susceptibility-related EDA+ (extra domain A of fibronectin) oncofetal
fibronectin.

* Szell M,
* Bata-Csorgo Z,
* Koreck A,
* Pivarcsi A,
* Polyanka H,
* Szeg C,
* Gaal M,
* Dobozy A,
* Kemeny L.

Dermatological Research Group of the Hungarian Academy of Sciences and
the University of Szeged, 6720 Szeged, Koranyi fasor 6, Hungary.
sz...@derma.szote.u-szeged-hu

The extra domain A of fibronectin (EDA+ oncofetal isoform of
fibronectin was recently reported to be overexpressed in psoriatic
uninvolved epidermis. It has been proposed that the abnormal presence
of EDA+ oncofetal protein at the dermal-epidermal junction in the
uninvolved skin may provide the "psoriatic" environment in which
keratinocytes are in a preactivated state with regard to mitogenic
signals (e.g., T cell lymphokines). To determine the possible sources
of cellular fibronectin in the non-lesional psoriatic skin, we aimed to
investigate whether keratinocytes could produce the EDA+ oncofetal form
of fibronectin. RT-PCR studies revealed that both cultured normal
keratinocytes and HaCaT cells express the EDA+ splice variant of
fibronectin mRNA, and in HaCaT cells the EDA+/EDA- transcript ratio was
elevated compared with normal keratinocytes. Cultured keratinocytes and
HaCaT cells showed intracytoplasmic staining with an EDA+
fibronectin-specific antibody and among the positively stained cells
many showed mitosis. Using RT-PCR, western blot analysis, and flow
cytometry, we showed that in synchronized HaCaT cells the amount of
both total fibronectin and its EDA+ isoform change with the
proliferation/differentiation state of HaCaT cells and peak in highly
proliferating cells. We show that in short-term ex vivo cultures, a
small population of EDA+ fibronectin containing cell population appear
among psoriatic uninvolved, but not normal epidermal cells. We also
demonstrate that cell attachment has a strong influence on the
expression of both total and EDA+ fibronectin. Our results suggest that
proliferating keratinocytes could be the sources of the psoriasis
susceptibility-related EDA+ oncofetal fibronectin in the epidermis.
PMID: 15304094

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=10733677&query_hl=5&itool=pubmed_docsum
Overexpression of the oncofetal Fn variant containing the EDA splice-in
segment in the dermal-epidermal junction of psoriatic uninvolved skin.

* Ting KM,
* Rothaupt D,
* McCormick TS,
* Hammerberg C,
* Chen G,
* Gilliam AC,
* Stevens S,
* Culp L,
* Cooper KD.

Departments of Dermatology and Microbiology and Molecular Biology, Case
Western Reserve University, University Hospitals of Cleveland,
Cleveland, Ohio 44106-5028, USA.

The extracellular matrix protein, Fn, has critical functions in cell
attachment, migration, differentiation, and proliferation. We have
previously shown that fibronectin (Fn) is abnormally expressed and
potentiates entry into the cell cycle of basal keratinocytes in
uninvolved psoriatic skin, in combination with T cell lymphokines. It
is not known what type of Fn is present in psoriatic skin, however, and
how this Fn may regulate signaling. Embryonic forms of cellular Fn
containing extra domains, designated EDA and EDB, are generated by
alternative splicing and are seen in proliferating, developing tissue
and in wound healing. Because the EDA segment enhances the integrin
binding sequence Arg, Gly, Asp (RGD), which, when present, has been
shown to be critical in integrin-extracellular matrix signaling, we
were particularly interested in determining whether or not
EDA-containing Fn (EDA+Fn) represented the aberrantly expressed Fn in
psoriasis. Increased EDA+ Fn protein was demonstrated by immunostaining
at the dermal-epidermal junction in clinically uninvolved skin from six
of six patients with psoriasis, but not in skin from control subjects.
Using reverse transcription polymerase chain reaction an increased
ratio of EDA+ Fn versus EDA- Fn mRNA was present in epidermal samples
from psoriatic but not control individuals. Interestingly, the EDA+Fn
in the psoriatic epidermis had the IIICS region spliced out (EDA+,
FDB-, IIICS-, III9+), which was shared with normal epidermis (EDA-,
EDB-, IIICS-, III9+). These results suggest a selective predominance of
the EDA+ Fn isoform at the dermal-epidermal junction of psoriatic skin.
The consistent aberrant localization of EDA+ Fn at the dermal-epidermal
junction in uninvolved skin of psoriatics may confer the
hyperresponsiveness of psoriatic uninvolved basal keratinocytes for
rapid cellular proliferation in response to T cell signals.

Key words: immunohistochemistry/integrin/keratinocyte/RT-PCR.

PMID: 10733677

We need to do the matrix and fibro? Sure,
http://www.med.unibs.it/~marchesi/extracellularmatrix.html

http://www.ks.uiuc.edu/Research/fibronectin/

http://www.callutheran.edu/Academic_Programs/Departments/BioDev/omm/fibro/fibro.htm

-------------------------------------------------

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16029324&query_hl=10&itool=pubmed_docsum
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, Juntendo University School of
Medicine, Tokyo, Japan. nbna...@med.juntendo.ac.jp

BACKGROUND: CDK5 is a member of proline-directed serine/threonine
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 Ca2+-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

===============================

The real mechanisms of the heartbreak of P
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=12763276&query_hl=10&itool=pubmed_docsum
Plasma homocysteine and its relationships with atherothrombotic markers
in psoriatic patients.

* Vanizor Kural B,
* Orem A,
* Cimsit G,
* Uydu HA,
* Yandi YE,
* Alver A.

Faculty of Medicine, Department of Biochemistry, Karadeniz Technical
University, Turkey.
BACKGROUND: Hyperhomocysteinemia may constitute an independent risk
factor for cardiovascular disease and may promote atherothrombosis.
Psoriasis is one of the diseases associated with increased
atherothrombosis. The aim of the present study was to examine serum
total homocysteine (tHcy) level and its relationships with
atherothrombotic markers. METHODS: The study group included 30 patients
with psoriasis (17 females and 13 males) with a mean age of 34.2 (age
range: 27-40) and 30 sex and age matched healthy volunteers (15 females
and 15 males) with a mean age of 36.7 (age range: 26-48). The
concentrations of lipids, lipoproteins, acute phase reactants, tHcy and
atherothrombotic markers [fibronectin, soluble vascular adhesion
molecules-1 (sVCAM-1), soluble intercellular adhesion molecules-1
(sICAM-1), tissue plasminogen activator (tPA), plasminogen activator
inhibitor-1 (PAI-1), autoantibodies against oxidized LDL (AuAb-oxLDL)]
were determined. RESULTS: The mean levels of serum tHcy, fibrinogen,
fibronectin, sICAM, PAI-1 and AuAb-oxLDL were increased in patients
whereas tPA, vitamin B(12) and folate levels were decreased
significantly. Increased levels of sVCAM were not statistically
significant. tHcy levels were negatively correlated with vitamin B(12)
(r=-0.40, P=0.027) and positively correlated with PAI-1 and AuAb-oxLDL
levels (r=0.46, P=0.011; r=0.39, P=0.035, respectively). CONCLUSIONS:
It was concluded that the increased homocysteine concentration and
altered endothelial cell-mediated proteins associated with increased
lipids and LDL oxidation may play an important role for the development
of atherothrombotic complications with psoriasis.

PMID: 12763276

++++++++++++++++++++++++++++++++++++

Let's face it, mABs are so yesterday. We need to go uPstream to knock
it all back.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=11857637&query_hl=10&itool=pubmed_docsum

randall... 2007 is cool!

randall

unread,

Jan 4, 2007, 2:23:55 AM1/4/07

Hi,

My P insights, based on lengthy empirical investigations has me focused
on
gut tissue as it is a first line of offense in the immunological Th1
haPPenings.

And MY iDea isn't the 88-th one! <w>

http://www.huliq.com/4394/cell-relocation-fixes-damage-to-the-gut-lining

Cell relocation fixes damage to the gut lining

The cells lining the intestine (epithelial cells) function as a barrier
that keeps the contents of our intestines separate from our body
tissues. Damage to the epithelial cell layer allows the contents of our
intestines, including our gut bacteria, access to our tissues and
bloodstream; large numbers of bacteria in the bloodstream can result in
the life-threatening condition septicemia.

Therefore, rapid repair of the epithelial cell layer after damage is
essential. In a study appearing in the January issue of the Journal of
Clinical Investigation, researchers from Washington University School
of Medicine, St. Louis, have identified what they believe is a new
mechanism by which the epithelial cell layer of the mouse intestine is
repaired after damage.

Thaddeus Stappenbeck and colleagues showed that repair of the
epithelial cell layer of the mouse rectum by proliferation of colonic
epithelial progenitors (ColEPs) required the presence of two proteins
-- Myd88 and Ptgs2. Myd88 is a signaling protein that was shown to be
upstream of the requirement for Ptgs2. Surprisingly, Myd88 signaling
did not induce increased expression of Ptgs2 and instead caused the
relocation of Ptgs2-expressing stromal cells in the intestinal tissues
to sites in the epithelial cell layer rich in ColEPs. Further studies
will be required to determine whether the Ptgs2-expressing stromal
cells directly or indirectly induce ColEP proliferation and whether
similar cellular relocation mechanisms control progenitor cell
proliferation in other tissues.

In an accompanying commentary, Seth Rakoff-Nahoum and Ruslan Medzhitov
from Yale University School of Medicine, propose a model whereby damage
to the epithelial cell layer of the intestine allows immune cells in
the intestinal tissues to sense gut bacteria and initiate Myd88
signaling, which results in them instructing nearby Ptgs2-expressing
stromal cells to relocate to sites in the epithelial cell layer rich in
ColEPs.

By Journal of Clinical Investigation

--------------

Checking for MYD88 and P hits in the P newsgroup (aka-here),
http://groups-beta.google.com/groups/search?q=myd88%2Bpsoriasis&qt_s=Search

A MYD88 gif for the gut,
http://www.iir.suite.dk/IIR/13auto/CrCARD15.htm

When I look at this site my mouth waters or Gi tract exudates. All the
players are there. We just need an answer or two to go along with them.

For searching sakes, i'll repost all but the image in the above link.

-----------------

Crohn's disease - role of CARD15/NOD2?

Crohn's disease (CD) is a chronic inflammatory disease of the
intestines. CD primarily causes ulcerations in the small and large
intestines, but can affect the digestive system anywhere between the
mouth and the anus (for a possible pathogenic role of cytokines, click
here).

CD is a polygenic disorder, i.e. several genes are associated with the
disease. One of these, the CARD15/NOD2 gene on chromosome 16, seems of
special importance. Mutations in CARD15 is the cause of Blau's
syndrome, a systemic granulomatous inflammatory disease of dominant
inheritance. However, mutations in the same gene has recently been
shown to increase the risk of developing CD. However, the mutational
sites in CARD15 are different in patients with CD and Blau's syndrome,
the former usually being located in the leucine-rich repeat (LRR)
domain or in its immediate vicinity (see figure). Interestingly, the
LRR domain of the intracellular CARD15 protein senses a muramyl
dipeptide (MDP) motif on a fragment of peptidoglycan (PG), which is a
major component of the cell wall of gram-positive bacteria (it is also
found in the periplasmic space in gram-negative bacteria). CARD15 is
under regulation by inflammatory cytokines, such as TNFalpha and
IFN-gamma.
It is thus possible that functional defects in CARD15 prevent innate
immunity from balancing resistance to microbes in the gut of CD
patients, leading to uncontrolled inflammation and mucosal damage.

---------------

The damage with crohn's is with the gut tissue. How does it translate
out to the skin?

Are P plaques so akin to crohn's and IBD that one small link is
overlooked?

http://www.iir.suite.dk/IIR/13auto/+CrCARD15.htm

---------
Crohn's disease (CD) is a chronic inflammatory disease of the
intestines. CD primarily causes ulcerations in the small and large
intestines, but can affect the digestive system anywhere between the
mouth and the anus (for a possible pathogenic role of cytokines, click
here).

http://www.iir.suite.dk/IIR/13auto/+Crohn.htm

-----------

Doing the search of myd88 on pubmed brings up this susPicious abstract,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17158234&query_hl=4&itool=pubmed_docsum
Vav proteins control MyD88-dependent oxidative burst.

* Miletic AV,
* Graham DB,
* Montgrain V,
* Fujikawa K,
* Kloeppel T,
* Brim K,
* Weaver B,
* Schreiber R,
* Xavier R,
* Swat W.

Dept of Pathology & Immunology, Washington University School of
Medicine & Siteman Cancer Center, St. Louis, MO, United States.

The importance of reactive oxygen intermediate (ROI) production in
antimicrobial responses is demonstrated in human patients who suffer
from chronic granulomatous disease (CGD) due to defective NADPH oxidase
function. Exactly how bacterial products activating Toll-like receptors
(TLRs) induce oxidative burst is unknown. Here, we identify the Vav
family of Rho GEFs as critical mediators of LPS-induced MyD88-dependent
activation of Rac2, NADPH oxidase, and ROI production, using mice
deficient in Vav1, Vav2, and Vav3. Vav proteins are also required for
p38 MAP kinase activation and for normal regulation of proinflammatory
cytokine production, but not for other MyD88-controlled effector
pathways such as those involving JNK, COX2 or iNOS and the production
of reactive nitrogen intermediates (RNI). Thus, our data indicate that
Vav specifically transduces a subset of signals emanating from MyD88.

PMID: 17158234

And that leads to this,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17156730&query_hl=9&itool=pubmed_docsum
[The adaptor protein 3BP2 in leukocyte signaling.]
[Article in French]

* Deckert M.

Inserm U576, Regulation des reponses immune et inflammatoire, Hopital
de l'Archet, Route Saint-Antoine de Ginestiere, 06202 Nice, France.
dec...@unice.fr.

Adaptor proteins that do not contain intrinsic enzymatic activity play
a critical role in cell biology by regulating the assembly of large
multimolecular signaling complexes involved in extracellular signal
transduction. The increasing number of diseases associated with
aberrant function or expression of adaptor proteins further illustrate
their key role in cellular regulation. The adaptor 3BP2 (or SH3BP2) was
originally identified more than 10 years ago as an c-Abl binding
protein, and next as a partner of Syk family kinases in 1998. 3BP2
displays the typical modular organization of an adapter protein with an
amino-terminal PH domain, a central proline rich region and a
carboxyl-terminal SH2 domain. Although its physiological function
remains unknown, studies have implicated a role for 3BP2 in
immunoreceptor signaling through its interaction with a number of
signaling molecules including Src and Syk families of protein tyrosine
kinases, the membrane adaptor __LAT__, Vav exchange factors, PLC-gamma,
and 14-3-3 proteins. Recently, the 3bp2/sh3bp2 locus was shown to be
mutated in a rare human disease involved in cranial-facial development
called cherubism, suggesting a role for 3BP2 in regulating osteoclast
and hematopoietic cell function. double dagger.

PMID: 17156730

And bingo on the _LAT_ linker for activation?

That's an old line of inquiry here,
http://groups-beta.google.com/groups/search?q=lat+linker+psoriasis&qt_s=Search

There has to be more then these? Let's take out linker and put in me!
:)

http://groups-beta.google.com/groups/search?q=lat+psoriasis+randall&qt_s=Search

There we go....

Now what? LOL

How about gammadelta T cells?

randall.... next time..or some time...who knows

Brett

unread,

Jan 4, 2007, 7:29:46 PM1/4/07

Hey Randall,

You know that I totally agree with you on the gut thing, and just want to
pass that along to the others on this site. About 2 years ago, I made a
firm decision to completely cut out alcohol, red meats, refined carbs, and
anything else that might stir-up an inflammatory response in the body. I
began by going all out on the pure fish oil idea, and at one point was
taking almost 3 tablespoons a day, which I eventually cut back to 2 (still
way more than the recommended amount). In that time, I haven't noticed any
ill effects from the oil, but the positive effects have been dramatic. The
only remaining stubborn areas I have are on both feet, where there are a few
spots of pinkish skin that haven't fully healed. I'd say I'm down to 1%
total coverage, compared to my worst when it was around 25-30%.
I took a chance this holiday season and drank 1/2 bottle of Champagne on 3
different occasions with some chocolate. Other than the giggly bubbly
sensation, I noticed absolutely no negative reactions on my body. Needless
to say I was quite surprised and quite happy at the same time. To this day
I'm still taking 1-2 tablespoons of fish oil a day, and eating lots of wild
salmon and veggies as well. Sweet potatoes and rice are my main sources of
carbs for the running and hiking I do.
All I can say from my own results is that by taking out the inflammatory
foods and loading up on the anti-inflammatory (fish oil, fish, veggies), the
psoriasis is almost completely gone. Randall's definitely been on the right
track with the gut idea, and my idea of "loading up" on the oils has
probably speeded things along. Allow the gut to heal, and it appears that
you might even be able to cheat every now and then, Champagne and chocolates
at least, and get away with it.

Brett

"randall" <ranh...@aol.com> wrote in message
news:1167895434.9...@i80g2000cwc.googlegroups.com...

randall

unread,

Jan 5, 2007, 12:48:30 AM1/5/07

Ring in the NEW YEAR with cheer!

>
> Brett
>
> "randall" <ranhu...@aol.com> wrote in messagenews:1167895434.9...@i80g2000cwc.googlegroups.com...
>
<sniP>

And it's still my position that a super bug (lacti loving or otherwise)
will be used to
imProve the gut terrain. And pumP out IL-10 and thereby lower the Th1
inflammatory
skew of psoriasis.

You Brett, through your hard work and diligence are living proof.

By controlling tregs via the gut using good flora, we can overcome
autoimmunity (Ai).
Or more appropriately now, IMIDs (immune mediated inflammatory
disorders).

The gut thymus linkage is to strong to keep fooling around with
biologicals. The
biologicals are downstream of a cure. Finding the point at which the Ai
teeter totter
goes astray will pay off big time for Th1 and Th2 diseases.

See: http://www.bdbiosciences.com/pdfs/brochures/06-790030-8-A1.pdf
Keywords: CD4+ Tr1 foxp3 cd25 cd122 TH3 CD8+ IL-10 TRN iTreg

Here are some articles I picked up in google news just now to support
diet and
Gi tract good bacteria.

---------------------------

Beneficial gut bacteria::
http://www.sciencedaily.com/releases/2007/01/070102135423.htm

Beneficial Bacteria Boost Intestinal Health

Science Daily - A probiotic supplement was found to stimulate the
immune system and improve nutrient absorption in two separate animal
studies recently conducted by Agricultural Research Service (ARS)
scientists. Probiotics are living microorganisms that, when added to
foods or dietary supplements in sufficient numbers, can benefit the
consumer in one or more ways.

The studies were led by microbiologist Gloria Solano-Aguilar with the
ARS Nutrient Requirements and Functions Laboratory, one of seven
research units at the Beltsville (Md.) Human Nutrition Research Center.
Solano-Aguilar received funding from Nestlé Nutrition of Glendale,
Calif.
Healthy animals and humans benefit every day from trillions of natural
intestinal bacteria. These friendly bacteria help keep "bad" bacteria
from gaining a foothold that could lead to illness or disease. In the
first study, the common probiotic strain Bb 12 was fed to three
pregnant sows, while a placebo treatment was fed to three pregnant
control sows. The scientists then fed the same Bb 12 treatment to half
of each sow's litters, resulting in four experimental groups.
Solano-Aguilar studied gene expression patterns in tissue taken from
each animal's lymph nodes, liver, spleen and intestine. She also
studied the animals' intestinal contents. The team then compared the
gene expression patterns in the pigs from all four groups. The
probiotic was found to induce innate immune activity in the colon where
the probiotic was in highest concentration.
In a separate study, half of a group of test pigs were treated with the
Bb 12 probiotic before all of the test pigs were exposed to a worm
infection. The researchers then compared the response to infection of
the group of pigs that received the probiotic treatment with the
response of those that did not receive the treatment. Preliminary
results show better response to the infection--and improved nutrient
absorption--in the group of pigs that were supplemented with the
probiotic treatment prior to the infection.
ARS is the U.S. Department of Agriculture's chief scientific research
agency.
Note: This story has been adapted from a news release issued by
USDA/Agricultural Research Service.

--------------------

Meat to vegetable ratio.
http://www.infozine.com/news/stories/op/storiesView/sid/19919/
Nutrition Notes: What's Your Vegetable-to-Meat Ratio?
By Karen Collins, MS, RD, CDN - Studies keep linking diets high in red
meat with increased cancer risk. Could part of the risk from large
amounts of meat reflect an unhealthful balance between vegetables and
meat? The Mediterranean and Asian eating patterns have a
well-established link with lower cancer risk. These diets both limit
meat and strongly emphasize an abundance of vegetables.

Washington, D.C. - American Institute for Cancer Research - infoZine
-One reason the vegetable-to-meat balance might be so important are
compounds in vegetables that act on potentially harmful substances
produced by meat. When meat is processed, smoked, grilled, fried or
cooked well done, it can lead to the formation of carcinogens that can
damage DNA and begin the process of cancer development. Several types
of compounds in vegetables (and fruits) stimulate enzymes that convert
such carcinogens to inactive forms, which are then excreted from the
body.

Cruciferous vegetables such as broccoli, cauliflower and cabbage are
especially known for compounds called isothiocyanates. These compounds
take aim at meat-formed carcinogens. Studies suggest that meat is one
of the major causes of colon cancer. Research shows that people who eat
about four, half-cup servings of cruciferous vegetables weekly may
reduce their risk of colon cancer by 20 to 50 percent.

Garlic and onions contain sulfide compounds that can also inactivate
meat-formed carcinogens. In a large analysis of several studies, people
who ate four to five cloves of garlic a week were 31 percent less
likely to develop colon cancer compared to people who ate from zero to
one clove per week.

Vegetables also provide dietary fiber, which can bind to heterocyclic
amines (HCAs), one class of carcinogens produced when meat is cooked at
high temperatures. When fiber binds to HCAs, it may prevent HCAs from
being absorbed out of the digestive tract. The HCAs are then excreted
before they can travel through the body and damage cells.

Diets high in meat and low in vegetables may promote inflammation
throughout the body. Inflammation can cause an increase in free
radicals, which can damage DNA. It can also lead to cells reproducing
too quickly, leaving less time to repair possible DNA damage that can
lead to cancer. Vegetables provide antioxidant vitamins and protective
compounds that prevent and possibly repair DNA damage from free
radicals. People who followed a Mediterranean-style diet for two years
had blood levels that showed a 40 percent lower level of inflammation
than that of a control group. The control group was asked to follow a
low-fat diet without the emphasis on such healthful foods as fruits,
vegetables and olive oil.

Researchers now suggest that one reason red meat is linked to so much
more cancer risk than poultry and fish may involve its higher content
of a particular form of iron called heme iron. Studies indicate that
heme iron may damage the lining of the colon. Some preliminary
laboratory studies show that heme iron may interact with estrogen in
promoting hormone-related cancers, such as breast and prostate cancers.

A diet high in vegetables may help to balance the risks of heme iron. A
recent study found that rats given food with added heme iron showed a
50 percent increase in colon cell growth. The amounts fed to the rats
are equivalent to humans eating two-and-a-half cups of cooked spinach
and five ounces of red meat daily.

Follow-up studies showed that chlorophyll the substance in vegetables
that makes them green kept heme iron from damaging colon cells and
beginning the cancer process. If this comparison to humans is accurate,
green vegetables have a reasonable chance to reduce risk from red meat
kept to the recommended limit of three ounces or less a day.

(Note:: randall uses IP6 every day to lower heme iron in the gut)

----------------------

http://www.sciencedaily.com/releases/2006/12/061227195238.htm

Inflammatory Genes Linked To Salt-sensitive Hypertension

Science Daily - One key to your high blood pressure might just be
your inflammatory genes.
It may sound odd but mounting evidence suggests that inflammation, a
part of the immune response implicated in diseases such as cancer,
Alzheimer's and diabetes, may also help translate stress into high
blood pressure.
"There is a concept that hypertension is an inflammatory
condition," says Dr. Haidong Zhu, molecular geneticist at the Medical
College of Georgia. She's among the scientists who believe the
connection between stress, inflammation and hypertension is the
kidneys' ability to release sodium.
When stress activates the sympathetic nervous system (the
fight-or-flight mechanism), the body increases production of
interleukin 6, a pro-inflammatory factor, which ultimately leads to
production of other inflammatory factors such as C reactive protein.
Stress also prompts the body to hold onto sodium to help temporarily
raise blood pressure so you can deal with the situation, says Dr.
Gregory Harshfield, director of MCG's Georgia Prevention Institute
and an expert on what happens when the body doesn't let go afterward.
It's called impaired stress-induced pressure natriuresis, which Dr.
Harshfield has documented in young, healthy teens.
Dr. Zhu is now leading research to see if the reactions are related -
if sodium handling goes awry under stress because the teens have
mutations in four sets of stress-activated inflammatory genes:
interleukin 6, interleukin 6 receptor, cytokine signal transducer and
C-reactive protein.
"Our long-term goal is to be able to identify a subgroup of
individuals with a certain genetic profile that has an increased risk
of developing high blood pressure in a stressful environment," says
Dr. Zhu, who recently received a two-year, $300,000 grant from the
National Heart, Lung and Blood Institute
If she's right, these individuals could likely benefit from targeted
therapy that might include a low-salt diet, physical activity and maybe
anti-inflammatory drugs, says Dr. Zhu. Nearly one in three Americans
is hypertensive and more than half have salt-sensitive hypertension,
she notes.
"Cardiovascular diseases, including hypertension, are complex
diseases with a lot of gene-environment interaction, and stress is now
a part of people's daily lives," she says.
"We have found hypertension associated with inflammation and we have
found stress associated with hypertension. There is evidence suggesting
that in salt-sensitive hypertension there are increased levels of
inflammation factors such as interleukin 6 and C-reactive protein,"
Dr. Zhu says. "Even high-normal blood pressure is associated with a
pro-inflammatory condition."
Additionally, animal studies have shown salt-sensitive hypertension
induced by the powerful blood-vessel constrictor angiotensin 2 can be
prevented by drugs that suppress the immune response and consequent
inflammation.
"There are many pieces of evidence and we are trying to link them
together," says Dr. Zhu.
Her research team is looking at genetic variations of four inflammatory
genes in 500 15- to19-year-olds with normal blood pressure. The teens,
already enrolled in studies at MCG's Georgia Prevention Institute
measuring the effects of stress on the cardiovascular system, were put
on a diet for four days to regulate sodium intake, then came to the GPI
where they rested for an hour, played a three-dimensional, racing video
game for an hour, then rested for an hour. Blood and urine samples were
taken throughout the period. For this study, researchers will also
collect DNA material from the mouths of as many parents as possible to
confirm their findings in the children.
Pilot data indicate that black teens with normal blood pressure and a
certain variation of the interleukin 6 gene have significantly reduced
sodium excretion in the urine following stress. Researchers have
further implicated the inflammatory factor's role in blood pressure
regulation by showing that following stress, circulating levels of
interleukin 6 rise and are still up an hour after the stressor is gone.
Dr. Zhu suspects that even without the genetic variations, inflammation
affects blood pressure under stress, so she'll be looking at its
impact alone and in concert with the mutations.
"We believe this research will provide novel insight into the
interactions between stress, inflammation and genetics and their
contribution to the pathogenesis of essential hypertension," she
says.
The relationship between inflammation and high blood pressure,
including how cytokines affect blood pressure elevation, also is the
subject of a five-year, $11 million National Heart, Lung and Blood
Institute Program Project grant underway at MCG under the leadership of
Dr. R. Clinton Webb, chair of the Department of Physiology.
Note: This story has been adapted from a news release issued by Medical
College of Georgia.

---------------------

randall.. Good Cheer and BE CLEAR!

randall

unread,

Jan 6, 2007, 3:13:10 AM1/6/07

Hi,

Will this rare gene help to unravel the autoimmune jig saw puzzle?

Rare condition provides information about common illnesses

http://nyheter.uib.no/?modus=vis_engelsk&id=34765

Anette S. Bøe Wolff has collected data about 36 Norwegian patients
suffering from the rare hormone disorder APS-1. This information may
benefit hundreds of thousands of Norwegians.

By Lars Holger Ursin

Patients suffering from psoriasis, multiple sclerosis, type 1 diabetes,
rheumatoid arthritis and lupus have one important thing in common: They
all suffer from an autoimmune disease, this means a condition where the
body's immune system reacts not only to foreign substances, as it is
supposed to do, but also to substances that belong in the body.

"Autoimmunity is not unnatural, it is a normal process which is out
of balance," Anette S. Bøe Wolff emphasises. She is one of the
scientists working on APS-1, one of the rarest autoimmune diseases.
Ironically, new knowledge about this rare disease can provide new
insight into the entire phenomenon of autoimmunity. APS-1 is very
suitable for use as a model disease.

"The reason for this is that it is a monogenic disease. This means
that a mutation in one gene is sufficient to develop the disease," Ms
Bøe Wolff explains.

Hope for autoimmunity patients
"In APS-1, the defect is in AIRE gene, which we know plays a central
part in the immune system," Ms Bøe Wolff explains.

If the underlying causality is this clear, then researchers can focus
on how the disease manifests itself, not only because this gives them
knowledge about autoimmunity in general, but also because it can give
patients who suffer from this rare disease hope of better treatment in
future.

Researchers from UiB have contacted hospitals all over Norway looking
for patients with certain symptoms that are characteristic for APS-1.
Ms Bøe Wolff has then collected tissue samples from the recruited
patients and tested them for mutations in the AIRE gene.

"All of them had a mutation in this gene. We identified a total of 11
different mutations - two of them are common, but we also found five
that have not been described before," she tells us.

New method for early diagnosis
Ms Bøe Wolff and her colleagues have also been interested in
identifying new diagnostic markers for the disease - that is, whether
there are simpler ways for doctors to find out at an early stage
whether patients have APS-1. For this reason, they have followed
patients over a period of time after they contracted the disease in
order to study the development of symptoms.

Among other things, APS-1 causes the cells of the body's immune
system to produce autoantibodies against a number of proteins
(antigens) which occur naturally in the body. Among other things, they
found autoantibodies against interferon omega in all the patients.

"We find this in patients before they develop the disease itself.
Therefore, this may be a method well suited to identifying patients
early so that they can start treatment sooner. Having a possible
diagnostic marker that can identify all patients is unusual in
medicine," Ms Bøe Wolff explains.

The research on APS-1 at the University of Bergen is part of a larger
international project coordinated by Uppsala University. The project
involves 17 partner institutions, including two Australian institutions
and one from Hong Kong. The great international interest is, among
other things, connected to the fact that APS-1 is a suitable model
disease for autoimmunity. At the same time, it is so rare that
obtaining a sufficiently large material demands coordinated
international efforts.

Helpful mice
"It is easier to study such processes in monogenic diseases than in
the more typical polygenically inherited autoimmune diseases, where it
is assumed that tens of genes may be involved - and much of the time
it is not mutations that are involved, but variations in different
genes," explains Professor Eystein Husebye of the Institute of
Medicine. He is the head of the research group in which Ms Wolff works
as a postdoc, and he is involved in the project coordinated by Uppsala,
which is financed by EU's Sixth Framework Programme.

"Among other things, we are trying to collect data about all patients
in Europe, and to study the mutations of the AIRE gene as well as which
autoantibodies they produce," he explains.

Animal tests on mice which do not have the AIRE gene have already
provided the researchers with a lot of new information, but, because of
a few small differences in how the disease manifests itself in mice and
humans, many questions remain unanswered.

"Data from mice have provided a lot of new knowledge, but it is
limited by the fact that the disease affects different organs in mice
- and they do not develop fungal infections, which is common in APS-1
patients. That makes these patient data quite invaluable. When we
finally obtain an overview of the effects of this defect in the AIRE
gene, that will increase our understanding of autoimmunity in
general," Mr Husebye explains.

------------------

Facts/APS-1
Autoimmune polyendocrine syndrome, or APS-1, is a serious monogenic
disease which affects about one in 90,000 Norwegians. It is less
widespread in other countries, but it is much more common in some
areas, such as Finland and Sardinia and among Iranian Jews, where it
may affect as many as one in 9,000.

The disease is caused by a mutation in the AIRE gene, which stands for
autoimmune regulator. This gene plays a very important part in the
structure of the immune system, in the thymus: It is responsible for
what is known in medicine as "central tolerance" - that the
immune system is able to distinguish between what belongs to its own
body and what is foreign.

When the immune system cells are exposed to antigens, substances from
outside the body that cause an immune response, they are supposed to
produce antibodies to neutralise the antigens. However, the cells must
not respond in the same way to antigens produced by the body itself,
the self antigens. They are therefore exposed to such self antigens in
the thymus. If an immune system cell recognises them, it will be
destroyed. It is a tough weeding-out process - only about 5 per cent
of the newly-formed immune system cells make it through.

"Isn't that a very complicated way of sorting the immune system
cells?"

"Not really. It ensures diversity in the immune system - after all,
the cells need to be able to respond broadly, to substances they have
never encountered before. Therefore, it is no good checking whether
they attack the right substances - it is more rational to check
whether they do not attack the ones that belong there," says Anette
S. Bøe Wolff.

However, only the self antigens present in the blood stream are present
in the thymus, and that is not enough to be sure that the cells will
not attack tissue in other parts of the body. This is where AIRE comes
into the picture: AIRE can express the genes of the tissue-specific
self antigens - for example the ones that the cells may later
encounter in the pancreas, the testicles or the adrenal glands.

If AIRE is disabled, the self antigens from other organs will not be
expressed in the thymus, the eye of the needle will widen, and immune
system cells which should have been destroyed will be released and
could harm the body. This causes great problems: These cells can then
attack healthy tissue that belongs in the body - first and foremost
in the hormone-producing glands. In all, about 15 organs in the body
can be attacked - and the disease could be fatal.

"But, if diagnosed early, patients can be treated with drugs and live
a good life," Ms Bøe Wolff explains.

------------

And on pubmed.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16876259&query_hl=5&itool=pubmed_docsum

Expression profiling of autoimmune regulator AIRE mRNA in a
comprehensive set of human normal and neoplastic tissues.

* Klamp T,
* Sahin U,
* Kyewski B,
* Schwendemann J,
* Dhaene K,
* Tureci O.

Department of Internal Medicine III, Johannes-Gutenberg University
Mainz, Obere Zahlbacherstr 63, 55131 Mainz, Germany.

Defects in the autoimmune regulator (AIRE) gene cause the monogenic
autoimmune disease autoimmune polyendocrinopathy syndrome type 1
(APS-1), which is characterized by a loss of self-tolerance to multiple
organs. In concordance with its role in immune tolerance, AIRE is
strongly expressed in medullary thymic epithelial cells (mTECs). Data
on mechanisms controlling AIRE activation and the expression of this
gene in other tissues are fragmentary and controversial. We report here
AIRE mRNA expression profiling of a large set of normal human tissues
and cells, tumor specimen and methylation deficient cell lines. On this
broad data basis we found that AIRE mRNA expression is confined to
mTECs in thymus and to lymph node tissue and that DNA hypomethylation
contributes to transcriptional control of this gene.

PMID: 16876259

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16792967&query_hl=5&itool=pubmed_docsum

[AIRE gene mutation in polyglandular syndrome type 1]
[Article in Spanish]

* Martinez Lopez MM,
* Gonzalez Casado I,
* Alvarez Doforno R,
* Delgado Cervino E,
* Gracia Bouthelier R.

Servicio de Endocrinologia Pediatrica, Hospital Universitario La Paz,
Melchior Fernandez Almagro 16, 11B, 28029 Madrid, Spain.
martine...@hotmail.com

Autoimmune polyglandular syndrome type 1 (APS-1) is an autosomal
recessive disorder characterized by chronic mucocutaneous candidiasis,
autoimmune hypoparathyroidism, and primary adrenal insufficiency. It
has recently been associated with mutations of a single gene found on
chromosome 21, designated AutoImmune Regulator (AIRE). We report two
patients with APS-1 referred to our hospital for evaluation. The first
patient was an 11-year-old girl with hypoparathyroidism, infectious or
immunological malabsorption, and autoimmune hepatitis.
Hypoparathyroidism associated with other processes with a probable
autoimmune origin suggested APS-1. Genetic study was performed
revealing deletion of 13 base pairs in exon 8 of the AIRE gene. The
second patient was a 17-year-old girl with autoimmune hepatitis,
hypoparathyroidism, mucocutaneous candidiasis, nail dystrophy, and
obliterating bronchiolitis with a probable autoimmune origin. We
suspected APS-1 and genetic study was performed. The only finding was
an AIRE gene polymorphism. In conclusion, the presence of a single
disease criterion is sufficient to suspect APS-1 and to indicate
genetic study. Further studies are required to confirm the involvement
of other genes in the development of this disease.

PMID: 16792967

OMIM,
http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=607358

http://www.ncbi.nlm.nih.gov/Omim/getmap.cgi?l607358

http://www.ncbi.nlm.nih.gov/mapview/maps.cgi?taxid=9606&CHR=21&maps=genes-r,pheno,morbid,genec&R1=on&query=AIRE&VERBOSE=ON&ZOOM=3

--------------

randall.... i don't see the linkage? Need more data? yep..

randall

unread,

Jan 8, 2007, 7:13:02 PM1/8/07

Hi,

New P gene? Early onset P gene for Hans, yeP.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17205061&query_hl=1&itool=pubmed_docsum

Evidence for a Novel Psoriasis Susceptibility Locus at 9q33-9q34 in
Chinese Hans.

* Sun LD,
* Li W,
* Yang S,
* Fan X,
* Yan KL,
* Liang YH,
* Gao M,
* Cui Y,
* Xiao FL,
* Du WH,
* Zhang KY,
* Huang W,
* Liu JJ,
* Zhang XJ.

[1] 1Institute of Dermatology and Department of Dermatology at No.1
Hospital, Anhui Medical University, Hefei, China [2] 2The Key
Laboratory of Gene Resource Utilization for Severe Diseases, Ministry
of Education, Hefei, China.

Psoriasis is a heterogeneous disease for which nine linkage loci (PSORS
loci 1-5 and PSORS7-10) have been accepted by the Human Genome
Nomenclature Committee and an additional 16 potential susceptibility
loci have been reported so far. Our previous genome-wide scan in 61
Chinese Han psoriasis vulgaris families found two susceptibility loci
at 6p21.3 and 4q31 and additional suggestive linkage evidence at other
regions, including 9q33. In this follow-up study, the linkage evidence
at 9q33 was further investigated using an expanded sample of 160
families and improved marker coverage. Our follow-up linkage analysis
of the 160 families demonstrated strong linkage evidence (P</=0.000022)
throughout a region between 133.38 and 146.23 cM with a maximum
nonparametric linkage (NPL) score of 4.64 (P=0.00000023) and a
heterogeneity LOD (HLOD) score of 5.03 (alpha=46%) at 142.39 cM near
the marker D9S290. By stratifying the 160 families into the subtypes of
130 early-onset and 30 late-onset families, we revealed stronger
linkage evidence in the early-onset psoriasis families with a maximum
multipoint HLOD score of 6.48 (alpha=58%) and a maximum NPL score of
4.69 (P=0.00000012) near marker D9S290. Our follow-up study has
confirmed a novel susceptibility locus at 9q33-34 for early-onset
psoriasis in the Chinese population.Journal of Investigative
Dermatology advance online publication, 4 January 2007;
doi:10.1038/sj.jid.5700671.

PMID: 17205061

A PsA gene to go along with the flake stuff. Yuck-O! I hate my PsA...
lol

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17204151&query_hl=1&itool=pubmed_docsum

VEGF, FGF1, FGF2 and EGF gene polymorphisms and psoriatic arthritis.

* Butt C,
* Lim S,
* Greenwood CM,
* Rahman P.

ABSTRACT: BACKGROUND: Angiogenesis appears to be a first-order event in
psoriatic arthritis (PsA). Among angiogenic factors, the cytokines
vascular endothelial growth factor (VEGF), epidermal growth factor
(EGF), and fibroblast growth factors 1 and 2 (FGF1 and FGF2) play a
central role in the initiation of angiogenesis. Most of these cytokines
have been shown to be upregulated in or associated with psoriasis,
rheumatoid arthritis (RA) or ankylosing spondylitis (AS). As these
diseases share common susceptibility associations with PsA,
investigation of these angiogenic factors is warranted. METHODS: Two
hundred and fifty-eight patients with PsA and 154 ethnically matched
controls were genotyped using a Sequenom chip-based MALDI-TOF mass
spectrometry platform. Four SNPs in the VEGF gene, three SNPs in the
EGF gene and one SNP each in FGF1 and FGF2 genes were evaluated.
Statistical analysis was performed using Fishers exact test, and the
Cochrane-Armitage trend test. Associations with haplotypes were
estimated by using weighted logistic models, where the individual
haplotype estimates were obtained using Phase v2.1. RESULTS: We have
observed an increased frequency in the T allele of VEGF +936
(rs3025039) in control subjects when compared to our PsA patients
[Fishers exact p-value = 0.042; OR 0.653 (95% CI: 0.434, 0.982)].
Haplotyping of markers revealed no significant associations.
CONCLUSIONS: The T allele of VEGF in +936 may act as a protective
allele in the development of PsA. Further studies regarding the role of
pro-angiogenic markers in PsA are warranted.

PMID: 17204151

-----------------

CombinatorX is back with a new toPical skin cocktail.
http://www.pharmalive.com/News/index.cfm?articleid=404309&categoryid=21

[...]
CRx-191 is a novel synergistic combination drug candidate which is
planned to enter clinical development as a topical cream for the
treatment of psoriasis and other steroid-responsive dermatoses. CRx-191
is a selective steroid amplifier containing a mid-potency steroid
mometasone and the anti-depressant nortriptyline. CRx-191 works through
a novel mechanism of action in which nortriptyline amplifies
mometasone's anti-inflammatory activities without expectation of
enhancing steroid side effects such as skin atrophy.
<sniP>

To get up to snuff,
http://groups-beta.google.com/groups/search?q=combinatorx+psoriasis&qt_s=Search

----------------

A return to the gut again. In less then one week no less. How risque!

Ring in the new year
Can a good old "leaky gut" be fixed? Is it even a player in the P game?

Is randalls whey insane? Are you betwixted with even the thought?

Well alrighty already. Examine the facts coming down the gut PiPe.

(note: this article has been run recently)

http://www.medicalnewstoday.com/medicalnews.php?newsid=60069
Cell Relocation Fixes Damage To The Gut Lining

TITLE: Myd88-dependent positioning of Ptgs2-expressing stromal cells
maintains colonic epithelial proliferation during injury

--------------------

So what the heck are coleps?
OK,
http://www.pnas.org/cgi/content/abstract/102/1/99

Can someone find a signal from coleps/gut cells that lights up the
genes in the skin?

H'm someone should go and try then.

-----------

Maybe Tregs will provide the gut linkage?

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17202386&query_hl=10&itool=pubmed_docsum

A defect of regulatory T cells in patients with autoimmune
polyendocrinopathy-candidiasis-ectodermal dystrophy.

* Kekalainen E,
* Tuovinen H,
* Joensuu J,
* Gylling M,
* Franssila R,
* Pontynen N,
* Talvensaari K,
* Perheentupa J,
* Miettinen A,
* Arstila TP.

Department of Immunology and.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy
(APECED), a monogenic recessive disease characterized by autoimmunity
against multiple tissues, offers a unique possibility to study the
breakdown of self-tolerance in humans. It is caused by mutations in the
autoimmune regulator gene (AIRE), which encodes a transcriptional
regulator. Work using Aire(-/-) mice suggests that Aire induces ectopic
expression of peripheral Ags and promotes their presentation in the
thymus. We have explored reasons for the difference between the
comparatively mild phenotype of Aire-deficient mice and human APECED
patients. We provide evidence that, unlike in the Aire(-/-) mice, in
the patients a key mediator of active tolerance, the CD4(+)CD25(+)
regulatory T (Treg) cell subset is impaired. This was shown by
significantly decreased expression of FOXP3 mRNA and protein, decreased
function, and alterations in TCR repertoire. Also, in the normal human
thymus a concentric accumulation of AIRE(+) cells was seen around
thymic Hassall's corpuscles, suggesting that in the patients these
cells may be involved in the observed Treg cell failure. In Aire(-/-)
mice the expression of FoxP3 was normal and even increased in target
tissues in parallel with the lymphocyte infiltration process. Our
results suggest that a Treg cell defect is involved in the pathogenesis
of APECED and emphasize the importance of active tolerance mechanisms
in preventing human autoimmunity.

PMID: 17202386

There are only two out of 461 abstracts that mention treg's.
The second one is a doozy,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=15981475&query_hl=12&itool=pubmed_docsum

------------
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17202333&query_hl=14&itool=pubmed_docsum

IL-21 Counteracts the Regulatory T Cell-Mediated Suppression of Human
CD4+ T Lymphocytes.

* Peluso I,
* Fantini MC,
* Fina D,
* Caruso R,
* Boirivant M,
* Macdonald TT,
* Pallone F,
* Monteleone G.

Dipartimento di Medicina Interna, Universita Tor Vergata, Rome, Italy;

High expression of IL-21 and/or IL-21R has been described in T
cell-mediated inflammatory diseases characterized by defects of
counterregulatory mechanisms. CD4(+)CD25(+) regulatory T cells (Treg)
are a T cell subset involved in the control of the immune responses. A
diminished ability of these cells to inhibit T cell activation has been
documented in immune-inflammatory diseases, raising the possibility
that inflammatory stimuli can block the regulatory properties of Treg.
We therefore examined whether IL-21 controls CD4(+)CD25(+) T cell
function. We demonstrate in this study that IL-21 markedly enhances the
proliferation of human CD4(+)CD25(-) T cells and counteracts the
suppressive activities of CD4(+)CD25(+) T cells on CD4(+)CD25(-) T
cells without affecting the percentage of Foxp3(+) cells or survival of
Treg. Additionally, CD4(+)CD25(+) T cells induced in the presence of
IL-21 maintain the ability to suppress alloresponses. Notably, IL-21
enhances the growth of CD8(+)CD25(-) T cells but does not revert the
CD4(+)CD25(+) T cell-mediated suppression of this cell type, indicating
that IL-21 makes CD4(+) T cells resistant to suppression rather than
inhibiting CD4(+)CD25(+) T cell activity. Finally, we show that IL-2,
IL-7, and IL-15, but not IL-21, reverse the anergic phenotype of
CD4(+)CD25(+) T cells. Data indicate that IL-21 renders human
CD4(+)CD25(-) T cells resistant to Treg-mediated suppression and
suggest a novel mechanism by which IL-21 could augment T cell-activated
responses in human immune-inflammatory diseases.

PMID: 17202333

------------------

randall

unread,

Jan 10, 2007, 1:32:34 PM1/10/07

Hi,

I'm on the gut Jihad this year. Any and all connects will be known and
shown.

Gut tissue inflammed with VAP-1 in this latest abstract for
psoriasis???

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17207171&query_hl=3&itool=pubmed_docsum

Vascular adhesion protein-1 (VAP-1) is overexpressed in psoriatic
patients.

* Madej A,
* Reich A,
* Orda A,
* Szepietowski J.

Department of Dermatology, Venereology and Allergology, University of
Medicine, Wroclaw, Poland.

Background Vascular adhesion protein (VAP)-1 is an adhesion molecule
with an enzymatic activity that partakes in the migration process of
lymphocytes. Objectives The aim of this study was to investigate the
expression of VAP-1 in the skin and serum of psoriatic patients.
Material and methods Seventy-one patients suffering from psoriasis aged
between 23 and 89 years were included in the study. The mean psoriasis
severity assessed according to the psoriasis area and severity index
was 14.2 +/- 9.6 points. The soluble VAP-1 serum concentration was
evaluated by ELISA and VAP-1 expression in the skin (nine patients)
immunohistochemically. Results The serum concentration of soluble VAP-1
was significantly higher in psoriatic patients than in healthy controls
(403.4 +/- 130.8 ng/mL vs. 246.4 +/- 68.0 ng/mL; P < 0.0001). No
significant relationships were found between sVAP-1 concentration and
studied clinical parameters, except the presence of pruritus. Mean
number of VAP-1 positive vessels in psoriatic skin, both lesional (19.8
+/- 1.4) and non-lesional (9.4 +/- 1.4), was significantly higher than
in healthy skin (5.4 +/- 1.5; P < 0.005). Lesional psoriatic skin
demonstrated significantly more VAP-1 positive vessels than
non-lesional skin (P < 0.01). Conclusions Significant overexpression of
VAP-1 in both lesional and non-lesional psoriatic skin and higher serum
level of soluble VAP-1 in psoriatic patients may indicate the role of
VAP-1 in chronic inflammation occurring in psoriasis. However, because
of lack of correlation between soluble VAP-1 serum levels and psoriasis
severity this hypothesis needs further investigation.

PMID: 17207171

-----------------

You'd think there would be a ton of science in this area. Let's look at
vap-1 and P.

OK,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&dispmax=100&term=%20psoria*+vap-1

Big whooP!

Here's an opportunity for some science geek seeking fame and fortune.

P is in the gut tissue??? Or at least some dna/rna trigger deals?

Or some how in these pathways?

Let's look you gut kook!

Ok, I will. First lend me your comb.

Alright,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&dispmax=100&term=%20psoria*+gut

Looks interesting as all get out to me....

Kookie, lend me your comb?

Taking HA is the only way.
http://www.google.com/search?hl=en&lr=&q=cocks+comb+hyaluronan&btnG=Search

I'm figuring on a defect in this pathway with ROS as a culprit now.

It's 77 Sunset striP time for putting the P puzzle together.

That's right Daddy-O!

This is so COOL it's HOT...
---------

The hot chile pePPer cure for P and cancer?
http://www.medicalnewstoday.com/healthnews.php?newsid=60504

Chile peppers cause permeability in the gut. May be good for cancer to
skew one
towards a Th1 profile loaded with cancer eating TNF-alpha. But not a
good idea for
psoriasis as we're already skewed with to much Th1 cells. So, while it
may taste
good, a toPical is as close to the liPs as it should get. :(

[...]
UK scientists have shown that capsaicin, the chemical that burns your
mouth when you eat chillies and an active ingredient of over the
counter drugs, can kill cancer cells with little or no harmful
side-effects.

The study is published in the journal Biochemical and Biophysical
Research Communications.

The team that conducted the research came from the Universities of
Nottingham in England and Cardiff, in Wales, and was led by Dr Timothy
Bates, who is a member of the Medical Research Council (MRC) College of
Experts.

The researchers believe that capsaicin, and other similar compounds,
attack the mitochondria of cancerous cells, causing them to "switch
off" and die (apoptosis, or cell death) without harming surrounding
tissue. Mitochondria are organelles (tiny granules of tissue with their
own DNA) that live inside the cells of our bodies and convert nutrients
into ATP - the chemical fuel that feeds our cells with energy.

Dr Bates, who is an international expert in anti-cancer drug
development and mitochondrial research in particular, said this
discovery might explain the low incidence of cancer in countries where
they eat a lot of chillies like Mexico and India.

>From a development view this discovery is exciting for two reasons.
First, because capsaicin and related compounds already exist in food
that is eaten regularly, they are already safe, readily available and
not unknown. Secondly, and perhaps more importantly as far as
development costs and timescales go, these compounds have already been
approved for use in a range of drugs such as skin ointments to treat
psoriasis and neuralgia. Converting their use to treat cancer would be
much cheaper and quicker compared to starting from scratch with a new
compound.

Dr Bates and his colleagues tested the capsaicin on H460 human lung
cancer cells, which is recognised as the "gold standard" for new
anti-cancer drugs. However, they also tested similar compounds on
pancreatic cancer cells and found the same effect - the tumour cells
died off leaving the surrounding tissue intact. This is a very exciting
result because pancreatic cancer has a five-year survival rate of less
than one per cent and is currently one of the most stubborn cancers to
treat.

The study that led to this discovery is the first to emerge from a
newly formed Nottingham UK-China Collaboration on Complementary and
Alternative Medicine (NUKCAM). The collaboration has members from the
University of Nottingham and the Chinese National Academy of Sciences,
for example Professor De-An Guo, who is head of the Shanghai Research
Centre for the Modernization of Traditional Chinese Medicine. Prof Guo
is working with Dr Bates to discover why traditional Chinese medicines
are successful in treating cancer and other diseases.

Traditional Chinese Medicine (TCM) is considered an alternative
medicine in the west. But in China it is an important part of the
public health care system.

The last twenty or so years have seen an increasing interest on the
part of the West and China to come together and explore this wealth of
knowledge that dates back thousands of years. The main thrust of joint
projects, like this one, is to examine the theories and uses of TCM
using western scientific methods and tools.

Another important milestone in this East-West collaboration will be
when The World Health Organization's (WHO) initiative to to standardize
TCM nomenclature reaches conclusion. It is said to be in its final
phases, and there is a paper on this by Tony Reid in the The Journal of
Chinese Medicine.

As lovers of Sichuan food and dishes will know, chillies do feature
prominently in the Chinese diet, and apart from adding fire and flavour
are believed by local followers of Chinese medicine to help ward off
the ills caused by their damp and muggy climate.

--------------

Speaking of stone cold hot Foxes. With P no less.

Caridee the 21 y/o fox with P has a modeling gig now!
http://www.realitytvworld.com/news/top-model-7-winner-caridee-english-appears-on-her-first-cover-4519.php

You go girl! It's a biological wonder.

Didn't she call her meds reptiva? REP or RaP, who cares so long as it
works. LOL

-----------

randall... OK Daddy-O?

randall

unread,

Jan 11, 2007, 3:49:54 PM1/11/07

Hi,

It's already the 11th? Boy this year is flying bye bye. <w>

Pretty soon it'll be groundhogs day and he'll be on vacation in Miami.

Do those hogs eat these?

Magic Mushrooms? For P and C?
http://www.spiritindia.com/health-care-news-articles-5526.html
Cure :: Red mushroom a cure for ailments

Red mushroom, the ancient Chinese secret of health and longevity, is
emerging as an elixir of life for many in India suffering from various
ailments, including cancer, claim doctors in Tamil Nadu and Kerala.
more..

"It is not disease-specific or organ-specific. It is a dietary
supplement which corrects the disorders of the body mainly by enhancing
immunity and rebuilding lost or da maged cells", says Dr S Ranjan, a
leading cardiologist here.

Dr N K Venugopal, a medical practitioner at Muvattupuzha in Kerala's
Ernakulam district, says he has been prescribing products made out of
ganoderma for over six years and claimed to have found total cure in
about 1,000 patients suffering from various ailments.

"The regular intake of ganoderma along with medication has proven that
cancer can be cured in early stages," he says, adding, the
polysaccharide fractions in ganoderma are mainly responsible in
developing immunity against tumours.

Prof K K Janardhanan of the Department of Microbiology, Amala Cancer
Research Institute, Thrissur, says he was impressed by anti-cancer
properties of ganoderma during various studies.

"Our investigations have shown that methanolic extract of ganoderma
lucidium, the variety commonly found in South India, possesses
significant anti-tumour and anti-oxidant activities," he says. "When
mice were administered a dose of 500mg of ganoderma per kg of body
weight after implanting a tumour, it was found that the tumour load was
reduced by 97.7 per cent within 10 days," he says.

Venugopal says he has noticed that even in patients in their final
stages of cancer, ganodema increases life-expectancy, reduces pain
substantially, improved quality of life and reduces the side-effects of
chemotherapy and radiation.

Dr Ranjan also says it was the anti-cancer effect of ganoderma on a
person with myelomonocytic leukemia that exposed him to the virtues of
the mushroom.

The effect of mushroom was found to be cent percent in diabetics,
psoriasis, liver and cardiovascular disorders, Dr Venugopal say.

-----

GANOderma seems like the right name for a P cure nostrum.

Lets look see,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=15199592&query_hl=4&itool=pubmed_docsum

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=15625685&query_hl=4&itool=pubmed_docsum
And these guys should team up with these guys,
http://news.biocompare.com/newsstory.asp?id=165687

[...]
Dorothy Supp, PhD, and her team found that skin cells that were
genetically altered to produce higher levels of a protein known as
human beta defensin 4 (HBD4) killed more bacteria than normal skin
cells.

HBD4 is one in a class of proteins that exist throughout the body as
part of its natural defense system. Researchers have only recently
begun targeting these tiny molecules as a way to combat infections.

"If we can add these genetically modified cells to bioengineered skin
substitutes, it would provide an important defense system boost during
the initial grafting period, when the skin is most susceptible to
infection," explains Supp <sniP>

Add in better defensins with magic mushrooms and the sky is the limit.
LOL

--------------------

Forgit about it. Lets go slumming back in the gut. Is their a microbe
switching on and off some
RNA down there or what?

OH! Look at this.

Is the GUT the main battleground for Aids?
http://www.aidsmap.com/en/news/4F5091CB-391F-47F1-AEF9-DB938ED08C81.asp
Gut microbes linked to immune activation, HIV disease progress, may
explain long-term CD4 loss

Leakage of microbes from the gut as a result of HIV-related damage to
the wall of the gut may be one of the major causes of the systemic
immune activation that drives the HIV disease process, according to a
United States-led research group reporting in Nature Medicine. Their
findings provide further evidence that the lymphoid tissue of the gut
is the chief site of the struggle between HIV and its host, and that
early HIV treatment must be targeted to this battleground.

The normal gut lining transports antigens associated with microbes and
food to immune cells located in clusters beneath its surface, called
Peyer's patches. The majority of the body's immune cells are
located here, and they provide the early warning system that decides
which microbes need to be eliminated or blocked from accessing the
circulating blood.

The normal gut is host to vast quantities of `friendly` bacteria that
actually protect the surface of the gut from inflammation and unwelcome
microbes.

However, when the gut lining is damaged these bacteria and food
antigens can leak through the tight junctions that normally present
them to immune cells, and find their way into the circulation, where
they trigger a generalised activation of immune cells. This is known to
happen during immunosuppressive treatment for transplantation, and
leads to exacerbation of graft-versus-host disease. This phenomenon is
called translocation.

In HIV disease, major injury to the gut immune environment begins to
occur immediately after infection. Extensive depletion of CD4+ memory
cells occurs in the gut lymphoid tissue within 4-6 weeks of infection,
while HIV itself damages the lining of the gut, making the lining
permeable.

Meanwhile, generalised immune activation causes the population of
activated CD4 cells to grow, and since these are the target cells for
HIV infection, a higher level of immune activation leads to a faster
progression of HIV disease.

In order to prove that translocation of microbes contributes to the
systemic immune system activation that drives HIV disease progression,
scientists at the Vaccine Research Center of the US National Institutes
of Allergy and Infectious Diseases and colleagues studied HIV-positive
individuals (n=205), uninfected human controls (n=47), primates
infected with simian immunodeficiency virus and uninfected primate
controls.

They tested all subjects for plasma levels of lipopolysaccharide (LPS),
a component of gram-negative bacterial cell walls that is a proven
predictor of gastrointestinal permeability.

LPS levels were significantly higher than the control group in
HIV-positive individuals with chronic HIV infection, but not in the 50
HIV-positive individuals tested less than four weeks after
seroconversion.

Using SIV-infected macaques, the group then demonstrated that gut
bacteria were the source of LPS by monitoring LPS levels before and
after treatment with an antibiotic regimen designed to eliminate gut
bacteria. LPS levels rose after SIV infection, then declined markedly
after one week of antibiotic treatment, concomitant with a substantial
decrease in faecal bacteria.

In HIV-infected individuals, antiretroviral therapy reduced LPS levels
when viral load was undetectable in 24 of 28 patients after 48 weeks on
treatment, and there was an inverse correlation between the reduction
in LPS and the increase in CD4 cell count on treatment (r=0.463,
p=0.015).

In individuals classified as `elite controllers` - those who control
HIV below the limit of detection without treatment - LPS levels were
elevated compared to the control group, but there was significantly
less immune activation than in HIV-positive individuals with detectable
viremia, suggesting that the immunmostimulatory effects of LPS are
neutralised in some HIV-positive individuals by higher levels of
endotoxin-core antibodies, which clear LPS from the circulation.

"These data point to a central role for HIV itself in perpetuating
microbial translocation, such that ongoing infection and depletion of
CD4 T cells throughout the chronic phase of the disease prevents the
re-establishment of competent immunological control of microbial
translocation. The complement to such events would be that microbial
translocation in its turn perpetuates viral replication through the
provision and activation of target T-cells for HIV."

This month another research group showed that the early loss of CD4
cells in the gut lymphoid tissue is rarely repaired by antiretroviral
therapy, despite long periods of viral suppression. Is there a link
between this finding and the NIAID finding that microbial translocation
is causing immune activation?

Daniel Douek of the Vaccine Research Center told aidsmap: "The link
could be that local immune activation in the gut is associated with the
same microbial translocation that causes systemic immune activation.
The lack of immune reconstitution would prevent restoration of the
mucosal barrier. Also - the immune activation could prevent immune
reconstitution and drive viral replication. So it's a vicious
circle."

Taken together the researchers say that the findings suggest the need
for new interventions which can "prevent or reduce the propagation of
HIV at mucosal surfaces, restore the immunological and epithelial
integrity of the mucosal barrier, and to block the cellular and
molecular pathways through which microbial products cause systemic
immune activation."

References

Brenchley JM et al. Microbial translocation is a cause of systemic
immune activation in chronic HIV infection. Nature Medicine.

Haynes BF.Gut microbes out of control in HIV infection. Nature Medicine
12 (12): 1351-1352, 2006.

----------------

LPS from endogenous gut sources plus permeability can be a definite Th1
skew mechanism.

Certainly adds to P severity in my book. Why?

Because it means more TNF-alpha. Then you need more biologicals, right?

yep

So lets learn more about LPS? Why not? What's not to like?

http://www.laboratorytalk.com/news/eus/eus110.html

The scope of this small pan-European meeting covered many of the
functions of heat shock proteins and was a reminder of how this family
of proteins interacts with many biological systems and has far reaching
implications in the manipulation of disease processes. Kathy
Triantafilou (Sussex, UK) has a long established interest in innate
immune recognition of microbial pathogens with particular respect to
LPS. Elegant fluorescent non radioactive energy transfer (Fret) studies
have been carried out on cells stimulated with LPS which demonstrate
the clustering of HSP70 and 90 around TLR4 in lipid rafts.

LPS and HSP70 compete for binding to TLR4 and using truncated fragments
of HSP70 the critical residues for LPS/HSP binding in the ATP binding
cleft were identified.

This work was carried out using human HSP70 and demonstrated that the
signalling pathways are MyD88 dependent.

Professor Gabrielle Multhoff (Regensburg, Germany) continued the theme
of innate immunity in the response to haematological disease.

NK cells incubated with low doses of IL-2 and a peptide derived from
HSP70 (TKD) acted as a danger signal initiating killing of autologous
and allogeneic blasts by NK cells.

This activity was shown to be IL-2 dependent and could not be
demonstrated with HSP70 peptide alone.

Responses to allogeneic haematopoietic stem cells in donor and
recipient and thereby allograft survival or the induction of graft
versus host disease (GvHD) was shown by Bogunia-Kubik (Poland) to be
dependent on polymorphisms within the HSP70 coding genes.

More than 70% of patients with acute GvHD present with elevated levels
of HSP70 in the serum and it was shown that homozygosity of the
HSP70-hom correlated with a greater risk of post transplantation
complications.

HSP as a danger signal was investigated by Professor John Williams
(Chester, UK) who emphasised the importance of the location and time
course of the 'danger' in the outcome of the interaction.

The interplay of both bacterial and host HSPs have a considerable
impact on the regulation of the immune response to infection and
Professor Henderson (London, UK) has investigated the adhesion function
of bacterial HSP and the receptor function of cell stress proteins for
bacterial pro-inflammatory cytokine production.

The chaperone activity of HSP was not neglected and Pawel Stocki gave
an interesting talk on the HSP70/100 machine and its function in
disaggregation of proteins.

Anton Evdonin (Russia) was able to show the transport of HSP through
squamous cell carcinoma cell line(A431) in secretory granules and that
the EGFR transactivation pathway was induced by HSP70 suggesting cross
communication between TLR and EGFR in these cells.

Heat shock proteins continue to fascinate and their multi-functional
properties have much to teach us regarding the interactions of host
with not only pathogens but also with the altered self as presented by
tumour cells and with allogeneic cells in the context of
transplantation.

These interactions a present fertile ground for the development of
intervention strategies in many disease processes.

A full report can be found online and another report is being published
in the January issue of the BioMedical Scientist Lesley Ann Bergmeier
is senior lecturer in applied mucosal immunology, clinical and
diagnostic oral sciences at Barts and the London, Queen Mary's School
of Medicine and Dentistry.

--------------------

How does an immune system become broken? Here's one take on it,
http://www.medicalnewstoday.com/medicalnews.php?newsid=60330
Chaos In The Cell Defect Gene Disrupts Signal Processing Within The
Cell And Damages The Immune System

Researchers from the Innsbruck Biocenter and the Hannover Medical
School in cooperation with the University of Freiburg have discovered a
genetic cause of disrupted signal transduction in cells. If a cellular
adaptor is missing, chaos breaks out within the cell, causing important
signalling actors not to be in the right place at the right time. For
affected patients this results in a complex impairment of the immune
system. The discovery is of wider importance, as disruptions in cell
cycle and cell differentiation play a decisive role in many diseases,
not least in cancer. The renowned journals Nature Medicine and The
Journal of Cell Biology report on these findings.

Cells in an organism receive a continuous stream of different signals
from their environment. Protein molecules at the cell surface register
these signals and pass them on into the cell where they are taken up,
interpreted and processed. Depending on the type of signal, the cells
are prompted to grow, differentiate, proliferate or to die a programmed
cell death. If these complex processes get out of control, it can
result in diseases such as cancer or in immune deficiencies. The
scientists around professor Lukas Huber of the Biocenter at Innsbruck
Medical University are convinced that the spatial and temporal
positioning of the signalling actors is essential: "Any disruption of
this carefully defined order within the cell triggers pathological
changes", Lukas Huber explains. "This is why we seek to understand the
spatio-temporal resolution of the signals within the cell".

Genetically triggered disorders

The clinical impact of this new direction of research became clear when
the clinical research groups around professor Christoph Klein of
Hannover Medical School (MHH) noticed a gene which is responsible for
cell adaptor protein p14. The clinicians at the Department of
Paediatrics, Paediatric Haematology and Oncology at the MHH (led by
professor Karl Welte) had identified a new immune deficiency disorder
which is characterized by impaired growth, impaired immunity and
albinism. Even small infections can become life-threatening for
affected patients. In a long-term search for the genetic cause, the
scientists applied new molecular-biological methods and succeeded, in
cooperation with the working group of Dr. Bodo Grimbacher at the
University of Freiburg and the Helmholtz Centre for Infection Research,
in identifying alterations that resulted in cell adaptor protein p14
being present in minute amounts only. As a result of this genetic
defect, the white corpuscles of the affected patients are reduced in
number and impaired in their function.

Long-term research perspective

Over the last four years, in painstaking detailed work within the
FWF-funded special research project "Cell proliferation and cell death
in tumors" in Innsbruck, professor Lukas Huber has developed a new
innovative mouse model. "This model allows us to selectively switch off
certain genes in individual organs or cell types," Huber explains. In
this way the researchers in Innsbruck were able to reproduce in mice
the results observed in German patients. "We succeeded in showing
unambiguously," said Huber, "that adaptor protein p14 deficiency leads
to total chaos within the cell. The scaffolding proteins put into
position by the adaptor are suddenly no longer in place. The signal
transduction via kinases, which is supported by the scaffolding
proteins, is disrupted." The scientists thus found a potential
objective for the therapy of this hitherto unknown disorder. Professor
Christoph Klein, a cancer specialist and expert at stem cell and gene
therapy, now sees not only possibilities for developing a targeted gene
therapy for affected patients but also envisages novel approaches for
new drugs in the treatment of tumor patients.

Professors Klein and Huber are convinced that "the international
cooperation across disciplines was essential for the success of this
research". They are looking forward to future cooperation yielding many
exciting results.

In the December issue of the Journal of Cell Biology the scientists
published data on the cell cycle and differentiation defect and on the
mouse model used. In the journal Nature Medicine they now explain in
detail the clinical importance of these findings for the immune system.

About the INNSBRUCK MEDIZINISCHE UNIVERSITAET

On the 1st of January, 2004, the Innsbruck Medical University became an
independent university. Until then and from its inception in 1669 - it
had been part of the Leopold Franzens Universitaet Innsbruck. The
Innsbruck Medical University is dedicated to the highest possible
standards in research, teaching and patient care, and aims to establish
itself over the next few years as one of Europe's leading medical
research and training institutions. In doing so it seeks to offer
students the best opportunity for careers in medicine or medical
research and teaching.

INNSBRUCK, MEDIZINISCHE UNIVERSITAET
Communications, Public Relations & Media
Christoph-Probst-Platz
Innrain 52
A-6020 Innsbruck
http://www.i-med.ac.at

------------------------------

randall... to little time.... sigh

randall

unread,

Jan 23, 2007, 2:18:15 AM1/23/07

Hi,

What haPPens when you have a gold mine? You mine it right?

So they tried to pull out as much as possible before a better mine came
along,
http://www.nytimes.com/2007/01/22/business/media/22drug.html?ref=media

Showdown Looms in Congress Over Drug Advertising on TV

[...]

Another F.D.A. letter told Amgen, a biotechnology company, to stop
running commercials for Enbrel, a treatment for the skin disease
psoriasis, that the F.D.A. said minimized "serious risks"
associated with the drug. Amgen immediately withdrew the commercial.
Last year, the company obtained F.D.A. approval of the contents of a
new Enbrel television ad before showing it, David Polk, an Amgen
spokesman said. Corporate lawyers say such advertising is protected by
the First Amendment under a doctrine of commercial free speech. But
some experts say the limits of the protection are murky. The closest
approach to clarity was in 2002 when the Supreme Court rejected, by a
5-to-4 vote, a federal restriction on advertising by pharmacists who
make their own compounds.

"It is a giant game of chicken between the government and the
industry," said R. Alta Charo, a law professor and bioethics
specialist at the University of Wisconsin in Madison. "I don't
believe either side really wants to see a definitive case go to the
Supreme Court because neither side is willing to take the risk that
they will lose."

Professor Charo was a member of a committee of experts of the Institute
of Medicine, which examined drug safety issues at the request of the
F.D.A. Last fall, the committee called on Congress to give the F.D.A.
new authority over advertising, including the power to require a
two-year moratorium on advertising before approving a new drug. <sniP>

-----------

And the tides turn. With change comes oPPortunity.

http://www.pharmaceutical-business-review.com/article_researchwire.asp?guid=16D516FD-2694-417F-AAAE-E06B0F02D133
Psoriasis market: Humira set to overtake Enbrel
22nd January 2007

The psoriasis market is experiencing a dynamic period, with the
approval of a number of anti-TNF therapies, which are more effective
than the initial biologic products launched in psoriasis. The approval
of Wyeth and Amgen's Enbrel for psoriasis in 2004 has made it the
market leader, but other anti-TNF's including Tanabe and
Schering-Plough's Remicade and Abbott's blockbuster brand Humira are
forecast to erode Enbrel's position. Approval for Humira in a psoriasis
indication in Europe and the US is expected in Q2 2008 in both regions.
Humira is forecast to have more sales than both Enbrel and Remicade in
this indication by 2012.

---------------

The P gene thing goes on with recent familiar players,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17236132&query_hl=1&itool=pubmed_docsum

A Large-Scale Genetic Association Study Confirms IL12B and Leads to the
Identification of IL23R as Psoriasis-Risk Genes.

* Cargill M,
* Schrodi SJ,
* Chang M,
* Garcia VE,
* Brandon R,
* Callis KP,
* Matsunami N,
* Ardlie KG,
* Civello D,
* Catanese JJ,
* Leong DU,
* Panko JM,
* McAllister LB,
* Hansen CB,
* Papenfuss J,
* Prescott SM,
* White TJ,
* Leppert MF,
* Krueger GG,
* Begovich AB.

Celera, Alameda, CA, USA.

We performed a multitiered, case-control association study of psoriasis
in three independent sample sets of white North American individuals
(1,446 cases and 1,432 controls) with 25,215 genecentric
single-nucleotide polymorphisms (SNPs) and found a highly significant
association with an IL12B 3'-untranslated-region SNP (rs3212227),
confirming the results of a small Japanese study. This SNP was
significant in all three sample sets (odds ratio [OR](common) 0.64,
combined P [Pcomb]=7.85x10-10). A Monte Carlo simulation to address
multiple testing suggests that this association is not a type I error.
The coding regions of IL12B were resequenced in 96 individuals with
psoriasis, and 30 additional IL12B-region SNPs were genotyped.
Haplotypes were estimated, and genotype-conditioned analyses identified
a second risk allele (rs6887695) located ~60 kb upstream of the IL12B
coding region that exhibited association with psoriasis after
adjustment for rs3212227. Together, these two SNPs mark a common IL12B
risk haplotype (OR(common) 1.40, Pcomb=8.11x10-9) and a less frequent
protective haplotype (OR(common) 0.58, Pcomb=5.65x10-12), which were
statistically significant in all three studies. Since IL12B encodes the
common IL-12p40 subunit of IL-12 and IL-23, we individually genotyped
17 SNPs in the genes encoding the other chains of these cytokines
(IL12A and IL23A) and their receptors (IL12RB1, IL12RB2, and IL23R).
Haplotype analyses identified two IL23R missense SNPs that together
mark a common psoriasis-associated haplotype in all three studies
(OR(common) 1.44, Pcomb=3.13x10-6). Individuals homozygous for both the
IL12B and the IL23R predisposing haplotypes have an increased risk of
disease (OR(common) 1.66, Pcomb=1.33x10-8). These data, and the
previous observation that administration of an antibody specific for
the IL-12p40 subunit to patients with psoriasis is highly efficacious,
suggest that these genes play a fundamental role in psoriasis
pathogenesis.

PMID: 17236132

---------------

More P genes.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17221218&query_hl=1&itool=pubmed_docsum

The CCHCR1 (HCR) gene is relevant for skin steroidogenesis and
downregulated in cultured psoriatic keratinocytes.

* Tiala I,
* Suomela S,
* Huuhtanen J,
* Wakkinen J,
* Holtta-Vuori M,
* Kainu K,
* Ranta S,
* Turpeinen U,
* Hamalainen E,
* Jiao H,
* Karvonen SL,
* Ikonen E,
* Kere J,_________________________*
* Saarialho-Kere U,
* Elomaa O.

Department of Medical Genetics, University of Helsinki, Helsinki,
Finland.

The HCR gene, officially called Coiled-Coil alpha-Helical Rod protein 1
(CCHCR1), located within the major psoriasis susceptibility locus
PSORS1, is a plausible candidate gene for the risk effect. Recently,
CCHCR1 was shown to promote steroidogenesis by interacting with the
steroidogenic acute regulator protein (StAR). Here, we examined the
role of CCHCR1 in psoriasis and cutaneous steroid metabolism. We found
that CCHCR1 and StAR are expressed in basal keratinocytes in
overlapping areas of the human skin, and CCHCR1 stimulated pregnenolone
production in steroidogenesis assay. Overexpression of either the
CCHCR1*WWCC risk allele or the non-risk allele enhanced steroid
synthesis in vitro. Furthermore, the cytochrome P450scc enzyme was
expressed in human keratinocytes and was induced by forskolin, a known
activator of steroidogenesis, and forskolin also upregulated CCHCR1.
CCHCR1 has an altered expression pattern in lesional psoriatic skin
compared to normal healthy skin, suggesting its dysregulation in
psoriasis. We found that the expression of CCHCR1 is downregulated
twofold at the mRNA level in cultured non-lesional psoriatic
keratinocytes when compared to non-psoriatic healthy cells. Our results
also suggest a connection between CCHCR1 and vitamin D metabolism in
keratinocytes. The expression of the vitamin D receptor (VDR) gene was
lower in non-lesional psoriatic keratinocytes than in healthy cells.
Furthermore, Vdr expression was downregulated in the keratinocytes of
mice overexpressing the CCHCR1*WWCC risk allele when compared to
keratinocytes from mice with the non-risk allele of CCHCR1. Finally, we
demonstrate that other agents relevant for psoriasis and/or the
regulation of steroidogenesis influence CCHCR1 expression in
keratinocytes, including insulin, EGF, cholesterol, estrogen, and
cyclosporin A. Taken the role of steroid hormones, including vitamin D
and estrogen, in cell proliferation, epidermal barrier homeostasis,
differentiation, and immune response, our results suggest a role for
CCHCR1 in the pathogenesis of psoriasis via the regulation of skin
steroid metabolism.

PMID: 17221218

Only one other pubmed abstract for CCHCR1 and here it is,

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16096103&query_hl=8&itool=pubmed_docsum
Mapping and identifying genes for asthma and psoriasis.

* Kere J.________________________*

Department of Biosciences at Novum, Karolinska Institute, 14157
Huddinge, Sweden. juha...@biosci.ki.se

Susceptibility genes for complex diseases are characterized by reduced
penetrance, caused by the influence of other genes, the environment or
stochastic events. Recently, positional cloning efforts have yielded
several candidate susceptibility genes in different complex disorders
such as Crohn's disease and asthma. Within a genetic locus, however,
the identification of the effector gene may pose further challenges and
require functional studies. I review two examples of such challenges:
the cloning of GPR154 (GPRA) and AAA1 on chromosome 7p14 at a
susceptibility locus for atopy and asthma, and the study of HLA-Cw6,
CCHCR1 (HCR) and CDSN on chromosome 6p21 at PSORS1, the major
susceptibility locus for psoriasis. The susceptibility locus for atopy
and asthma contains two genes and only one of them is protein coding.
We studied its isoform-specific expression in bronchial biopsies and in
a mouse model of ovalbumin-induced inflammation of bronchial epithelia.
In the PSORS1 locus, strong linkage disequilibrium between genes has
made it difficult to distinguish the effects of the three nearby genes.
We engineered transgenic mice with either a HCR non-risk allele or the
HCR*WWCC risk allele controlled by the cytokeratin-14 promoter. The
results suggested that the overexpression of HCR in mouse skin was
insufficient to induce a psoriasiform phenotype, but it appeared to
induce allele-specific gene expression changes that were similar to
those observed in psoriatic skin.

PMID: 16096103

--------------

Old news on FAE's MOA? What receptor or pathway does glutathione
uPregulate/downregulate at the expense of psoriasis?

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17235328&query_hl=1&itool=pubmed_docsum

Dimethylfumarate Induces Immunosuppression via Glutathione Depletion
and Subsequent Induction of Heme Oxygenase 1.

* Lehmann JC,
* Listopad JJ,
* Rentzsch CU,
* Igney FH,
* von Bonin A,
* Hennekes HH,
* Asadullah K,
* Docke WD.

1CRBA Inflammation, Schering AG, Berlin, Germany.

A mixture of different fumaric acid esters (FAE) is established for
systemic therapy of psoriasis, a frequent inflammatory skin disease.
The main active compound of FAE, however, has not been identified so
far, and the mechanisms of activity are only partially understood. We
analyzed the impact of FAE on in vitro immune function and aimed to
gain knowledge about the mode of action. Dimethylfumarate (DMF) and
diethylfumarate (DEF), but not fumaric acid, methylhydrogenfumarate and
ethylhydrogenfumarate, exhibited potent depression of inflammatory
cytokine secretion (e.g., tumor necrosis factoralpha, IL-12, and
IFNgamma) in activated human peripheral blood mononuclear cells.
Moreover, solely DMF and DEF inhibited alloreactive T-cell
proliferation in mixed leukocyte reaction. Interestingly, these
immunosuppressive effects were accompanied by the strong induction of
the anti-inflammatory stress protein heme oxygenase 1 (HO-1).
Supplementation with exogenous glutathione (GSH), which is known to
bind DMF, prevented both HO-1 induction as well as the
anti-inflammatory effects of DMF. Moreover, inhibition of HO-1 activity
restored the diminished IL-12 and IFNgamma production after FAE
treatment. These results suggest that DMF acts as active compound
within the FAE mixture and at least partially mediates its
immunomodulatory activity by the induction of the anti-inflammatory
stress protein HO-1 ascribed to the functional depletion of reduced
GSH.Journal of Investigative Dermatology advance online publication, 18
January 2007; doi:10.1038/sj.jid.5700686.

PMID: 17235328

----------

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17225734&query_hl=1&itool=pubmed_docsum

[The immune system of the skin and stereotyped reaction patterns in
inflammatory skin diseases]
[Article in Dutch]

* Jaspars EH.

VU Medisch Centrum, afd. Pathologie, Postbus 7057, 1007 MB Amsterdam.
eh.ja...@vumc.nl

The clinical and histological presentation of inflammatory disease in
the skin is exceedingly heterogeneous. Nonetheless, most inflammatory
dermatoses can be classified according to five stereotypical
tissue-reaction patterns: the spongiotic, the lichenoid, the
psoriasiform, the vesiculo-bullous and the vasculopathic. By means of
potent antigen-presenting cells, cytokine and chemokine cascades and a
skin-specific cutaneous lymphocyte antigen (CLA)-positive lymphocyte
population, the skin is able to respond very efficiently to pathogens
that threaten the individual. Inflammatory skin diseases follow the
rules and routes of the physiological reaction to inflammation but
however for various reasons the immune response may be inadequate,
enhanced or chronic. In allergic contact dermatitis, which is a
prototype of the spongiotic reaction pattern, the inflammation is
directed against an otherwise harmless antigen, for which the body is
sensibilized. Lichenoid dermatitis (like erythema multiforme, graft
versus host disease or lupus erythematodes) is based on a primary
cytotoxic reaction against the basal epithelial cell, due to
alterations in its antigenic make-up or due to an altered immune
response. In psoriasis, an example of psoriasiform dermatitis, the
interaction between inflammatory cells, antigen presenting cells and
epithelial cells is disturbed.

PMID: 17225734

-----------

This one makes me wonder what haPPened.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17223889&query_hl=1&itool=pubmed_docsum

Psoriasis after cord blood stem cell transplantation.

* Hubiche T,
* Leaute-Labreze C,
* Lepreux S,
* Perel Y,
* Taieb A.

Paediatric Dermatology Unit, Hopital Pellegrin-Enfants, CHU De
Bordeaux, France.

PMID: 17223889

Wow. Stem cells and a P test. What will they think of next?

------------

And a new clue to immunosupressants.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17223881&query_hl=1&itool=pubmed_docsum

Severe psoriasis treated with a new macrolide: everolimus.

* Frigerio E,
* Colombo MD,
* Franchi C,
* Altomare A,
* Garutti C,
* Altomare GF.

Institute of Dermatology, Ospedale Galeazzi, University of Milan, Via
R. Galeazzi 4, 20161 Milan, Italy.

Psoriasis is an immune-mediated disease with a chronic relapsing
course, and the particularly severe forms that are refractory to
traditional therapies are often difficult to manage. Everolimus
(Certican((R)); Novartis, Basel, Switzerland) is a new
rapamycin-derived macrolide that is used in the prophylaxis of
rejection in heart and kidney transplant patients. The mechanism
underlying its immunosuppressant and antiproliferative activity is
different from, but complementary to, that of calcineurin inhibitors
such as ciclosporin. We describe a woman with severe psoriasis treated
with everolimus combined with subtherapeutic doses of ciclosporin.

PMID: 17223881

Immunosuppresants
http://en.wikipedia.org/wiki/Immunosuppressant

-------------

randall....

JXStern

unread,

Jan 23, 2007, 10:26:27 AM1/23/07

On 22 Jan 2007 23:18:15 -0800, "randall" <ranh...@aol.com> wrote:

>What haPPens when you have a gold mine? You mine it right?
>
>So they tried to pull out as much as possible before a better mine came
>along,
>http://www.nytimes.com/2007/01/22/business/media/22drug.html?ref=media
>
>Showdown Looms in Congress Over Drug Advertising on TV
>
>[...]
>
>Another F.D.A. letter told Amgen, a biotechnology company, to stop
>running commercials for Enbrel, a treatment for the skin disease
>psoriasis, that the F.D.A. said minimized "serious risks"
>associated with the drug. Amgen immediately withdrew the commercial.

I think it's the Humira ad (for RA) that cheerily says, "oh, the
following side effects have occurred!" and then lists them all,
exactly the same as for Enbrel. I think they should have someone
dress up like Satan to list the side effects in ALL drug ads.

>-----------
>
>And the tides turn. With change comes oPPortunity.
>
>
>http://www.pharmaceutical-business-review.com/article_researchwire.asp?guid=16D516FD-2694-417F-AAAE-E06B0F02D133
>Psoriasis market: Humira set to overtake Enbrel
>22nd January 2007
>
>The psoriasis market is experiencing a dynamic period, with the
>approval of a number of anti-TNF therapies, which are more effective
>than the initial biologic products launched in psoriasis. The approval
>of Wyeth and Amgen's Enbrel for psoriasis in 2004 has made it the
>market leader, but other anti-TNF's including Tanabe and
>Schering-Plough's Remicade and Abbott's blockbuster brand Humira are
>forecast to erode Enbrel's position. Approval for Humira in a psoriasis
>indication in Europe and the US is expected in Q2 2008 in both regions.
>Humira is forecast to have more sales than both Enbrel and Remicade in
>this indication by 2012.

I haven't heard that Humira is more effective than Enbrel, just that
you inject it less often - which is a mixed blessing, because if and
when you get sick, you may want to turn it *off* as quickly as
possible.

> Moreover, inhibition of HO-1 activity
>restored the diminished IL-12 and IFNgamma production after FAE
>treatment. These results suggest that DMF acts as active compound
>within the FAE mixture and at least partially mediates its
>immunomodulatory activity by the induction of the anti-inflammatory
>stress protein HO-1 ascribed to the functional depletion of reduced
>GSH.

It promotes HO activity and keeps your pimp hand strong!

> We describe a woman with severe psoriasis treated
>with everolimus combined with subtherapeutic doses of ciclosporin.

>and a little paper umbrella.

Cocktail time! But why?

randall

unread,

Jan 26, 2007, 1:51:21 AM1/26/07

Hi,

We're only a week from Groundhog's day and the radiation imPaired
madness begins.

Will you see your shadow in this next one? Cabin fever or one degree of
stuPidity?

http://www.westword.com/Issues/2007-01-25/news/whatssofunny.html

The only thing better than a teenage girl's body is a tan teenage
girl's body. Lao Tzu said that, and it makes perfect sense if you think
about it. Would you rather sleep with Lindsay Lohan in Mean Girls or
Lindsay Lohan in Herbie Fully Loaded? For Mean Girls, they sexed the
little whore right up, whitened her teeth, padded her bra, gave her a
tan. Herbie Fully Loaded was more of a family flick, so there was no
need to tan the trollop for that one. They just gave viewers a bland,
mildly attractive redhead and expected the whimsical adventure of a
Volkswagen come to life to carry you through an hour and a half. Which
it did, since you were not in the back of the movie theater getting all
Pee-wee on that Herman; you were paying attention. Because Lohan wasn't
tanned. And even though the correct answer to the original question is
that you would rather curb-stomp Lindsay Lohan in a desolate barrio
cul-de-sac than sleep with her, the point remains the same: Teenage
girls look best bronzed.

So why are state senator Bob Hagedorn and state representative Anne
McGihon -- aka Team Never Got Laid in High School -- trying to deprive
us of tanned teens? Why are they trying to strip away the very essence
of what makes America so great? What's next? Banning apple pie and corn
on the cob? Putting an end to toddler beauty pageants and rodeos in
which animals are abused for our enjoyment?

It's a slippery slope.

Hagedorn and McGihon -- aka Team Party's Over Everybody Out -- recently
introduced a bill that, if passed, "prohibits the use of an artificial
tanning device by a minor unless specifically prescribed by a
physician." Say, if a physician fears your kid may die from being pale,
a malady that has claimed so many Irish tweens. According to what I
read of their proposal before I got bored and looked up Lindsay Lohan
on www.imdb.com, the FDA considers ultraviolet radiation bad, the
lawmakers think that artificial tanning can be as bad for your skin as
tanning outdoors, blah, blah, blah, we've got a new governor so we need
to look busy and make a good impression, quick, write a tanning bill,
blah, blah, blah, melanoma. "We talk about cancer prevention, but skin
cancer is not as highlighted as it should be in Colorado," comments
McGihon. "If kids are given free rein, it's a health risk."

Still, Hagedorn and McGihon -- aka Team Will Somebody Please Sign My
Yearbook -- is this really such a pressing matter?

VaNita Kravig doesn't think so. "I don't really see what the big deal
is," says Kravig, who manages the At the Beach Tanning Salon in
Englewood. "Anyone who is under eighteen has to have a parent sign off
to allow them to tan, anyway. They can't just walk in and tan."

And while McGihon worries that kids can fake parental consent, teens
aren't really flocking to tanning salons like crazed UV junkies,
yearning for just one more taste of the fake sun. "Kids these days
don't seem to be that into tanning," Kravig says. "Maybe before prom or
something, but I estimate that about 10 percent or less of our
clientele is underage."

Besides, Kravig explained, while the sun emits about 35 percent harmful
UV-B radiation rays, most of the tanning beds at At the Beach and other
salons emit about 6.5 percent. That means it's safer to be in a tanning
bed than it is to be outside! Yet I didn't see either Hagedorn or
McGihon line up last legislative session to co-sponsor the bill I
introduced to destroy the sun -- a plan, I might add, that involved
both rockets and chimpanzees.

In addition to being safer than the sun, salon tanning also offers
numerous health benefits. People with ____psoriasis______ tan to help
their ailment, as do people who need more vitamin D. Many people find
that the heat from tanning beds alleviates back pain and stress, and it
can even help clear up acne! But apparently Hagedorn and McGihon don't
think that teens need acne relief -- which just shows how out of touch
they are. That's right, voters, in addition to wanting to keep our
teens pale, Hagedorn and McGihon also want them zit-faced. And that's
just wrong. Not many people I know have logged on to
www.barelylegalpaleacnedteens.com, even back when they had that Lindsay
Lohan spread.

So, in conclusion, members of the 66th General Assembly of the State of
Colorado, vote down Senate Bill 07-023, and vote it down hard. Let's
send a message to Hagedorn and McGihon -- aka Team Probably Never Heard
of What's So Funny Until an Intern Placed This Column in Front of Them
-- and let them know that we like our teens bronzed and we like our
teens beautiful.

Thank you, and God bless America.

-----------

A tanned lohan- http://media.westword.com/474170.0.jpg

So Lao Tzu said loham looked better tanned?

OK, what else did he say?
http://www.chebucto.ns.ca/Philosophy/Taichi/lao.html

How about this instead?
http://en.wikipedia.org/wiki/Laozi

And on to,
http://en.wikipedia.org/wiki/I_Ching

-------

Ok, I know.

You want the one degree of separation of P.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17239583&query_hl=1&itool=pubmed_docsum

The UVB-induced synthesis of vitamin D(3) and
1alpha,25-dihydroxyvitamin D(3) (calcitriol) in organotypic cultures of
keratinocytes: Effectiveness of the narrowband Philips TL-01 lamp
(311nm).

* Lehmann B,
* Knuschke P,
* Meurer M.

Department of Dermatology, Carl Gustav Carus Medical School, Dresden
University of Technology, D-01307 Dresden, Germany.

Both calcitriol and UVB radiation exert potent antipsoriatic effects.
We hypothesize that the therapeutical effect of UVB radiation may be
attributed at least in part to UVB-triggered cutaneous synthesis of
calcitriol. The optimum wavelength for initiation of the vitamin D(3)
pathway was found to be in the range of 300+/-5nm in vitro and in vivo.
The narrowband Philips TL-01 lamp which is commonly used as UVB source
for phototherapy of psoriasis has maximum spectral irradiance at around
311nm which is presumed to be, however, of lesser importance in
photochemical activation of the vitamin D(3) pathway. The aim of this
study was to compare the vitamin D(3) and calcitriol-inducing potential
of UVB from the TL-01 lamp with that of monochromatic UVB at
300+/-2.5nm and 310+/-2.5nm in organotypic cultures of keratinocytes
supplemented with 25muM 7-DHC. We found that maximum
calcitriol-generating capacity of the TL-01 lamp at 500mJ/cm(2) and 16h
after irradiation still amounts up to 44% of that found after
monochromatic irradiation at 300+/-2.5nm and 30mJ/cm(2). Thus, the
antipsoriatic effect of UVB emitted from the TL-01 lamp may, at least
in part, based on the antiproliferative and prodifferentiative action
of newly synthesized calcitriol on epidermal keratinocytes.

PMID: 17239583

-------

And a kicker from a drug producer.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17243489&query_hl=1&itool=pubmed_docsum

Drug evaluation: the C5a receptor antagonist PMX-53.

* Kohl J.

Cincinnati Children's Hospital Research Foundation, Division of
Molecular Immunology, MLC 7021, Cincinnati, OH 45229, USA.
Joerg...@chmcc.org

Peptech is developing PMX-53, a complement C5a inhibitor for the
potential treatment of inflammatory disorders, including rheumatoid
arthritis and psoriasis. Phase Ib/IIa clinical trials have been
completed for both indications.

PMID: 17243489

I'll find a C5a pathway illustration. Or i'll try,

http://www.medscape.com/content/2003/00/45/36/453656/453656_fig.html

---------

Maybe all we need is sarcasm?

No. Not sarcasm, srcasm?

Yep!

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17244028&query_hl=1&itool=pubmed_docsum
Srcasm overexpression in psoriasis-insights into pathogenesis.

* Pulitzer M,
* Li W,
* Hanson M,
* Singh F,
* Elenitsas R,
* Gelfand JM,
* Vanvoorhees A,
* Seykora JT.

Department of Dermatology, University of Pennsylvania Medical School,
Philadelphia, PA, USA.

Background: Psoriasis is a prevalent, chronic cutaneous disorder
associated with a T-cell lymphocytic infiltrate and altered
keratinocyte growth. Some of the molecular features of enhanced
keratinocyte growth include increased growth factor receptor activation
leading to enhanced cellular tyrosine kinase activity. Receptor
tyrosine kinases, including the epidermal growth factor (EGF) receptor,
are important regulators of keratinocyte growth, and increased activity
of this receptor has been detected in psoriasis. A recently discovered,
novel regulator of Src tyrosine kinases, termed Src-activating and
signaling molecule (Srcasm), has been shown to modulate EGF signaling
and promote differentiation in human keratinocytes. Given the
properties of Srcasm, it would be of interest to characterize its
expression in psoriasis. In this study, the levels of Srcasm mRNA and
protein are characterized, and the relationship of these experimental
observations to the psoriasis pathogenesis is discussed. Methods: The
levels of Srcasm mRNA were determined by quantitative reverse
transcriptase polymerase chain reaction (RT-PCR) on RNA isolated from
unremarkable and lesional patient tissue. These data were supplemented
by performing radioactive in situ hybridization on formalin-fixed
biopsy specimens of psoriatic lesions and unremarkable epidermis.
Expression of Srcasm protein was evaluated by protein
immunohistochemistry and Western blotting of protein lysates derived
from patient samples. Results: All experimental modalities show that
levels of Srcasm mRNA and protein were elevated in psoriatic lesions
compared to unremarkable epidermis. Conclusions: Increased levels of
Srcasm mRNA and protein are seen in psoriasis. Given what is known
regarding Srcasm function, increased levels of this molecule in
keratinocytes may represent a cell compensatory mechanism that is
primed to re-establish a physiologic differentiation program. Pulitzer
M, Li W, Hanson M, Singh F, Elenitsas R, Gelfand JM, VanVoorhees A,
Seykora JT. Srcasm overexpression in psoriasis-insights into
pathogenesis.

PMID: 17244028

---------

randall...Face the sun, forget the shadows.

randall

unread,

Jan 26, 2007, 1:47:08 PM1/26/07

Hi,

Want to quit smoking? "Forgit about it!"

Cig smoker who forgot to smoke may lead to addiction cure.
http://www.abc.net.au/science/news/stories/2007/1834202.htm?health

[keywords: Bechara insula ]

Finding the uPstream inflammation links beyond Th1/Th2 pathways.

http://www.bioresearchonline.com/content/news/article.asp?DocID=%7B747DD35B-3186-4477-BEB2-452A892AADD3%7D&Bucket=Current+Headlines&VNETCOOKIE=NO
Molecular Link Between Inflammation And Cancer Discovered
1/26/2007

A team led by biochemists at the University of California, San Diego
has found what could be a long-elusive mechanism through which
inflammation can promote cancer. The findings may provide a new
approach for developing cancer therapies.

Normal dialogue between cell defense and development (left) and chronic
inflammation leading to hyperactive developmental signaling that may
promote cancer (right).
Credit: Alexander Hoffmann, UCSD

The study, published in the January 26 issue of the journal Cell, shows
that what scientists thought were two distinct processes in cells—the
cells’ normal development and the cells’ response to dangers such
as invading organisms—are actually linked. The researchers, who were
also from the Salk Institute for Biological Studies and the La Jolla
Institute for Allergy and Immunology, say that the linkage of these two
processes may explain why cancer, which is normal growth and
development gone awry, can result from chronic inflammation, which is
an out-of-control response to danger.

“Although there is plenty of evidence that chronic inflammation can
promote cancer, the cause of this relationship is not understood,”
said Alexander Hoffmann, an assistant professor of chemistry and
biochemistry at U.C. San Diego, who led the study. “We have
identified a basic cellular mechanism that we think may be linking
chronic inflammation and cancer.”

Cellular defense is a rapid process compared to cellular development,
just as a state’s response to terrorist threats is swifter than the
construction of new infrastructure. However, in both settings,
safeguarding against threats and building structures have certain steps
in common and require similar types of workers, or molecules.

Hoffmann referred to the parallel sets of steps in cellular defense and
development as “mirror image pathways.” His team showed that these
pathways are not distinct from one another because they are linked by a
protein called p100. They found that inflammation leads to an increase
in p100, but that p100 is also used in certain steps in development.
Therefore p100 allows communication between inflammation and
development.

A small amount of dialogue between inflammation and development is
beneficial, say the researchers, akin to how information from
anti-terrorism efforts could be useful to crews building the state’s
infrastructure. On the other hand, the constant influence of defense
processes on development is detrimental.

“Studies with animals have shown that a little inflammation is
necessary for the normal development of the immune system and other
organ systems,” explained Hoffmann. “We discovered that the protein
p100 provides the cell with a way in which inflammation can influence
development. But there can be too much of a good thing. In the case of
chronic inflammation, the presence of too much p100 may overactivate
the developmental pathway, resulting in cancer.”

In the paper, the researchers propose that thinking of the processes of
defense and development as part of a single large system “represents
an opportunity for therapeutic intervention.” For example, it might
be easier to break the link between inflammation and cancer by
targeting the developmental pathway, rather than the inflammation
pathway.

“Many of the developmental signals that cells use are sent outside
the cell, so they should be easier to block with drugs than
inflammation signals, which tend to be confined within cells,” said
Hoffmann. “It’s more challenging to design drugs that will enter
cells.”

Because the molecules that play a role in the inflammation and
development pathways have been extensively studied for many years, the
researchers say that it is surprising to find a new molecule that
significantly revises scientists’ understanding about the
interactions between inflammation and development. They credit their
discovery to an approach that combines biochemical techniques and
computation.

“Our mathematical model of inflammation and development includes 98
biochemical reactions,” said Soumen Basak, a postdoctoral fellow
working with Hoffmann. “ When we ran the model, it predicted that
p100 levels would be elevated for a significant period of time when the
inflammation pathway was stimulated. We confirmed the prediction using
biochemical techniques with cells in the laboratory.”

“ The finding is exciting because it means that p100 provides cells
with a memory to inflammatory exposure,” added Basak, who was the
first author on the paper.

Also contributing to the study were Hana Kim, Jeffrey D. Kearns, Ellen
O’Dea, Shannon L. Werner and Gourisankar Ghosh from U.C. San Diego,
Vinay Tergaonkar and Inder M. Verma from the Salk Institute for
Biological Studies, and Chris A. Benedict and Carl F. Ware from the La
Jolla Institute for Allergy and Immunology.

The study was supported by the National Institutes of Health, the
Leukemia and Lymphoma Society of America and the American Heart
Association.

SOURCE: University of California

------------

Fixing the gut damage. Will it point to a direction to fix us?

--------------
We're on a roll with the gut thing. Let's go for more.

New Gene for crohn's
http://www.genomicsproteomics.com/index.aspx?ID=79240
Researchers from the University Hospital of the Christian-Albrechts
University in Kiel, Germany and Applied Biosystems, an Applera
Corporation Business, have identified and characterized a genetic
variation in a gene not previously associated with the disorder that
can provide further evidence that an abnormal immune response to
bacteria in the digestive tract may lead to the intestinal inflammation
characteristic of the disease.

The results of the team’s three-year collaboration will be published
in the February issue of Nature Genetics.

The research team tested DNA samples from patients with Crohn’s
disease using the Applied Biosystems SNPlex™ Genotyping System, which
employs pre-designed assays on the company’s capillary
electrophoresis DNA analysis platform.

As part of the genotyping study, the team conducted a genome-wide
association scan of approximately 20,000 coding genetic variants that
are thought to produce functional changes at the protein level.

According to the researchers, among their findings, they identified a
protein-coding genetic variation in the autophagy-related 16-like
(ATG16L1) gene. Neither the ATG16L1 gene, nor this specific genetic
variation, has been previously implicated in Crohn’s disease. The
ATGI6LI gene is part of the autophagosome biological pathway, which
normal cells use to destroy harmful bacteria.

“With the discovery of APG16L1 as a new gene associated with
Crohn’s disease, we have demonstrated the power of a targeted,
genome-wide investigation of coding SNPs,” said Stefan Schreiber,
M.D., Ph.D., Professor of Medicine at the Christian-Albrechts
University in Kiel, Germany, and senior author of the study.

“We also have discovered a further piece of evidence that highlights
epithelial cells in the digestive tract and therefore a weakened
barrier function as the most likely target for the underlying etiology
of chronic inflammatory bowel disease,” said Schreiber.

Further Information: http://www.appliedbiosystems.com/

Could P be up or downstream of this gene? Will it take long for the
scientist to understand the
ramifications here?

Nope.
------------

How stressed are you this time of year? Want to go back in to your hole
on groundhog's day or
even sooner?

What are you a man or a hog?

Your both made up of the same stuff.

Are your cells stressed?
http://www.laboratorytalk.com/news/eus/eus110.html

--------------------

Are the real scientists using this info to cure us yet?

Maybe the horizon for cancer (Th2) is coming in to view.

http://home.businesswire.com/portal/site/google/index.jsp?ndmViewId=news_view&newsId=20070111005192&newsLang=en

And gosh, it's only .22 cents.

randall... at least the sunshine is still cheaPer!

randall

unread,

Jan 28, 2007, 8:34:16 PM1/28/07

Hi,

The Sunny little ground hog quest continues.

Or is it a P quest in search of your shadow?

I don't know.

We'll let the venue unfold regardless.

How can we stoP the mess otherwise?

http://www.newscientist.com/article/dn11039-how-sunshine-triggers-skin-
repair.html
How sunshine triggers skin repair

A blast of sunshine could help fight skin diseases and cancer by
attracting immune cells to the skin surface, according to a new study.

Eugene Butcher at Stanford University in California, US, and
colleagues discovered an interesting immune process in human skin.
Immune cells in the skin, called dendritic cells, convert vitamin D3
(produced in exposed skin in response to sunlight) into its active
form.

This "active" vitamin D3 then causes T-cells to migrate to the
uppermost layer of the skin, Butcher's team found. T-cells are the
immune cells that destroy damaged and infected cells, and they also
regulate other immune cells.

The findings explain how T-cells "know" to go to the skin's surface
once the skin has suffered some sun-induced DNA-damage, the
researchers say.

"Sunshine is good for you, as long as it's not too much," says team
member Hekla Sigmundsdottir. She points out that the skin disorder
psoriasis is sometimes treated with vitamin D3 creams - it may work by
moving T-cells into the skin, she speculates.

The finding adds to a growing body of evidence that dendritic cells,
which live in tissues that are exposed to the outside environment,
such as the skin and nose, run "traffic control" for the immune
system, interpreting local conditions and directing T-cells to where
they are needed.

Journal reference: Nature Immunology (DOI: 10.1038/ni1433)

-----------

Holy craP-a-zoid I wondered how this happened. You toast with UVR
(ultra violet radiation)
And the good witch comes to the skin surface and kicks P arse behind.
Or something like that.

----------

Let's add some more science to the above sunny factoids.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?
db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17255956&query_hl=1&
itool=pubmed_docsum

IL-20 Gene Expression Is Induced by IL-1beta through Mitogen-Activated
Protein Kinase and NF-kappaB-Dependent Mechanisms.

* Otkjaer K,
* Kragballe K,
* Johansen C,
* Funding AT,
* Just H,
* Jensen UB,
* Sorensen LG,
* Norby PL,
* Clausen JT,
* Iversen L.

1Department of Dermatology, Aarhus University Hospital, Aarhus
University, Aarhus, Denmark.

IL-20 is a novel member of the IL-10 cytokine family with pleiotropic
effects. Current knowledge of what triggers and regulates IL-20 gene
expression is sparse. The aim of this study was to investigate the
regulation of IL-20 expression in cultured normal human keratinocytes.
The expression of IL-20 was rapidly induced by proinflammatory
stimuli, in particular IL-1beta, IL-6, and UVB irradiation. Using
kinase inhibitors and small-interfering RNA, we discovered that the
p38 mitogen-activated protein kinase (MAPK) as well as inhibitory
kappaB kinase -NF-kappaB signaling pathways are crucial for IL-20
expression. By electrophoretic mobility shift assay two kappaB-binding
sites were identified upstream from the start codon in the IL-20 gene.
Supershift analysis revealed binding of the p50/p65 heterodimer.
Furthermore, the p38 MAPK was shown to exert its effects on IL-20
expression through activation of the downstream kinase mitogen- and
stress-activated kinase 1 (MSK1), indicating transactivation of NF-
kappaB driven IL-20 messenger RNA transcription as an important
mechanism of action. IL-20 is assumed to be a key cytokine in the
pathogenesis of psoriasis and possibly cancer, and therefore the p38
MAPK, MSK1, and NF-kappaB may be important new molecular targets for
the modulation of IL-20 expression in these diseases.Journal of
Investigative Dermatology advance online publication, 25 January 2007;
doi:10.1038/sj.jid.5700713.

PMID: 17255956

--------------

The gene things are hard on the little grey cells.

The rube goldberg machine nearly has all the known parts? Or does it?

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?
db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17255201&query_hl=1&
itool=pubmed_docsum

Prolactin Enhances Interferon-{gamma}-Induced Production of CXCL9,
CXCL10, and CXCL11 in Human Keratinocytes.

* Kanda N,
* Watanabe S.

Department of Dermatology, Teikyo University School of Medicine, Tokyo
173-8605, Japan.

Psoriasis vulgaris is an autoimmune dermatosis characterized by type 1
T cell infiltration. Prolactin may be involved in the pathogenesis of
psoriasis. CXCL9, CXCL10, and CXCL11 recruit type 1 T cells, and their
production by keratinocytes is enhanced in psoriatic lesions. CXCL9,
CXCL10, and CXCL11 production by keratinocytes depend on nuclear
factor-kappaB (NF-kappaB) and signal transducer and activator of
transcription (STAT)1 and that of CXCL11 depends on IFN-regulatory
factor (IRF)-1. We examined in vitro effects of prolactin on CXCL9,
CXCL10, and CXCL11 production in human keratinocytes. Though prolactin
alone was ineffective, it enhanced interferon-gamma (IFN-gamma)-
induced secretion and mRNA expression of CXCL9, CXCL10, and CXCL11 in
parallel to the activation of STAT1, NF-kappaB, and IRF-1. Inhibitors
of Janus kinase (JAK), p38 MAPK and MAPK/ERK kinase (MEK) suppressed
prolactin plus IFN-gamma-induced CXCL9, CXCL10, and CXCL11 production,
NF-kappaB, STAT1, and IRF-1 activities. Prolactin induced
phosphorylation of JAK2 and ERK, while IFN-gamma induced
phosphorylation of JAK1, JAK2, and p38 MAPK. Prolactin modestly or IFN-
gamma greatly induced tyrosine-phosphorylation of STAT1, and both were
suppressed by JAK inhibitor. Prolactin modestly or IFN-gamma greatly
induced serine-phosphorylation of STAT1, which was suppressed by MEK
or p38 MAPK inhibitor, respectively. Prolactin induced phosphorylation
of inhibitory kappaBalpha and NF-kappaB p65, which was suppressed by
MEK inhibitor. These results suggest that prolactin may enhance IFN-
gamma-induced CXCL9, CXCL10, and CXCL11 production in keratinocytes
via activation of STAT1, NF-kappaB, and IRF-1 through JAK2 and MEK/ERK
pathways. Prolactin may promote type 1 T cell infiltration into
psoriatic lesions via these chemokines.

PMID: 17255201

Lets find a current article on prolactin. OK, lets, here's one from
the bbc,
http://www.timesonline.co.uk/article/0,,2090-2546904,00.html

[...]
Brody claimed levels of prolactin, the hormone that provides the body
with sexual gratification, were 400% higher among male and female
couples who had heterosexual intercourse. Those who abstained from sex
had the highest blood pressure response to stress. <sniP>

That was interesting! LOL

OK and for Prolactin,
http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/hypopit/
prolactin.html

How do we get any clearer now?

WE join the phone teams over at the PCN I guess.

Don't look at this as a downer! lol

It could be an uPPer.

http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=104&STORY=/www/story/
01-24-2007/0004511944&EDATE=
Psoriasis Cure Now Launches Online Volunteer Center to Mobilize
Psoriasis Community

KENSINGTON, Md., Jan. 24 /PRNewswire-USNewswire/ -- "Psoriasis
Cure
Now," a nonprofit patient advocacy group, today launched its online
volunteer center to mobilize the psoriasis community, which is
scattered
across the nation. By answering a few questions, people with psoriasis
and
psoriatic arthritis, and those who care about them, can add themselves
to
Psoriasis Cure Now's volunteer database to be contacted only when a
project
meets their specifications. The volunteer center is on the web here:
http://www.psoriasis-cure-now.org/volunteer.php .
"Whether someone has one hour a year to contribute, or 100 hours,
our
online volunteer center will enable us to mobilize talented
individuals
from Honolulu to Nantucket," said Michael Paranzino, president of
Psoriasis
Cure Now. "Prior to this launch, the labor required to process a
volunteer
who lived far from our base in Washington, DC, could exceed the time
the
volunteer had available. This online questionnaire eliminates that
burden
and makes every volunteer, no matter his or her location or limited
time
available, a valuable addition to the battle for a psoriasis cure."
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. In many cases, people also experience pain,
stiffness and swelling in the joints (psoriatic arthritis). Recent
studies
have found a higher risk of heart attack and higher incidence of
cardiovascular death among patients with severe psoriasis. Children
with
psoriasis report impairment in their quality of life that equals the
impairment reported by children with other chronic illnesses including
asthma, epilepsy and diabetes. Studies in adults have produced similar
results, with a 1999 study finding that "Patients with psoriasis
reported
reduction in physical functioning and mental functioning comparable to
that
seen in cancer, arthritis, hypertension, heart disease, diabetes, and
depression." People with psoriasis also have higher rates of
depression and
suicidal ideation.
This year, the federal government plans to spend about one dollar
in
psoriasis research for each American with the disease, which equals
two
percent of the amount Congress had set aside last year for the Bridge
to
Nowhere.
CONTACT: Michael Paranzino of Psoriasis Cure Now, +1-202-253-4863,
michael @psoriasis-cure-now.org

--------------------------

randall... P gets weirder and stranger!

randall

unread,

Jan 29, 2007, 4:11:09 PM1/29/07

Hi,

For those of you that have followed this thread the last few weeks,
haven't you wondered
about the gut skin to outside skin and psoriasis/immunity connections?

It's been my area of research for a cure since i've started posting
here six years ago and
twenty plus years before that.

It's really starting to come together or so it appears

I know the empirical results that are achievable, i've never known why
exactly.

So, lets continue the daily venue!

Here's another link for today. I've re-posted a few others from this
thread after these below ((((((((())))))).

http://www.the-scientist.com/news/home/44290/

By Chandra Shekhar

Vitamin D protects the skin?

Sunlight-induced vitamin D triggers an immune response in the skin, a
finding that adds to an ongoing debate over the potential benefits of
sun exposure

[Published 29th January 2007 06:31 PM GMT]

Vitamin D generated by sunlight may help protect the skin from
cellular damage, including damage caused by sunlight itself, suggests
a new study published in this week's Nature Immunology. The
researchers found that dendritic cells can convert vitamin D3 --
generated under the skin by sunlight -- into its active hormonal form,
and induce T cells to migrate to the skin.

"It's a new action for a chemical we've known to be present for a long
time," said Clay Cockerell, a dermatologist at the University of Texas
Southwestern Medical Center at Dallas, who was not involved in the
study. "We may eventually find that [the T cell response] is
protective in some way against skin cancer."

However, this does not mean that more time in the sun is good for the
skin, Cockerell stressed. On the contrary, he said, the study implies
that excessive sun exposure could trigger a cutaneous inflammation --
providing yet another reason to stay out of the sun.

Previous studies found that vitamin D3 generated under the skin by the
sun's ultraviolet rays can be converted into its active form,
calcitriol (1,25 dihydroxy-vitamin D3), by enzymes in the liver and
kidneys. The new study shows that human dendritic cells could
accomplish the same conversion without involving the endocrine system
at all. "We propose that the whole thing could be happening in the
skin itself," first author Hekla Sigmundsdottir of the Stanford
University School of Medicine told The Scientist.

In 2004, research showed that vitamin A could induce T cells to move
to the gut. Since the receptors for vitamins A and D are very similar
in structure, and the chemokines expressed by epithelial cells in the
gut and skin are also closely related, Sigmundsdottir and her
colleagues hypothesized a similar T cell homing function for vitamin
D, but with the skin as the target.

Using a chemotaxis assay on a co-culture of T and dendritic cells,
they showed that vitamin D did attract T cells towards CCL27, a
chemokine expressed by skin cells. Indeed, vitamin D not only
activated the T cells' skin-homing receptor CCR10, it suppressed the
corresponding gut-homing receptor CCR9 that vitamin A activates. "The
two vitamins seem to compete with each other," Sigmundsdottir noted.

Vitamin D2, the primary nutritional form of the prohormone, was much
less effective in inducing CCR10 expression in T cells than vitamin
D3, the sun-induced version. "A little sunshine may be good for your
immune system," Sigmundsdottir concluded. "This is what attracts T
cells to the skin."

This study adds to a long-standing debate between two research groups:
Vitamin D experts, some of whom who argue some sun exposure may be
beneficial, and dermatologists (such as Cockerell) who generally
advise against any sun exposure, and recommend supplements to meet the
body's vitamin D requirements. The new study determined, however, that
the levels of vitamin D needed to initiate a T cell response exceed
those found in normal serum, even when taking supplements. "This
suggests that UV production -- leading to the high local vitamin D
levels -- is necessary," said James Fleet of Purdue University in West
Lafayette, Ind., who studies nutrition and vitamin D, but was not
involved in the study.

Fleet offered a possible compromise -- a topical application of
vitamin D, which would protect the skin without putting it at risk
from sunlight exposure. (Fleet said he has no financial ties to
companies marketing topical vitamin D products.) Sigmundsdottir
acknowledged that topical vitamin D -- just like its sun-induced
counterpart -- might also be able to draw T cells to the skin. That
could perhaps explain why topical vitamin D is effective against
psoriasis and other skin conditions, she added.

Chandra Shekhar
mail @the-scientist.com

Links within this article

H. Sigmundsdottir, et al., "DCs metabolize sunlight-induced vitamin D3
to 'program' T cell attraction to the epidermal chemokine CCL27," Nat
Immunol, Jan 28, 2007.
http://www.nature.com/ni/index.html

Clay Cockerell
http://www.utsouthwestern.edu/findfac/contact/0,2359,11378,00.html

A. W. Norman, "Sunlight, season, skin pigmentation, vitamin D, and 25-
hydroxyvitamin D: integral components of the vitamin D endocrine
system," Am J Clin Nutr, 67:1108-10, 1998
'http://www.the-scientist.com/pubmed/15485630

A. McCook, "Vitamin D expert loses post," The Scientist, April 16,
2004
http://www.the-scientist.com/article/display/22116

James Fleet
http://www.purdue.edu/aging/people/faculty/fleet.htm

M. Kira, et al., "Vitamin D and the skin," J Dermatol, 30:429-37, 2003
http://www.the-scientist.com/pubmed/12810989

(((((((((((((((((((((((()))))))))))))))))))))))))))))

And another on the same theme posted in this thread on January 28th
(yesterday).(from a different link)
http://www.dailyindia.com/show/108395.php/A-blast-of-sunshine-helps-
fight-skin-diseases-and-cancer

CCL27 (ctack) brings up these skin links (visuals).
http://www.nature.com/nm/journal/v8/n2/fig_tab/nm0202-157_F1.html
&
http://www.nature.com/nm/journal/v8/n2/fig_tab/nm0202-157_F3.html

FULL ARTICLE:
CCL27−CCR10 interactions regulate T cell−mediated skin inflammation
http://www.nature.com/nm/journal/v8/n2/full/nm0202-157.html

(((((((((()))))))))))))

These gut, skin and sunshine (Vitamin D3) links aren't just a
coincidence lately.

Another recent link was:
http://www.medicalnewstoday.com/medicalnews.php?newsid=60069

Bringing up this gene as another to hook up with the usual suspects:

PTGS2:prostaglandin-endoperoxide synthase 2 (prostaglandin G/H
synthase and cyclooxygenase)
Chromosomal Location: 1q25.2-q25.3

((((((((())))))))))

The only thing missing in recent research is the good gut flora and
immunity.

How about some chicory?

http://www.50connect.co.uk/index.asp?main=http%3A//www.50connect.co.uk/
50c/articlepages/foodanddrink_index.asp%3Fsc%3Dorientalcuisine%26aID
%3D14963

We have all heard of pre and probiotic these days and most of us
understand that we need healthy bacteria in our gut to help prevent
the whole range of bowel problems that are an increasing concern to
the NHS.

The market for 'active milk drinks and yoghurts ' with good bacteria
is £200 million and fast growing, costing consumers around £2 per week
for the recommended dose. According to a recent report by the
University of Reading they should contain at least ten million
lactobacilli or bifidobacteria but around half contain the wrong
bacteria and are of no benefit. Even bread manufacturers are getting
in on the act and adding prebiotic supplements to the loaf, which is
no bad thing but have you stopped to consider a more natural way
without 'playing about' with food?

What most people do not know is that the supplement added is usually
inulin extracted from the chicory plant. Inulin is a carbohydrate like
starch found in just a few plants and they are chicory, dahlias,
sunflower and Jerusalem artichokes. However it is not digested like
starch but fermented in the gut, naturally promoting the growth of the
good bacteria like bifidobacteria in the place where they are needed.

Anyone eating a healthy diet does not need to go to the expense or
trouble of supplements. Chicory is a delicious vegetable cooked or in
salads and any vegetable rich in dietary fibre will contribute to a
healthy gut flora, and in case you still aren't convinced, take a look
at these fabulous recipes and try it for yourself.

(click above links for recipes) salads, steaks and more. YummmO!

-------------------------

randall.... sweet whey is the way! + D3 of course and Tregs and YMMV

randall

unread,

Jan 30, 2007, 1:57:36 PM1/30/07

Hi,

I know you think i'm gonna find that rat hole the groundhog goes down
when he see's his P,
um, I mean his shadow and hide till SUNNY days are upon our beautiful
naked P bespeckled
bodies.

NOT now!

The end is nigh for P in this race for a P cure. While i've stuck with
the gut thing, the
real scientists have tinkered with the actual rube goldberg immunity
machine.

Immune system BRAKES found!

"It acts like an internal brake to dial down the speed and intensity
of an immune response"
Professor Jun Liu
Johns Hopkins University

http://news.bbc.co.uk/2/hi/health/6271781.stm

Scientists say they have learnt how the body controls the machinery it
uses to fight infections and foreign invaders.

The advance, published in the journal Nature, may one day help find
ways to tackle unwanted immune reactions following transplant surgery.

The Johns Hopkins University researchers say a protein molecule called
_carabin_ may be the body's way of restraining its defences.

The US-based team describes it as a "built-in timer" for the immune
system.

Immunity is vital to human survival - the body is constantly
confronted with things that should not be there, including bacteria
and viruses.

The system is constantly adapting when faced with new threats from
unknown organisms.

However, an over-powerful or runaway immune response can be a
disadvantage too, as some illnesses involve the immune system
attacking parts of our own bodies after failing to recognise them.

Damping down

The Johns Hopkins team, led by Professor Jun Liu, has been hunting for
body chemicals that might shed light on how the immune system is
controlled.

They found that a protein called carabin appeared to be important,
latching onto microscopic cells active during an infection.

It is made by white blood cells, one of the most important immune
system cells.

However, its role actually appears to restrict their ability to mount
a response to infection.

They found that when there was more carabin in a cell, it appeared to
"damp down" its activity.

Professor Liu said: "It acts like an internal brake to dial down the
speed and intensity of an immune response so that it doesn't go too
fast or too far, or career out of control and attack healthy cells.

"It's like having a built-in timer to keep the immune system in
check."

Carabin appears to work in a similar manner to drugs such as
cyclosporin, which are used to control rejection of transplanted
organs.

Professor Liu suggested that one eventual use might be a new drug to
do this, and perhaps also help control "auto-immune" illnesses such as
multiple sclerosis.

Drug alternative

Dr Peter Peachell, a pharmacologist from Sheffield University, UK,
said that the paper offered "interesting possibilities".

But he cautioned that the practical difficulties of developing and
manufacturing a drug incorporating a large molecule such as carabin
could be substantial.

He said: "Carabin appears to act on the same target as immune
suppressing drugs such as cyclosporin, so offers a potential
alternative.

"What this research does is tell us more about how the immune system
is regulated, so it brings the possibility of more effective
treatments for a variety of autoimmune diseases, although this is
certainly some way off."

He said that in some circumstances, there might be benefits to
switching carabin off, not increasing it - such as in the early stages
of infection by viruses such as HIV, when a robust and sustained
immune response might be useful.

-----------

What the hell is carabin?

Same story different link (sciam),
http://www.sciam.com/article.cfm?
chanID=sa022&articleID=2EAC42424D12436BDD6A5B8A88480CC3

Let's pubmed it instead of web searching it.

Found the abstract for it:

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?
db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17230191&query_hl=2&
itool=pubmed_docsum
Feedback inhibition of calcineurin and Ras by a dual inhibitory
protein Carabin.

* Pan F,
* Sun L,
* Kardian DB,
* Whartenby KA,
* Pardoll DM,
* Liu JO.

Department of Pharmacology and Molecular Sciences, Johns Hopkins
University School of Medicine, Baltimore, Maryland 21205, USA.

Feedback regulation of adaptive immunity is a fundamental mechanism
for controlling the overall output of different signal transduction
pathways, including that mediated by the T-cell antigen receptor
(TCR). Calcineurin and Ras are known to have essential functions
during T-cell activation. However, how the calcineurin signalling
pathway is terminated in the process is still largely unknown.
Although several endogenous inhibitors of calcineurin have been
reported, none fulfils the criteria of a feedback inhibitor, as their
expression is not responsive to TCR signalling. Here we identify an
endogenous inhibitor of calcineurin, named Carabin, which also
inhibits the Ras signalling pathway through its intrinsic Ras GTPase-
activating protein (GAP) activity. Expression of Carabin is
upregulated on TCR signalling in a manner that is sensitive to
inhibitors of calcineurin, indicating that Carabin constitutes part of
a negative regulatory loop for the intracellular TCR signalling
pathway. Knockdown of Carabin by short interfering RNA led to a
significant enhancement of interleukin-2 production by antigen-
specific T cells in vitro and in vivo. Thus, Carabin is a negative
feedback inhibitor of the calcineurin signalling pathway that also
mediates crosstalk between calcineurin and Ras.

PMID: 17230191

And I'm not seeing any other abstracts in this department. Looks like
this is a biggy if in fact carabin is whats needed to slow down
inflammation or the cascade of the same.

Here's another similar link:
http://www.medicalnewstoday.com/medicalnews.php?newsid=61080

If it can cure the common cold, then P is lining up for the SAME
treatments!

*************************************

Do you really want to help others with their lives? With their P?

And why would we do that?

Seems like humans are hard wired to help each other. We may not
be here otherwise.

I know I want me and you to be clear. Can I be any clearer then that?

Why yes! ToPically sPeaking!

http://www.app.com/apps/pbcs.dll/article?AID=/20070130/
LIFE11/701300341/1006/LIFE
Brain study offers clues into why humans do good
Posted by the Asbury Park Press on 01/30/07

HEALTHDAY

People may not perform selfless acts just for an emotional reward, a
new brain study suggests.

Instead, they may do good because they're acutely tuned into the needs
and actions of others.

Scientists say a piece of the brain linked to perceiving others'
intentions shows more activity in unselfish vs. selfish types.

"Perhaps altruism did not grow out of a warm-glow feeling of doing
good for others, but out of the simple recognition that that thing
over there is a person that has intentions and goals. And therefore, I
might want to treat them like I might want them to treat myself,"
explained study author Scott Huettel, an associate professor of
psychology at Duke University Medical Center, in Durham, N.C.

He and lead researcher Dharol Tankersley, a graduate student at Duke,
published their findings in the Jan. 21 online issue of Nature
Neuroscience.

For decades, psychologists and neuroscientists have puzzled over the
tendency of humans to engage in altruistic acts — defined by Huettel's
group as acts "that intentionally benefit another organism, incur no
direct personal benefit, and sometimes bear a personal cost."

Experts note that altruism doesn't seem to provide individuals with
any survival edge, so how and why did it evolve? To help solve that
puzzle, Huettel's team had a group of healthy young adults either
engage in a computer game or watch as the computer played the game
itself. In some sessions, the computer and participants played for
personal gain, while in other sessions, they played for charity.

The researchers used high-tech functional MRI (fMRI) to observe "hot
spots" of activity in the participants' brains as they engaged in
these tasks.

Participants were also asked to complete a questionnaire aimed at
assessing their personal levels of selfishness or altruism.

Huettel said he was surprised by the study results.

"We went into this experiment with the idea that altruism was really a
function of the brain's reward systems — altruistic people would
simply find it more rewarding," he said.

But instead, a whole other brain region, called the posterior superior
temporal cortex (pSTC), kicked into high gear as altruism levels rose.

The pSTC is located near the back of the brain and is not focused on
reward. Instead, it focuses on perceiving others' intentions and
actions, Huettel said.

"The general function of this region is that it seems to be associated
with perceiving, usually visually, stimuli that seem meaningful to us
— for example, something in the environment that might move an object
from place to place," he explained.

This type of perception would have allowed humans' more primitive
ancestors to quickly pick out a potential threat — a crouching lion,
for example — from amid a mass of less important stimuli.

It's much less clear why pSTC activity gets ramped up in the brains of
altruistic people, however. "That was really surprising to us,"
Huettel said.

The researchers found that pSTC activity was highest when study
participants were observing the computer play the game on its own -
not when they were playing themselves. "That gets to this idea of
agency - watching somebody else play the game," Huettel said. "You are
thinking, "Oh, the computer pressed the button — somebody else did
that.' "

The bottom line, he said, is that altruism may rely on a basic
understanding that others have motivations and actions that may be
similar to our own.

"It's not exactly empathy," he said, but something more primitive. "We
think that altruism may have grown out of — at least in part — such a
system."

Another expert said the Duke study raises even more questions than it
answers.

"It's a really interesting study," said Paul Sanberg, director of the
Center of Excellence for Aging and Brain Repair at the University of
South Florida College of Medicine, in Tampa. "It would be really
interesting, now though, to see if people who had damage to that brain
area were much less altruistic."

Huettel said he's pondered that possibility. "For example, we don't
know if people who are sociopaths, or people who are autistic, might
show differences in this region," he said. "It's a good question, but
we don't have data that shows anything one way or another. This is
just a jumping-off point."

Sanberg said the study also showed only an association between
heightened pSTC activity and altruism, not a direct cause-and-effect
relationship. "That needs further study," he said.

But the Florida neuroscientist said this type of work is helping
unravel the mysteries of human consciousness and behavior.

"These functional studies with high-level human behaviors are shedding
important light on the contribution of different brain areas," Sanberg
said.

----------------

(link: same as above)

Winter skin care tip soften season's bite

During winter, cold temperatures, biting winds, low humidity and
indoor heating can cause dry, itchy, cracked skin and chapped lips and
exacerbate conditions such as eczema, psoriasis and seborrhea.

But there are some simple steps you can take to protect your skin from
winter's harsh conditions, says dermatologist Dr. Deborah A. Scott,
director of the Center for Laser Dermatology and Skin Health at
Brigham and Women's Hospital, in Boston.

Scott recommends that you:

Stay hydrated. Drinking adequate amounts of water benefits your
overall health and helps hydrate your skin from within. You should try
to drink at least eight 8-ounce glasses of water a day.

Keep showers short and warm. Long, hot showers strip natural oils from
your skin. You should spend no more than 10 minutes in the shower and
keep the water temperature below 90 degrees.

Use mild skin care products. The best choices are creams, ointments
and lotions that are formulated for sensitive skin and don't contain
alcohol. Do not use deodorant or antibacterial soaps, or soaps or
shampoos with skin irritants such as fragrances and lauryl sulfates.

Moisturize daily. Immediately after a shower, pat skin dry (do not
rub) and apply moisturizer to help trap moisture in the outer layers
of your skin. Carry a travel-size container of lotion with you so you
can replenish your skin moisture throughout the day.

Take care when exfoliating. While gentle exfoliation can help
eliminate the buildup of dead skin cells, too much exfoliation can
irritate skin and dry it out. Exfoliate once a week in moderation.

Consider using a humidifier in your home. Central heating systems can
dry indoor air to as low as 10 percent humidity. To counter this,
place a humidifier in the room in which you spend the most time and
aim for moisture levels of 30 percent to 50 percent humidity.

Wear sunscreen. Apply SPF 15 in the winter and use a higher SPF
sunscreen if you're vacationing on the slopes or at the beach.

Protect your lips. Lips can be especially prone to dryness because the
skin there does not have oil glands. Do not lick your lips to hydrate
them. Instead, use a petroleum- or beeswax-based lip balm.

-----------------

PCN on the move again.

http://www.prweb.com/releases/2007/1/prweb501119.htm

Psoriasis Cure Now Launches Online Volunteer Center to Mobilize
Psoriasis Community

"Psoriasis Cure Now," a nonprofit patient advocacy group, has launched
its online volunteer center to mobilize the psoriasis community from
coast to coast. By answering a few questions, people with psoriasis

and psoriatic arthritis, and those who care about them, can add
themselves to Psoriasis Cure Now's volunteer database to be contacted

only when a project meets their specifications, no matter his or her
location or limited time available.

Kensington, MD (PRWEB) January 30, 2007 -- "Psoriasis Cure Now," a
nonprofit patient advocacy group, has launched its online volunteer

center to mobilize the psoriasis community, which is scattered across
the nation. By answering a few questions, people with psoriasis and
psoriatic arthritis, and those who care about them, can add themselves
to Psoriasis Cure Now's volunteer database to be contacted only when a
project meets their specifications. The volunteer center is on the web
here: http://www.psoriasis-cure-now.org/volunteer.php .

"Whether someone has one hour a year to contribute, or 100 hours, our
online volunteer center will enable us to mobilize talented
individuals from Honolulu to Nantucket," said Michael Paranzino,

president of Psoriasis Cure Now. "This online questionnaire makes

every volunteer, no matter his or her location or limited time
available, a valuable addition to the battle for a psoriasis cure."

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. In many cases, people also experience pain,
stiffness and swelling in the joints (psoriatic arthritis). Recent
studies have found a higher risk of heart attack and higher incidence
of cardiovascular death among patients with severe psoriasis. Children

with psoriasis report impairment in their quality of life that equals
the impairment reported by children with other chronic illnesses

including asthma, epilepsy and diabetes. Studies in adults have
produced similar results, with a 1999 study finding that "Patients
with psoriasis reported reduction in physical functioning and mental
functioning comparable to that seen in cancer, arthritis,
hypertension, heart disease, diabetes, and depression." People with
psoriasis also have higher rates of depression and suicidal ideation.

This year, the federal government plans to spend about one dollar in
psoriasis research for each American with the disease, which equals

two percent of the amount the last Congress had originally set aside

for the Bridge to Nowhere.

--------------

http://www.pharmalive.com/News/index.cfm?
articleid=408275&categoryid=40

RegeneRx Biopharmaceuticals, Inc. (Amex:RGN) (www.regenerx.com)
reported today that researchers at the Wayne State University School
of Medicine and the Kresge Eye Institute in Detroit, Michigan, found
that thymosin beta 4 (Tβ4) inhibits the activation and nuclear
translocation of the transcription factor NFκB, (pronounced: N-F-kappa-
B), widely implicated as a major regulator of inflammatory response.
The research team, headed by Gabriel Sosne, M.D., Assistant Professor
of Ophthalmology and Anatomy/Cell Biology at the Kresge Eye Institute,
of the Wayne State University School of Medicine, published their
latest findings in Experimental Eye Research, January 23, 2007. Dr.
Sosne is a member of RegeneRx’s Medical and Scientific Advisory Board.

“The discovery and identification of novel agents that can mitigate
the adverse host inflammatory/immune responses to diseases and
injuries would be a major therapeutic breakthrough and could have
significant cost benefits as well,” according to Dr. Sosne. “Emerging
evidence from our laboratory shows that Tβ4 has significant potential
for development as a drug candidate in indications where an over-
active immune response may exacerbate the original injury and/or be
detrimental to the patient’s recovery. Since NFκB activation and
translocation are involved in such a wide array of inflammatory-based
entities, these findings may also help us better understand how Tβ4
regulates physiological processes such as wound repair, suppressing
inflammation and inhibiting apoptosis.”

Inflammation is part of the host immune response to tissue injury and
is linked to a wide spectrum of potentially debilitating diseases
including diabetes, asthma, inflammatory bowel disease, rheumatoid
arthritis, cardiovascular disease, the common cold, cancer and HIV/
AIDS, as well as traumatic injuries associated with the brain and
spinal cord. The increasing prevalence, economic burden, morbidity,
and mortality from these and other inflammatory-related diseases and
injuries are major public health issues.

About RegeneRx Biopharmaceuticals, Inc.

RegeneRx is focused on the discovery and development of novel
molecules to accelerate tissue and organ repair. Currently, RegeneRx
is developing Tβ4, a 43 amino acid peptide, in part, under an
exclusive world-wide license from the National Institutes of Health.
Preliminary research suggests that Tβ4 may prove efficacious for
multiple indications; therefore, RegeneRx is developing Tβ4 as the
cornerstone of its therapeutic platform. The technology platform has
many potential applications in both the pharmaceutical and consumer
products sectors. RegeneRx holds nearly 60 world-wide patents and
patent applications related to dermal, ocular, and internal wounds and
tissue repair, cardiac and neurological injuries, septic shock and
several consumer product areas. RegeneRx is currently sponsoring three
Phase 2 chronic dermal wound healing clinical trials and has
additionally targeted ophthalmic and cardiac trials in 2007 as part of
its ongoing clinical development program.

The RegeneRx Technology Platform

Tβ4 is a synthetic version of a naturally occurring peptide present in
virtually all human cells. It is a first-in-class drug candidate that
promotes endothelial cell differentiation, angiogenesis in dermal
tissues, keratinocyte migration, collagen deposition, and down-
regulates inflammation. One of Tβ4’s key mechanisms of action is its
ability to regulate the cell-building protein, actin, a vital
component of cell structure and movement. Of the thousands of proteins
in cells, actin represents up to 10% of the total protein and, thus,
plays a major role in the physiology of the cell. RegeneRx has
identified several molecular variations of Tβ4 that may affect the
aging of skin, among other properties, and could be important
candidates as active ingredients in pharmaceutical and consumer
products. Researchers at the National Institutes of Health, and at
other academic institutions throughout the U.S., have published
numerous scientific articles indicating that Tβ4 is effective in
accelerating dermal and corneal wound healing in several animal
models, under a variety of conditions. In two articles published in
the scientific journal, Nature, researchers found that Tβ4 protects
heart tissue following a myocardial infarction (heart attack) and can
regenerate coronary vessels in laboratory animals. Abstracts of
scientific papers related to Tβ4’s mechanisms of action may be viewed
at RegeneRx’s web page: www.regenerx.com.

--------------------------

randall

unread,

Jan 31, 2007, 3:49:39 AM1/31/07

Hi,

The immune thing continues:

Cracking Open The Black Box Of Autoimmune Disease

http://www.medicalnewstoday.com/medicalnews.php?newsid=61290

Autoimmune diseases such as type 1 diabetes, lupus and rheumatoid
arthritis occur when the immune system fails to regulate itself. But
researchers have not known precisely where the molecular breakdowns
responsible for such failures occur. Now, a team of scientists from
the Whitehead Institute and the Dana-Farber Cancer Institute have
identified a key set of genes that lie at the core of autoimmune
disease, findings that may help scientists develop new methods for
manipulating immune system activity.

"This may shorten the path to new therapies for autoimmune disease,"
says Whitehead Member and MIT professor of biology Richard Young,
senior author on the paper that will appear January 21 online in
Nature. "With this new list of genes, we can now look for possible
therapies with far greater precision."

The immune system is often described as a kind of military unit, a
defense network that guards the body from invaders. Seen in this way,
a group of white blood cells called T cells are the frontline soldiers
of immune defense, engaging invading pathogens head on.

These T cells are commanded by a second group of cells called
regulatory T cells. Regulatory T cells prevent biological "friendly
fire" by ensuring that the T cells do not attack the body's own
tissues. Failure of the regulatory T cells to control the frontline
fighters leads to autoimmune disease.

Scientists previously discovered that regulatory T cells are
themselves controlled by a master gene regulator called Foxp3. Master
gene regulators bind to specific genes and control their level of
activity, which in turn affects the behavior of cells. In fact, when
Foxp3 stops functioning, the body can no longer produce working
regulatory T cells. When this happens, the frontline T cells damage
multiple organs and cause symptoms of type 1 diabetes and Crohn's
disease. However, until now, scientists have barely understood how
Foxp3 controls regulatory T cells because they knew almost nothing
about the actual genes under Foxp3's purview.

Researchers in Richard Young's Whitehead lab, working closely with
immunologist Harald von Boehmer of the Dana-Farber Cancer Institute,
used a DNA microarray technology developed by Young to scan the entire
genome of T cells and locate the genes controlled by Foxp3. There were
roughly 30 genes found to be directly controlled by Foxp3 and one,
called Ptpn22, showed a particularly strong affinity.

"This relation was striking because Ptpn22 is strongly associated with
type 1 diabetes, rheumatoid arthritis, lupus and Graves' disease, but
the gene had not been previously linked to regulatory T-cell
function," says Alexander Marson, a MD/PhD student in the Young lab
and lead author on the paper. "Discovering this correlation was a big
moment for us. It verified that we were on the right track for
identifying autoimmune related genes."

The researchers still don't know exactly how Foxp3 enables regulatory
T cells to prevent autoimmunity. But the list of the genes that Foxp3
targets provides an initial map of the circuitry of these cells, which
is important for understanding how they control a healthy immune
response.

"Autoimmune diseases take a tremendous toll on human health, but on a
strictly molecular level, autoimmunity is a black box," says Young.
"When we discover the molecular mechanisms that drive these
conditions, we can migrate from treating symptoms to developing
treatments for the disease itself."

--------------

http://www.medicalnewstoday.com/medicalnews.php?newsid=61810
Autoimmune Disease Breakthrough Gained By Identification Of 30 Errant
Genes

A report in the January issue of Nature magazine announces that one
more step in understanding what may cause the body to attack itself in
its war against autoimmune disease has been discovered by researchers
at the Massachusetts Institute of Technology's Whitehead Institute,
says the Autoimmune Related Diseases Association (AARDA), a national
nonprofit patient advocacy organization.

What happens in certain cases to cause the body's immune system to go
wild with an over reaction when it encounters invading viruses or
bacteria, thus resulting in one or more autoimmune diseases--such as
rheumatoid arthritis, lupus, multiple sclerosis, thyroid disease
(Graves', Hashimoto's), juvenile (type 1) diabetes?

Researchers Richard Young and Alexander Marson, an M.D./Ph.D. student
working in Young's laboratory, have reported discovering 30 genes that
go awry in autoimmune diseases. According to Young, the regulatory T
cells (called "T regs") that normally control the immune system may
have genetic defects. In that case, the T regs protective powers are
weakened.

The "brain" of the T regs is a protein called Foxp3. It can send the
message to increase or decrease the production of other genes. Dr.
Marson, study lead author, said, "We identified a set of roughly 30
genes that are clearly regulated by Foxp3 and, surprisingly, a lot of
them are suppressed by Foxp3." Mutation in more of the genes, PTPN22,
is associated with a number of autoimmune disorders. It is speculated
that altering the Foxp3 gene might be one way to reach a cure of
autoimmune diseases.

Two significant implications have emerged from this research. Marson
commented, "One is that we've identified this core set of genes that
are probably likely to play key roles in preventing autoimmune more
disease." He added, "The second implication, which is maybe more long-
term, is that we hope that identifying these targets will allow us to
screen for drugs to mimic the function of Foxp3 and, thus, treat
autoimmune disease."

Autoimmune disease pioneer Noel R. Rose, M.D., Director of the Johns
Hopkins Center for Autoimmune Disease Research, says that treating
autoimmune disorders will require enhancing either the number or
effectiveness of regulatory T cells. He remarked that the MIT study is
"certainly important in trying to understand how these regulatory T
cells work." He cautions, "Whether this will have important functional
implications, only time will tell."

Commenting on the study results, Virginia Ladd, AARDA president and
executive director, observes, "The discovery adds weight to the reason
why autoimmune diseases should be considered a disease category
similar to the way that cancer is viewed rather than as singular
diseases." She adds, "It also lends proof to the genetic connection
among these diseases and an understanding as to why these diseases run
in families."

Ms. Ladd points out that the public is unaware of the genetic
connection among various autoimmune diseases, and patients are seldom
queried by healthcare professionals regarding the family history in
autoimmune disease. AARDA is pressing for federal legislation that
would bring more awareness to autoimmune diseases and the fact that
collectively they affect millions of Americans.

American Autoimmune Related Diseases Association (AARDA)
Michigan National Bank Bldg., 15475 Gratiot Ave.
Detroit, MI 48205
United States
http://www.aarda.org/

More of the same with picture of dr young and interview:
http://www.msnbc.msn.com/id/16738416/site/newsweek/

-------------------

Treating severe autoimmune conditions now in the doctors office.

http://news.monstersandcritics.com/health/features/article_1253164.php/Quicker_autoimmune-disorder_Rx
Quicker autoimmune-disorder Rx

NEW YORK, NY, United States (UPI) -- A new discovery might mean
patients with autoimmune diseases can be treated with a quick shot in
a doctor`s office, instead of enduring the current, cumbersome process
of going to the hospital for a three-hour infusion, say U.S. and
international researchers.
A team at Cornell Weill Medical Center in New York City say they have
found a way to isolate the active ingredient in the intravenous immune
globulin (IVIG) used to treat autoimmune diseases like multiple
sclerosis and lupus. That active ingredient blocks the function of
interferon gamma, a major culprit in the chronic inflammation seen in
these diseases.
Thus, this tiny portion -- 0.5 percent -- of the IVIG solution that
actually does the work can be reduced to a simple injection, the
researchers said.
'If this becomes available and is as effective as the full intravenous
treatment, it would be very helpful to patients: more convenient, less
expensive, and safer,' Virginia Ladd, president of the American
Autoimmune and Related Diseases Association, told United Press
International.
If the discovery can be translated to medical practice, the resulting
simplified treatment would be easier for patients and also safer, the
researchers said.
The standard IVIG treatment is made by harvesting gamma globulin from
thousands of blood samples. The risk of contamination by dangerous
organisms, such as HIV or hepatitis C, is high, and sometimes whole
batches are recalled because of this problem.
In addition, when there is a shortage in blood donations, there is a
shortage of IVIG as well, and people with immunodeficiency diseases,
whose life is dependent on IVIG, can be in serious trouble, the
researchers noted.
IVIG is also time-consuming and expensive to make and administer.
People with autoimmune problems must come to the hospital for three to
four hours a day on three consecutive days to receive enough IVIG to
have an effect on their disorder. They can have allergic reactions to
the product and the sheer amount of fluid they must receive can
overload their kidneys.
'We may be able to eliminate many of these problems,' Lionel Ivashkiv,
rheumatologist and director of Basic Research at the Hospital for
Special Surgery/Cornell Weill Medical Center in New York, N.Y., told
United Press International. 'Our study showed us that we can make the
immune complexes that are the active component of IVIG in the
laboratory using antibody/antigen systems that are commonplace and
innocuous. Doing so would eliminate all the risks of contamination
associated with human blood products and the problems associated with
intravenous infusions, because they could be given in a single
injection in a doctor`s office.'
However, Ivashkiv cautioned that the new approach appears limited to
use in people with autoimmune diseases. People with immune
deficiencies will still be dependent on IVIG, he said.
Ivashkiv and his colleagues happened upon the discovery while trying
to find a way to block the inflammatory factors responsible for
autoimmune disorders, such as multiple sclerosis, lupus erythematosus,
Kawasaki disease, and chronic lymphocytic leukemia, so they decided to
study how IVIG works in more detail.
They and others had discovered that IVIG attaches to a receptor on the
outside of cells called FcyRllb and stops it from activating
inflammatory factors. The team wondered if interferon gamma, which is
found in high amounts in many chronic autoimmune diseases, was one of
the factors IVIG impacts. To find out, they treated mouse and human
white blood cells called macrophages with IVIG. Macrophages are
scavenger cells that use interferon gamma to kill invading bacteria,
but when treated with IVIG, they couldn`t do so.
The next step was to see what part of IVIG was actually doing the
work. IVIG is comprised of 99.5 percent gamma globulin and 0.5 percent
immune complexes. When macrophages were treated with gamma globulin
alone, their performance was not affected, but when they were cultured
with immune complexes, the macrophages were again stopped in their
tracks.
When asked how soon patients could benefit from the experimental
treatment, Ivashkiv said he thought the discovery might be able to get
to the bedside in little more than three years.
That is because the researchers have already tested the therapy on
human cells with no adverse effects, the components of the treatment
have been in use for many years and are already approved in the United
States and abroad, and because other researchers are also working on
the same problem, he noted.
'Our coalition involved scientists here in the United States, Canada,
and Australia,' said Ivashkiv, 'plus there is a Canadian group led by
Vinayakimar Siragam and Alan Lazarus who are working on a similar
immune complex preparation to treat immune thrombocytopenic purpura
(ITP), which causes low platelet counts. We are happy about their
work, because it uses a different mechanism than ours, so it will work
better for different problems.'
Ivashkiv said that, since there were no safety or toxicity issues with
the new treatment, human clinical trials could begin in the very near
future.
'Really, there are no barriers to human testing, (except for) deciding
on the kind of immune complex that should be used,' said Ivashkiv. 'As
soon as we find a partner with experience developing pharmaceutical
products to help us do this, we can begin.'

Same story different link:
http://www.sciencedaily.com/releases/2007/01/070128141807.htm
Discovery May Lead To Novel Treatments For Autoimmune And Chronic
Inflammatory Diseases
Science Daily - By pinpointing the mechanism through which an
intravenous therapy combats chronic inflammatory diseases, researchers
have discovered that they may be able to replace the time-consuming
infusion therapy with an injection that could be given during a quick
office visit. Investigators at Hospital for Special Surgery in New
York City have discovered that intravenous immune globulin (IVIG) or
antibody therapy works, in part, by attaching to a receptor known as
Fc³RIII and blocking the function of interferon gamma, a major
inflammatory factor. Only a small component of the IVIG solution,
0.5%, is responsible for blocking this receptor.

"The study suggests that it's not the whole preparation itself, but
the immune complexes within the preparation that are causing the
therapeutic effect," said Lionel Ivashkiv, M,D, <sniP>

---------------------------

http://www.medicalnewstoday.com/medicalnews.php?newsid=60663&nfid=nl
Regulatory T Cells Require WASp If They Are To Prevent Self-
destruction
n humans, mutation of the gene encoding a protein known as WASp leads
to susceptibility to infections and systemic autoimmunity. Most
studies have focused on understanding the defects in T cell activation
caused by the WASp deficiency, but researchers at the University of
Washington in Seattle have now found that in mice and humans a
population of T cells known as regulatory T cells (Treg), which keep
other immune cells from attacking the body's own tissues and causing
autoimmunity, are also impaired in the absence of WASp.

In the study, which appears online on January 11 in advance of
publication in the February print issue of the Journal of Clinical
Investigation, David Rawlings and colleagues show that like WASp-
deficient humans, WASp-deficient mice develop systemic autoimmune
disease. This was not due to a defect in the number of Treg that
developed in the mice, but due to a defect in their ability to control
autoimmunity. Consistent with this, the peripheral blood of a WASp-
deficient patient in whom a spontaneous revertant mutation occurred
had substantial numbers of WASp+ Treg. These cells were able to
ameliorate this individual's recurrent episodes of autoimmune
hemolytic anemia, indicating that a defect in Treg function is likely
to contribute to the systemic autoimmunity from which individuals
lacking WASp suffer.

--------------------

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http://www.medicalnewstoday.com/medicalnews.php?newsid=60675&nfid=nl

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acne blemishes. Clearogen's topical approach balances the skin's
hormones without affecting the hormones through out the body.

Clearogen is formulated by Alex Khadavi MD, Board Certified
Dermatologist and Associate Professor of Dermatology at the University
of Southern California. He states: "The impact of hormonal imbalance
on acne has been a major point of interest to me because over 80% of
my patients have acne; yet, none of the available topical acne
treatments address the hormonal cause of this condition. This led me
to develop Clearogen that works for both men and women by reducing the
negative effects of DHT on the skin through an effective and safe
topical treatment."

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prescription. Clearogen can be ordered without prescription from
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----------------------

http://news.biocompare.com/newsstory.asp?id=166070
Why Doesn't The Immune System Attack The Small Intestine?

Answering one of the oldest questions in human physiology, researchers
at Dana-Farber Cancer Institute have discovered why the body's immune
system - perpetually on guard against foreign microbes like bacteria -
doesn't attack tissues in the small intestine that harbor millions of
bacteria cells.

In a study in the February issue of Nature Immunology, and which is
currently available on the journal's Web site as an advanced online
publication, investigators led by Shannon Turley, PhD, of Dana-Farber
identify an unlikely group of peacemakers: lymph node cells that
instruct key immune system cells to leave healthy tissue alone. The
finding, which illuminates a previously unknown corner of the human
immune system, may lead to new forms of treatment for autoimmune
diseases such as Type 1 diabetes and multiple sclerosis.
"We've discovered that cells not generally thought of as part of the
immune system actually play an important role in protecting the
intestine from immune system attack," says Turley. "Because the cells
are found in lymph nodes throughout the body, they may offer a way of
suppressing a variety of autoimmune diseases," which result from
immune system assault on healthy tissue.
The immune system distinguishes between normal and foreign agents by
small proteins, called antigens, on the cell surface. In parts of the
body, such as the pancreas, that are sheltered from the outside
environment, cells known as dendritic cells display the antigens of
their normal neighbors in a way that puts the immune system "at ease."
By reading those antigens without being on alert, the immune system's
T cells learn that such cells are off-limits to attack.
For years, scientists have wondered whether the same mechanism is at
work in tissues that come in regular contact with bacteria and other
microbial organisms. The small intestine, for example, which absorbs
essential nutrients from food and drink and protects the body from
invasive microbes, is literally teeming with bacteria, which help
break down waste. The presence of so many bacteria is a potential
trigger for an immune system response. Why do T cells almost always
ignore the small intestine, leaving this vital tissue unharmed?
"It's obvious that T cells must be able to ignore - or become
'tolerized' to - normal intestinal tissue," states Turley, who is also
an assistant professor of pathology at Harvard Medical School. "But it
has been unclear how dendritic cells, which are extremely sensitive to
microbial agents such as bacteria, teach T cells to resist attacking
healthy intestinal cells."
In the new study, Turley and her colleagues found that, in fact,
dendritic cells aren't essential in creating tolerance in T cells.
Instead, and unexpectedly, tolerance is produced by stromal cells from
nearby lymph nodes. Although they aren't classified as "professional
antigen-presenters," as dendritic cells are, the stromal cells serve
the same purpose: exhibiting normal-cell antigens to the immune
system.
"Our study points to a previously unknown mechanism of immune system
tolerance," Turley explains. "When you think of the conditions in the
small intestine, with so many millions of bacteria cells and so much
opportunity for dendritic cells to stimulate an immune attack, it's
remarkable that intestinal tissue is so rarely the target of an immune
attack. Our findings demonstrate that the immune system has features
that remain to be discovered."

http://www.medicalnewstoday.com/medicalnews.php?newsid=61206&nfid=nl
Cellular Waste Disposal, A Target For Drug Therapies - Nobel Laureate
Professor Aaron Ciechanover Delivers Key Note Lecture

A cell contains tens of thousands of proteins, the building materials
and the machinery of life. Proteins that are defectively produced and
misfolded and no longer function properly must be disposed to prevent
damage. This is true also for "healthy" functional proteins that must
be removed when they are no longer needed - when the processes they
control must be stopped.

Thus, the body simultaneously generates and disposes of numerous
proteins. The disposal process is a highly controlled one and
conducted by the ubiquitin-proteasome system. Proteins prone for
disposal are labelled with the molecule ubiquitin and transported to
the proteasomes where they are then chopped into pieces and destroyed.

Aberrations in this important cellular waste disposal can lead to a
wide array of diseases ranging from cancer to neurodegenerative
disorders such as some forms of Alzheimer's and Parkinson's Disease,
genetic diseases such as cystic fibrosis, and different immune and
inflammatory disorders.

"Because of its crucial role for many basic cellular processes, it is
very challenging to develop drugs which can modulate this system",
Professor Ciechanover said in his keynote lecture at the New Year's
Reception of the Berlin-Buch Campus at the Max Delbrück Communications
Center (MDC.C) in Berlin, Germany on Friday, January 19, 2007. The
physician and biologist from the Faculty of Medicine of the Technion
Israel Institute of Technology in Haifa, Israel is one the discoverers
of the ubiquitin-proteasome system and shared the Nobel Prize in
Chemistry in 2004 for this pioneering research.

Professor Ciechanover pointed out that one successful drug to combat
multiple myeloma, a form of leukaemia (blood cancer), is already on
the market and has revolutionized the treatment of this disease. The
drug, Velcade (Bortezomib) is a proteasome inhibitor. It was licensed
in the USA in 2003 and was also approved in Germany in 2004. The drug
inhibits the degradation of certain abnormal proteins resulting in the
literal suffocation of the tumor cells in their own protein waste.

Professor Ciechanover is convinced that a better understanding of the
very complex processes and the identification of the components
involved in the degradation of key regulatory proteins will eventually
lead to the development of novel, mechanism-based drugs that will
target only the involved proteins.

Aaron Ciechanover was born in Haifa, Israel on October 1, 1947. He
received his Doctor`s degree in medicine in 1975 at the Hebrew
University of Jerusalem, and his doctoral degree in biology in 1982 at
the Technion Israel Institute of Technology in Haifa. He is
Distinguished Professor at the Center for Cancer and Vascular Biology,
the Rappaport Faculty of Medicine and Research Institute at the
Technion.

------------

http://www.medicalnewstoday.com/medicalnews.php?newsid=60893&nfid=nl
An Ingenious New Delivery System For Antioxidant SOD

Scientists in Georgia are reporting successful lab tests of new
polymer microparticles that show promise as a long-sought way to
deliver drugs directly into the cell structures responsible for
inflammation. Those immune system structures, macrophages, devour and
destroy foreign substances such as invading bacteria and cellular
debris. However, they also release so-called reactive oxygen species
that help cause arthritis, acute liver failure and other inflammatory
diseases.

In a report scheduled for the Jan. 17 issue of ACS' Bioconjugate
Chemistry, a bi-monthly journal, Georgia Tech's Niren Murthy and
colleagues at Emory University School of Medicine describe successful
cell culture experiments with microparticles encapsulating superoxide
dismutase (SOD). That compound is getting wide attention as a
potential treatment for inflammatory diseases because it scavenges
reactive oxygen species. One roadblock to clinical use of SOD, the
researchers note, is the lack of a delivery system for SOD.

The new polymer microparticles have several advantages over other
potential delivery systems, the researchers state. The particles
remain intact until reaching acid environments such as the phagosomes
-- literal death chambers -- that form after macrophages engulf
bacteria and other particles. Then the polymers breakdown, releasing
their SOD directly at the site where inflammation begins.

-----------------
http://www.medicalnewstoday.com/medicalnews.php?newsid=60018&nfid=nl
Sugars In Liver Found To Clear Fats From The Bloodstream

Maybe you ate a big, juicy steak for dinner last night, adding a large
amount of fat scientifically known as triglycerides to your system.
For one in ten of us, that could be a big problem.

Although we try to reduce fat in our diet, our bodies use it for
energy. But patients with elevated levels of fat in their bloodstream
nearly 10 percent of Americans are more likely to develop
arthrosclerosis, or build-up of plaque in the arteries, which can lead
to a heart attack or stroke.

In work with mice, researchers at the University of California, San
Diego (UCSD) School of Medicine discovered a factor that could be
responsible for many unexplained cases of elevated triglyceride
levels.

In humans, this condition can be diabetes-related, diet-induced, or
caused by drug interactions or chronic alcohol consumption. The
problem can also run in families. But it turns out that another
important factor is sugar a complex one produced by all cells in the
body called heparan sulfate, which is related to the anti-coagulant
heparin.

The UCSD team found that heparan sulfate in the liver helps the body
clear triglycerides from the blood. Their study, published in the
January 1 issue of the Journal of Clinical Investigation, suggests
that some patients with elevated triglyceride levels could have
changes in heparan sulfate in the liver. The discovery could pave the
way for new therapies for a major and growing medical problem.

"The work confirms that heparan sulfate in the liver plays a crucial
role in clearing fat," said Jeffrey D. Esko, Professor of Cellular and
Molecular Medicine at UCSD's School of Medicine. "These molecules
clear triglycerides and cholesterol from the blood, working alongside
the better known LDL receptors"

The UCSD researchers created a mouse model with a mutation of heparan
sulfate, which resulted in elevated triglyceride levels, like those
seen in many patients with diabetes. The researchers made mutations in
only in the liver, because such mutations throughout all tissues would
lead to the death of an embryo or death shortly after birth.

"By selectively mutating a single tissue in mice, in this case the
liver, we avoided a lethal effect," said Esko. In the lab, the
researchers combined the heparan sulfate mutation with a mutation in
the LDL receptor, which has long known to be responsible for clearing
cholesterol from the arteries. The UCSD team showed that heparan
sulfate is involved in clearing not only triglycerides, but also
cholesterol, from the blood.

"The finding, that the LDL receptor plus heparan sulfate work together
to clear triglyceride and cholesterol-rich particles from the blood in
a healthy person is very exciting," Esko said. The study suggests the
possibility that mutations in one of 40 or so genes involved in
production of heparan sulfate in the liver could result in high blood-
fat levels and lead to complications such as arthrosclerosis,
according to Esko.

In animal models with induced diabetes, changes in liver heparan
sulfate consistent with the UCSD researchers' findings often appear.
One of the team's next steps will be to induce diabetes in animals and
examine the role of heparan sulfate in more detail.

"Such studies could lead to new drugs that change heparan sulfate in
order to lower fat levels in patients," said Esko.

----------------

http://www.medicalnewstoday.com/medicalnews.php?newsid=60069&nfid=nl

expressing stromal cells to relocate to sites in the epithelial cell
layer rich in ColEPs.

------------

This next story was posted on January 3rd or 5th of 2007 from a
different link. I felt it
was important enough to use it again.

http://www.medicalnewstoday.com/medicalnews.php?newsid=60330&nfid=nl

Genetically triggered disorders

Long-term research perspective

---------------

Prebiotics Important for Artery Health
Breaking News
VRP Staff

The prebiotics known as oligofructose (also called
Fructooligosaccharide) and inulin significantly inhibited plaque build
up in the arteries of rodents, a new study has found.

Scientists studied the effects of inulin and oligofructose on
atherosclerotic plaque formation in male mice deficient in
apolipoprotein-E, which is required for the normal breakdown of
triglyceride-rich lipoprotein constituents. The apolipoprotein-E
deficiency increased the animals? risk of heart disease.

Thirty-two mice were randomly divided into five groups. The control
group received a semi-purified sucrose-based diet for 16 weeks. In the
other groups, the sucrose was replaced in part by either inulin
fructans, long-chain inulin, oligofructose, or an oligofructose-
enriched inulin. The researchers then assessed the presence of
atherosclerotic plaques.

The mice fed long-chain inulin or an oligofructose-enriched inulin had
approximately 35 percent and 25 percent reduced atherosclerotic lesion
area compared with the control group. Feeding long-chain inulin
significantly reduced plasma cholesterol concentrations, and the
inulin-type fructans reduced triglyceride concentrations compared with
the control group. Both the long-chain inulin and the oligofructose-
enriched inulin significantly lowered liver cholesterol concentrations
compared with the control diet. Liver triglyceride concentrations also
were significantly lower in all three groups fed the fructan-
supplemented diets compared to the control group.

According to the study authors, ?The results of the present study
suggest that inhibition of atherosclerotic plaque formation is more
potent in the presence of long-chain inulin, either alone or in
combination with oligofructose (an oligofructose-enriched inulin), and
that this probably is related to changes in lipid metabolism.?

Reference:
Rault-Nania MH, Gueux E, Demougeot C, Demigne C, Rock E, Mazur A.
Inulin attenuates atherosclerosis in apolipoprotein E-deficient mice.
Br J Nutr. 2006 Nov;96(5):840-4.

-------------------

http://www.life.ca/nl/113/intestines.html
The 30-foot Pathway - A Guide to Intestinal Health
by Charles Remington
There is a 30-foot pathway that, in the Western world, is overlooked
and at times ignored. The condition of this passageway plays and
important role in an individual's quality of life and longevity. It is
the gateway that guards us from invaders, which may lead to disease
and eventual death. So where is this 30-foot tract found? It is found
in the abdomen region of every human and is called the intestinal
tract.
In Eastern medical practice, the condition or health of the intestinal
tract is extremely important. Ayurvedic medicine, which dates back
some 5,000 years, places great importance on cleansing and detoxifying
the intestinal tract. A therapy called Shodan is used to rid the body
of toxins and to aid in healing and restoring health. Ayurvedic
medicine views toxins as the root cause of all disease; toxins are
believed to stem from undigested and unabsorbed food, which builds up
on the walls of the large intestine or colon and becomes a breeding
ground for bacteria and parasites.
In Western medicine, many of the antibiotics that some experts believe
are over-used to treat infection and rid the body of bacteria may
actually weaken intestinal health and compromise our bodies' natural
healing powers. Dr. Mark Pochapin, Director of Gastrointestinal Health
at New York Presbyterian Hospital, has been quoted as saying,
"Indiscriminate killing of good and bad bacteria is too drastic."
Pochapin further states that, "In fact some doctors point to reduced
bacterial counts in the intestines for the upsurge in intestinal
disorders such as Irritable Bowel Syndrome and Crohn's Disease." It's
time for East to meet West and to develop a system of health where its
foundations are built on prevention rather than repair.
The intestinal tract transforms the foods we eat into macro (protein,
carbohydrate and fats) and micro (vitamins, minerals, enzymes,
phytochemicals and fiber) nutrients, which provide the building blocks
for cellular repair and energy for life. The intestines also remove
the by-products of waste and toxins from the transformed food, which,
if allowed to remain in our system, could lead to disease and possible
death.
The three functions of the intestinal tract are digestion, absorption
and elimination. The first 25 feet of the intestines, called the small
intestine, consists of three parts - the duodenum, ileum and jejunum.
Together, they perform the function of digestion and absorption. The
cells in the wall of the small intestine, called the mucosa, secrete
mucus, peptidase, maltase, lactase and lipase , along with the enzymes
and digestive bile secreted from the liver, pancreas and gallbladder,
to digest food and make it available to be absorbed through the small
intestine's walls to enter the blood to be used by all cells.
The last five feet of the intestines, the large intestine or colon,
consists of five parts the cecum colon, ascending colon, transverse
colon, descending colon and sigmoid colon, which completes the
function of absorption of certain vitamins, minerals and water. The
colon then performs the function of formation and elimination of feces
consisting of nutrient-void food, along with toxins that are the
byproducts of chemical digestion. Unlike the small intestines, the
mucosa cells in the walls of the large intestine produce only mucus,
which protect the cells from the toxins in the waste material as it
passes by. It takes three to ten hours for the partially digested food
called chyme to pass through the small intestine and enter into the
large intestine. The transit time of waste material in the large
intestine can be hours or days. It is this extended period of
digestion, absorption and elimination that provides the battleground
for bacterial microorganisms to play a major role in keeping our
defense mechanisms free of disease. We don't catch diseases; we create
them when our natural defense mechanisms are broken down.
What are your first thoughts when you think of bacteria? Are they good
or bad? If you're thinking of the kitchen counter or toilet seat, your
anti-bacterial conditioning will have you saying bacteria is bad.
However, when it comes to your intestinal health, the correct answer
is both. We need good bacteria to digest food, to synthesize vitamins
and minerals, to clean up toxins and dead cells and to compete with
the bad bacteria for nutrients. The bad bacteria are pathogenic and
disease-causing. They attempt to overtake our immune systems and
compete for the same nutrients that bring life to our bodies. So, for
optimum health, we must understand the intestinal world of friendly or
harmful bacteria. The lyrics in Dave Mason's hit song say, "There
ain't no good guys, there ain't no bad guys, there's only you and me
and we just disagree." I hope you and I agree on this: He was not
singing about your intestinal tract. There is a war taking place in
our intestinal tracts between the good guys (good bacteria) and the
bad guys (bad bacteria) each day.
Dr. Todd Klaenbaner, professor at North Carolina State University and
recognized expert in intestinal bacterial flora, states, "The number
of bacterial cells found in the intestinal tract outnumbers the human
cells ten to one." He estimates there are 500 strains of bacteria in
the human intestinal tract. The good news, Dr. Klaenbaner says, is
that the good bacteria outnumber the bad bacteria - good 80 percent,
bad 20 percent - in individuals experiencing good health. The bad news
is that the ratios can be reversed - bad 80 percent and good 20
percent in patients experiencing intestinal disturbances.
Dr. Mark Pimentel, co-director of the gastrointestinal motility
program at Cedars-Sinai Medical Center, reports that 78 percent of
Irritable Bowel Syndrome (IBS) patients in their research projects
have an overgrowth of bad bacteria in the small intestine. This study
suggests that IBS, a chronic condition that plagues an estimated 20
percent of the adult population, may be caused by too much bad
bacteria in small intestine.
The educators from the Global College of Natural Medicine (G.C.N.M.)
report that recent medical studies have estimated that 85 percent of
the North American adult population is infected with at least one form
of a parasite. Built-up fecal material on the colon walls provides the
ideal birthing ground for parasites. A GCNM course on Toxicity and
Detoxification reveals that humans can play host to more than 100
different kinds of parasites. Parasites, which are organisms that
feed, grow and live off a host, can be microscopic or can grow as
large as several feet. Parasites are found mostly in the large
intestine but they try to permeate the intestinal wall and migrate to
other parts of the body. The most common source of infections from
parasites are under-cooked meats, unwashed fruits and vegetables, time
spent in developing countries, contaminated water and infection by
mosquitoes. The most commonly occurring parasites in North America are
roundworm, hookworm, pinworm and tapeworm.
Parasites can devastate our health in the following ways:
1. They weaken the immune system.
2. They prevent the proper absorption of macro and micro nutrition of
foods eaten.
3. They cause inflammation, and irritation to all tissues.
4. They produce toxic wastes, which are absorbed into the blood
system.
5. They perforate and damage the intestinal wall lining, as they try
to work their way to other regions in the body.
6. They can cause intestinal and pancreatic bile duct obstruction.
What is the best offense to defend us from these invading mutants? A
nutritional lifestyle will naturally keep the intestinal tract spic
and span, using nutritional sponges and scrubbing pads found in whole
grains, fruits and vegetables. These foods are an abundant source of
vitamins, minerals, enzymes and phytochemicals, and are rich in fiber.
Add to this microbe-fighting powerhouse three things: organic,
organic, organic. Learn to use only organic whole grains, fruits and
vegetables, which are devoid of pesticides. Pesticides might make
economical sense to some farmers, but they can bankrupt our intestinal
environment.
To maintain good intestinal health, our bodies require 30 or more
grams of fiber daily. Fiber is divided into two types: soluble and
insoluble. Insoluble fiber is vital in formation of stools and
decreases the time that it takes for waste to be eliminated from our
systems. Poor transit time of waste material increases the feeding
time for bad bacteria and the risk of certain colon cancers. Insoluble
fibers prevent the buildup of mucus and fecal material on intestinal
walls, which lead to poor absorption of nutrients into the body, which
in turn can lead to deficiencies such as anemia or osteoporosis. In
addition, soluble fiber acts to absorb digestive bile, which is made
from cholesterol, so when eliminated causes more cholesterol to be
converted to digestive bile, thereby lowering blood cholesterol (LDL)
levels.
The knowledge to bring healing and prevent disease by maintaining
intestinal health is thousands of years old. Greek and Roman writings
that are 2,000 years old describe fermented milk (lactobacillus),
garlic and onion (which feed Bifidobacteria) as standard practices for
physicians treating intestinal disorders and preventing sickness and
disease. Indian writings called the Vedas, which are 5,000 years old,
describe the use of enemas for intestinal cleansing. The modern
science of Microbiology has expanded on this knowledge and documented
its effect on intestinal wellness. Probiotics, prebiotics and
symbiotics are the latest cutting edge use of these ancient healing
techniques.
The word probiotic comes from the Greek, and means pro-life. It is
administered by eating live bacterial organisms. Probiotic bacteria
not only survive digestion, but aide in digestion. The most numerous
of the probiotic bacteria are Lactobacillus, Acidophilus and
Bifidobacteria, however there are hundreds of others strains. The best
food sources of these bacteria are yogurt and kefir, but they can also
be taken in liquid, powder, capsule or pill forms.
Look for organic yogurt (made without the use of antibiotics and toxic
pesticides) and be sure the label certifies it contains live active
cultures like Lactobacillus (L) Acidophilus, Bifidus, L. Casei and L.
Reuteri. The challenge is for the bacteria to survive the hostile
gastric juice environment of the stomach, on its way to the small
intestines to add to the colony of existing bacteria and become food
for future bacteria.
Prebiotics are non-digestible fiber foods that act as a host to feed
and promote bacterial colonies - most notably bifidobacteria - mainly
in the large intestine. The formation of short chain fatty acids from
these fiber foods not only feed the good bacteria, but also the
muscosa cells in the colon wall. Prebiotics play a role in the muscosa
cells' ability to absorb the minerals calcium, magnesium and iron,
along with the vitamins niacin, folic acid, B-6 and vitamin K.
Probiotic foods contain the phytochemicals inulin and oligosaccharids,
and are found in garlic, onions, asparagus, artichokes, chicory,
bananas, wheat, barley and rye. It is estimated that Americans eat
less than three grams daily of these foods, far less than what is
needed for optimum intestinal health.
Symbiotic refers to the combining of both probiotic and prebiotic in
the same product. A good example are the latest yogurts that contain
live active cultures (probiotic) and add inulin (prebiotic). This
makes for a winning combination to add to the number of good bacteria,
both in the small intestine (lactobacillus) and large intestine
(bifidobacteria).
Autointoxication is self-poisoning caused by bad bacteria, metabolic
wastes and other toxins produced within the large intestine. It
originates in an unhealthy colon and often results in constipation.
What steps can be taken to maintain optimum intestinal health? A
detoxification program is a good start, but those with extremely weak
immune systems should use caution. Eat a diet of organic whole grains,
fruits and vegetables, with 30 grams daily of both soluble and
insoluble fiber. Incorporate a daily routine of both probiotic and
prebiotic foods. Drink eight to ten glasses of pure water to assist
the elimination process. A lifestyle of three to four hours of
exercise weekly will aid in mechanical digestion and reduce transit
time of waste elimination. Avoid all processed foods, white flour,
simple sugars and alcohol, which are the foods of choice for bad
bacteria.
Avoid eating beef and poultry that are raised on antibiotics. Almost
half of all antibiotics used in U.S. each year are given to livestock.
Be aware that continued use of aspirin or drugs like acetaminophen,
ibuprofen or oral contraceptives deplete the good bacteria. Flatulence
and abdominal bloating may occur in the initial stage of introducing
foods that are probiotic and prebiotic; this is the result of the
breakdown of unfriendly bacteria and the fermentation of the friendly
bacteria. If it becomes too unpleasant, introduce these foods more
slowly to your daily routine. Taking a digestive enzyme is helpful
when increasing fiber to a minimum of 30 grams daily, especially if
you have been consuming, like most people, 10 grams or less daily.
In closing, I'm reminded of a meeting I once had with a couple on the
techniques of good nutrition. They had brought their son Jarred, who
at the time was four years old. During the meeting he interrupted and
asked, "Charlie why is there bad?" I looked into his eyes and said,
"Good always takes care of bad; always keep your eyes on good and you
won't have to be concerned about bad." That could not be more true
when it comes to our intestinal health. Develop a lifestyle committed
to organic whole grains, fruits and vegetables. Avoid the overuse of
antibiotics and keep the immune system in peak performance,
maintaining the good bacterial flora that brings life and health and
lowering the bad bacterial flora that can lead to illness.

-----------

randall....

randall

unread,

Feb 1, 2007, 3:28:18 AM2/1/07

Hi,

I loved that black box of immunity thing yesterday.

If ptpn22 is in it, i'm on it.

WhooPs!

PtPn22 may be in he black box for RA autoimmunity, but not for p?
http://psoriasis.researchtoday.net/archive/3/6/338.htm
Evidence for susceptibility determinant(s) to psoriasis vulgaris in or
near PTPN22 in German patients.

Hüffmeier U, Steffens M, Burkhardt H, Lascorz J, Schürmeier-Horst F,
Ständer M, Kelsch R, Baumann C, Küster W, Mössner R, Reich K, Wienker
TF, Traupe H, Reis A

Institute of Human Genetics, University of Erlangen-Nuremberg, 91054
Erlangen, Germany.

INTRODUCTION: Variant R620W of protein tyrosine phosphatase non-
receptor type 22 (PTPN22) has consistently been reported as a
susceptibility factor for several autoimmune diseases. We investigated
its role in susceptibility to psoriasis, the relevance of possibly
other disease-causing variants, and interdependency of the major risk
factor for psoriasis at PSORS1. METHODS: R620W was tested in a case-
control study initially with 375 German patients and then with an
enlarged sample of an additional 418 patients. Analyses were extended
to linkage disequilibrium (LD) based haplotypes. Potential interaction
between risk haplotypes of PTPN22 and the PSORS1 associated risk
allele was tested by regression analysis. PTPN22 coding sequence was
determined in 20 patients carrying the risk haplotype. Association and
regression analysis were also performed in the extended case-control
study. RESULTS: R620W was not associated in either case-control study,
while significant association (corrected for multiple testing) with
one haplotype (C-4) of the LD block encompassing PTPN22 as well with
another haplotype (B-3) within an adjacent telomeric LD block was
detected. No evidence for interaction between risk haplotype C-4 and
the PSORS1 associated risk allele was found. Sequencing excluded other
coding variants within PTPN22 as a basis for association findings.
Analysis of the extended study group confirmed association for
haplotypes B-3 and C-4 and independence of risk haplotypes C-4 and
PSORS1. DISCUSSION: We exclude a major role of *620W in German
psoriasis patients but suggest that other susceptibility
determinant(s) within non-coding regions of PTPN22 or its proximity
might exist acting independently of the major PSORS1 risk factor.

Published 2 June 2006 in J Med Genet, 43(6): 517-22.

____________________

>From a few years back:

http://www.nature.com/ng/journal/v37/n12/abs/ng1205-1300.html

Nature Genetics 37, 1300 - 1302 (2005)
doi:10.1038/ng1205-1300
Gaining insight into PTPN22 and autoimmunity

Peter K Gregersen

Peter K. Gregersen is at the Feinstein Institute for Medical Research,
North Shore Long Island Jewish Health System, Manhasset, New York
11030, USA. peterg @nshs.edu
The protein tyrosine phosphatase PTPN22 (also called LYP) is the
leading example of a genetic variant that confers risk of developing
diverse human autoimmune diseases, including type 1 diabetes,
rheumatoid arthritis, autoimmune thyroid disease and systemic lupus. A
new study now shows that the PTPN22 risk-associated variant, Trp620,
results in a gain of PTPN22 phosphatase activity in T cells, opening
up new avenues for exploring disease mechanisms.

-----

http://www.nature.com/ng/journal/v37/n12/fig_tab/ng1205-1300_F1.html

--------------------------

http://www.medscape.com/viewarticle/550827

PTPN22 Shown to Be an Autoimmunity Susceptibility Gene

By Megan Rauscher

NEW YORK (Reuters Health) Jan 16 - A large-scale genetic study
provides proof that the PTPN22 gene is a rheumatoid arthritis (RA)
susceptibility gene. "Rheumatoid arthritis is the second autoimmune
disease, after type 1 diabetes, for which a linkage with PTPN22 gene
is demonstrated. This makes of PTPN22 a 'linkage-proven' autoimmunity
gene," Dr. Laetitia Michou told Reuters Health.

"PTPN22 accounts for ___1%___ of the rheumatoid arthritis familial
aggregation, whereas HLA-DRB1 gene, the first rheumatoid arthritis
gene discovered 28 years ago, accounts for ____19%__," added Dr.
Michou from Lariboisiere Hospital, Paris, France.

She and her colleagues explain in PNAS Early Edition published online
January 15 that the PTPN22 gene on chromosome 1 is involved in
suppression of T cell activation, "and thereby in T-dependent antibody
production."

Dr. Michou and a multicenter European team conducted genetic analyses
of 1,395 West European Caucasian individuals from 465 "trio" families
-- one case with early RA onset and both parents.

The researchers estimated 63% over-transmission of the PTPN22 1858T
allele in RF+ families (p < 0.0007), compared with the 50%
transmission expected.

The 1858T allele frequency increased from 11.0% in controls to 17.4%
in RF+ RA for the French Caucasian population (n = 319 families), and
the susceptibility genotype (1858T/T or T/C) increased from 20.2% to
31.6% (OR = 1.8).

Dr. Michou told Reuters Health: "Although this result is reliable only
for the studied population, this is a success for multifactorial
diseases genetics, laying solid grounds for research on autoimmune
diseases, including ultimately definitive therapy."

PNAS Early Edition 2007.

----------------

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17237219&query_hl=4&itool=pubmed_docsum
Linkage proof for PTPN22, a rheumatoid arthritis susceptibility gene
and a human autoimmunity gene.

* Michou L,
*<sniP a bunch of authors>
* Cornelis F.

GenHotel-EA 3886, University Evry-Paris 7 Medical School, Member of
the AutoCure European Consortium, CP5727, 91057 Evry-Genopole Cedex,
France; Federation de Rhumatologie, Pole de l'Appareil Locomoteur,
Lariboisiere Hospital, AP-HP, 2 Rue Ambroise Pare, 75010 Paris,
France; Unite de Genetique Clinique, Pole des Laboratoires Medicaux-
Imagerie-Pharmacie, Lariboisiere Hospital, AP-HP, 2 Rue Ambroise Pare,
75010 Paris, France; Pisa University, 56126 Pisa, Italy; La Paz
Hospital, 28046 Madrid, Spain; Katholieke Universiteit Leuven, BE-3000
Leuven, Belgium; Nijmegen University, 6500HB Nijmegen, The
Netherlands; Porto San Joao Hospital, 4200 Porto, Portugal; Fondation
Jean Dausset, Centre d'Etude du Polymorphisme Humain, 27 Rue Juliette
Dodu, 75010 Paris, France; Service de Biologie, Centre Hospitalier Sud
Francilien, 59 Boulevard H. Dunant, 91106 Evry-Corbeil, France;
Laboratoire Statistique et Genome, Centre National de la Recherche
Scientifique, Evry University, 91000 Evry-Genopole, France;
Rheumatology Department, Bichat Hospital, AP-HP, 46 Rue H. Huchard,
75018 Paris, France.

The tyrosine phosphatase PTPN22 allele 1858T has been associated with
rheumatoid arthritis (RA) and other autoimmune diseases. RA is the
most frequent of those multifactorial diseases. The RA association was
usually restricted to serum rheumatoid factor positive disease
(RF(+)). No interaction was shown with HLA-DRB1, the first RA gene.
Many case-control studies replicated the RA association, showing an
allele frequency increase of approximately 5% on average and large
variations of population allele frequencies (2.1-15.5%). In
multifactorial diseases, the final proof for a new susceptibility
allele is provided by departure from Mendel's law (50% transmission
from heterozygous parents). For PTPN22-1858T allele, convincing
linkage proof was available only for type 1 diabetes. We aimed at
providing this proof for RA. We analyzed 1,395 West European Caucasian
individuals from 465 "trio" families. We replicated evidence for
linkage, demonstrating departure from Mendel's law in this subset of
early RA onset patients. We estimated the overtransmission of the
1858T allele in RF(+) families: T = 63%, P < 0.0007. The 1858T allele
frequency increased from 11.0% in controls to 17.4% in RF(+) RA for
the French Caucasian population and the susceptibility genotype (1858T/
T or T/C) from 20.2% to 31.6% [odds ratio (OR) = 1.8 (1.2-2.8)]. In
conclusion, we provided the linkage proof for the PTPN22-1858T allele
and RF(+) RA. With diabetes and RA, PTPN22 is therefore a "linkage-
proven" autoimmunity gene. PTPN22 accounting for approximately 1% of
the RA familial aggregation, many new genes could be expected that are
as many leads to definitive therapy for autoimmune diseases.

PMID: 17237219

-----------

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17230194&query_hl=4&itool=pubmed_docsum

Expression of human PTPN22 alleles.

* Nielsen C,
* Barington T,
* Husby S,
* Lillevang ST.

1Department of Clinical Immunology, Odense University Hospital,
Odense, Denmark.

Considering the female predominance in most of the autoimmune
disorders that associate with the PTPN22 Trp620 variant and the
complexity by which this variant influences immunologic tolerance, the
objective of this study was to ascertain if the allele-specific
expression of the disease-associated Arg620Trp polymorphism is
affected by cis-acting or sex-specific trans-acting factor/s (e.g. sex-
hormones). The use of the allele-specific transcript quantification of
the Arg620Trp encoding 1858T polymorphism revealed no difference in
the expression of the 1858C- and T-alleles in non-stimulated
peripheral blood mononuclear cells (PBMCs) from non-pregnant female
subjects, male subjects or pregnant female subjects in first or third
trimester (P=0.70), respectively. While the transcription of PTPN22 in
anti-CD3/anti-CD28 stimulated PBMCs increased fourfold (P<0.0001) and
13-fold (P<0.0001) after 48 and 72 h of activation, respectively, the
expression of PTPN22 1858C- and T-alleles increased to the same extent
(P=0.64). The present result essentially excludes such phenomena as a
partial explanation for the female predominance in most of the
autoimmune disorders that associate with the PTPN22 Trp620
variant.Genes and Immunity advance online publication, 18 January
2007; doi:10.1038/sj.gene.6364369.

PMID: 17230194

-----------

&
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17130568&query_hl=11&itool=pubmed_docsum

--------------

Ai (autoimmune) conditions seem to favor the female sex, which may
explain prolactin correlating with p severity?
http://en.wikipedia.org/wiki/Prolactin

When a woman is pregnant prolactin levels are low and p is low and
usually rebounds after child birth iirc, when breastfeeding increases
prolactin levels once again?

I don't know, my logic isn't convincing me here.

Lets look to the p newsgroup.

------------

Even the erstwhile "Father" of the P group, Ed Anderson was hep to
prolactin,
http://groups.google.com/groups/search?qt_s=1&q=prolactin+psoriasis

Post #29 in that thread::

"" JRStern <JRSt...@gte.net> wrote:
> I've been amazed to hear that, in many cases, Neoral produces dramatic
> clearing in two weeks, maximal effects in four. I wonder if that
> represents a lower limit -- maybe subtract a few days for the drug to
> reach max level in the bloodstream, I dunno.

Two weeks, bah! Did you catch mention of the combination treatment of
il-2
antibodies and cyclosporin (neoral) back in a previous response? In
two
independent case reports, the il-2 MAB injection cleared severe
psoriasis
in a matter of days, when the patient were already failing on
cyclosporin.

http://pinch.com/skinny?skin=basiliximab

BTW, all this wild speculation from medline abstracts is great fun...

<sarcasm>
No, really. Let's assume that the pantethine is really just a good
prolactin inhibitor, prolactin bineg of course the REAL cause of
psoriasis
(not to mention insulin resistance, baldness, infertility, and weak
orgasms.) As long as we're all being asked to be human guinea pigs,
why
not try dosing us all with bromocriptine to inhibit our raging
prolactin
levels. That way, we can have some fun while we're at it! See:

http://pinch.com/skinny?medline=pantethine+prolactin
http://pinch.com/skinny?medline=psoriasis+prolactin
http://pinch.com/skinny?medline=prolactin+bromocriptine
http://pinch.com/skinny?medline=prolactin+orgasm
http://pinch.com/skinny?medline=prolactin+insulin+resistance

This may be especially important advice for members who don't actually
have psoriasis, but seborrheic dermatitis:

http://pinch.com/skinny?medline=prolactin+seborrheic

It's all self-evident. Just read it for youself!
</sarcasm>

-- Ed "cranky from the solar storm" Anderson ""

------------------------

And lets go back to pubmed now:

Prolactin and autoimmunity:

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16411065&query_hl=13&itool=pubmed_docsum
Prolactin and autoimmunity.

* De Bellis A,
* Bizzarro A,
* Pivonello R,
* Lombardi G,
* Bellastella A.

Department of Clinical and Experimental Medicine and Surgery F.
Magrassi, A. Lanzara, Second University of Naples, via Pansini N. 5,
80131, Napoli, Italy. annamaria...@unina2.it

The interrelationship between prolactin (PRL) and the immune system
have been elucitaded in the last decade, opening new important
horizons in the field of the immunoendocrinology. PRL is secreted not
only by anterior pituitary gland but also by many extrapituitary sites
including the immune cells. The endocrine/paracrine PRL has been shown
to stimulate the immune cells by binding to PRL receptors. Increased
PRL levels, frequently described in autoimmune diseases, could depend
on the enhancement of coordinated bi-directional communications
between PRL and the immune system observed in these diseases.
Hyperprolactinemia has been described in the active phase of some non
organ-specific autoimmune diseases, as systemic lupus erythematosus
(SLE) and rheumatoid arthritis (RA) and organ-specific autoimmune
diseases, as celiac disease, type 1 diabetes mellitus, Addison's
disease, autoimmune thyroid diseases. In these diseases PRL increases
the syntesis of IFNgamma and IL-2 by Th1 lymphocytes. Moreover, PRL
activates Th2 lymphocytes with autoantibody production. Of particular
interest is the association between hyperprolactinemia and levels of
anti DNA antibodies, islet cell antibodies (ICA), thyreoglobulin
antibodies (TgAb), thyroperoxidase antibodies (TPOAb), adrenocortical
antibodies (ACA), transglutaminase antibodies (tTGAb) in SLE, in type
1 diabetes mellitus, in Hashimoto's thyroiditis, in Addison's disease
and in celiac disease, respectively. High levels of PRL have been also
frequently detected in patients with lymphocytic hypophysitis (LYH).
Several mechanisms have been invoked to explain the hyperprolactinemia
in LYH. The PRL increase could be secondary to the inflammatory
process of the pituitary gland but, on the other hand, this increase
could have a role in enhancing the activity of the immune process in
LYH. Moreover, the detection of antipituitary antibodies targeting PRL-
secreting cells in some patients with idiopathic hyperprolactinemia
suggests the occurrence of a possible silent LYH in these patients.
Finally, the role of anti-prolactinemic drugs to inactivate the immune
process in LYH is still discussed.

PMID: 16411065

-----------

Oh well. Pantethine isn't going to cure psorasis in this laundry list,
http://www.pantethine.org/reference/abstracts.php

----

Has anyone used pantethine to lower Ai conditions?

Dr. Atkins used it here,
http://candidapage.com/aldehyde.shtml

[...]
And for autoimmune problems, Dr. Atkins states, " For all conditions
that a doctor might prescribe prednisone -- allergies, asthma,
rheumatoid arthritis, psoriasis, lupus, and olther autoimmune
diseases, pantethine can be safely, effectively substituted. I
routinely use it for all of those conditions on hundreds of my
patients, and it's valuable in weaning them off steroidal drugs, or
certainly in allowing a lower dose....

By upping body levels of a body enzyme, pantethine counteracts brain
fog, certain allergic sensitivities, and some consequences of
alcoholism. (And here it is --) ... In people with candidiasis, the
enzyme fights off a toxic byproduct called acetaldehyde, which is
thought to cause brain fog, often-suffered but rarely diagnosed....
Acetaldehyde also is suspected of being responsible for some symptoms
of alcoholism, including alcoholic heart muscle disease. The
pantethine-stimulated enzyme also detoxifies formaldehyde, an all too
frequent offender for chemically sensitive individuals."

In summary, Dr. Atkins is saying that Pantethine, without toxic
consequences, can reduce cholesterol, counuteract oxidation, stimulate
the growth of friendly bacteria, and fight allergies, inflammation,
autoimmune disruptions, and alcoholism.

In case you wondered, Dr. Cooter and Dr. Schmtt suggest 300 micrograms
of Molybdenum in three divided doses per day, and further suggests
staying on it for at least 4 months.. Dr. Atkins suggests 450 to 900
miligrams daily of Pantethine with an equal amount of Pantethenic
Acid. <end>

--------------------

OMIM:
http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=600716

If they don't find a quick fix for this gene, that could be ten years
down the road, I suppose we
could cocktail pantethine with some of the known suPPlements in our
current arsenal?

randall...

randall

unread,

Feb 2, 2007, 4:44:17 PM2/2/07

Hi,

HaPPy Groundhog day!

Did you see your P? I didn't bother to look. Well the stuff on the
elbows didn't
look to awfully bad.

The sun is out after a few days of rain and looks tempting.

Back to my hole!

And search the sunny news to find a cure! LOL

Seems hyPocritical huh?

Here goes:

http://www.pharmalive.com/News/index.cfm?articleid=411056&categoryid=21
New Report Says Biotechs Studying a Record 70 Psoriasis Treatments

KENSINGTON, Md., February 01, 2007 /PRNewswire-USNewswire/ --
"Psoriasis Cure Now," a nonprofit patient advocacy group, today
reported that biotech and pharmaceutical companies are investigating a
record 70 potential new treatments for psoriasis and psoriatic
arthritis. The data, culled from published reports and clinical trial
recruitment websites, shows continued, strong business interest in the
psoriasis market. A New York Times article last week called into
question the profitability of the psoriasis sector, lighting up
psoriasis message boards with concerns that the psoriasis drug
pipeline could dry up. The full report of psoriasis treatments under
clinical development is available on the Psoriasis Cure Now website
here:

http://www.psoriasis-cure-now.org/hope.php .

"For the millions of Americans battling psoriasis, these clinical
trials, and the breakthrough new treatments that have reached patients
in recent years, represent hope, pure and simple, that the future for
us will be brighter than the past," said Michael Paranzino, president
of Psoriasis Cure Now. "From the potentially toxic, Korean War-era
chemotherapy drug methotrexate, to the powerfully effective but kidney-
damaging cyclosporine, many psoriasis patients today continue to face
difficult choices when psoriasis strikes hard. Maybe one or more of
these new options being studied will free us from that."

The release of the report coincides with the beginning of the American
Academy of Dermatology's Annual Meeting in Washington, DC.
Dermatologists face a steep learning curve educating themselves about
the new treatment options that have recently emerged. This report
shows that challenge will likely continue.

But even as the private sector makes record investments in psoriasis
research, that commitment has not been matched by the federal
government. Psoriasis research at the National Institutes of Health
(NIH) is down 22% over the last decade, even as NIH research on other
diseases doubled.

"Let's hope the new majorities in Congress reverse this unfortunate
slide in psoriasis research funding," Paranzino said.

-----------

After winter comes spring and vaccine time?

http://www.newscientist.com/channel/health/mg19325894.000-vaccine-zapsallergyinrecord-time.html
Vaccine zaps allergy in record time

ALLERGY sufferers could bid farewell to their sneezes with a new
generation of vaccines that take effect within weeks.

Existing vaccines for allergies involve three to five years of regular
injections with increasing amounts of allergen - the substance that
triggers an allergy. All the while the immune response slowly changes
from a predominance of T-helper 2 (TH2) cells, immune cells
responsible for triggering allergic reactions, to T-helper 1 (TH1)
cells, which stimulate the production of protective antibodies.

Because nothing is directing allergens to the right place in immune
cells, it takes a lot of allergen to generate a response.

Now researchers at the Swiss Institute of Allergy and Asthma Research
(SIAF) in Davos Platz have developed "modular antigen translocating
molecules" (MAT), which make vaccines more efficient by delivering the
antigens - foreign substances that trigger an immune response - right
to where they're needed within an immune cell.

The MAT vaccines trigger the same protective response as conventional
vaccines but in a fraction of the time and with much less allergen,
according to a study in human cells. "They lower the dose needed to
induce a T-cell response by a factor of about 100," says Reto Crameri
of SAIF, lead author of the study.

The molecules have three parts: a translocation unit, a targeting unit
and an allergen. The translocation unit gets the allergen into antigen-
presenting cells that are responsible for engineering the switch to
TH1 cells. The targeting unit then chauffeurs the antigens to the part
of the cell that packages them up for presentation to TH1 cells,
ensuring more TH1 cells meet the antigen and respond to it.

Crameri's team has so far developed vaccines for dust mites, pollen,
cat hair and bee venom and tested them on cells from susceptible
humans. In each case the vaccines produced a stronger immune response
than injecting the allergen by itself (Allergy, DOI: 10.1111/j.
1398-9995.2006.01292.x). Crameri says his group is getting similar
results with mice injected with these vaccines, and clinical trials on
a MAT vaccine for cat allergy will begin later this year. The trial
will involve three shots over a four-week period.

The approach is one of several new strategies for tackling allergies.
Another vaccine, developed by Allergy Therapeutics of West Sussex, UK,
entered phase III clinical trials last week. It stimulates a stronger
response by tricking the immune system into thinking it is being
attacked by a bacterium. "In the past few years we have really begun
to understand the cell signalling mechanisms involved in the allergic
response," says Katherine Gundling of the Allergy Immunology Clinic at
the University of California, San Francisco. "Now we're asking, 'Can
we find a way to take advantage of those mechanisms?'"

-----------

HGH (human growth hormone) no "magic bullet"

http://www.usnews.com/usnews/health/articles/070117/17health.hormone.htm

---------

And how about CoQ10 for those like J that take it?

New news:
CoQ10-H2 ( a reduced form of Co-q10)
http://www.vrp.com/art/2030.asp?thenews=vn00a000b00207-2030

Is it worth-less?
http://www.rice.edu/~jenky/sports/coq10.html

Guess I need to look at the patent on it to get really confused!

randall.... holed uP or not have a nice day anyway!

randall

unread,

Feb 5, 2007, 7:59:56 PM2/5/07

On Feb 2, 1:44 pm, "randall" <ranhu...@aol.com> wrote:
> Hi,
>
> HaPPy Groundhog day!
>
> Did you see your P? I didn't bother to look. Well the stuff on the
> elbows didn't
> look to awfully bad.
>

Darn! Just looked at my legs. YIKES!

I smoked some pork butt last week and have been a very bad boy.

So, I doubled down on IP6 the last few days and now i'm starving
for some clearings and OH yeah, worshiping the sun.

I'm not going down that hog hole again.

And i'm not going to put any hog down my pie hole.

Well, just a little more! Now that I can get away with it and
still be under 10% PASi this time of year i'm not all that worried.

How about some carnitas tonight? I'm so BAD! LOL

How many folks with P are doing nada?

Nothing, ziPPo! And live with the p craP?

Try 40%!!

40% of us are living in a P-- CRAPaZOID!

Here, look,

40% of us say screw it, when it comes to treating P.
http://www.upi.com/ConsumerHealthDaily/view.php?StoryID=20070205-120629-6809r

Many with psoriasis don't get treatment

PORTLAND, Ore., Feb. 5 (UPI) -- Nearly 40 percent of U.S. patients
with chronic moderate to severe psoriasis are not currently receiving
treatment, found a survey of 1,142 patients.
In addition, more than half of moderate to severe patients on
treatment are not being treated in accordance with American Academy of
Dermatology guidelines, which state that patients diagnosed with
chronic moderate to severe plaque psoriasis are candidates for
phototherapy or systemic therapy, including biologic agents, according
to the survey by the National Psoriasis Foundation and Amgen.
AAD therapy guidelines advise patients diagnosed with chronic moderate
to severe plaque psoriasis are candidates for phototherapy or systemic
therapy, including biologic agents. Despite the increased number of
psoriasis treatment options, the findings show no significant change
in treatment patterns across three survey years.
"Psoriasis is not a cosmetic disease, but rather a chronic
inflammatory condition that can have a profound negative impact on a
person's ability to function," said Dr. Mark Lebwohl, chairman of the
National Psoriasis Foundation Medical Board. "It's important for
patients to openly discuss with their dermatologist how the condition
may be impacting them, so that together they can determine the most
appropriate treatment option." <sniP>

-----------------------------

And look at this NEW finding, that may affect us. Brand NEW craP on
our skin?
Will it help to clear or cure psoriasis?

Maybe. It's still way to early to know the pathways and consequences
of this discovery.

http://www.newswise.com/articles/view/526968/

Human Skin Harbors Completely Unknown Bacteria

Newswise — It appears that the skin, the largest organ in our body, is
a kind of zoo and some of the inhabitants are quite novel, according
to a new study. Researchers found evidence for 182 species of bacteria
in skin samples. Eight percent were unknown species that had never
before been described.

It is the first study to identify the composition of bacterial
populations on the skin using a powerful molecular method. Not only
were the bacteria more diverse than previously estimated, but some of
them had not been found before, says Martin J. Blaser, M.D., Frederick
King Professor and Chair of the Department of Medicine and Professor
of Microbiology at NYU School of Medicine, one of the authors of the
study.

“The skin is home to a virtual zoo of bacteria,” he says. This study
is published
February 5, 2007, in the online edition of the Proceedings of the
National Academy of Sciences.

The researchers analyzed the bacteria on the forearms of six healthy
subjects; three men and three women. “This is essentially the first
molecular study of the skin,” says Dr. Blaser. The skin has been, he
says, terra incognita, an unknown world that he and his colleagues
have set out to understand much like explorers.

“There are probably fewer than ten labs in the U.S. looking at this
question,” says Dr. Blaser. “It is very intensive work,” he adds. Zhan
Gao, M.D., senior research scientist in Dr. Blaser’s lab, led the
research, which took more than three years to complete.

Some of the bacteria on the skin appear to be more or less permanent
residents; others are transient, according to the study.

This research is part of an emerging effort to study human microbial
ecology. Dr. Blaser’s laboratory has previously examined the bacterial
population in the stomach and the esophagus. “Many of the bacteria of
the human body are still unknown,” he says. “We all live with bacteria
all our lives and occasionally we smile, so they’re not that bad for
us.”

The most numerous cells in our body are microbial—they outnumber our
cells 10 to 1. The body has microbes native to the body, including the
skin, and these populations change according to how we live, he says.
“Ultimately what we want to do is compare disease and health,” says
Dr. Blaser. Keeping bacterial populations in our body stable may be
part of staying healthy, he says.

In the new study, the researchers took swabs from the inner right and
left forearms of six individuals picking the region halfway between
the wrist and the elbow for its convenience. “It’s not where they wash
their hands,” explains Dr. Blaser. “And they don’t have to undress.”
The researchers wanted to be able to compare two similar parts of the
body. Because they also wanted to study change over time, they took
swabs from four of the individuals 8-10 months after the first test.

Roughly half, or 54.4%, of the bacteria identified in the samples
represented the genera Propionibacteria, Corynebacteria,
Staphylococcus and Streptococcus, which have long been considered more
or less permanent residents in human skin.

The six individuals differed markedly in the overall composition of
the bacterial populations on their skin. They only had four species of
bacteria in common: Propionibacterium acnes, Corynebacterium
tuberculostearicum, Streptococcus mitis, and Finegoldia AB109769.
“This is a surprise,” says Dr. Gao. “But many things affecting the
skin affect bacteria, such as the weather, exposure to light, and
cosmetics use.”

Almost three-quarters, or 71.4%, of the total number of bacterial
species were unique to individual subjects, suggesting that the skin
surface is highly diversified in terms of the bacteria it harbors,
according to the study.

Three bacterial species were only found in the male subjects:
Propionibacterium granulosum, Corynebacterium singulare, and
Corynebacterium appendixes. While the sample is too small to draw
conclusions, the scientists believe that women and men may harbor some
different bacterial species on their skin.

In each individual, the bacterial populations varied over time while
revealing a core set of bacteria for each individual. “The predominant
bacteria don’t change much,” says Dr. Gao. “But the more transient
bacteria did change over time,” she says.

“What that suggests,” adds Dr. Blaser, “is that there is a scaffold of
bacteria present in everybody’s skin. Some stay and others come and
go.”

Finding the method

To obtain a sample Dr. Gao rubbed a swab on each individual’s
forearms. “We didn’t tell them to be particularly clean, we just made
sure they didn’t take antibiotics up to one month prior to the test,”
Dr. Gao explains. She chose three men and three women to have a
balance of genders. She set up a clean room so the samples didn’t risk
contamination.

Traditionally, bacteria are cultured in the lab in petri dishes, which
contain a medium to grow bacteria. But the method leads to
inaccuracies, she explains, because only a fraction of bacteria in a
sample grow in that medium. So the team used a powerful molecular
method that involved extracting a subunit of genetic material called
16S ribosomal DNA from the samples. “It is kind of a common currency,
it’s a conserved gene,” says Dr. Blaser. Another advantage is that
there is a large database of 16S ribosomal DNA available to
scientists.

The ambitious task for this study was to gather samples, prepare them,
amplify the bacteria creating colonies of each single species of
bacteria present in the skin samples. Then Dr. Gao used established
tools—primers—to pick out the species-specific genetic regions in the
bacteria. After sequencing those regions, the 16S ribosomal DNA (rDNA)
in each colony, she consulted 16S rDNA databases to determine the
bacterial species present in each sample. Many bacteria in the
database only exist as sequences and have nether been named or
extensively studied. Those are termed SLOTUs, or species-level
taxonomic units.

Taxonomy and the study results

To distinguish organisms from one another, biologists group and
categorize them. Species or SLOTUs are small categories. There are
larger groupings such as genera and phyla. Humans, for example, belong
to the phylum chordata, the genus Homo and the species Homo sapiens.

The molecular method used in this study revealed differences between
the bacterial populations in individuals. Other methods had previously
not shown those differences.

The team found a total of 182 species or SLOTUs and 91 genera of
bacteria in the skin samples.

The samples yielded mainly three phyla of bacteria: Actinobacteria,
Firmicutes, and Proteobacteria. Some ninety-four percent of the
bacteria were in these phyla. These phyla were found in all six tested
individuals. When compared with earlier studies, the researchers found
that these three phyla are also dominant in the esophagus and the
stomach. In terms of bacterial species, however, the insides of the
body, for example the stomach, and the exterior of the body, the skin,
show vast differences in bacterial populations.

Skin condition can change markedly due to a variety of factors such as
climate, diet, personal hygiene, and disease. But skin is never devoid
of bacteria, particularly its more permanent residents. That is not
bad news, after all, in healthy individuals these bacteria are not
pathogens. “Without good bacteria, the body could not survive,” says
Dr. Gao.

The next step for the research team is to look at diseased skin. “We
plan to ask the question: Are the microbes in diseased skin, in
certain diseases like __________psoriasis_________ or eczema,
different than the microbes in normal skin?” says Dr. Blaser.

The study was funded by the National Institutes of Health (NIH), by a
Senior Scholar Award from the Ellison Medical Foundation, and by the
Diane Belfer Program in Human Microbial Ecology in Health. The authors
of the study are Zhan Gao, M.D, Chi-hong Tseng, Ph.D., Zhiheng Pei,
M.D., Ph.D, and Martin J. Blaser, M.D.

-----------------

http://www.sciencedaily.com/upi/index.php?feed=Science&article=UPI-1-20070205-15540100-bc-us-crohns.xml
Naltrexone may help Crohn's sufferers

STATE COLLEGE, Pa., Feb. 5 (UPI) -- A U.S. pilot study suggests a low
dose of a pharmaceutical used to ease symptoms of drug addition may
also help sufferers of Crohn's disease.

Researchers at the Penn State College of Medicine suggest a low dose
of the drug naltrexone may also bring relief to people with Crohn's --
a chronic inflammatory disorder of the intestine that affects an
estimated 500,000 people in the United States.

A team of scientists led by Dr. Jill Smith, a gastroenterologist, and
Ian Zagon, a professor of neural and behavioral sciences, received
federal funding last summer to initiate the phase 2 trial.

The results indicated 89 percent of patients with diagnosed Crohn's
disease showed an improvement after receiving a low dose of naltrexone
for 12 weeks. In addition, 67 percent achieved remission of all
symptoms.

The results are detailed online this week in the American Journal of
Gastroenterology.

-----
Google LDN for group posts on this topic.

http://groups.google.com/groups/search?qt_s=1&q=ldn+psoriasis
-------------------

Advitech, makers of dermylex (sweet whey isolate- my favorite by the
way) have a new
website and COO/VP,
http://www.marketwire.com/mw/release_html_b1?release_id=211465
The NEW Dermylex™ website is now online at www.dermylex.ca.

I love these guys. Not only the product, but things they say, LIKE:
"Effective and safe, these products play a role in the prevention of
Immune-Mediated Inflammatory Disorders (IMID), such as psoriasis and
inflammatory bowel ..."

P is an IMID. And is to be treated with sweet whey. All music to my
skin!

-----------------------

Do you want to blow off 75% of your crud in the next few weeks?

Here's the 75% solution:

http://news.google.com/news?qt_s=1&tab=gn&ie=UTF-8&scoring=d&q=psoriasis+75+percent&btnG=Search

----------------

randall.... stop groundhog's day NOW + get clearer

Fizziwig2

unread,

Feb 6, 2007, 4:32:57 PM2/6/07

Hi Randall

Sun (or the lack of it) doesn't seem to affect my P at all. February in
Scotland is not suitable for sunbathing even when the sun comes out.
I am still clear of skin P and even have one perfect nail (thumb) at
present!

I was just going to send you the skin flora info. as I also found it here -
http://www.livescience.com/humanbiology/070206_microbe_zoo.html

I use the Sanex range of skin washes myself as they "claim" to protect the
skin's flora and seem to be working in my case. That and E45 cream.

I went mad on food and drink at Christmas for two weeks when visiting
relatives and suffered no ill effects so am wondering if P is a bug that I
am getting over.

Skeats

"randall" <ranh...@aol.com> wrote in message

news:1170723596.4...@m58g2000cwm.googlegroups.com...

Try 40%!!

Here, look,

-----------------------------

http://www.newswise.com/articles/view/526968/

Newswise - It appears that the skin, the largest organ in our body, is

The most numerous cells in our body are microbial-they outnumber our

Finding the method

tools-primers-to pick out the species-specific genetic regions in the

-----------------

http://groups.google.com/groups/search?qt_s=1&q=ldn+psoriasis
-------------------

The NEW DermylexT website is now online at www.dermylex.ca.

randall

unread,

Feb 7, 2007, 12:46:49 PM2/7/07

On Feb 6, 1:32 pm, "Fizziwig2"

<atthebackofthenorthw...@kingdomcom.co.uk> wrote:
> Hi Randall
>
> Sun (or the lack of it) doesn't seem to affect my P at all. February in
> Scotland is not suitable for sunbathing even when the sun comes out.
> I am still clear of skin P and even have one perfect nail (thumb) at
> present!
>

> I was just going to send you the skin flora info. as I also found it here -http://www.livescience.com/humanbiology/070206_microbe_zoo.html

>
> I use the Sanex range of skin washes myself as they "claim" to protect the
> skin's flora and seem to be working in my case. That and E45 cream.
>
> I went mad on food and drink at Christmas for two weeks when visiting
> relatives and suffered no ill effects so am wondering if P is a bug that I
> am getting over.
>
> Skeats
>

Your situation is most illustrative of my gut quest.

Let's examine
Your 25 degrees of Northern latitude above me as the sunshine killer.

Latitude,
http://en.wikipedia.org/wiki/Latitude

So, you may need 8X's more light? You could freeze in that time. LOL

http://en.wikipedia.org/wiki/Effect_of_sun_angle_on_climate

And with less light, and the shorter wavelengths (300-312nm) required
for psoriasis
i'm not sure what one could do, outside of visiting your derm for
sunny office visits. :)

Here it says that irradiance (flux of solar radiation) is not only
affected by latitude but also by ozone.
http://uvb.nrel.colostate.edu/UVB/publications/uvb_primer.pdf
(About half way down the page) And note solar zenith angle at figure-4
about 6/10's of the way
down the page.

------------

At this time the sunBURN effects on DNA are being dissected:
http://www.medicalnewstoday.com/medicalnews.php?newsid=62156
Scientists See DNA Get "Sunburned" For The First Time

For the first time, scientists have observed DNA being damaged by
ultraviolet (UV) light.

Ohio State University chemists and their colleagues in Germany used a
special technique to watch strands of DNA in the laboratory sustain
damage in real time.

They observed the most common chemical reaction among a family of
reactions on the DNA molecule that are linked to sunburn, and
discovered that this key reaction happens with astounding speed -- in
less than one picosecond, or one millionth of one millionth of a
second.

Scientists are studying UV damage to understand the role it plays in
sunburn and diseases such as skin cancer. This new finding, reported
in the current issue of the journal Science, shows that the damage
depends greatly on the position of the DNA at the moment the UV
strikes the molecule.

UV light excites the DNA molecule by adding energy, said Bern Kohler,
associate professor of chemistry at Ohio State. Some exited energy
states last a long time, and others a short time. The energy often
decays away harmlessly, but occasionally it triggers a chemical
reaction that alters the DNA's molecular structure.

Previously, scientists believed that the longer a DNA molecule was
excited by UV energy, the greater the chance that it would sustain
damage. So long-lived excited states were thought to be more dangerous
than short-lived ones. But this study shows that the most common UV
damage is caused by a very short-lived excited state.

"The speed of this reaction has important consequences for
understanding how DNA is damaged by UV light," said Kohler. "In this
study, we didn't see any evidence that long-lived energy states are
responsible for damage. Now it seems more likely that short-lived
states cause the most common chemical damage to DNA."

That damage consists of two tiny molecular bonds that form where they
shouldn't -- between two thymine bases stacked together among the
billions of bases in the DNA double helix.

DNA employs some chemical reactions of its own to heal itself. But
when DNA sustains too much damage, it can't replicate properly. Badly
damaged cells simply die -- the effect that gives sunburn its sting.
Scientists also believe that chronic damage creates mutations that
lead to diseases such as skin cancer.

For this study, the chemists used a technique called transient
absorption to observe the DNA damage. Transient absorption is based on
the idea that molecules absorb light at specific wavelengths, and it
allows researchers to study events that happen in less than a
picosecond.

They took specially designed strands of DNA -- ones made solely of
thymine bases, in order to boost the chance of observing a reaction
between adjacent thymines -- and exposed them to UV light. Then they
timed the reactions that caused the new thymine bonds to form.

Kohler stressed that he and his colleagues examined damage to isolated
DNA strands, not DNA within a cell. Sunburn results from a series of
chemical reactions in a living cell, and so this experiment did not
allow them to see a cell sustain sunburn.

This is, however, the first time anyone has observed the initial
molecular events behind damage to DNA. Kohler thinks the results might
make scientists attack the problem of UV damage in a new way.

DNA in a cell is always moving, he explained. It bends and twists one
way or another because it is a relatively flexible molecule. This
flexibility enables the normal chemical reactions that are constantly
happening in the cell. Each shape-shift can require anywhere from a
few to several hundred picoseconds to complete.

That's fast, but this new study shows that UV damage happens many
times faster. On the timescale that the unwanted bonds form, even a
rapidly moving DNA molecule would essentially appear frozen.

That means that whether or not two thymine bases are damaged depends
on the position of the DNA during the extremely brief time required
for it to absorb UV light. Either two thymine bases are lined up in
just the right way to bond when the UV hits, or they're not.

"This insight explains why some pairs of thymine bases get damaged
more frequently than others, and it suggests that scientists can
understand damage patterns to DNA by studying the factors that
influence how the bases are arranged in space," Kohler said.

"In our efforts to understand photo-damage, this new result shifts our
attention to the DNA structure, and the kinds of arrangements that
exist at the moment DNA absorbs light."

His coauthors on the paper include Carlos E. Crespo-Hernandez, a
former postdoctoral researcher at Ohio State ; and Wolfgang J.
Schreier, Tobias E. Schrader, Florian O. Koller, Peter Gilch, Wolfgang
Zinth, Vijay N. Swaminathan, and Thomas Carell, all of Ludwig
Maximilians University in Munich .

The research was funded in part by the National Institute of General
Medical Science at the National Institutes of Health, and by the
Alexander von Humboldt Foundation of Germany.

------------

And if you get to much sun, not likely for some of us severe
psoriatics, then BMTd's can
be used to fix those ugly wrinkles:
http://www.medicalnewstoday.com/medicalnews.php?newsid=62234

----------

Baby your skin:
http://www.medicalnewstoday.com/medicalnews.php?newsid=62162

----------

We're in a world where science is figuring out how to turn genes/DNA
on/off,
http://www.sciencedaily.com/releases/2007/02/070205115157.htm

And some folks are doing research and receiving Nobel prizes for
being,

Human Guinea pigs:
http://news.bbc.co.uk/1/hi/health/6335295.stm
The British Medical Journal recently asked people to vote for the
greatest medical breakthrough of the last 160 years.

The shortlist included vaccines, x-rays, the discovery of the
structure of DNA, sanitation - and anaesthesia.

There is no doubt the discovery of drugs capable of blocking pain is
one of the greatest inventions of all time - it utterly transformed
surgery from a barbaric and savage act of desperation into a life-
saving science.

What few people realise, however, is that it came about largely
through the work of people who carried out experiments on themselves.

Men like dentist Horace Wells who, to test the power of nitrous oxide,
had one of his teeth extracted while inhaling the gas.

Or Dr William Morton who almost died testing ether on himself, but
whose work led to the word "anaesthesia" (meaning "without feeling")
being coined.

It is astonishing how many of the great medical breakthroughs, from
vaccines to treatments for infectious disease, are the result of self-
experimentation. And it is a tradition that is still alive today.

Infected with bacteria

In 1984 a young Australian, Dr Barry Marshall, did what many fellow
doctors at the time saw as little more than a reckless publicity
stunt.

It was obvious that most doctors didn't believe us
Dr Barry Marshall

He deliberately infected himself with a newly discovered strain of
bacteria called helicobacter pylori.

These bacteria had been discovered by a colleague, Robin Warren, in
the stomachs of patients with ulcers.

Dr Marshall and Dr Warren were convinced that these bacteria were a
significant cause of gastric bleeding and stomach ulcers. As Barry
recalls, they met a lot of scepticism.

"It was obvious that most doctors didn't believe us," he said.

"You're wrong Dr Marshall, these bacteria are harmless and people with
ulcers just catch the harmless bacteria - you're getting all excited
about nothing."

Dr Marshall tried to infect animals with helicobacter, without
success.

So in the end he decided he had no option but to infect himself.

Unappetising drink

First he was gastroscoped; a fibre optic tube passed down into his
stomach and a biopsy of his stomach lining taken. It was normal. Next
he asked a lab technician to help.

"Barry asked me to culture the bacteria, which I did. Smelt terrible,
like swamp water. When I'd grown enough I gave him a ring, " said
technician Neil Noakes.

"He came into the lab, I handed him the beaker and he knocked it back.
Just skulled it down. Not the sort of thing you'd want to sip, I
guess."

Swallowing several thousand million bacteria in one go made Barry
almost as ill as he had expected.

"Within a few days I was in pain and started vomiting," he said.

"Every morning I woke first thing, at the crack of dawn, raced out to
the bathroom and vomited into the toilet."

Ten days later he again had himself gastroscoped and another sample of
his stomach lining taken.

"Sure enough I had very, very severe gastritis (inflammation of the
stomach wall). Those bacteria were in my stomach by the millions.

"So I was very, very excited at that point because I had proved that
the bacteria could infect a healthy person and cause damage in the
stomach."

Huge impact

He treated himself with a complex regime of antibiotics and his
symptoms eased. His experiment triggered research which has
transformed millions of lives.

"At least 10 million people a year used to bleed from ulcers and most
of those people don't have any trouble any more," Dr Marshall said.

"Something which people had spent decades and hundreds of millions of
dollars studying is now very simple.

"Two guys in Perth, Western Australia discovered the cause and the
treatment and really that's the end of it."

In 2005 Barry Marshall and Robin Warren won the Nobel Prize for
Medicine.

Barry did the experiment on himself because he didn't feel it was
ethical to ask someone else to go first.

Hookworm

For similar reasons Professor David Pritchard and colleagues at
Nottingham University recently infected themselves with hookworm.

They had discovered that hookworm produce chemicals which can calm the
human immune system, reducing symptoms of allergic diseases like hay
fever and asthma.

But before testing the worms on patients they needed to find out just
how safe worm infestation is. So they volunteered themselves.

"We did it to show our commitment and because we felt it would only be
appropriate to proceed once we had found a dose that was safe to try
as part of a clinical trial."

At a time when the ethical basis of much medical research is
increasingly under question it is rather wonderful to discover that
scientists are still prepared to put their bodies on the line.

------------

That last one always gives me hoPe!

_______

The Fix for H. pylori:
http://www.medicalnewstoday.com/medicalnews.php?newsid=62375

----------

Not only are psoriatics benefitted by increased vitamin D, but so are
other IMID folks. MS comes to mind. :
http://www.medicalnewstoday.com/medicalnews.php?newsid=59755

And if your at risk for the MS IMID, then get under the sun:
http://www.medicalnewstoday.com/healthnews.php?newsid=59529

If you have an IMID like P or MS, start walking now:
http://www.medicalnewstoday.com/medicalnews.php?newsid=58847

Preventing CANCER with vitamin D:
http://www.medicalnewstoday.com/medicalnews.php?newsid=62413

[...]
Vitamin D3 is available through diet, supplements and exposure of the
skin to sunlight, or ultraviolet B (UVB). In the paper, the
researchers underscored the importance of limiting sun exposure such
that the skin does not change color (tan) or burn. For a typical fair-
skinned Caucasian individual, adequate vitamin D could be
photosynthesized safely by spending 10 to 15 minutes in the noontime
sun on a clear day with 50 percent of skin area exposed to the sun.
Darker skinned individuals may require more time in the sun, such as
25 minutes. For people with photosensitivity disorders, or anyone with
a personal or family history of nonmelanoma skin cancer, any amount of
extra sun exposure would be inadvisable. <sniP>

----------

If you smoke and want to die young keep doing it:
http://www.mprize.org/index.php?ctype=news&pagename=blogdetaildisplay&BID=20070112-12070000&detaildisplay=Y

----------

\randall.... sun and groundhogs we have more to learn-gut hunches

randall

unread,

Feb 7, 2007, 6:46:18 PM2/7/07

Hi,

This should be,

Part II to the last post to skeats. I wanted to do a long post on new
gut articles
and went on the vitamin D quest instead. Sorry! I simply found to many
interesting
links in that area. :)

And now we have breaking news from one of the two ---P-- Kruegers.
This one does work for the NPF and i've spoken with Him when
he came to town with Gail Zimmerman.

Big Daddy Krueger has a new treatment for psoriasis that targets its
key inflammatory mediators (IL-12 and IL-23) is highly effective,
according to a study by University of Utah researchers to be published
in the Feb. 8 issue of The New England Journal of Medicine.

http://www.newswise.com/articles/view/527154/

Newswise - A new treatment for psoriasis that targets its key
inflammatory mediators (IL-12 and IL-23) is highly effective,
according to a study by University of Utah researchers to be published
in the Feb. 8 issue of The New England Journal of Medicine.

Current treatments for psoriasis include topical medicines and UV
light therapy to treat the symptoms of the disease. Many of these
treatments are messy, time consuming, have cumulative toxicities, and
are not very effective, according to Gerald Krueger, M.D., principal
investigator for the study. Krueger is a professor of dermatology and
a Benning Presidential Endowed Chair at the University of Utah School
of Medicine.

He says the results of the study are especially intriguing because of
what it may mean for other immune mediated diseases that share the
same signaling pathways, specifically inflammatory bowel disease
(IBD).

In 2005 another team of researchers (Mannon et al for the anti-IL-12
Study Group) showed that a different human monoclonal antibody to p40
was effective in the treatment of IBD. "These results suggest that
therapeutics that target the IL-12 and IL-23 signaling pathway appear
to effectively treat both psoriasis and IBD," he said.

According to Krueger, the story of the link between psoriasis and IBD
gains intrigue by events independent of these reports of treatment
success. In October of last year the University of Utah and Celera
Group of Applera Corporation reported at the American Association of
Human Genetics annual meeting that psoriasis patients carry a common
polymorphism in the gene for p40 (IL12B) more often than control
subjects. Further exploration led to a discovery of a second
polymorphism in the receptor for IL-23 that also associates with
psoriasis. These results were recently published in the American
Journal of Human Genetics (Cargill et al. 2007). Duerr and colleagues
(2006) have reported that the same variant in the IL-23 receptor is
associated with IBD. The common forms of these polymorphisms are
associated with risk of both psoriasis and IBD, while the uncommon
forms are protective, according to Krueger.

"This is really an alignment of the stars. It's unusual that targeting
a new inflammatory pathway in two different diseases provides patients
with dramatic improvement," he said. "And then, almost simultaneously,
we find disease-associated genetic variants in this same pathway."

Krueger and colleagues at Celera predict that refinement of disease
association patterns to specific genetic variants within IL-12/23 and
the IL-23 receptor will play an important role in the elucidation of
the causes of psoriasis, and IBD.

Krueger says that, "Further studies should help determine whether any
of the identified differential risk polymorphisms are also associated
with response to therapy and possible toxicities and thereby help
determine the most effective dosage of these new monoclonal antibody
therapies."

Researchers from Dalhousie University in Halifax, Nova Scotia; St.
Louis University, St. Louis; Mount Sinai School of Medicine, New York;
and Centocor, Inc. of Malvern, Penn.; participated in the study. The
study published was funded by Centocor, Inc.

About Psoriasis:

Psoriasis is a chronic (long-lasting) skin disease of scaling and
inflammation that affects 2 to 2.6 percent of the United States
population, or between 5.8 and 7.5 million people. Although the
disease occurs in all age groups, it primarily affects adults. It
appears about equally in males and females. Psoriasis occurs when skin
cells quickly rise from their origin below the surface of the skin and
pile up on the surface before they have a chance to mature. Usually
this movement (also called turnover) takes about a month, but in
psoriasis it may occur in only a few days. In its typical form,
psoriasis results in patches of thick, red (inflamed) skin covered
with silvery scales. These patches, which are sometimes referred to as
plaques, usually itch or feel sore. They most often occur on the
elbows, knees, other parts of the legs, scalp, lower back, face,
palms, and soles of the feet, but they can occur on skin anywhere on
the body. About 25% of patients who develop psoriasis go on to develop
psoriatic arthritis.

Information courtesy of: http://www.niams.nih.gov/hi/topics/psoriasis/
psoriasis.htm#1

----

More of the same:
http://content.nejm.org/cgi/content/short/356/6/580

[...]
Conclusions This study demonstrates the therapeutic efficacy of an
interleukin-12/23 monoclonal antibody in psoriasis and provides
further evidence of a role of the interleukin-12/23 p40 cytokines in
the pathophysiology of psoriasis. Larger studies are needed to
determine whether serious adverse events might limit the clinical
usefulness of this new therapeutic target. (ClinicalTrials.gov number,
NCT00320216

---------

We may as well list the most recent abstracts to find those that can
shed light on these pathways.

------

IL-18: Key P pathway player for regulation?
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17274000&query_hl=1&itool=pubmed_docsum
IL-18 enhances IFN-gamma-induced production of CXCL9, CXCL10, and
CXCL11 in human keratinocytes.

* Kanda N,
* Shimizu T,
* Tada Y,
* Watanabe S.

Department of Dermatology, Teikyo University School of Medicine,

Tokyo, Japan.

IL-18 is involved in the pathogenesis of atopic dermatitis, psoriasis,
and allergic contact dermatitis. CXCL9, CXCL10, and CXCL11 recruit
type 1 T cells, and the production of these chemokines by
keratinocytes is enhanced in these dermatoses. We examined the in
vitro effects of IL-18 on IFN-gamma-induced CXCL9, CXCL10, and CXCL11
production in human keratinocytes. IL-18 enhanced the IFN-gamma-

induced secretion and mRNA expression of CXCL9, CXCL10, and CXCL11 in

parallel to the activation of NF-kappaB, STAT1, and IFN-regulatory
factor (IRF)-1. Antisense oligonucleotides against NF-kappaB p50, p65,
or STAT1 suppressed CXCL9, CXCL10, and CXCL11 production, and
antisense IRF-1 suppressed CXCL11 production. Inhibitors of PI3 K, p38
MAPK, and MEK suppressed IL-18 plus IFN-gamma-induced CXCL9, CXCL10,
and CXCL11 production and NF-kappaB, STAT1, and IRF-1 activities.
IL-18 induced phosphorylation of ERK and Akt, while IFN-gamma induced
phosphorylation of p38 MAPK. These results suggest that IL-18 may
potentiate IFN-gamma-induced CXCL9, CXCL10, and CXCL11 production in
keratinocytes by activating NF-kappaB, STAT1, or IRF-1 through PI3 K/
Akt and MEK/ERK pathways. These effects of IL-18 may promote the
infiltration of type 1 T cells into lesions with inflammatory
dermatoses and amplify the skin inflammation. IL-18 may act as a pro-
inflammatory cytokine in these dermatoses and thus is a candidate
therapeutic target.

PMID: 17274000

------------

And don't forget IL-20:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17277128&query_hl=1&itool=pubmed_docsum
The Effects of IL-20 Subfamily Cytokines on Reconstituted Human
Epidermis Suggest Potential Roles in Cutaneous Innate Defense and
Pathogenic Adaptive Immunity in Psoriasis.

* Sa SM,
* Valdez PA,
* Wu J,
* Jung K,
* Zhong F,
* Hall L,
* Kasman I,
* Winer J,
* Modrusan Z,
* Danilenko DM,
* Ouyang W.

Department of Pathology.

IL-19, IL-20, IL-22, IL-24, and IL-26 are members of the IL-10 family
of cytokines that have been shown to be up-regulated in psoriatic
skin. Contrary to IL-10, these cytokines signal using receptor complex
R1 subunits that are preferentially expressed on cells of epithelial
origin; thus, we henceforth refer to them as the IL-20 subfamily
cytokines. In this study, we show that primary human keratinocytes
(KCs) express receptors for these cytokines and that IL-19, IL-20,
IL-22, and IL-24 induce acanthosis in reconstituted human epidermis
(RHE) in a dose-dependent manner. These cytokines also induce
expression of the psoriasis-associated protein S100A7 and keratin 16
in RHE and cause persistent activation of Stat3 with nuclear
localization. IL-22 had the most pronounced effects on KC
proliferation and on the differentiation of KCs in RHE, inducing a
decrease in the granular cell layer (hypogranulosis). Furthermore,
gene expression analysis performed on cultured RHE treated with these
cytokines showed that IL-19, IL-20, IL-22, and IL-24 regulate many of
these same genes to variable degrees, inducing a gene expression
profile consistent with inflammatory responses, wound healing re-
epithelialization, and altered differentiation. Many of these genes
have also been found to be up-regulated in psoriatic skin, including
several chemokines, beta-defensins, S100 family proteins, and
kallikreins. These results confirm that IL-20 subfamily cytokines are
important regulators of epidermal KC biology with potentially pivotal
roles in the immunopathology of psoriasis.

PMID: 17277128

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17269723&query_hl=1&itool=pubmed_docsum

Combination of Abundant Protein Depletion and Multi-Lectin Affinity
Chromatography (M-LAC) for Plasma Protein Biomarker Discovery.

* Plavina T,
* Wakshull E,
* Hancock WS,
* Hincapie M.

Biogen Idec, Inc., Boston, Massachusetts 02142, and Barnett Institute
and Department of Chemistry and Chemical Biology, Northeastern
University, Boston, Massachusetts 02115.

We report on the development of a robust and relatively high-
throughput method for in-depth proteomic analysis of human plasma
suitable for biomarker discovery. The method consists of depletion of
albumin and IgG and multi-lectin affinity chromatography (M-LAC),
followed by nanoLC-MS/MS analysis of digested proteins and label-free
comparative quantitation of proteins. The performance of the method is
monitored by multiple quality control points to ensure reproducibility
of the analysis. The method identifies proteins that are reported to
be present in normal plasma at concentrations of 10-100 ng/mL and that
may be of particular interest when studying a variety of disease
conditions. Numerous tissue leakage proteins of potentially even lower
concentrations are also identified. When the method was used in a
study to identify potential biomarkers of psoriasis, the differential
abundance of proteins present at low mug/mL level was quantitated and
later verified by ELISA measurements. Keywords: plasma * multi-lectin
affinity chromatography (M-LAC) * abundant protein depletion *
biomarker discovery * ELISA.

PMID: 17269723

Possible new drug for an old pathway to slow psoriasis?
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17273162&query_hl=1&itool=pubmed_docsum
Targeting Effector Memory T Cells with the Small Molecule Kv1.3
Blocker PAP-1 Suppresses Allergic Contact Dermatitis.

* Azam P,
* Sankaranarayanan A,
* Homerick D,
* Griffey S,
* Wulff H.

1Department of Medical Pharmacology and Toxicology, University of
California, Davis, California, USA.

The voltage-gated potassium channel Kv1.3 has been recently identified
as a molecular target that allows for selective pharmacological
suppression of effector memory T (T(EM)) cells without affecting the
function of naive and central memory T cells. We here investigated
whether PAP-1, a small molecule Kv1.3 blocker (EC(50)=2 nM), could
suppress allergic contact dermatitis (ACD). In a rat model of ACD, we
first confirmed that the infiltrating cells in the elicitation phase
are indeed CD8(+) CD45RC(-) memory T cells with high Kv1.3 expression.
In accordance with its selective effect on T(EM) cells, PAP-1 did not
impair sensitization, but potently suppressed oxazolone-induced
inflammation by inhibiting the infiltration of CD8(+) T cells and
reducing the production of the inflammatory cytokines IFN-gamma, IL-2,
and IL-17 when administered intraperitoneally or orally during the
elicitation phase. PAP-1 was equally effective when applied topically,
demonstrating that it effectively penetrates skin. We further show
that PAP-1 is not a sensitizer or an irritant and exhibits no toxicity
in a 28-day toxicity study. Based on these results we propose that
PAP-1 could potentially be developed into a drug for the topical
treatment of inflammatory skin diseases such as psoriasis.Journal of
Investigative Dermatology advance online publication, 1 February 2007;
doi:10.1038/sj.jid.5700717.

PMID: 17273162

Curcumin again:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17273796&query_hl=1&itool=pubmed_docsum
Curcumin attenuates the expression of IL-1beta, IL-6, and TNF-alpha as
well as cyclin E in TNF-alpha-treated HaCaT cells; NF-kappaB and MAPKs
as potential upstream targets.

* Cho JW,
* Lee KS,
* Kim CW.

Department of Dermatology, School of Medicine, Keimyung University,
Daegu 700-712, Korea.

TNF-alpha induces some proinflammatory cytokines including IL-1beta,
IL-6, IL-8, and itself by activation of NF-kappaB or MAPKs (p38, JNK,
ERK). These cytokines play important roles in various inflammatory
skin diseases, such as psoriasis. Recently it was also reported that
expression of cyclin E is up-regulated by ERK pathway after TNF-alpha
treatment. However, it was unknown whether curcumin, showing
inhibitory effects on NF-kappaB and MAPKs, attenuates the expression
of TNF-alpha-induced IL-1beta, IL-6, IL-8, and TNF-alpha as well as
cyclin E expression in HaCaT cells. In this study, we investigated the
inhibitory effect of curcumin on expression of proinflammatory
cytokines and cyclin E in TNF-alpha-treated HaCaT cells. We found that
curcumin inhibited the expression of TNF-alpha-induced IL-1beta, IL-6,
and TNF-alpha, but not IL-8, in TNF-alpha-treated HaCaT cells as well
as the TNF-alpha-induced cyclin E expression. In addition, curcumin
inhibited the activation of MAPKs (JNK, p38 MAPK, and ERK) and NF-
kappaB in TNF-alpha-treated HaCaT cells. Taken together, curcumin
exerts anti-inflammatory and growth inhibitory effects in TNF-alpha-
treated HaCaT cells through inhibition of NF-kappaB and MAPK pathways.

PMID: 17273796

--------

randall... out of the hog hole today!

randall

unread,

Feb 9, 2007, 3:47:15 PM2/9/07

I said:
>
> Doctor Krueger has a new treatment for psoriasis that targets

> key inflammatory mediators (IL-12 and IL-23) is highly effective,
> according to a study by University of Utah researchers to be published
> in the Feb. 8 issue of The New England Journal of Medicine.
>
> http://www.newswise.com/articles/view/527154/
>

Here is the abstract to go with the above link.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17287478&query_hl=5&itool=pubmed_docsum
A human interleukin-12/23 monoclonal antibody for the treatment of
psoriasis.

* Krueger GG,
* Langley RG,
* Leonardi C,
* Yeilding N,
* Guzzo C,
* Wang Y,
* Dooley LT,
* Lebwohl M;
* CNTO 1275 Psoriasis Study Group.

University of Utah, Salt Lake City, USA.
gerald....@derm.med.utah.edu

BACKGROUND: Skin-infiltrating lymphocytes expressing type 1 cytokines
have been linked to the pathophysiology of psoriasis. We evaluated the
safety and efficacy of a human interleukin-12/23 monoclonal antibody
in treating psoriasis. METHODS: In this double-blind, placebo-
controlled trial, 320 patients with moderate-to-severe plaque
psoriasis underwent randomization to treatment with the
interleukin-12/23 monoclonal antibody (one 45-mg dose, one 90-mg dose,
four weekly 45-mg doses, or four weekly 90-mg doses) or placebo; 64
patients were randomly assigned to each group. Patients assigned to
the interleukin-12/23 monoclonal antibody received one additional dose
at week 16 if needed. Patients assigned to placebo crossed over to
receive one 90-mg dose of interleukin-12/23 monoclonal antibody at
week 20. RESULTS: There was at least 75% improvement in the psoriasis
area-and-severity index at week 12 (the primary end point) in 52% of
patients who received 45 mg of the interleukin-12/23 monoclonal
antibody, in 59% of those who received 90 mg, in 67% of those who
received four weekly 45-mg doses, and in 81% of those who received
four weekly 90-mg doses, as compared with 2% of those who received
placebo (P<0.001 for each comparison), and there was at least 90%
improvement in 23%, 30%, 44%, and 52%, respectively, of patients who
received the monoclonal antibody as compared with 2% of patients who
received placebo (P<0.001 for each comparison). Adverse events
occurred in 79% of patients treated with the interleukin-12/23
monoclonal antibody as compared with 72% of patients in the placebo
group (P=0.19). Serious adverse events occurred in 4% of patients who
received the monoclonal antibody and in 1% of those who received
placebo (P=0.69). CONCLUSIONS: This study demonstrates the therapeutic

efficacy of an interleukin-12/23 monoclonal antibody in psoriasis and
provides further evidence of a role of the interleukin-12/23 p40
cytokines in the pathophysiology of psoriasis. Larger studies are
needed to determine whether serious adverse events might limit the
clinical usefulness of this new therapeutic target.

(ClinicalTrials.gov number, NCT00320216 [ClinicalTrials.gov].).
Copyright 2007 Massachusetts Medical Society.

PMID: 17287478

So, we do a search of keywords: interleukin-12 23 p40

And the abstracts that stand out to me anyway.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17053051&query_hl=5&itool=pubmed_docsum

Selective abrogation of Th1 response by STA-5326, a potent IL-12/IL-23
inhibitor.

* Wada Y,
* Lu R,
* Zhou D,
* Chu J,
* Przewloka T,
* Zhang S,
* Li L,
* Wu Y,
* Qin J,
* Balasubramanyam V,
* Barsoum J,
* Ono M.

Synta Pharmaceuticals Corp, Lexington, MA 02421, USA.
yw...@syntapharma.com

The interleukin-12 (IL-12) cytokine induces the differentiation of
naive T cells to the T helper cell type 1 (Th1) phenotype and is
integral to the pathogenesis of Th1-mediated immunologic disorders. A
more recently discovered IL-12 family member, IL-23, shares the p40
protein subunit with IL-12 and plays a critical role in the generation
of effector memory T cells and IL-17-producing T cells. We introduce a
novel compound, STA-5326, that down-regulates both IL-12 p35 and IL-12/
IL-23 p40 at the transcriptional level, and inhibits the production of
both IL-12 and IL-23 cytokines. Oral administration of STA-5326 led to
a suppression of the Th1 but not Th2 immune response in mice. In vivo
studies using a CD4+CD45Rbhigh T-cell transfer severe combined
immunodeficiency (SCID) mouse inflammatory bowel disease model
demonstrated that oral administration of STA-5326 markedly reduced
inflammatory histopathologic changes in the colon. A striking decrease
in interferon-gamma (IFN-gamma) production was observed in ex vivo
culture of lamina propria cells harvested from animals treated with
STA-5326, indicating a down-regulation of the Th1 response by
STA-5326. These results suggest that STA-5326 has potential for use in
the treatment of Th1-related autoimmune or immunologic disorders.
STA-5326 currently is being evaluated in phase 2 clinical trials in
patients with Crohn disease and rheumatoid arthritis.

PMID: 17053051

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17007011&query_hl=5&itool=pubmed_docsum

Interleukin-12 and Th1 immune response in Crohn's disease:
pathogenetic relevance and therapeutic implication.

* Peluso I,

* Pallone F,
* Monteleone G.

Crohn's disease (CD) and ulcerative colitis (UC) are chronic
inflammatory disorders of the gastrointestinal tract that share
clinical and pathological characteristics. The most accredited
hypothesis is that both CD and UC result from a deregulated mucosal
immune response to normal constituents of the gut microflora.
Evidence, however, indicates that the main pathological processes in
these two diseases are distinct. In CD, the tissue-damaging
inflammatory reaction is driven by activated type 1 helper T-cell
(Th1), whereas a humoral response predominates in UC. Consistently, a
marked accumulation of macrophages making interleukin (IL)-12, the
major Th1-inducing factor, is seen in CD but not in UC mucosa.
Preliminary studies also indicate that administration of a monoclonal
antibody blocking the IL-12/p40 subunit can be useful to induce and
maintain clinical remission in CD patients. Notably, the recently
described IL-23 shares the p40 subunit with IL-12, raising the
possibility that the clinical benefit of the anti-IL-12/p40 antibody
in CD may also be due to the neutralization of IL-23 activity. This
review summarizes the current information on the expression and
functional role of IL-12 and IL-12-associated signaling pathways both
in patients with CD and experimental models of colitis, thus
emphasizing major differences between IL-12 and IL-23 activity on the
development of intestinal inflammation.

PMID: 17007011

============================================

One intreresting article in the NEWs:

http://www.smalltimes.com/news/display_news_story.cfm?Section=WireNews&Category=HOME&NewsID=144630

[...]
The drug, discovered by Glick and coworkers and called
benzodiazepine-423 (Bz-423), is a chemical cousin of anti-anxiety
medications such as Valium and Xanax. In previous work, Glick's group
showed that Bz-423 reduces effects of arthritis and the autoimmune
disease lupus in mice and may be useful in treating psoriasis. Unlike
conventional drugs for these conditions, which can't discriminate
between healthy and disease-causing cells, Bz-423 is highly selective,
homing in on disease-causing cells.

In an attempt to better exploit its therapeutic properties, the
researchers have been studying the details of Bz-423's activity. They
learned that the compound targets an enzyme inside mitochondria, the
energy factories of cells. The specific enzyme, F1F0-ATPase, is
responsible for producing most of the cell's ATP. That's a critical
role because ATP, often referred to as the cell's energy currency, is
the molecule that captures chemical energy from food and transfers it
to energy-demanding processes, such as muscle contraction and the
transmission of nerve signals.

Ultimately, the findings may have applications not only for lupus,
arthritis and psoriasis, but also for other conditions, Glick
believes. "There are other diseases - certain cancers and a number of
other immune diseases - where we think the way the cells make and
utilize energy is fundamental to the disease process. Combining that
knowledge with our new knowledge of how to regulate the energy of the
cell could open up new avenues for treating disease and monitoring the
effectiveness of treatment."

--------------

randall.... enough of any anti-anxiety medication and your not to
concerned with the P!

randall

unread,

Feb 12, 2007, 2:17:18 PM2/12/07

On Feb 9, 12:47 pm, "randall" <ranhu...@aol.com> wrote:
> I said:
>
>
>
> > Doctor Krueger has a new treatment for psoriasis that targets
> > key inflammatory mediators (IL-12 and IL-23) is highly effective,
> > according to a study by University of Utah researchers to be published
> > in the Feb. 8 issue of The New England Journal of Medicine.
>
> >http://www.newswise.com/articles/view/527154/
>
> Here is the abstract to go with the above link.
>

> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&...

> A human interleukin-12/23 monoclonal antibody for the treatment of
> psoriasis.

OK.

So once these drugs come out of some University. Then what?

http://www.tradingmarkets.com/.site/news/TOP%20STORY/501039/

[...]
Johnson & Johnson - the conglomerate with more than 230 operating
companies around the world, which is working its way to outflank its
own psoriasis drug Remicade with a new treatment CNTO 1275, met with
only partial success. The clinical study conducted with the drug
showed that the proposed drug was linked to serious side effects even
though it produced marked improvement in psoriasis patients.<sniP>

-------

CNTO 1275 being published in the February 8 issue of
the New England Journal of Medicine. In the Phase Two trial, 81
percent of
patients receiving four weekly 90 mg doses of CNTO 1275 achieved at
least
75 percent improvement in their psoriasis, as measured by the
Psoriasis
Area Severity Index (PASI 75)

Previous posts to the P NG-
http://groups.google.com/groups/search?q=1275%2Bpsoriasis%2Bcnto&qt_s=Search

Current revelations:

http://news.google.com/news?hl=en&pwst=1&resnum=0&ie=UTF-8&oe=UTF-8&tab=wn&q=psoriasis+1275&btnG=Search

http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=104&STORY=/www/story/02-07-2007/0004523037&EDATE=

--------------

How does these pathways fare for Th1/Th2 and these cytokines?

Let's do them on pubmed.

First let's frame them for the psoriasis paradigm:
http://psoriasis.researchtoday.net/archive/1/2/273.htm

And what have I harPed on since J posted the good article?

Ans: LPS

Are we going to figure out how it fits in the P paradigm?

Please!

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17289816&query_hl=1&itool=pubmed_docsum

Involvement of mast cells in IL-12/23 p40 production is essential for
survival from polymicrobial infections.

* Nakano N,
* Nishiyama C,
* Kanada S,
* Niwa Y,
* Shimokawa N,
* Ushio H,
* Nishiyama M,

* Okumura K,
* Ogawa H.

Atopy (Allergy) Research Center, Juntendo University School of
Medicine, Tokyo, Japan.

Interleukin (IL)-12, a heterodimeric cytokine (p35/p40) mainly
produced from macrophages and dendritic cells, is an important
regulator of T-helper 1 cell responses and for host defense. We found
that interferon (IFN) consensus sequence binding protein (ICSBP),
which is a transcription factor essential for the expression of p40,
was expressed in mouse bone marrow-derived mast cells (BMMCs). The
transcription levels of p35 and p40 were increased by stimulation of
BMMCs with IFN-gamma/lipopolysaccharide (LPS). IL-12 was secreted from
BMMCs in response to
____________________LPS___________________________ but not by
FcepsilonRI cross-linking. The p40 levels in peritoneal cavity of mast
cell-deficient W/W(v) and W/W(v) reconstituted with p40(-/-) BMMCs
were significantly lower than those of WBB6F1(+/+) and wild-type (WT)
BMMCs-reconstituted W/W(v) in the acute septic peritonitis model. The
survival rate of W/W(v) reconstituted with p40(-/-) BMMCs was
significantly decreased lower than those of WBB6F1(+/+) and WT-BMMC-
reconstituted W/W(v), which was due to reduced production of IFN-gamma
and subsequent impaired activation of neutrophils in peritoneal
cavity. Survival rate of p40(-/-) mice was also restored by adoptive
transfer of WT BMMCs. These results demonstrate that mast cells play a
significant role in the production of IL-12 required for host defense.
This is the first report to demonstrate that mast cells are a crucial
source of functional IL-12.

PMID: 17289816

These pathways are giving up their secrets:

And P is a stat thingy, in more ways then one.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17277312&query_hl=4&itool=pubmed_docsum

STAT3 regulates cytokine-mediated generation of inflammatory helper T
cells.

* Yang XO,
* Panopoulos AD,
* Nurieva R,
* Chang SH,
* Wang D,
* Watowich SS,
* Dong C.

Immunology, MD Anderson Cancer Center, Houston, TX 77030.

IL-17-producing helper T (TH) cells, named as THIL-17, TH17 or
inflammatory TH (TH1), have been recently identified as a novel
effector lineage. However, how cytokine signals mediate THi
differentiation is unclear. We found that IL-6 functioned to
upregulate IL-23R and that IL-23 synergized with IL-6 in promoting TH1
generation. STAT3, activated by both IL-6 and IL-23, plays a critical
role in TH1 development. A hyperactive form of STAT3 promoted TH1
development, whereas this differentiation process was greatly impaired
in STAT3-deficient T cells. Moreover, STAT3 regulated the expression
of RORgt, a THi-specific transcriptional regulator; STAT3 deficiency
impaired RORgt expression and led to elevated expression of T-bet and
Foxp3. Our data thus demonstrate a pathway whereby cytokines regulate
THi differentiation through a selective STAT transcription factor that
functions to regulate lineage-specific gene expression.

PMID: 17277312

---------

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17289553&query_hl=1&itool=pubmed_docsum

Autoimmune inflammation from the Th17 perspective.

* Furuzawa-Carballeda J,
* Vargas-Rojas MI,
* Cabral AR.

Department of Immunology and Rheumatology, Instituto Nacional de
Ciencias Medicas y Nutricion Salvador Zubiran, Vasco de Quiroga 15
Tlalpan, Mexico City, 14000, Mexico.

Recent studies demonstrated an IL-17-producer CD4(+) T cell
subpopulation, termed Th17, distinct from Th1 and Th2. It represents a
different pro-inflammatory Th-cell lineage. This notion is supported
by gene-targeted mice studies. Mice lacking IL-23 (p19(-/-)) do not
develop experimental autoimmune encephalomyelitis (EAE) or collagen-
induced arthritis (CIA), while knockout mice for the Th1 cytokine
IL-12 (p35(-/-)) strongly develop both autoimmune diseases. Disease
resistance by IL-23 knockout mice correlates well with the absence of
IL-17-producing CD4(+) T lymphocytes in target organs despite normal
presence of antigen-specific-IFN-gamma-producing Th1 cells. This
finding may thus explain previous contradictory reports showing that
anti-IFN-gamma-treated mice, IFN-gamma- or IFNR-deficient mice develop
CIA or EAE. TGF-beta, IL-6 and IL-1 are the differentiation factors of
Th17 cells. IL-23 is dispensable for this function, but necessary for
Th17 expansion and survival. The master regulator that directs the
differentiation program of Th17 cells is the orphan nuclear receptor
RORgammat. IL-27, a member of the IL-12/IL-23 family, potently
inhibits Th17 development. Evidence suggesting rheumatoid arthritis
and multiple sclerosis as primarily IL-17 autoimmune inflammatory-
mediated diseases is rapidly accumulating. The IL-17/23 axis of
inflammation and related molecules may rise as therapeutic targets for
treating these and perhaps other autoimmune diseases.

PMID: 17289553

--------------

Randall... Once we fully understand, we can stand it better!

JXStern

unread,

Feb 12, 2007, 10:47:23 PM2/12/07

was: P NEWs 2007

On 12 Feb 2007 11:17:18 -0800, "randall" <ranh...@aol.com> wrote:

>On Feb 9, 12:47 pm, "randall" <ranhu...@aol.com> wrote:
>http://www.tradingmarkets.com/.site/news/TOP%20STORY/501039/
>
>[...]
>Johnson & Johnson - the conglomerate with more than 230 operating
>companies around the world, which is working its way to outflank its
>own psoriasis drug Remicade with a new treatment CNTO 1275, met with
>only partial success. The clinical study conducted with the drug
>showed that the proposed drug was linked to serious side effects even
>though it produced marked improvement in psoriasis patients.<sniP>
>
>-------
>
>CNTO 1275 being published in the February 8 issue of
>the New England Journal of Medicine. In the Phase Two trial, 81
>percent of
>patients receiving four weekly 90 mg doses of CNTO 1275 achieved at
>least
>75 percent improvement in their psoriasis, as measured by the
>Psoriasis
>Area Severity Index (PASI 75)

http://www.sciam.com/article.cfm?chanID=sa003&articleID=372DE59E40CD1024223255D84DA97AF5

4% of the target group - 2 people - had heart attacks.

Were they predisposed? Were there cardiac symptoms in any others?
WHY would there be?

So is this good news or bad?

I think good, but ... wait for phase III.

randall

unread,

Feb 13, 2007, 11:21:12 PM2/13/07

On Feb 12, 7:47 pm, JXStern <JXSternChange...@gte.net> wrote:
> was: P NEWs 2007
>

> On 12 Feb 2007 11:17:18 -0800, "randall" <ranhu...@aol.com> wrote:
>
>
>
> >On Feb 9, 12:47 pm, "randall" <ranhu...@aol.com> wrote:
> >http://www.tradingmarkets.com/.site/news/TOP%20STORY/501039/
>
> >[...]
> >Johnson & Johnson - the conglomerate with more than 230 operating
> >companies around the world, which is working its way to outflank its
> >own psoriasis drug Remicade with a new treatment CNTO 1275, met with
> >only partial success. The clinical study conducted with the drug
> >showed that the proposed drug was linked to serious side effects even
> >though it produced marked improvement in psoriasis patients.<sniP>
>
> >-------
>
> >CNTO 1275 being published in the February 8 issue of
> >the New England Journal of Medicine. In the Phase Two trial, 81
> >percent of
> >patients receiving four weekly 90 mg doses of CNTO 1275 achieved at
> >least
> >75 percent improvement in their psoriasis, as measured by the
> >Psoriasis
> >Area Severity Index (PASI 75)
>

> http://www.sciam.com/article.cfm?chanID=sa003&articleID=372DE59E40CD1...

>
> 4% of the target group - 2 people - had heart attacks.
>
> Were they predisposed? Were there cardiac symptoms in any others?
> WHY would there be?
>
> So is this good news or bad?
>
> I think good, but ... wait for phase III.
>
> J.

I'm not so sure I wouldn't go my own whey!

http://www.cbc.ca/cp/HealthScout/070213/6021302AU.html

[...]
Upper respiratory tract infection, headache and nasopharyngitis were
the most common side effects reported by patients in the study. <sniP>

---------------

A truer study would be right here amongst those who are willing to
share.

What good is a bunch of psoriatics without any clue whatsoever?

Did their clearings precipitate the cardiac events?

Then again, i'm not so sure it isn't what the masses demand. <sigh> :(

randall... Truth and knowledge are a match made in Heaven!

JXStern

unread,

Feb 14, 2007, 12:03:04 AM2/14/07

On 13 Feb 2007 20:21:12 -0800, "randall" <ranh...@aol.com> wrote:

>I'm not so sure I wouldn't go my own whey!
>
>http://www.cbc.ca/cp/HealthScout/070213/6021302AU.html
>
>[...]
>Upper respiratory tract infection, headache and nasopharyngitis were
>the most common side effects reported by patients in the study. <sniP>

That one is Humira, not CNTO.

randall

unread,

Feb 14, 2007, 2:42:31 PM2/14/07

On Feb 13, 9:03 pm, JXStern <JXSternChange...@gte.net> wrote:

> On 13 Feb 2007 20:21:12 -0800, "randall" <ranhu...@aol.com> wrote:
>
> >I'm not so sure I wouldn't go my own whey!
>
> >http://www.cbc.ca/cp/HealthScout/070213/6021302AU.html
>
> >[...]
> >Upper respiratory tract infection, headache and nasopharyngitis were
> >the most common side effects reported by patients in the study. <sniP>
>
> That one is Humira, not CNTO.
>
> J.

Oh Great! I'm the clueless one. LOL

I should go see their new movie. Couldn't find the preview on youtube.
http://www.adweek.com/aw/creative/article_display.jsp?vnu_content_id=1003545580

It's cnto not humira!

I wonder what the diff is?

First i'm headed out in to the sunshine.

randall... roll camera's

randall

unread,

Feb 15, 2007, 12:27:19 AM2/15/07

> I should go see their new movie. Couldn't find the preview on youtube.http://www.adweek.com/aw/creative/article_display.jsp?vnu_content_id=...
>

If anyone goes to see this, let us know what you think.

http://sev.prnewswire.com/medical-pharmaceuticals/20070214/PHW02014022007-1.html#
HORSHAM, Pa., Feb. 14 /PRNewswire/ -- Centocor, Inc. is proud to
announce the world premiere of INNERSTATE, a first-of-its-kind
documentary providing insight into the "inner states" of three
everyday adults facing chronic, life- altering inflammatory diseases.
As they confront daily challenges and life's experiences, they tell
the emotional stories of their journeys toward living "normal" lives
in a film that is sure to touch the hearts of all viewers, including
the millions of Americans who suffer from these conditions. The
premiere will take place on Wednesday, February 21, 2007 at the
Directors Guild of America Theatre in New York.

To view the Multimedia News Release, go to
http://www.prnewswire.com/mnr/dorland/26983/

http://www.myinnerstate.com/

http://www.myinnerstate.com/subscribe/screening.jsp

---------------

randall...

randall

unread,

Feb 20, 2007, 5:48:06 PM2/20/07

Hi,

A new way to look at P from the NPF,
http://www.pharmalive.com/News/index.cfm?articleid=416492&categoryid=40

_____________________________________

http://news.biocompare.com/newsstory.asp?id=169809
Scientists Learn The Origin Of Rogue B Cells
2/7/2007

Source: NIH/National Institute of Arthritis and Musculoskeletal and
Skin Diseases
Doctors have long wondered why, in some people, the immune system
turns against parts of the body it is designed to protect, leading to
autoimmune disease. Now, researchers at the National Institutes of
Health's (NIH) National Institute of Arthritis and Musculoskeletal and
Skin Diseases (NIAMS), in collaboration with the Oklahoma Medical
Research Foundation, have provided some new clues into one likely
factor: the early development of immune system cells called B cells. B
cells are formed in the bone marrow and produce antibodies. Antibodies
are generated from the cutting and splicing of immunoglobulin genes
early in B-cell development, and have the potential to develop strong
and highly specific affinity for different pathogens. When an
infectious pathogen (a disease-causing agent) enters the body, B cells
are activated and release antibodies into the bloodstream to combat
the pathogen. When antibodies encounter the pathogen, they bind to it,
rendering it incapable of causing further harm. Antibody molecules
also serve as receptors on the surface of B cells. The problem occurs
when the random cutting and splicing of immunoglobulin genes results
in an antibody that recognizes a component of one's own body. While
the body has a built-in mechanism to correct these errant cells, the
NIAMS researchers discovered this doesn't always work the way it was
intended. "What happens is that, if the body ever produces a cell with
a self-reactive antibody molecule, that cell will get arrested in
development at the point where it is actually combining and creating
an antibody receptor," says Rafael Casellas, Ph.D., an investigator in
NIAMS's Genomic Integrity and Immunity Group. Often, rather than
killing off the cell, the body edits - or corrects - the receptor,
like one might edit a paper, he says. In normal circumstances, this
new, good receptor replaces the bad one, but what Casellas and Dr.
Patrick C. Wilson of the Oklahoma Medical Research Foundation found
was that about 10 percent of the body's B cells retain both receptors:
a good, useful one and the faulty self-reactive one that the good
receptor was designed to replace. This means that the aberrant B cells
have escaped the body's mechanism to correct them. "Our research goes
against the theory that B cells should only express a single
receptor," says Casellas. Using a technique in which they inserted a
piece of human gene into the cells of laboratory mice, the researchers
created a model for visualizing the process in live animals. "Most of
what scientists do is to create systems to visualize complex
phenomena, then to allow nature to give you the answers to your
questions," says Casellas. Their new findings raise the question of
how this knowledge might eventually help people with autoimmune
disease. That question, says Casellas, is one that will take time to
answer. "This is only one step," he says. "We all carry these cells
around, but not all of us develop autoimmunity. Our work provides one
explanation for the origin of these self-reactive B cells." "If you
understood the system extremely well and were able to delete the
editing cells during development, for instance, then you would only
have lymphocytes that don't express self-receptors at all," he says.
For now, the step forward to understand where these self-directed
cells are coming from is a big one. "Our objective is to understand
the ins and outs of this process," says Casellas. The research was
also funded by the NIH's National Center for Research Resources as
part of its Institutional Development Award Program (IDeA). The
program fosters health-related research and improves the
competitiveness of investigators in states that historically have not
received significant levels of research funding from NIH.

---------------------

http://news.biocompare.com/newsstory.asp?id=171245

Antibody Signal May Redirect Inflammation To Fuel Cancer
2/19/2007

Source: University of California - San Francisco

As evidence mounts that the body's normally protective inflammation
response can drive some precancerous tissues to become fully
malignant, UCSF scientists report discovering an apparent trigger to
this potentially deadly process.

Typically, the "innate" immune system's Pac-Man-like white blood
cells, or leukocytes, engulf and destroy invading microbes when
receptors on their surface receive a signal from serum in the blood --
often an antibody produced by a B cell in the separately evolved
"acquired" immune system.

Now UCSF researchers have found that in the presence of precancerous
tissue, leukocyte antibody receptors can also be activated to turn on
a dangerously different program: inducing leukocytes to boost cell
growth, increase the number of blood vessels and "remodel" tissue in
the area -- all of which help cancer develop.

The finding adds a critical and surprising detail to the emerging view
that inflammation, usually a helpful response to invading pathogens,
can become misdirected and fuel cancer.

The new research was presented today (February 19) by UCSF scientist
Lisa M. Coussens, PhD, at the annual meeting of the American
Association for the Advancement of Science (AAAS) in a session titled
"healthy aging: inflammation and chronic diseases."

"Immunologists have known for decades that B cells of the so-called
adaptive or acquired immune system are activated following a bacterial
infection and in response, produce antibodies that signal leukocytes
to attack," said Coussens, associate professor of pathology in the
UCSF Cancer Research Institute. "But in precancerous tissue in mice,
we have found that leukocytes apparently receive signals to switch
programs, stimulating cell growth and increasing blood supply --
processes that would normally help healing from an infection, but can
instead fuel cancer cell development."

The researchers have not yet identified what specific signal or
signals are involved, but preliminary evidence indicates that
antibodies may signal specific receptors on leukocytes to enhance the
cancer-promoting pathway. Part of the receptor for the antibody known
as immunoglobulin appears to be involved, Coussens said.

The good news, she adds, is that potential drugs to block this pathway
are already being tested in clinical trials to treat B cell lymphoma
and auto-immune diseases made worse by inflammation, such as
rheumatoid arthritis.

"We already know that inflammation accelerates skin, cervical and
colon cancer, and most likely also lung and breast cancer," she said.
"If we confirm that what we've discovered in the mice studies also
occurs in human cancers, we may soon be in a good position to slow
this cancer process using drugs already under study for severe immune
disorders."

Coussens envisions a therapeutic strategy similar to treating people
with HIV. The goal would not be to necessarily eliminate every last
cancer cell, but to control the inflammation process needed for the
cancer to progress to a more threatening stage.

The new UCSF finding comes from studies with mice genetically
engineered to carry some of the genes of the human papilloma virus
(HPV), a pathogen that is known to cause human cervical cancer. By
comparing cancer progression in these mice compared with gene "knock-
out mice" that lacked the antibody receptors normally active on the
leukocyte surfaces, Coussens and her colleagues discovered that the
receptors were involved for the cancer to progress rapidly.

The new discovery follows one by Coussens and colleagues two years
ago, published in "Cancer Cell" (1) that determined that antibody-
producing B cells are essential for the harmful redirection of the
leukocyte response. The finding startled many in the field because the
B cells do not act at the site of inflammation where the leukocytes
are located, so they apparently send the crucial signals remotely
through the blood's serum. The surprising nature of the discovery and
its implications were explored in a June 2005 commentary in
"Nature" (2).

A review this month by Coussens and Ting-Ting Tan, PhD, a postdoctoral
fellow in Coussens' laboratory, brings together many related threads
of research in this fast-evolving area of inquiry. It was published
February 1 in "Current Opinion in Immunology" (3).

Coussens stresses that because of the unique antibody makeup of each
person, there is no evidence and no likelihood that periodic booster
shots of the immunoglobulin antibody, or even blood transfusions from
someone with precancerous tissue could trigger cancer progression in a
recipient.

________________________________

New Study May Show How To Forestall A Fatal, Virus-Caused Immune-
System Meltdown
2/14/2007

Source: University of Texas Medical Branch at Galveston

When a virus infects a person, it triggers a series of biochemical
reactions in immune-system cells that literally may have life or death
consequences.

Usually, the result is an effective immune response, leading to the
elimination of the virus and the infected person's recovery. But in
the case of some of the world's deadliest pathogens - including the
Ebola, Marburg and Lassa fever viruses, as well as the influenza virus
strain responsible for the 1918 flu pandemic - the immune system
itself actually becomes the most dangerous element of the disease. All
too often, a sudden immune overreaction sends the infected person into
a shock-like state from which he or she may never recover.

Now, researchers at the University of Texas Medical Branch at
Galveston (UTMB) believe they've found a way to spot the biochemical
profile of an inappropriate immune response to viral infection - an
important step toward developing new therapies that may head off or
stop an otherwise fatal immune system meltdown.

In a paper published in the February 14 issue of the Journal of
Virology, highlighted in the journal's "Spotlight" section and
available now online, the scientists describe using a newly developed
protein-scanning chip and a uniquely capable computer database to
examine the activation and deactivation of more than a thousand
proteins in cells from guinea pigs infected with two different strains
of Pichinde virus. Guinea pigs infected with one of the Pichinde
strains experience no ill effects, while those infected with the other
strain develop symptoms similar to those seen in humans infected by
the much more dangerous Lassa virus, which can cause an acute
hemorrhagic fever and kills about 5,000 people a year in West Africa.
(During some Lassa fever epidemics, as many as 50 percent of those
diagnosed with the disease have died from it.)

"With these two forms of the virus and this new technology, we were
able to compare pathogenic immune response and protective immune
response on a broad, global level," said lead author and UTMB
postdoctoral fellow Gavin Bowick. He said that checking almost 1,200
interactions simultaneously let the researchers see the big picture of
immune response, avoiding the contradictory results often produced by
studies that focus on only a single biochemical pathway.

To better understand their results, the investigators plugged their
data into the Ingenuity Systems "pathways analysis" program, which
draws on a large-scale computer database of biochemical interactions
that have been described in a wide variety of peer-reviewed scientific
papers. "Applying this massive Ingenuity database, which includes all
sorts of cellular pathways that would normally not occur to us -
pathways discovered by people studying endocrinology, cancer, cystic
fibrosis and so on - we find that things suddenly begin to make
sense," said UTMB professor Norbert Herzog, one of the paper's senior
authors. "Cell signaling networks are like spider webs-pulling on one
strand causes all the strands to move, and the Ingenuity system helped
us see and comprehend connections we would have missed otherwise."

Connecting those strands is critical to diagnosing and restoring
balance to an immune system gone haywire in a disease like Lassa
fever. "Early on, you can't really differentiate these nasty
hemorrhagic fever viruses from their symptoms - they just resemble the
flu," Herzog said. "But if you have biomarkers to go along with viral
diagnostic techniques you can tell which virus it is and where you are
on the continuum of infection. And if you understand the signaling
pathways well enough, you can stimulate or suppress the immune
response in the right way at the right time to create safe and
effective therapies."

According to Bowick, the Pichinde experiments have already generated
some therapeutic leads, thanks to the unexpected discovery that a
growth factor receptor molecule normally associated with cancers was
activated late in infection with the lethal strain of the virus. "We
can go in and design an experiment where we can start testing drugs
that already have FDA approval," Bowick said. "If we can go straight
from discovery to drug candidates, that's quite a big leap for us, and
one that may be very helpful, since there's really no incentive for
drug companies to go out and develop new antiviral compounds for
viruses that may or may not ever make it out of places like West
Africa."

"This could be of critical importance to the people who live there,
and for us if one of these diseases makes it across to here, either
naturally like West Nile or as a result of bioterrorism," Bowick
continued. He noted that the Lassa, Ebola and Marburg fever viruses
have been identified as Category A biothreat agents by the National
Institute of Allergy and Infectious Diseases (NIAID).

Other authors of the Journal of Virology paper included UTMB research
associates Susan Fennewald, LiHong Zhang and Barry Elsom, associate
professor of pathology Judith Aronson, biochemistry and molecular
biology instructor Heidi Spratt, and biochemistry and molecular
biology professors David Gorenstein and Bruce Luxon. Funding for the
investigation was provided by the Defense Advanced Research Projects
Agency, the National Institutes of Health, and the NIAID's Western
Regional Center of Excellence for Biodefense and Emerging Infectious D

-------------------

Simulating psoriasis by altering transit amplifying cells.

* Grabe N,
* Neuber K.

Department of Medical Informatics, Institute of Medical Biometry and
Informatics, University Hospital Heidelberg, 69120 Heidelberg, Germany
and.

Computational models of tissue homeostasis will facilitate a deeper
understanding of many diseases. They link molecular networks, cellular
differentiation and the spatial and temporal organization of tissues.
Here we show an approach which is able to computationally turn a
healthy in-silico epidermis into one with four central properties of
psoriatic epidermis. We achieve this by altering a single simulation
parameter in the cellular differentiation program of the simulated
epidermal keratinocytes: the fractional time period during which
transit amplifying cells proliferate (tau). Prolonging tau results in
the four main pathological characteristics of psoriatic skin: (1) an
absolute increase of the germinative compartment, (2) an absolute
increase of the differentiated compartment, (3) a higher proportion of
germinative cells, and (4) a marked reduction in turnover time. The
prolongation of tau is able to increase the proliferation capacity of
the epidermal tissue without altering the cell cycle frequency.

PMID: 17308343

---------------------------

randall

JXStern

unread,

Feb 21, 2007, 1:07:40 AM2/21/07

On 20 Feb 2007 14:48:06 -0800, "randall" <ranh...@aol.com> wrote:

>Hi,

Good articles, Randall, but they all still sound like the wise men and
the elephant, they know there's something there, and they each have a
small piece of it, but nobody's got the whole picture.

But even ten years ago, nobody even knew there was an elephant in the
room.

randall

unread,

Feb 21, 2007, 2:06:39 PM2/21/07

On Feb 20, 10:07 pm, JXStern <JXSternChange...@gte.net> wrote:

> On 20 Feb 2007 14:48:06 -0800, "randall" <ranhu...@aol.com> wrote:
>
> >Hi,
>
> Good articles, Randall, but they all still sound like the wise men and
> the elephant, they know there's something there, and they each have a
> small piece of it, but nobody's got the whole picture.
>
> But even ten years ago, nobody even knew there was an elephant in the
> room.
>
> J.

It's a tusk one to cure for sure.

I know i've got my hands firmly on his inner guts. I already suspect
my plaques
are about as smooth as his outer skin. lol

Still i concentrate on my innerskin

Isn't that the area the J&J (centocor) movie (innerstates) is all
about?

One drug for three conditions, (watch the movie! starts today in 14
cities--its free!)
http://news.google.com/news?qt_s=1&tab=gn&ie=UTF-8&scoring=d&q=psoriasis+remicade+crohn%27s+arthritis&btnG=Search

RA, P and crohn's all treated with remicade, not to mention the M's of
$ in,
http://www.remicade.com/global/index.jsp
other usages.

Blocking TNF once again isn't my idea of the ultimate uPstream answer
for P,
http://www.pnas.org/cgi/content/full/103/22/8303

Block buster autoimmune drugs from Norwegian Dirt Fungi,
http://www.google.com/search?hl=en&q=norwegian+dirt+cyclosporine&btnG=Search
to the biological baby block busters still aren't good enough in my
book. :)

In your low dose cocktails i'll concede their usage. :)

Toss in the FAE's and some herbs like oregon grape and fern leaf and
i'm there. Almost!

And i'll still agree to adhere to your metaPhorages,
http://groups.google.com/groups/search?qt_s=1&q=elephant+psoriasis

That una smith post from 1998 about her psoralen loaded elephant ears
was news to
me. :)

So, P is a zoo with all these critters and pathways.

And we keep feeling uP that elePhant.

And,

I'm still working on the inside of his guts.

And while i've looked at caco-2 cells and arginine many times, here's
some more clues.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17309102&query_hl=2&itool=pubmed_docsum

Arginine deficiency in preconfluent intestinal Caco-2 cells modulates
expression of proteins involved in proliferation, apoptosis, and heat
shock response.

* Lenaerts K,
* Renes J,
* Bouwman FG,
* Noben JP,
* Robben J,
* Smit E,
* Mariman EC.

Maastricht Proteomics Center, Nutrition and Toxicology Research
Institute Maastricht (NUTRIM), Department of Human Biology, Maastricht
University, Maastricht, The Netherlands.

Arginine is classified as a conditionally essential amino acid
required exogenously during catabolic disease states and periods of
rapid growth, both characterized by increased arginine utilization.
Arginine plays an important role in the intestine, where it is
extensively metabolized, and enhances its immune-supportive function
and mucosal repair. Cell proliferation is important for the latter
process. This study aimed for a better molecular insight in the
response to arginine deprivation/supplementation of preconfluent and 5-
day-confluent, differentiated Caco-2 intestinal cells. The potential
of citrulline to counteract the effects of arginine deprivation was
investigated in preconfluent cells. 2-DE combined with MALDI-TOF-MS
and the antibody microarray technology were applied. Evidence is
provided that arginine deficiency modulates the protein expression
profiles of preconfluent Caco-2 cells differently than that of
postconfluent differentiated cells. In preconfluent cells, certain
proteins changed in direct response to arginine deficiency, whereas
other proteins did not, but instead responded during the recovery
phase after an arginine/citrulline resupplementation. The protein
changes suggest that arginine deprivation decreases cell proliferation
and heat shock protein expression, and enhances the cells
susceptibility to apoptosis. These processes are critical for proper
cell function, and hence a state of arginine deficiency can be
detrimental for intestinal cells which proliferate actively in vivo.

PMID: 17309102

And glutamine for the obvious questions of why it makes me flare.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17308248&query_hl=5&itool=pubmed_docsum
Glutamine Transporter ASCT2 Was Down-Regulated in Ischemic Injured
Human Intestinal Epithelial Cells and Reversed by Epidermal Growth
Factor.

* Huang Q,
* Li N,
* Zhu W,
* Li Q,
* Li J.

Research Institute of General Surgery, Jinling Hospital, Nanjing,
China.

BACKGROUND: Clinically, nutrition support has been an important
component of the care of the hypoperfusion traumatized patient who is
unable to accept complete volitional nutrition. However, enterocyte
transport function during states of intestinal hypoperfusion remains
unclear. Glutamine is essential for the viability and growth of
intestine epithelial cells, and the Na(+)-dependent neutral amino acid
transporter ASCT2 is thought to mainly mediate glutamine transport.
This study aims to quantify the change of glutamine transporter ASCT2
expression in ischemic injured Caco-2 cell lines and the regulatory
action of epidermal growth factor (EGF) on glutamine transport and its
transporter. METHODS: Cells were cultured under ischemic conditions
for 2 hours. After ischemia was performed, Caco-2 cells were incubated
with or without EGF (100 mug/mL) for 0-8 hours. Then we studied the
cell membrane l-glutamine transport, the expression of ASCT2 protein,
and mRNA. RESULTS: After ischemia was performed, Caco-2 cell membrane
glutamine transport decreased significantly (p < .01), and the
expression of ASCT2 proteins decreased significantly compared with
control (p < .01). Under ischemic conditions, expression of ASCT2 mRNA
was down-regulated by a real-time polymerase chain reaction (PCR)
method. After EGF incubation for 1-2 hours, the proteins and mRNA of
ASCT2 were reversed to normal levels (p > .05). CONCLUSIONS: In
ischemic injured Caco-2 cells, ASCT2 protein expression and mRNA
transcription were involved in the down-regulation of Na(+)-dependent
glutamine transport. The decrease of glutamine transport and its
transporter under ischemic conditions could be reversed by EGF action.
These findings may help in the choice of the nutrition support manner
and clinical therapy of ischemia-damaged intestinal epithelial cells.

PMID: 17308248

This one would have been appreciated, if they had provided the
abstract.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17298696&query_hl=5&itool=pubmed_docsum
The effect of marine oil-derived n-3 fatty acids on transepithelial
calcium transport in Caco-2 cell models of healthy and inflamed
intestines.

* Gilman J,
* Cashman KD.

PMID: 17298696

---------------

I suspect all these parts will tell the story sooner then later.

And in the meantime i'll stay away from excess arginine, L-glutamine,
soy bean oils (n-6)
and a bunch of other things.

And enjoy the ultimate P-blues clue of sunbathing.

randall... P Odyssey in the stream of james joyce under the sun?

randall

unread,

Feb 22, 2007, 11:56:34 AM2/22/07

Hi,

Nanoparticles for P

http://media.www.arbiteronline.com/media/storage/paper890/news/2007/02/22/News/Bsu-Research.Team.Presents.Findings-2734816.shtml

A Boise State University research team will present its findings on
nanoparticles at an international conference Feb. 12-16.

Denise Wingett, a biology professor at BSU, will present the team's
research at the Keystone Symposia's Conference on Nanotechnology in
Biomedicine in Tahoe City, Calif.

Physics professor Alex Punnoose, biology professor Kevin Feris and
several undergraduate, graduate and post-doctoral students are also
part of the BSU team, which studies how nanoparticles could someday be
used to help treat
multiple sclerosis, psoriasis and other diseases.

[...]
The particles, just atoms wide, are small enough to easily penetrate
cells in lungs, brains and other organs. In laboratory experiments,
BSU researchers have shown that nanoparticles have the ability to kill
certain types of bacteria while having a minimal effect on human
immune cells. The researchers have also successfully linked a variety
of antibodies to the nanoparticles.

According to Wingett, the initial results are encouraging because they
suggest that nanoparticles could be used to target viruses, bacteria
or infected body cells by selectively delivering nanoparticles to the
disease site.

In addition, the BSU researchers have shown that at considerably
higher concentrations, the nanoparticles preferentially target
activated human immune cells and destroy them.

These findings suggest that nanoparticles could also be useful to
treat auto-immune diseases such as multiple sclerosis, psoriasis and
rheumatoid arthritis, where human immune cells attack normal body
tissues.

The next step for BSU researchers is to conduct laboratory experiments
to see what happens when antibodies are linked to nanoparticles and a
cell is then targeted for destruction.

"This is a very promising area of study, and we are very much looking
forward to continuing our research in the months ahead," Wingett said.

---------------------------------

Nature Insight
Skin Biology

Our skin is not only the biggest organ of the body, but also one of
the most multifaceted. Skin uniquely senses our surroundings and
forms a protective barrier against many different insults, such as UV
light or pathogens.

This Insight on the biology of skin brings together review articles
that cover many of these facets. In particular, it highlights the
molecular processes underlying skin development, pigmentation and
sensory transduction and the cellular and molecular changes
underlying skin diseases such as cancer and psoriasis.

Read the Insight in the 22nd February issue of Nature or access it
free online at:
http://ealerts.nature.com/cgi-bin24/DM/y/eccg0SoZM70Hjv0BMaV0Eo

---------------------------------------------------------------------

We are pleased to acknowledge the support of Johnson & Johnson
Consumer Companies, Inc. in producing this Insight.

Bringing Science to the Art of Beauty.

The Johnson & Johnson Dermatological Companies are pleased to sponsor
the Nature Insight on Skin Biology. We are a global leader in the
research,development and marketing of innovative consumer and
professionally preferred science-based solutions for healthy and
beautiful skin. For more information please visit www.jnj.com
---------------------------------------------------------------

There was an article about the NPF and P severity the other day.

Now the abstract for that story is available:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17310004&query_hl=1&itool=pubmed_docsum
National psoriasis foundation clinical consensus on disease severity.

* Pariser DM,
* Bagel J,
* Gelfand JM,
* Korman NJ,
* Ritchlin CT,
* Strober BE,
* Van Voorhees AS,
* Young M,
* Rittenberg S,
* Lebwohl MG,
* Horn EJ.

Author Affiliations: Department of Dermatology, Eastern Virginia
Medical School, Norfolk.

Objectives A task force of the National Psoriasis Foundation Medical
Board was convened to evaluate the current severity criteria of mild,
moderate, and severe psoriasis and to make recommendations concerning
a 2-tiered categorization of severity based on current clinical
practice and related to intent to treat. PARTICIPANTS: This volunteer
task force, led by David M. Pariser, MD, included Jerry Bagel, MD,
Joel M. Gelfand, MD, MSCE, Neil J. Korman, MD, PhD, Christopher T.
Ritchlin, MD, Bruce E. Strober, MD, PhD, Abby S. Van Voorhees, MD, and
Melodie Young, MSN, RN, ANP. Meetings were held by teleconference and
were coordinated and funded by the National Psoriasis Foundation.
Evidence This task force reviewed psoriasis severity criteria and
other published psoriasis consensus statements. Current standards of
care and expert opinion were used to inform the process. Consensus
Process Based on meetings of the task force and under the guidance of
David M. Pariser, MD, a statement was drafted by Elizabeth J. Horn,
PhD, presented to the task force, and reviewed and approved by the
task force. This statement was then reviewed and approved by Robert E.
Kalb, MD, Gerald G. Krueger, MD, and Alan Menter, MD. The National
Psoriasis Foundation Medical Board reviewed and endorsed this
statement by a majority vote on March 2, 2006, at the medical board
meeting. CONCLUSIONS: This clinical consensus statement proposes a 2-
tiered system for plaque psoriasis therapy that reflects more
accurately than the current system how patients are treated in
clinical practice. This statement, focused on plaque psoriasis, is
intended to assist medical professionals and insurance payers in
understanding these 2 categories of patients with psoriasis and
choosing appropriate therapies for these patients.

PMID: 17310004

--------------

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17311742&query_hl=1&itool=pubmed_docsum

Treatment of childhood psoriasis.

* Ceovic R,
* Pasic A,
* Lipozencic J,
* Murat-Susic S,
* Skerlev M,
* Husar K,
* Kostovic K.

Romana Ceovic, MD, PhD, University Department of Dermatology and
Venereology Zagreb University Hospital Center, Salata 4, 10000
Zagreb , Croatia; romana...@zg.htnet.hr.

Psoriasis is a common disease in children and adolescents. Because of
the chronic course of the disease, appropriate choice of therapy in
particular stage of the disease, so-called rotation therapy, is of
paramount importance. This article provides a review of therapeutic
options for childhood psoriasis. Local therapy for psoriasis in
children consists of corticosteroid preparations, calcipotriol, tars
and dithranol, local retinoids, and local immunomodulators.
Phototherapy (narrow band UVB, photochemotherapy PUVA baths) is now a
part of psoriasis therapy in children. Systemic therapy retinoids
(acitretin) methotrexate, cyclosporine is only used in severe forms of
the disease such as erythrodermic, pustular and arthritic psoriasis.
All these therapeutic options can be used as monotherapy or in various
combinations.

PMID: 17311742

---------------

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17311998&query_hl=1&itool=pubmed_docsum

The mitochondrial effects of novel apoptogenic molecules generated by
psoralen photolysis as a crucial mechanism in PUVA therapy.

* Caffieri S,
* Di Lisa F,
* Bolesani F,
* Facco M,
* Semenzato G,
* Dall'acqua F,
* Canton M.

Department of Pharmaceutical Sciences, University of Padova, Padova,
Italy.

The generation of photoproducts of psoralen (POP) might be relevant in
cell death induced by psoralen + UVA, namely PUVA, which is a
recognized effective treatment for cutaneous T-cell lymphoma, chronic
graft-versus-host disease and psoriasis. We investigated the
occurrence of POP-induced cell death and the underlying mechanisms.
POP were produced by irradiating a psoralen solution with UVA. Jurkat
cells treated in the dark with these mixtures died mainly through an
apoptotic mechanism. POP were separated by HPLC, and cells were added
with each of these fractions. Two dimers of psoralen and 6-formyl-7-
hydroxycoumarin (FHC) were identified in the apoptogenic fractions.
Apoptosis was preceded by mitochondrial dysfunction caused by the
opening of the mitochondrial permeability transition pore (PTP). In
fact, both mitochondrial depolarization and cell death were prevented
by the PTP inhibitor cyclosporin A (CsA). PTP opening was also
documented in isolated mitochondria added with POP suggesting that
apoptosis is caused by a direct effect of POP on mitochondria. In fact
FHC alone induced PTP opening and CsA-inhibitable cell death of Jurkat
cells whereas non-transformed T-lymphocytes were resistant. Along with
identifying novel apoptogenic molecules, the present results indicate
that POP generation directs transformed cells to apoptosis.

PMID: 17311998

-----------------

A real recent P odyssey for the EADV: (see: www.eadv.org)
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17311744&query_hl=1&itool=pubmed_docsum
Fifteenth eadv congress on the island of history.

* Lipozencic J.

This year's EADV Congress venue Rhodos (October 3-8, 2006) welcomed
nearly 6500 attendees. It is near the homeland of Hippocrates (the
island of Kos), the 'father of medicine' and Hellenistic philosopher
who has bequeathed some terms to dermatology, e.g., 'alopecia' and
'exanthema' as well as standard therapy for many centuries. The
scientific program of the 15th EADV Congress was based on the
pathophysiological mechanisms of skin diseases, as Hippocrates pleaded
for understanding the suffering patient and his disease. As Professor
Johannes Ring, past President of EADV said, EADV has put special
emphasis on the high level of postgraduate education. So, there were
combined scientific sessions with young researchers presenting
original data in the form of poster or free communication, with
courses and symposia devoted to education. Dermatologists in private
practice benefited from the scientific program with due accounts of
novel treatments, recipes, instruments and techniques to use them upon
return to their office. What was special at the Rhodes EADV Congress?
Promising future: new techniques in molecular biology as well as new
diagnostic/therapeutic tools in dermatology, such as polymerase chain
reaction, protein and DNA microarrays, antibody based therapies;
protein microarrays can be used for profiling of IgE antibodies in the
diagnosis of type-1 related allergic diseases; DNA-based methods to
investigate the genetic background of different dermatoses (e.g., in
basal cell carcinoma, Darier's disease, different hair and nail
disorders); there has been an exciting increase in the knowledge of
the central role of the immune system in the pathogenesis of
psoriasis; more specific, immunologically directed therapeutic
strategies (biologicals) for psoriasis treatment have been developed
(infliximab, etanercept, efalizumab); nucleic acid based molecular
techniques have been introduced in the diagnosis of cancer as well;
many studies have assessed the presence of tyrosinase mRNA by reverse
transcriptase polymerase chain reaction (RT-PCR) in peripheral blood
from melanoma patients as a specific marker for circulating melanoma
cells; infectious diseases represent an important health problem,
especially because of the growing resistance to the antibiotic
treatment and photodynamic therapy could be a viable alternative for
skin infections (ALA plus visible light against yeasts and
dermatophytes); treatment options of AIDS Kaposi's sarcoma are
increasing (antiretroviral therapy HAART), liposomal doxorubicin (20
mg/m2 every 2-3 weeks), paclitaxel (100 mg/m2 every two weeks), and
irinotecan, matrix metalloproteinase inhibitor (e.g., COL-3),
herpetivirus G protein coupled receptor as a new therapeutic target
for the treatment of Kaposi's sarcoma; revisited and reclassified
specific dermatoses of pregnancy (pemphigoid gestation (PG),
polymorphic eruption of pregnancy (PEP), intrahepatic cholestasis of
pregnancy (ICP), atopic eruption of pregnancy (AEP); there is much
evidence suggesting that the epidemic of atopic dermatitis has stopped
in parts of the western world; teleconsulting is relatively new in
dermatology (videoconferences and store-and-forward-systems and images
sent by e-mail or shared on a web-hosed system), but teledermatology
is changing the way of health service delivery and teleconsulting by
specialized centers will be soon the gold standard of medical care;
diagnostic and therapeutic procedures in leukocytoclastic vacsulitis
(LcV), (immune-complex-mediated LcV (corticosteroids, colchicin as a
first line therapy in chronic or relapsing LcV and dapsone as a second
line therapy).As Professor Ring said: 'Dermatovenereology faces
presently a variety of challenges. The most actual themes of interest
are skin cancer/oncology, allergy and environmental hazards,
infectious disease and 'new venereology', genetic dermatoses and skin
hygiene with prevention of loss of skin functions including aesthetic
dermatology, general dermatology with autoimmune and inflammatory
disease (like psoriasis), always stays in the centre of our
endeavours'. During his two-year presidency, EADV achieved many
things: new statutes, clear financial structure, the Academy moved to
Switzerland, the EADV Board introduced new Task Forces on various and
diverse areas of dermatovenereology, witnessed outstanding congresses
like last year in London and two Spring Symposia in Sophia and in
Saariselka, and looking forward to the next big congress in Vienna
(2007) and Spring Symposium in Istanbul (2008), had strong alliance
with sister European societies of ESDR, EDF and UEMS in an European
liaison committee, layer partnership with ILDS and special welcoming
the newly designated board members from countries of Eastern Europe
(12 members, among them Prof. Lipozencic from Croatia).Professor
Andreas Katsambas, President of the 15th EADV Congress, made great
effort for full success of the Congress, which it really proved to be.
As the new EADV President, he will steer EADV successfully into the
future.

PMID: 17311744

randall

unread,

Feb 23, 2007, 1:34:02 PM2/23/07

Hi,

Ticked off Union members Picket the J&J (centocor) movie!

But wait a minute. The movie is free. <w>

What got their Panties in a bunch?

http://www.dailylocal.com/WebApp/appmanager/JRC/DailyLocal;PORTAL_TAU=fJhTFpdKgn1ns4gG5rQChLtd4kh219gSVZHxkZJ75rNjRxDSZzdT!2047679073?_nfpb=true&_pageLabel=pg_article&r21.pgpath=%2FDLN%2FBusiness&r21.content=%2FDLN%2FBusiness%2FHeadlineList_Story_76102
Union Pickets Drug Firm's Promotional Film
By SARAH E. MORAN

Union activists handed out leaflets calling attention to a four-year-
old class-action lawsuit against what they called Centocor Inc.'s
"deceptive drug pricing" on Remicade.

The drug is Centocor's expensive flagship treatment for several
serious inflammatory diseases of the immune system.

A dozen members of the Service Employees International Union Local
32BJ protested outside the Manhattan premiere Wednesday of InnerState,
a one-hour promotional documentary produced and paid for by Centocor.

Centocor began in Chester County and, though it sold out to drug
industry behemoth Johnson & Johnson in 1999, still has several
locations in the county.
Advertisement

Protesters handed out dozens of leaflets to the 300 who attended the
InnerState premiere, said union spokesman Matthew Nerwig.

InnerState follows the lives of three people affected by inflammatory
diseases of the immune system - rheumatoid arthritis, Crohn's disease
and psoriasis - that can be treated with Remicade, which can cost
upward of $24,000 a year.

But Centocor is mentioned only in the closing credits and Remicade not
at all - a fact that makes many physicians edgy.

The free movie, whose audiences will be gleaned from support and
advocacy groups for the immune system diseases Remicade treats, will
debut in a dozen cities between now and June.

Its Philadelphia-area debut will occur April 28 at the Regal Stadium
16 movie

theater in King of Prussia.

Wayne MacManiman, Local 32BJ Philadelphia district chair for the union
that represents janitors, office cleaners, concierges and other
building services workers, contended, "Skyrocketing health care costs
threaten the well-being of our members, our communities and our
country. The practices alleged in this lawsuit against Centocor drive
up health care costs, making quality health care unaffordable to
working families and people everywhere."

The class-action suit, filed in 2003 in a Massachusetts U.S. District
Court, alleges that numerous pharmaceutical companies, Centocor among
them, "fraudulently overstate the published 'average wholesale price'
of many of their prescription drugs, which results in inflated
payments for such drugs."

Payments at prices 30 percent higher than what physicians pay for
Remicade give doctors "the potential to profit from administering the
drug and artificially raises the costs of the drugs to patients and
insurance providers," the union declared in a statement.

But other reasons are also behind why the union is targeting Centocor.

"It's not a responsible community player," Nerwig stated.

The union represents 85,000 members in six states, Pennsylvania among
them.

Separately, Centocor revealed that it received a subpoena connected to
a probe into its Remicade pricing policies. Centocor parent Johnson &
Johnson said earlier this week that it received the subpoena in late
November, in connection with an investigation by the Office of the
U.S. Attorney for California's central district.

Centocor spokesman Michael Parks said the company is cooperating with
the investigation but would not elaborate further.

_____________________________

Duh! Drugs cost to much! Lets protest by not using them till they drop
50%..

Yeah at $12K a year i'd use them like crazy. lol

---------------

And if the pharmo's aren't your bag, your faith may save you. Or will
it?

http://www.sun-sentinel.com/features/lifestyle/sfl-jradiofeb23,0,724697.story?coll=sfla-features-headlines

[...]
Gideon Shavit, regional director of the Jewish National Fund,
recently talked about the organization's projects and role in
education in Israel and how "our vision is to bring 250,000 people to
the Negev [desert] in the next five years."

And Andy Henschel, from the National Psoriasis Foundation, explained
that the disease is not contagious, although people often "feel like
they are a leper."

Amar replied with a note of hope built on the Bible: "Moshiach [the
Messiah] comes and eradicates all sickness in the world."

The rabbi says he hopes the program both inspires and educates.

"I'm not here to try to tell people my opinion of life, or my view of
things. I try to share the ancient wisdom of Torah and apply it to
modern life."

-------------

Excuse me? Doesn't the torah say that P means we have bad karma or
some such nonsense?

I can find this one in no time at all:

http://groups.google.com/groups/search?qt_s=1&q=torah+tzara%27at+psoriasis

http://www.google.com/search?qt_s=1&q=torah%20tzara'at&sa=N&tab=gw

If there is a spiritual problem with this condition, what comes first?

God rolls the genetic dice with the universe to begin with?

-------

And if your faith is weak or craPPed out try this cheaPish cure from
Monterey today,
http://www.montereyherald.com/mld/montereyherald/living/health/16765715.htm

[...]
Dear Dr. Gott: I thought I would share this information with you and
your readers for what it's worth.

I've been diagnosed with, and have endured, psoriasis on various parts
of my body for years. These last couple of years it has invaded my
hands.

I have seen numerous dermatologists and have been prescribed salves,
creams and lotions for years, none of which worked for any length of
time.

After applying a topical, the intense itching and burning would begin,
and I would need to relieve it by scratching until it bled. It became
a vicious cycle; however, I am happy to say my psoriasis is completely
gone. I owe my thanks to you for the advice I read in one of your
columns on using Vicks VapoRub for toenail fungus.

I thought, "What do I have to lose"? I used Vicks religiously
throughout the day whenever possible. I still keep a jar in my car,
one next to my bed and one by my kitchen sink. I tried to massage it
in well, reaching the deep cracks. As it started to callous over, I
would clip the larger pieces, careful not to clip too deep. After
about a month or so, it healed.

Dear Reader: I'd say that this information is truly worth paying
attention to. Thanks for writing.

<sniP>

---------

randall... How's your innerstates today? Mine is fine! P genes are
still screwed!

randall

unread,

Feb 28, 2007, 3:48:07 AM2/28/07

Hi,

P abstracts:

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17320795&query_hl=1&itool=pubmed_docsum
SU-011248, a vascular endothelial growth factor receptor-tyrosine
kinase inhibitor, controls chronic psoriasis.

* Keshtgarpour M,
* Dudek AZ.

Division of Hematology, Oncology and Transplantation, University of
Minnesota Medical School, Minneapolis, Minn.

PMID: 17320795

--------------

Psoriasis as a bunch of good genes selected to protect against bad
bugs?
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17317489&query_hl=1&itool=pubmed_docsum
Psoriasis, innate immunity, and gene pools.

* Bos JD.

Department of Dermatology, Academic Medical Centre, University of
Amsterdam, Amsterdam, The Netherlands. j.d...@amc.uva.nl

Recently, emphasis has shifted from T cells to innate (natural)
immunity as the possible major culprit in psoriasis. All known
elements of innate immune responses are up-regulated in psoriasis
lesions, which must have a polygenetic origin. We hypothesize that
urbanized populations have been under evolutionary pressure that
selects for increased innate immunity responses because those offer
relative but immediate protection from epidemic infections. That would
have resulted in a changing gene pool, in which alleles of
polymorphisms associated with increased innate immunity responses have
amplified in these populations. Having too many of these genes
together in one individual would result in a relatively low number of
infections. On the other hand, it would also result in a higher
prevalence of diseases related to increased innate immunity, such as
psoriasis, and perhaps also multiple sclerosis and rheumatoid
arthritis. Indeed, in indigenous people (Inuit, Aborigines, Ami) who
have not been under this selection pressure, morbidity due to
infections is high and the prevalence of psoriasis is low or even
absent.

PMID: 17317489

If they know enough to make skin, maybe they'll be able to fix broken
skin?
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17314974&query_hl=1&itool=pubmed_docsum
Progress and opportunities for tissue-engineered skin.

* MacNeil S.

The Tissue Engineering Group, Department of Engineering Materials and
Division of Biomedical Sciences and Medicine, Kroto Research
Institute, North Campus, University of Sheffield, Broad Lane,
Sheffield S3 7HQ, UK.

Tissue-engineered skin is now a reality. For patients with extensive
full-thickness burns, laboratory expansion of skin cells to achieve
barrier function can make the difference between life and death, and
it was this acute need that drove the initiation of tissue engineering
in the 1980s. A much larger group of patients have ulcers resistant to
conventional healing, and treatments using cultured skin cells have
been devised to restart the wound-healing process. In the laboratory,
the use of tissue-engineered skin provides insight into the behaviour
of skin cells in healthy skin and in diseases such as vitiligo,
melanoma, psoriasis and blistering disorders.

PMID: 17314974

Bowcock and Krueger team uP to solve the P riddle.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17314973&query_hl=1&itool=pubmed_docsum
Pathogenesis and therapy of psoriasis.

* Lowes MA,
* Bowcock AM,
* Krueger JG.

Laboratory for Investigative Dermatology, The Rockefeller University,
1230 York Avenue, Box 178, New York, New York 10021, USA.

Psoriasis is one of the most common human skin diseases and is
considered to have key genetic underpinnings. It is characterized by
excessive growth and aberrant differentiation of keratinocytes, but is
fully reversible with appropriate therapy. The trigger of the
keratinocyte response is thought to be activation of the cellular
immune system, with T cells, dendritic cells and various immune-
related cytokines and chemokines implicated in pathogenesis. The
newest therapies for psoriasis target its immune components and may
predict potential treatments for other inflammatory human diseases.

PMID: 17314973

I wonder when these three are going to agree to the chagrin of the
pharmO's that it's gonna be a gut fix. Or is that a hunch?

------------------------

Is it milk that tips the immune system towards our vigilant T cells?
http://news.biocompare.com/newsstory.asp?id=172108

Creating New Life Forms That May Help Eradicate Cancer Affecting Women
2/26/2007

Instead of using the usual cancer-fighting modalities, surgery,
chemotherapy, or radiation, researchers from a drug development
company called Advaxis, have embarked on a novel approach to fighting
cancer: Engaging the immune system to attack cancer in the same the
way it would a flu vaccine, by creating new life forms.

Dr. Vafa Shahabi, Advaxis' Director of Research and Development,
reports that because the human immune system is not designed to fight
cancer on its own, she and her colleagues are trying to harness its
power through a new kind of life form: specifically a family of
vaccines, which they call Lovaxin. The vaccines are comprised of new
strains of bacteria created in Advaxis' laboratory that are programmed
to kill off specific cancers.

The Key: A Microbe Found in Dairy Products

Central to this startling discovery is the microbe Listeria
monocytogenes, a common bacterium found in milk, cheese and other
dairy products. This microorganism apparently aids in fighting cancer
by activating the body's own killer (cytotoxic T) cells to elicit a
stronger than normal immune response to the presence of cancer cells.
The vaccines "teach" the immune system to mount a specialized,
targeted response that is lethal to cancer.

When Listeria is introduced in the body, it has a powerful, direct
stimulatory effect on the activities of tumor-killing T cells.
"Essentially the modified Listeria vaccines harness the power of the
immune system against this infectious agent," explains Dr. Shabahi,
"and then directs it to successfully attack cancer cells. The
bacterium in effect then becomes a cancer-fighting 'Trojan horse,'
with the enemy tucked inside."

For breast cancer, Dr. Shababi's team fused Listeria with a tumor-
associated protein, HER-2/Neu, to immune cells, to create a vaccine
called Lovaxin B. What these cells do is enlist killer T cells to seek
and destroy tumor cells that over-express the HER-2/Neu molecule. This
is significant because HER-2/Neu is over- expressed in 20%- 40% of all
breast cancers.

As Dr. Shababi explains: "We not only created a new breast cancer
vaccine, but also have a new life form, since the modified Listeria
becomes a new strain, not seen in nature. In effect, it becomes a
cancer fighting "superbug" capable of treating breast cancer in
patients whose tumors express the HER-X/Neu protein." Advaxis has
already created several strains for potential use in future vaccines
to treat other cancers. The company is also currently testing its
cervical cancer vaccine, Lovaxin C, in phase I/II trials.

For more information, log on to www.advaxis.com

------------
http://www.medicalnewstoday.com/medicalnews.php?newsid=63688&nfid=nl
Killing The Messenger RNA -- But Which One?

Tiny molecules called microRNAs, only 19 to 21 nucleotides in length,
are able to effectively silence sometimes large sets of genes. They do
this by specifically binding to and neutralizing another form of RNA
called messenger RNA, responsible for conveying the information from
genes to the cellular machinery that uses that information to create
proteins, the building blocks of the body. Several hundred species of
microRNAs have been identified to date, and increasingly they are
being seen as vitally important players in regulating the genome.

Now, a new study led by researchers at The Wistar Institute shows that
these microRNAs can undergo a kind of molecular editing with
significant physiological consequences. A single substitution in their
sequence can redirect these microRNAs to target and silence entirely
different sets of genes from their unedited counterparts. Further,
errors in the editing can lead to serious health problems. The team's
findings appear in the February 23 issue of Science.

"What we found was that, in certain cases, edited versions of these
microRNAs are being produced that differ from the unedited versions by
only a single nucleotide change," says Kazuko Nishikura, Ph.D., a
professor in the Gene Expression and Regulation Program at Wistar and
senior author on the study. "These edited microRNAs are not encoded in
the DNA, which means that at least two versions can being produced by
one gene. This was not anticipated - it was something really new.

"Looking more closely, we realized that the substitution we'd
identified occurred in a particularly critical region of the molecule,
the first 7 or 8 nucleotides - out of a total of only 19 or 21 - that
define the molecule's target specificity. This suggested that the
change might well redirect these edited microRNAs to silence entirely
different sets of genes from the unedited versions."

Using bioinformatics tools to compare the unedited and edited versions
of only one species of microRNA against data banks of known gene
sequences, the scientists identified two different groups of about 80
genes each likely to be targeted by the two versions of the molecule.
They then selected three genes from each group for a closer look,
testing to see whether their expression was in fact altered, up or
down, by the microRNAs. It was.

Then they chose one potentially affected gene at random to explore the
ramifications of microRNA editing in depth. As it turned out, the gene
they selected, known as PRPS1, codes for an essential enzyme involved
in synthesizing uric acid. If levels of the enzyme are poorly
regulated, a number of health problems can arise. For example, too-
high levels of the enzyme can cause uric acid levels to rise in the
blood, triggering painful episodes of gout. Similarly, in the brain,
excess uric acid can damage sensory neurons and cause deafness.

Working with a strain of transgenic mice unable to perform RNA editing
and normal control mice, the researchers found that a complete lack of
the edited version of the microRNA in question had the effect of
driving production of the PRPS1 enzyme to about double its normal
levels. This, in turn, drove levels of uric acid up to about two times
what they should be.

"This confirmed that our original computer prediction of differential
targeting by unedited and edited microRNAs of different sets of genes
is likely to be correct," Nishikura says. "And in at least the case of
the one gene we investigated, this differential has physiological
consequences seen in the elevated uric acid levels."

Given the fact that the PRPS1 gene was randomly selected for
investigation by the researchers, the findings suggest that a number
of other as-yet unidentified disorders may also have their roots in
this newly identified microRNA editing process.

---------
http://www.medicalnewstoday.com/medicalnews.php?newsid=63395&nfid=nl

Three years ago Mark Kay, MD, PhD, published the first results showing
that a biological phenomenon called RNA interference could be an
effective gene therapy technique. Since then he has used RNAi gene
therapy to effectively shut down the viruses that cause hepatitis and
HIV in mice.

With three human RNAi gene therapy trials now under way - two in
macular degeneration and one in RSV pneumonia - the technique Kay
pioneered may be among the first to find widespread use for treating
human diseases. "We've worked on a gene therapeutic approach against
viral hepatitis for about 10 years and this is the first thing we've
done that really looks promising," said Kay, professor of genetics and
of pediatrics at the Stanford University School of Medicine.Three
years ago Mark Kay, MD, PhD, published the first results showing that
a biological phenomenon called RNA interference could be an effective
gene therapy technique. Since then he has used RNAi gene therapy to
effectively shut down the viruses that cause hepatitis and HIV in
mice.

<sniP>

---------

Bad taste in genes
http://www.medicalnewstoday.com/medicalnews.php?newsid=63383&nfid=nl

---------

Crush your garlic for high allicin 10 minutes before cooking
http://www.medicalnewstoday.com/medicalnews.php?newsid=63484&nfid=nl

---------

Stem Cell Future Shaped By Epigenetics

-------

I'll be a monkeys uncle!

Bad gut bugs from humans infecting chimps!
http://news.biocompare.com/newsstory.asp?id=171925

----------

Gluten redux
http://news.biocompare.com/newsstory.asp?id=171918

Researchers Study The Possible Relationship Between Myopathies And
Coeliac Disease
2/22/2007

Source: Universitat Autonoma de Barcelona

Inflammatory myopathies are immunological diseases that lead to
inflammations in muscular tissue. As of yet, little is known about the
cause of these myopathies, but it is believed to be an abnormal immune
response by our bodies. Since coeliac disease has occasionally been
reported in patients with inflammatory myopathies, UAB researchers are
investigating the relationship between myopathy and intolerance to
gluten.

Inflammatory myopathies are inflammatory infiltrates in the muscle.
This group of diseases includes polymyositis, dermatomyositis, and
inclusion-body myositis. Little is known about the cause and the
etiopathogenic mechanisms of these myopathies, but it is believed to
be an abnormal immune response by our bodies, which identify body
parts as alien. In this particular case, the body parts are the skin
and the muscle, though other parts, such as the lungs and the
myocardium, may also be affected.

The research team observed that it is not a rare occurrence for
various autoimmune diseases to exist in the same patient. Indeed,
coeliac disease -- caused by a reaction to gluten found in cereals --
has been reported in patients with inflammatory myopathy, especially
those with inclusion-body myositis.

Researchers at the Teaching Unit at the UAB's Vall d'Hebron Hospital
have investigated these links by looking at coeliac patients whose
cases suggest a similar immunopathogenic mechanism in coeliac disease
and certain myopathies, as well as a common genetic substrate.

The scientists are considering the possibility that, at least in part,
some inflammatory myopathies are a clinical expression of intolerance
to gluten, though they point out the need for more studies to be
carried out to confirm or support these findings. The results are
particularly important in the case of inclusion-body myositis -- for
which there is no effective treatment -- since we can now suggest that
a gluten-free diet may improve the situation of a patient. This
hypothesis must now be tested using immunosuppressants, as has been
done with other extraintestinal manifestations of reactions to
gluten.

----------

An old cancer fighter (pre: watson and crick) talks about DNA and
cancer:
http://www.medicalnewstoday.com/medicalnews.php?newsid=63403&nfid=nl

---------

Stat3 a psoriasis pathway culprit is also involved in 52,000 deaths a
year due to colon cancer.
http://www.medicalnewstoday.com/medicalnews.php?newsid=63491&nfid=nl

[...[
"The finding that STAT3 is important for the growth of colon cancer is
highly novel, and provides new impetus to the development of drugs
that will target this molecule", said Dr. Sanford Markowitz, Ingalls
Professor of Cancer Genetics at Case Western Reserve University School
of Medicine and Investigator in The Howard Hughes Medical Institute,
Case Medical Center. <sniP>

research into controlling stat3 may help psoriatics!

----------

12 myths about colon cancer
http://www.medicalnewstoday.com/medicalnews.php?newsid=63811&nfid=nl

-----

Out of Africa

When man made his way out of Africa some 60,000 years ago to populate
the world, he was not alone: He was accompanied by the bacterium
Helicobacter pylori, which causes gastritis in many people today.
Together, man and the bacterium spread throughout the entire world.
This is the conclusion reached by an international team of scientists
led by Mark Achtman from the Max Planck Institute for Infection
Biology in Berlin, Germany. The researchers also discovered that
differences developed in the genetic makeup of the bacteria
populations, just as it did in that of the various peoples of the
world. This has also given scientists new insight into the paths taken
by man as he journeyed across the Earth (Nature online, February 7,
2007).

More than half of all human beings are infected with Helicobacter
pylori, a bacterium that can cause stomach ulcers. Like humans, the
bacteria are also split up into numerous regional populations. A team
of scientists led by Mark Achtman at the Max Planck Institute for
Infection Biology, Francois Balloux at the University of Cambridge and
Sebastian Suerbaum at Hanover Medical University have found signs of
the parallel evolution of man and H. pylori. Using mathematical
simulations, the researchers demonstrated that H. pylori must have
left East Africa at the same time as man - around 60,000 years ago.
This astonishing conformity was uncovered by scientists when they
compared the nucleotide sequencing patterns in the DNA of human and H.
pylori populations.

In order to characterise the individual populations, the scientists
employed the principle of isolation by distance. According to this
principle, the genetic distance between two populations has a linear
correlation with the length of the migration paths taken since they
were separated. "It's actually quite logical," explains Dr. Mark
Achtman, "because in the time that elapses after a population leaves
its point of origin, the number of mutations in its genetic makeup
continually increases."

However, while man was spreading throughout the world, human
populations had to repeatedly pass through what scientists call
genetic bottlenecks: when a population shrinks, the gene pool also
becomes smaller. These losses in genetic diversity linger, even when
the population starts once again to increase in number. Since the Homo
sapiens populations usually had to pass through several genetic
bottlenecks on their way across the globe, their genetic diversity
declined the further they journeyed from their origin in East Africa.

Scientists have now uncovered similar signs of historical population
migration in the genetic makeup of H. pylori. However, the genetic
diversity of the bacteria is larger than that of man. This paves the
way for researchers to use H. pylori data to work out the migratory
movements of modern man. "The parallels between the spread of man and
of H. pylori are truly astonishing," says Achtman. "This bacterium
could help us attain further information on aspects of human history
that are still hotly disputed today if we analyzed H. pylori in
conjunction with human data." For example, after leaving East Africa,
the H. pylori population spread through limited localities in southern
Africa, West Africa, Northeast Africa, India and East Asia. The genes
of bacteria isolated in Europe, for instance, reveal influences from
Central Asia - an indication that human immigrants came to Europe from
Asia.

---------

randall.. whew! i'm posted out!

randall

unread,

Mar 3, 2007, 12:32:58 PM3/3/07

Hi,

Some reasons/pathways why the bilogicals may not work in all cases or
over time.

http://www.signaling-gateway.org/update/updates/200703/nri2042.html

Building bridges with NF-κB

The discovery of a nuclear factor-κB inhibitor that modulates the NF-
κB-mediated response to both inflammation and developmental stimuli
bridges these two seemingly disparate NF-κB functions.

The identification of a fourth inhibitor of nuclear factor-κB (IκB)
protein by Alexander Hoffmann and colleagues has bridged the gap
between the canonical and non-canonical nuclear factor-κB (NF-κB)
signalling pathways. This signalling crosstalk describes the molecular
mechanism for previously proposed links between inflammatory and
developmental stimuli in the immune system

NF-κB activation in response to inflammatory stimuli, such as tumour-
necrosis factor (TNF), occurs through the canonical pathway. This
pathway involves IκB kinase-γ (IKKγ; also known as NEMO)-dependent and
IKK2-dependent phosphorylation, and proteolysis of the canonical IκBα,
IκBβ and IκBε proteins to release NF-κB RelA–p50 heterodimers for
translocation to the nucleus and activation of target genes. By
contrast, developmental stimuli, such as signalling through the
lymphotoxin-β receptor (LTβR), induce NF-κB-inducing kinase (NIK)-
dependent and IKK1-dependent phosphorylation, and partial proteolysis
of the NFKB2 gene product p100 to generate p52, which translocates to
the nucleus as a RelB–p52 heterodimer (the non-canonical pathway).
However, LTβR signalling can also activate RelA–p50 dimers through a
previously unknown mechanism.

In accordance with this, stimulation of mouse embryonic fibroblasts
with an agonistic LTβR-specific antibody led to the accumulation of
RelA–p50 dimers in the nucleus, but no IKKγ activity or decrease in
levels of the three canonical IκB proteins, which indicates that the
canonical signalling pathway was not involved. Using a RelA- and IκB-
deficient cell line reconstituted with an epitope-tagged form of RelA,
the authors showed that RelA–p50 is bound by p100, in the absence of
stimuli. Depletion of p100 from wild-type cells eliminated the DNA-
binding activity of RelA–p50 dimers that could otherwise be revealed
by treatment with the detergent deoxychlorate (which disrupts NF-κB–
IκB binding). LTβR stimulation led to a decrease in RelA–p50-
associated p100 protein. Knockdown of Nfkb2 expression in IκB-
deficient cells resulted in a fivefold increase in NF-κB activity,
mainly consisting of RelA–p50 dimers. Together, these results indicate
that p100 functions as an IκB protein by sequestering RelA–p50 dimers
in the cytoplasm and thereby inhibiting their translocation to the
nucleus and DNA-binding activity. In the absence of IκBα, IκBβ and
IκBε, LTβR signalling resulted in strong NF-κB activation, but this
was abrogated in cells that also lacked p100. Therefore, p100 is
sufficient for RelA–p50 activation in response to LTβR stimulation.

As RelA–p50 activity was absent in response to LTβR signalling in
cells deficient for IKK1 and/or NIK, but was not affected by IKKγ
deficiency, Hoffmann and colleagues propose that p100 be identified as
a new IκB protein of the non-canonical signalling pathway. The
discovery of a non-canonical IκB protein provides an important link
between canonical and non-canonical signalling pathways, which
Hoffmann and colleagues explored using a mathematical model. For
example, as Nfkb2 is an NF-κB target gene, cells primed with the
canonical stimulus TNF contain a larger number of p100–RelA–p50
complexes than unprimed cells, and therefore have a greater NF-κB
response to non-canonical signalling through LTβR. This could explain
the role of canonical, inflammatory signals, such as TNF, in the
maintenance of lymph-node architecture, which was previously thought
to be the result of non-canonical developmental stimuli, such as
lymphotoxins.

-------------------------------

Wow, I knew something was accounting for the inevitable lapses in our
biological drugs. But when these pathways are driven my so many
factors, I see how we can't win without a JX sternian P
cocktail. Low dose or high dose we'll have a ball. lol

-----

Add one more Treg to the P fire. But don't loose the ones you've got.

Will a low dose compound come available to raise Tregs?

Yes!

------------

Increasing gut Tregs naturally seems like a winner that I continue to
hang my hat on.

Here's a company that's worked on this for years. While their drug is
for MS, it should
work for us as well....

http://sev.prnewswire.com/health-care-hospitals/20070228/LAW11501032007-1.html

[...]
NeuroVax(TM), which is based on the Company's patented T-cell receptor
(TCR) peptide vaccine technology, has shown potential clinical value
in the treatment of relapsing forms of MS. NeuroVax(TM) has been shown
to stimulate strong, disease-specific cell-mediated immunity in nearly
all patients treated and appears to work by enhancing levels of FOXP3+
Treg cells that are able to down regulate the activity of pathogenic T-
cells that cause MS. Increasing scientific findings have associated
diminished levels of FOXP3+ Treg cell responses with the pathogenesis
and progression of MS and other autoimmune diseases such as rheumatoid
arthritis (RA), psoriasis and Crohn's disease. In addition to MS, the
Company has open Investigational New Drug Applications (IND) with the
FDA for clinical evaluation of TCR peptide-based immune-based
therapies for RA and psoriasis.
<sniP>
-----------------------------------

This next one came from www.askbillsardi.com

In the sunshine of your love!

If you want the link for this and can't find it, let me know.

The sun cures all if you know how to use it! Or does it?

------------

Humanity is on the verge of a gigantic leap forward in health
promotion with rapid-fire discoveries that a single vitamin pill may
vanquish cancer and heart disease, the two leading causes of mortality
in the U.S., as well as quell autoimmune disease (rheumatoid
arthritis, lupus),-

[my note: should say psoriasis as well]

-, diminish the occurrence of diabetes, reduce obesity, and
effectively treat multiple sclerosis, osteoporosis, Parkinson’s
disease, schizophrenia and high blood pressure, plus conquer the
common cold and even defeat tuberculosis, an infectious lung disease
that affects one-third of the people of the world.
Literally leading medicine "out of dark ages" is the sunshine vitamin
– vitamin D. Long mischaracterized as a vitamin that can be toxic if
taken in amounts that exceed what is found in common multivitamins,
and mistakenly said that vitamin D must be chemically altered to
produce a man-made molecular version that does not induce over-
calcification, most physicians, pharmacists and dieticians have been
incorrectly trained to warn the public away from higher doses of
vitamin D.
Most multivitamins provide no more than 400 IU (international units –
a trivial 10 micrograms, or 1/100th of one milligram) of vitamin D,
and the National Academy of Sciences says 2000 IU (50 micrograms) is
the safe upper limit, with toxicity beginning around 10,000 IU (250
micrograms).
But Reinhold Vieth PhD, researcher at the University of Toronto, notes
that blood levels don’t even measurably rise till 4000 IU (100
micrograms) is consumed and toxicity begins at 40,000 IU (1000
micrograms or 1 milligram) only after many weeks of use.
To demonstrate just how ridiculous the warnings of vitamin D overdose
have been, a person standing in the summer sun for an hour at noontime
in a Southern latitude (Arizona, Florida) in swim trunks would
naturally produce about 10,000 IU (250 micrograms) of vitamin D
through skin exposure. Sun poisoning from vitamin D overdose has never
been reported. [Am J Clinical Nutrition 73 (2): 288-94, Feb 2001; Am J
Clinical Nutrition 69(5): 842-56, May 1999]
Researchers recently stated that the Food & Nutrition Board’s 2000 IU
(50 microgram) upper safe limit is not based on current evidence and
that the absence of any toxicity in healthy adults at 10,000 IU (250
micrograms) should be supported as the completely safe upper daily
limit. [American Journal Clinical Nutrition 85: 6-18, Jan. 2007]
What doesn’t vitamin D cure?
The fast-paced publication of reports extolling the virtues of vitamin
D is astounding. William B Grant PhD of the Sunlight, Nutrition and
Health Research Center in San Francisco, says there is compelling
evidence that low vitamin D levels lead to increased risk of rickets
(soft bones), osteoporosis (loss of bone), 16 cancers (including
prostate, breast, colon, ovary, Hodgkin’s lymphoma), as well as
psoriasis, diabetes, high blood pressure, heart disease, multiple
sclerosis and susceptibility to tuberculosis. [Journal Cosmetic
Dermatology 2: 86-98, 2003]
Dr. Robert P Heaney of Creighton University says that efforts to
elevate vitamin D beyond prevailing levels in North Americans improves
calcium absorption, reduces falls and hip fractures, protects against
various cancers and autoimmune disorders and says that "a strong case
can be made for immediate improvement in vitamin D status of the
general population." [Journal Steroid Biochemistry Molecular Biology
Jan 9, 2007]
Vitamin D and heart disease
It is increasingly becoming apparent that it is excessive calcium, and
not cholesterol, that causes hardening of the arteries and heart
attacks. Only about 3% of arterial plaque is cholesterol while 50% is
calcium. Vitamin D is an anti-calcifying agent. [Osteoporosis
International 18: 251-59, 2007] Kidney disease patients, who are
plagued with arterial calcifications, have 10 times the cardiac death
rate compared to the general population.
What most doctors and the public have been told is that high-dose
vitamin D can induce calcifications of arteries. But Armin Zittermann,
PhD, of the Northrhine Westfalia Heart Center in Germany, reports that
both extremely high and commonly low intake levels of vitamin D induce
calcification of arteries. Calcification from overdose of vitamin D
requires many hundreds of thousands of international units and is
rare, whereas hundreds of millions of adults are deficient in vitamin
D and suffer from calcified arteries as a result of deficiency. Dr.
Zitterman points to a study conducted in Japan where adequate vitamin
D levels achieved via supplementation reduced the death risk from
cardiovascular disease by 70% compared to those who did not use
vitamin D supplements. [Current Opinion Lipidology 18: 41-46, Feb.
2007]
Cancer reduction
In February of 2006 a research team led by Cedric F. Garland of the
University of California at San Diego, reported that vitamin D
supplementation would reduce the occurrence of a wide variety of
cancers by 30-50%. [American Journal Public Health 96: 252-61, 2006]
It is estimated that 50,000-63,000 individuals in the United States,
and 19,000-25,000 in Great Britain, die prematurely from cancer
annually due to insufficient vitamin D. [Photochemistry Photobiology
81: 1276-86, 2005]
The geographical colon, breast, ovarian and prostate cancer belt that
encircles the world is in the Northern latitudes. Cities like Seattle,
Toronto, Boston, London, Dublin, Helsinki, Copenhagen, Berlin, Moscow,
Anchorage, fall within this global belt and have high rates of these
cancers.
Recently it was reported that 1000-2000 IU (25-50 micrograms) of
vitamin D, obtained from dietary supplements, sunlight exposure, or
the diet, would cut the risk of colon cancer in half. [American
Journal Preventive Medicine 32: 210-16, 2007]
The common cold
Dr. John Cannell MD, who captains the Vitamin D Council, recently
authored a paper which shows the winter increase in colds and flu is
attributed to low seasonal vitamin D levels. Dr. Cannell cites the
earlier work of R. Edgar Hope-Simpson who first proposed that
variations in exposure to solar radiation explains the seasonality of
influenza epidemics. [Epidemiological Infection 134: 1129-40, Dec.
2006] Dr. Cannell even has a challenge for visitors to the Vitamin D
Council website.

www.vitamindcouncil.com

He suggests high-dose vitamin D (50,000 IU – 1.25 milligrams) be
consumed for 3 days at the first sign of a cold or the flu. So far,
Dr. Cannell is receiving many reports of how quickly high-dose vitamin
D overpowers the common cold (this writer tried high-dose vitamin D
with the first sign of sniffles this winter, and the vitamin D therapy
worked rapidly both times).
How did vitamin D escape notice?
Just how vitamin D has not drawn greater attention is difficult to
fathom. In winter, when vitamin D levels are low, death rates around
the world rise. Winter is the season for heart attacks. The diagnosis
of cancer in winter months shortens survival times. There is a decline
in mood in winter months, leading to an increase in carbohydrate
consumption and obesity. In older adults, low vitamin D levels are
associated with mental depression. [American Journal Geriatric
Psychiatry 14: 1032-40, 2006]
It’s not like vitamin D hasn’t been brought to center stage. Feature
articles in Newsweek and US News & World Report in December of 2006
have been published. But are doctors informing their patients of the
revolution underway and prescribing vitamin D? Not yet. Will they
ever?
Cutting cancer rates by 30-50%, heart disease by up to 70%, may be too
much of a shock now that health care is an industry that relies upon
volumes of patients to treat. Prevention is anathema. Medical centers
depend upon large numbers of patients to treat to pay off mortgages
for building projects. Medical device and drug companies must churn
high numbers not only to remain profitable, but to prop up their stock
prices on Wall Street. One wonders whether modern medicine will ever
let this vitamin D revolution happen? It appears health authorities
have misdirected the public.
So far, there has been no response from the National Institutes of
Health (NIH) regarding this breakthrough. No press conferences like
the NIH typically conducts for breakthrough drugs. The reports of
vitamin D’s health benefits are coming from independent researchers
rather than public health authorities, who are dragging their feet on
this surprising development.
Sun, diet or pills?
It’s difficult for most people to get optimal amounts of vitamin D.
The diet, at best, will only provide a few hundred units of vitamin D.
Milk is fortified with synthetic vitamin D2, which is not nearly as
potent as natural D3, which is used in most dietary supplements. A
glass of milk provides only 100 IU (2.5 micrograms).
Fifteen minutes of sun exposure to 40-percent of the body is suggested
daily for fair-skinned individuals, and more time for dark-skinned
people. People with dark skin pigmentation simply don’t make as much
vitamin D as Caucasians. A recent study conducted in a northern state
(Michigan) found 50% of black mothers and 65% of their newborn infants
were vitamin D deficient. [Clinical Pediatrics 46: 42-44, 2007] Even
adults who receive adequate sun exposure have been found to be
deficient in vitamin D. [Menopause Feb 6, 2007]
Virtually all of northern Europe is either deficient or
undernourished, and in sunny middle-eastern countries, vitamin D
deficiency is rampant because of clothing that covers most of the
skin. [Journal Steroid Biochemistry Molecular Biology Feb. 5, 2007]
Humans have been made phobic about sunlight exposure, fearful of skin
cancer and the deadly malignant melanoma. But it is interesting to
note that mortality rates for melanoma rose steeply after sunscreens
came into common use, not before. Sunscreen lotion blocks the vitamin
D-producing UV-B rays, while allowing the deeper-penetrating, cancer-
causing UV-A rays to burn the skin.
Calculating the cost of deficiency
Researchers Cedric Garland, William B Grant and Edward D. Gorham claim
it would cost about $1 billion a year to provide 1000 IU (250
micrograms) of vitamin D to all adult Americans, and the expected
benefits for cancer would be in the range of $16-25 billion. [Recent
Results Cancer Research 174: 225-34, 2007] The total U.S. economic
burden due to vitamin D insufficiency from inadequate exposure to
solar UV-B radiation, diet, food fortification and supplements is
estimated at $40-56 billion annually (2004). [Photochemistry
Photobiology 81: 1276-86, 2005]
Many health food stores stock 1000 IU and 2000 IU vitamin D pills.
Higher-dose 5000 IU and 50,000 IU vitamin D pills are more difficult
to find and can be purchased from this trusted website.

www.lifespannutrition.com

February 20, 2007
Bill Sardi is a consumer advocate and health journalist, writing from
San Dimas, California. He offers a free downloadable book, The
Collapse of Conventional Medicine, at his website. Bill Sardi is a
spokesperson for various dietary supplement companies.

---------------------

randall.... to treg or not to treg! Does the vitamin D do it!!

randall

unread,

Mar 13, 2007, 4:26:42 PM3/13/07

Hi,

Fruit flies to the rescue? Aids research points to TOLL.

http://news.biocompare.com/newsstory.asp?id=173808

[...]
The evidence that a fruit fly's immune response can adapt to - or
retain memory of - an earlier infection contradicts the long-held
dogma that immune memory cannot exist in invertebrates such as
insects. Such memory of a specific pathogen, known as adaptation, is
supposed to be a hallmark of the higher-level immune system response
of humans and other vertebrates.

[...]
"AIDS patients are like fruit flies in the sense that they don't have
properly functioning T cells," said Schneider. "If there is anything
we could do to make their remaining innate immunity better through
adaptation, that would be really helpful."

[...]
In the study, the researchers conclude that a much-studied receptor
called Toll is involved, as are other processes. <sniP>

----------------

Tlr4 (toll-4) and LPS as culprits with genetic flaws have been on the
radar around here. Lets
search that with the fruit fly/aids toll revelations and Tregs/foxp3.

I only want to be clear, here. LOL

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17312170&query_hl=4&itool=pubmed_docsum
TLR4 Hyperresponsiveness via Cell Surface Expression of Heat Shock
Protein gp96 Potentiates Suppressive Function of Regulatory T Cells.

* Dai J,
* Liu B,
* Ngoi SM,
* Sun S,
* Vella AT,
* Li Z.

Department of Immunology, University of Connecticut School of
Medicine, Farmington, CT 06030.
As one of the main mediators of the endoplasmic reticulum unfolded
protein response, heat shock protein gp96 is also an obligate
chaperone for multiple TLRs including TLR4. We demonstrated recently
that enforced cell surface expression of gp96 in a transgenic (Tg)
mouse (96tm-Tg) conferred hyperresponsiveness to LPS and induced TLR4-
dependent lupus-like autoimmune diseases. In this study, we
investigated the function of CD4(+)CD25(+) Foxp3(+) regulatory T cells
(T(reg)) in these mice in light of the important roles of T(reg) in
the maintenance of peripheral tolerance against self-Ag as well as the
increasing appreciation of TLR signaling on the regulation of T(reg).
We found that the development of T(reg) was not impaired in 96tm-Tg
mice. Contrary to the prediction of dampened T(reg) activity, we
discovered that the suppressive functions of T(reg) were increased in
96tm-Tg mice. Inactivation of T(reg) during the neonatal stage of life
exacerbated not only organ-specific diseases but also systemic
autoimmune diseases. By crossing 96tm-Tg mice into the TLR4 null
background, we demonstrated the critical roles of TLR4 in the
amplification of T(reg) suppressive function. These findings
illustrate that gp96 plays dual roles in regulating immune responses
by augmenting proinflammatory responses and inducing T(reg) function,
both of which are dependent on its ability to chaperone TLR4. Our
study provides strong support to the notion of compensatory T(reg)
activation by TLR ligation to dampen inflammation and autoimmune
diseases.

PMID: 17312170

So LPS hyperresponsiveness could be a genetic glitch for us as it
slows Tregs! Now thats a
a gene to be examined. Or have they already?

Lets look for more of the same with IL-10. As psoriatics have to
little in that area. Aids people
btw have way to much IL-10.

It would be cool if we could hook up a line with them and swap high
TNF for their high IL-10.
A real win win situation.

Back to IL-10 Sorry for the gay/psoriatic hook up thingy? LOL

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17339055&query_hl=4&itool=pubmed_docsum
An alteration in the levels of populations of CD4(+) Treg is in part
responsible for altered cytokine production by cells of aged mice
which follows injection with a fetal liver extract.

* Gorczynski RM,
* Alexander C,
* Bessler W,
* Brandenburg K,
* Fournier K,
* Mach JP,
* Mueller S,
* Rietschel ET,
* Ulmer AJ,
* Waelli T,
* Zahringer U,
* Khatri I.

Department of Surgery, University Health Network, Toronto, Ont.,
Canada; Department of Immunology, University Health Network, Toronto,
Ont., Canada.

We have shown previously that a fetal sheep liver extract (FSLE)
containing significant quantities of fetal ovine gamma globin chain
(Hbgamma) and LPS injected into aged (>20 months) mice could reverse
the altered polarization (increased IL-4 and IL-10 with decreased IL-2
and IFNgamma) in cytokine production seen from ConA stimulated
lymphoid cells of those mice. The mechanism(s) behind this change in
cytokine production were not previously investigated. We report below
that aged mice show a >60% decline in numbers and suppressive function
of both CD4(+)CD25(+)Foxp3(+) Treg and so-called Tr3
(CD4(+)TGFbeta(+)), and that their number/function is restored to
levels seen in control (8-week-old) mice by FSLE. In addition, on a
per cell basis, CD4(+)CD25(-)Treg from aged mice were >4-fold more
effective in suppression of proliferation and IL-2 production from
ConA-activated lymphoid cells of a pool of CD4(+)CD25(-)T cells from 8-
week-old mice than similar cells from young animals, and this
suppression by CD25(-)T cells was also ameliorated following FSLE
treatment. Infusion of anti-TGFbeta and anti-IL-10 antibodies in vivo
altered Treg development following FSLE treatment, and attenuated FSLE-
induced alterations in cytokine production profiles.

PMID: 17339055

(((((((((((((((((((((((((((((((((((((((((((((()))))))))))))))))))))))))))))))))))))))))))))))))

PCN is working for you again!

http://www.emediawire.com/releases/2007/3/emw510905.htm

Psoriasis Cure Now -- Podcast Series Resumes with Program on Treating
Hand and Foot Psoriasis

"Psoriasis Cure Now," a nonprofit patient advocacy group, today

released the newest in its series of free psoriasis podcasts, this one
focused on treating hand and foot psoriasis, a type of psoriasis that
can be highly resistant to treatment, while interfering with a
patient's quality of life.

Kensington, MD (PRWeb) March 13, 2007 -- "Psoriasis Cure Now," a
nonprofit patient advocacy group, today released the newest in its
series of psoriasis podcasts, this one focused on treating hand and
foot psoriasis. Psoriasis on the hands and feet often proves to be
highly resistant to treatment, while interfering with a patient's
quality of life. The free podcast is available on the Psoriasis Cure
Now website at http://www.psoriasis-cure-now.org/podcasts.php , or
through iTunes.

The podcast includes a pair of interviews. Craig Leonardi, M.D., a
board-certified dermatologist in private practice in St. Louis,
Missouri, and a Clinical Assistant Professor of Dermatology at St.
Louis University, speaks about his recent study of a biologic
treatment for hand and foot psoriasis. The podcast also includes an
interview with Tim Savage, a sign language interpreter from Virginia
who has psoriasis on his hands. He shares his treatment experiences
with us.

"Hand and foot psoriasis can be physically painful, emotionally
damaging, and can even interfere with one's ability to work or live
normally," said Michael Paranzino, president of Psoriasis Cure Now.
"This makes treating it effectively all the more important. This
podcast will help psoriasis patients with hand or foot psoriasis
understand that we now have proven treatment options that may work for
them. Those suffering with this particularly troubling form of
psoriasis should not lose hope, but should instead visit a
dermatologist and consider the full range of options available to
them. Hand and foot psoriasis is simply too painful to go
undertreated."

Previous Psoriasis Cure Now podcasts have covered topics including
strategies for treating children with psoriasis, and the future of
psoriasis treatments. They are all available free from the Psoriasis
Cure Now website and via iTunes. Psoriasis Cure Now podcasts are made
possible by unrestricted educational grants from Amgen and Genentech,
and from contributions from psoriasis patients and their loved ones.

---------

Good work Michael. KeeP it uP!

----------------

More genes in the mix for P offers multiple layers of treatments?

http://www.innovations-report.de/html/berichte/biowissenschaften_chemie/bericht-80675.html
Treating Psoriasis: The Pharmacogenomic Approach
13.03.2007
This study published in the journal "Dermatology" shows that
investigating individual gene characteristics of patients with
psoriasis improves the possibilities of pharmacotherapy using
pharmacogenomic approaches, which in future could be further
stratified according to the subtypes of psoriasis.
A total of 293 patients with plaque psoriasis, 82 patients with
psoriasis guttata and 202 control subjects were enrolled in this
study. Investigations focused on 3 polymorphisms in retinoid X
receptors RXRA and RXRB gene associations. The possible association of
their variability with psoriasis was investigated.

A marginally significant increase in AA allelic frequency of the RXRA
A39526AA polymorphism in plaque psoriatic men compared to healthy ones
was proven. In women with psoriasis guttata, a higher risk for
genotypes AA and TT in the RXRB 3'+140A/T polymorphism compared to
healthy women was identified. The genotypes A/A and AA/AA were more
frequent in plaque psoriasis patients with a positive family history
of psoriasis compared to patients with a negative family history of
psoriasis. The A/A genotype was more frequent in patients with plaque
psoriasis and repeated tonsillitis/tonsillectomy. In the RXRB
polymorphism, no genotype TT was observed in patients with psoriasis
guttata with a positive personal history of repeated tonsillitis.

Accordingly, these two RXR polymorphisms seem to be susceptibility
genes for psoriasis. This knowledge contributes to improving the
results of psoriasis therapy using a pharmacogenomic approach.

-------

The abstract for the above,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17341859&query_hl=3&itool=pubmed_docsum
Three Retinoid X Receptor Gene Polymorphisms in Plaque Psoriasis and
Psoriasis Guttata.

* Vasku V,
* Bienertova Vasku J,
* Pavkova Goldbergova M,
* Vasku A.

1st Department of Dermatology, St. Ann's Faculty Hospital, Masaryk
University, Brno, Czech Republic.

Aim: Polymorphisms in retinoid X receptors (RXRs) are very interesting
from the point of view of a possible association of their variability
with psoriasis. Methods: A total of 293 patients with plaque
psoriasis, 82 patients with psoriasis guttata and 202 control subjects
were enrolled in this study focused on 3 polymorphisms in RXRA and
RXRB gene associations. Results: A marginally significant increase in
AA allelic frequency of the RXRA A39526AA polymorphism in plaque
psoriatic men compared to healthy men was proved. In women with
psoriasis guttata, the higher risk for genotypes AA and TT in the RXRB
3'+140A/T polymorphism compared to healthy women was identified
(p(corr) = 0.01). The genotypes A/A and AA/AA are more frequent in
plaque psoriasis patients with a positive family history of psoriasis
compared to the patients with a negative family history of psoriasis
(p(corr) = 0.02). The A/A genotype is more frequent in patients with
plaque psoriasis and repeated tonsillitis/tonsillectomy (p = 0.02). In
the RXRB polymorphism, no genotype TT is observed in patients with
psoriasis guttata with a positive personal history of repeated
tonsillitis (p(corr) = 0.001). Conclusion: Individual gene
characteristics of patients with psoriasis improve the possibilities
of pharmacotherapy using pharmacogenomic approaches which could be
further stratified in future according to the subtypes of psoriasis.
Copyright (c) 2007 S. Karger AG, Basel.

PMID: 17341859

---------------------------

New protein found in mucosal genitalia linings to fight Aids
http://news.biocompare.com/newsstory.asp?id=173231

Researchers have discovered that cells in the mucosal lining of human
genitalia produce a protein that "eats up" invading HIV -- possibly
keeping the spread of the AIDS more contained than it might otherwise
be.
Even more important, enhancing the activity of this protein, called
Langerin, could be a potent new way to curtail the transmission of the
virus that causes AIDS, the Dutch scientists added.

Langerin is produced by Langerhans cells, which form a web-like
network in skin and mucosa. This network is one of the first
structures HIV confronts as it attempts to infect its host.

However, "we observed that Langerin is able to scavenge viruses from
the surrounding environment, thereby preventing infection," said lead
researcher Teunis Geijtenbeek, an immunologist researcher at Vrije
University Medical Center in Amsterdam.

"And since generally all tissues on the outside of our bodies have
Langerhans cells, we think that the human body is equipped with an
antiviral defense mechanism, destroying incoming viruses," Geijtenbeek
said.

The finding, reported in the March 4 online issue of Nature Medicine,
"is very interesting and unexpected," said Dr. Jeffrey Laurence,
director of the Laboratory for AIDS Virus Research at the Weill
Cornell Medical College, in New York City. "It may explain part of the
relative inefficiency of HIV in being transmitted."

Even though HIV has killed an estimated 22 million people since it was
first recognized more than 25 years ago, it is actually not very good
at infecting humans, relatively speaking.

For example, the human papillomavirus (HPV), which causes cervical
cancer, is nearly 100 percent infectious, Laurence noted. That means
that every encounter with the sexually transmitted virus will end in
infection.

"On the other hand, during one episode of penile-vaginal intercourse
with an HIV-infected partner, the chance that you are going to get HIV
is somewhere between one in 100 and one in 200," Laurence said.

Experts have long puzzled why HIV is relatively tough to contract,
compared to other pathogens. The Dutch study, conducted in the
laboratory using Langerhans cells from 13 human donors, may explain
why.

When HIV comes in contact with genital mucosa, its ultimate target --
the cells it seeks to hijack and destroy -- are immune system T-cells.
But T-cells are relatively far away (in lymph tissues), so HIV uses
nearby Langerhans cells as "vehicles" to migrate to T-cells.

For decades, the common wisdom was that HIV easily enters and infects
Langerhans cells. Geijtenbeek's team has now cast doubt on that
notion.

Looking closely at the interaction of HIV and Langerhans cells, they
found that the cells "do not become infected by HIV-1, because the
cells have the protein Langerin on their cell surface," Geijtenbeek
said. "Langerin captures HIV-1 very efficiently, and this Langerin-
bound HIV-1 is taken up (a bit like eating) by the Langerhans cells
and destroyed."

In essence, Geijtenbeek said, "Langerhans cells act more like a virus
vacuum cleaner."

Only in certain circumstances -- such as when levels of invading HIV
are very high, or if Langerin activity is particularly weak -- are
Langerhans cells overwhelmed by the virus and infected.

The finding is exciting for many reasons, not the least of which is
its potential for HIV prevention, Geijtenbeek said.

"We are currently investigating whether we can enhance Langerin
function by increasing the amount of Langerin on the cell surface of
Langerhans cells," he said. "This might be a real possibility, but it
will take time. I am also confident that other researchers will now
also start exploring this possibility."

The discovery might also help explain differences in vulnerability to
HIV infection among people.

"It is known that the Langerin gene is different in some individuals,"
Geijtenbeek noted. "These differences could affect the function of
Langerin. Thus, Langerhans cells with a less functional Langerin might
be more susceptible to HIV-1, and these individuals are more prone to
infection. We are currently investigating this."

The finding should also impact the race to find topical microbicides
that might protect women against HIV infection. Choosing compounds
that allow Langerin to continue to work its magic will enhance any
candidate microbicide's effectiveness, the Dutch researcher said.

Laurence did offer one note of caution, however.

"In the test tube, this is a very important finding," he said. "But
there are many things in the test tube that don't occur when you get
into an animal or a human. Having said that, though, this is a very
intriguing finding."

------------------------------

Better cut it short and save the rest for later.

randall...

randall

unread,

Mar 17, 2007, 12:59:56 PM3/17/07

Hi,

Is this good or bad news? Th17 has been in a few posts.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17363300&query_hl=3&itool=pubmed_docsum
Interleukin-2 Signaling via STAT5 Constrains T Helper 17 Cell
Generation.

* Laurence A,
* Tato CM,
* Davidson TS,
* Kanno Y,
* Chen Z,
* Yao Z,
* Blank RB,
* Meylan F,
* Siegel R,
* Hennighausen L,
* Shevach EM,
* O'shea JJ.

Molecular Immunology and Inflammation Branch, National Institute of
Arthritis, Musculoskeletal and Skin Diseases, National Institutes of
Health, Bethesda, MD 20892, USA.

Recent work has identified a new subset of effector T cells that
produces interleukin (IL)-17 known as T helper 17 (Th17) cells, which
is involved in the pathophysiology of inflammatory diseases and is
thought to be developmentally related to regulatory T (Treg) cells.
Because of its importance for Treg cells, we examined the role of IL-2
in Th17 generation and demonstrate that a previously unrecognized
aspect of IL-2 function is to constrain IL-17 production. Genetic
deletion or antibody blockade of IL-2 promoted differentiation of the
Th17 cell subset. Whereas STAT3 appeared to be a key positive
regulator of RORgammat and IL-17 expression, absence of IL-2 or
disruption of its signaling by deletion of the transcription factor
STAT5 resulted in enhanced Th17 cell development. We conclude that in
addition to the promotion of activation-induced cell death of
lymphocytes and the generation of Treg cells, inhibition of Th17
polarization appears to be an important function of IL-2.

PMID: 17363300

----------------

http://groups.google.com/groups/search?qt_s=1&q=th17+psoriasis

43 for Th17,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&dispmax=100&term=%20Th17

For Th1 over 18,000 hits.

Lets try Th1 plus IL-2,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&dispmax=100&term=%20Th1+IL-2

Add in some TNF,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&dispmax=100&term=%20Th1+IL-2+tnf

And thats all for now,

randall....

randall

unread,

Mar 19, 2007, 5:57:26 PM3/19/07

Hi,

A very big WOW for this first story.

http://arthritis.about.com/b/a/257442.htm

Rheumatoid Arthritis May Not Be Autoimmune Disease

It's a widely accepted theory that rheumatoid arthritis is an
autoimmune disease. Researchers from the University of Michigan
Medical School suggest in a new study that there may be another
explanation for what causes rheumatoid arthritis. The disease has been
associated with a common sequence of DNA on HLA-DRB genes (also
referred to as a shared epitope). Approximately 95 percent of
rheumatoid arthritis patients have the DNA sequence, though the reason
for this association is unclear. HLA genes have previously been linked
to antigen recognition and immune function. The researchers found that
the shared epitope may actually be the cause of nitric oxide
overproduction which is seen in rheumatoid arthritis patients.
According to the study, which has been published in the November 2006
issue of Arthritis & Rheumatism, nitric oxide production was found to
be much higher in patients with the shared epitope. Overproduction of
nitric oxide inhibits the natural process which leads to cell death.
Resistance to this natural process is commonly seen in cells of the
synovium (joint lining) in rheumatoid arthritis patients

-----------------------

It would be even funnier to think psoriasis isn't Ai. But it is
I.M.I.D. Isn't it?

________________

http://www.app.com/apps/pbcs.dll/article?AID=/20070319/LIFE11/70319011/1006/LIFE

Stem cell finding could help fight autoimmune disease

In a finding that could help researchers better understand autoimmune
disease,
scientists say a process called autophagy prompts dying embryonic stem
cells to send out "eat me" and "come and get me" signals to ensure
their elimination by healthy cells.

"Our findings also suggest that defects in autophagy might trigger
autoimmune
diseases and, if so, reversing the defects could potentially help
treat such diseases," Dr. Beth Levine, chief of the division of
infectious diseases at the University of Texas Southwestern Medical
Center, in Dallas, said in a prepared statement.

Her team described its findings in a study published in the March 8
online issue of Cell.

In mouse embryos incapable of activating autophagy, dying cells aren't
able to
produce the chemical signals that instruct healthy cells to remove
them, the study
found. An accumulation of dead cells can result in abnormal
development, inflammation and autoimmune disease.

"The activation of autophagy in cells destined to die may serve to
clear dead cells
and prevent detrimental inflammation during normal development or when
cell death occurs in certain diseases," Levine explained.

--------------

http://www.infozine.com/news/stories/op/storiesView/sid/21714/
Research Could Result in New Treatments for Autoimmune Disorders and
Common Infections
Science & TechnologyUniversity of Missouri-Kansas City researcher
Brian Geisbrecht, Ph.D., has discovered how the pathogen
Staphylococcus aureus (S. aureus) disables an essential component of
the human immune system. S. aureus is a leading cause of community
acquired and hospital-related infections. These so-called "Staph
infections" are widely regarded as a growing threat to public health
as the incidence of antibiotic-resistant strains continues to climb.

Kansas City, Mo. - infoZine - To overcome S. aureus infection, the
body requires immune molecules called complement proteins. These
proteins circulate in the bloodstream as inactive precursors and
represent the first line of defense against invading microbes. Upon
encountering invading microbes such as Staphylococcus, complement
proteins are processed into smaller subunits that summon more immune
cells and trigger other downstream defense mechanisms.

S. aureus produces a protein, called Efb, which suppresses activation
of the complement response, and Geisbrecht and fellow researcher John
D. Lambris, Ph.D., from the University of Pennsylvania School of
Medicine have discovered how this happens. In a study published in the
journal "Nature Immunology," Geisbrecht's and Lambris' research has
shown that Efb changes the shape of complement proteins. This change
prevents the proteins from being cleaved into the smaller subunits,
and renders the complement response ineffective. In turn, this
prevents both the destruction of microbe and recruitment of more
immune cells to the site of infection.

Geisbrecht and Lambris hope their research can be used to keep Efb
from altering and preventing the complement protein activation
process. Even though this may result in an important new class of
antibiotics, the scientists believe that there may be more to the
story.

"While complement is an important component of healthy immune systems,
other studies have shown that over-activation of complement proteins
can contribute to autoimmune diseases, such as lupus, and to the
damage of healthy tissue following either transplantation or loss of
circulation, as is seen in heart attacks," Geisbrecht said. "By
studying the properties of bacterial anti-inflammatory proteins, such
as Efb, we may eventually identify new approaches to treating these
diseases through clinical inhibition of the complement response."

"Brian is one of our truly talented young scientists at the School of
Biological Sciences," Lawrence Dreyfus, Ph.D., dean of the SBS, said.
"His most recent discovery detailing the structure of the Efb-
complement C3 complex is a milestone in our understanding of how
Staphyloccus aureus, a significant cause of human disease and death,
is able to circumvent our innate immunity and establish an infection.
Brian is one growing cadre of structural biology researchers at the
School who are presently researching some of the most fundamental
problems in molecular biology. We are very fortunate to have Brian as
one of our own and look forward to his continued success."

"These findings are a major step forward in life sciences research,"
John Bauman, vice provost for research at UMKC, said. "Dr. Geisbrecht
is one of UMKC's many bright, young researchers and we're fortunate to
have his skills and expertise on our team."

Geisbrecht is an assistant professor in UMKC's School of Biological
Sciences. He joined the faculty of the School of Biological Sciences
in 2004 after completing post-doctoral studies in structural biology
the Department of Biophysics and Biophysical Chemistry at the Johns
Hopkins University School of Medicine in Baltimore, MD. Dr. Geisbrecht
was awarded a Ph.D.in biological chemistry from the same institution
in 2000, and graduated with a B.S. in chemistry/biochemistry from
Saint Vincent College in Latrobe, PA in 1996.

--------------

randall

JXStern

unread,

Mar 19, 2007, 8:32:34 PM3/19/07

That's not an alternate, it's an explanation of the autoimmune
problem. Sheesh. If we have an autoimmune problem, it'll be in the
DNA, and it could easily involve overproduction of NO, though that
doesn't square exactly with TNF, probably be co-processes, unless
TNF's MOA involves NO.

When they say 95% of RA have this epitope, they neglected to say what
percent of NON-RA people have it. If that's also 95%, then we'd have
nothing. (one presumes the % at large is much lower, hopefully much,
much lower, under 50% or who cares, under 10% would really impress!)

(that's non-RA, also non-P, for that matter, what percent of P people
have it? but it would be interesting even if it only held for RA)

randall

unread,

Mar 20, 2007, 2:21:06 AM3/20/07

On Mar 19, 4:32 pm, JXStern <JXSternChange...@gte.net> wrote:
> That's not an alternate, it's an explanation of the autoimmune
> problem. Sheesh. If we have an autoimmune problem, it'll be in the
> DNA, and it could easily involve overproduction of NO, though that
> doesn't square exactly with TNF, probably be co-processes, unless
> TNF's MOA involves NO.

The primary reason for a low arginine diet iirc.

http://en.wikipedia.org/wiki/Arginine

http://en.wikipedia.org/wiki/Nitric_oxide

This one explains why my glutamine experiment went so sour,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16082501&query_hl=1&itool=pubmed_docsum

Almost all about citrulline in mammals.

* Curis E,
* Nicolis I,
* Moinard C,
* Osowska S,
* Zerrouk N,
* Benazeth S,
* Cynober L.

Laboratoire de Biomathematiques, E.A. 2498, Faculte de Pharmacie,
Universite Rene Descartes, Paris, France. emmanuel.curis@univ-
paris5.fr

Citrulline (Cit, C6H13N3O3), which is a ubiquitous amino acid in
mammals, is strongly related to arginine. Citrulline metabolism in
mammals is divided into two fields: free citrulline and citrullinated
proteins. Free citrulline metabolism involves three key enzymes: NO
synthase (NOS) and ornithine carbamoyltransferase (OCT) which produce
citrulline, and argininosuccinate synthetase (ASS) that converts it
into argininosuccinate. The tissue distribution of these enzymes
distinguishes three "orthogonal" metabolic pathways for citrulline.
Firstly, in the liver, citrulline is locally synthesized by OCT and
metabolized by ASS for urea production. Secondly, in most of the
tissues producing NO, citrulline is recycled into arginine via ASS to
increase arginine availability for NO production. Thirdly, citrulline
is synthesized in the gut from ____glutamine___ (with OCT), released
into the blood and converted back into arginine in the kidneys (by
ASS); in this pathway, circulating citrulline is in fact a masked form
of arginine to avoid liver captation. Each of these pathways has
related pathologies and, even more interestingly, citrulline could
potentially be used to monitor or treat some of these pathologies.
Citrulline has long been administered in the treatment of inherited
urea cycle disorders, and recent studies suggest that citrulline may
be used to control the production of NO. Recently, citrulline was
demonstrated as a potentially useful marker of short bowel function in
a wide range of pathologies. One of the most promising research
directions deals with the administration of citrulline as a more
efficient alternative to arginine, especially against underlying
splanchnic sequestration of amino acids. Protein citrullination
results from post-translational modification of arginine; that occurs
mainly in keratinization-related proteins and myelins, and
insufficiencies in this citrullination occur in some auto-immune
diseases such as rheumatoid arthritis, psoriasis or multiple
sclerosis.

PMID: 16082501

And this one makes more sense for psoriasis then RA,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=15780765&query_hl=1&itool=pubmed_docsum
Arginase-1 overexpression induces cationic amino acid transporter-1 in
psoriasis.

* Schnorr O,
* Schuier M,
* Kagemann G,
* Wolf R,
* Walz M,
* Ruzicka T,
* Mayatepek E,
* Laryea M,
* Suschek CV,
* Kolb-Bachofen V,
* Sies H.

Institute for Biochemistry and Molecular Biology I, Building 22.03,
Heinrich-Heine-University Duesseldorf, Universitaetsstr.1, D-40225
Duesseldorf, Germany. sch...@uni-duesseldorf.de

Regulated uptake of extracellular l-arginine by cationic amino acid
transporters (CATs) is required for inducible nitric oxide synthase
and arginase activity. Both enzymes were recently recognized as
important in the pathophysiology of psoriasis because of their
contribution to epidermal hyperproliferation. We here characterize the
expression pattern of CATs in psoriatic skin compared to healthy skin.
CAT-1 mRNA expression was strongly upregulated in lesional and
nonlesional areas of psoriatic skin compared to healthy skin, whereas
expression of CAT-2A and the inducible isoform CAT-2B was unaltered in
psoriatic skin. Furthermore, we tested the hypothesis that arginase-1
overexpression regulates CAT expression via intracellular l-arginine
concentration. In in vitro experiments with arginase-1 overexpressing
HaCaT cells, CAT-1 mRNA expression was increased. Likewise, this
occurs in l-arginine-starved HaCaT cells. Both CAT-2 isoforms were not
affected. Arginase-1 overexpression limits the synthesis of NO at
physiological, but not supraphysiological, l-arginine levels. Plasma l-
arginine concentration was diminished in psoriasis patients and the
arginase product l-ornithine was significantly increased compared to
healthy controls. In summary, arginase-1 overexpression leads to
upregulated CAT-1 expression in psoriatic skin, which is due to
lowered intracellular l-arginine levels and limits NO synthesis at
physiological l-arginine concentrations.

PMID: 15780765

Have a ball,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&dispmax=100&term=%20psoria*+arginine

>
> When they say 95% of RA have this epitope, they neglected to say what
> percent of NON-RA people have it.

It would be really small. Let's look.

http://en.wikipedia.org/wiki/Epitope

To many hits for me,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&dispmax=100&term=%20psoria*+epitope

What shall we reduce it with?

We have to take out psoriasis, no hits with that term left in. So,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&dispmax=100&term=%20arginine+epitope

You can run with it.

randall

> If that's also 95%, then we'd have
> nothing. (one presumes the % at large is much lower, hopefully much,
> much lower, under 50% or who cares, under 10% would really impress!)
>
> (that's non-RA, also non-P, for that matter, what percent of P people
> have it? but it would be interesting even if it only held for RA)
>
> J.
>

randall

unread,

Mar 21, 2007, 3:55:52 AM3/21/07

Hi,

This looks interesting. If you check it out, please give us your
critique.

http://www.prweb.com/releases/2007/3/prweb512909.htm
Psoriasis Cure Now Releases New Podcast on Documentary Movie
InnerState

"Psoriasis Cure Now," a nonprofit patient advocacy group, today

released its latest podcast, about the new documentary movie
"InnerState," which chronicles the lives of three people as they
battle chronic diseases, including psoriasis. The podcast includes
interviews with the psoriasis patient who stars in the film and the
film's director.

Kensington, MD (PRWEB) March 21, 2007 -- "Psoriasis Cure Now," a
nonprofit patient advocacy group, today released the latest in its
series of psoriasis podcasts, this one about the new movie
"InnerState." InnerState is a documentary produced by the biomedicine
company Centocor. The film chronicles the lives of three people as
they battle chronic diseases, including psoriasis. The podcast
includes a roundtable discussion with the psoriasis patient who stars
in the film, the director of the film, and the president of Psoriasis
Cure Now. The free podcast is available on the Psoriasis Cure Now

website at http://www.psoriasis-cure-now.org/podcasts.php , or through
iTunes.

"InnerState is a powerful film that will prove compelling not just to
people with psoriasis and other chronic diseases, but to the general
public as well," said Michael Paranzino, president of Psoriasis Cure
Now. "After seeing it, psoriasis patients will feel a new kinship with
people who have Crohn's disease and rheumatoid arthritis, as we face
much in common as we battle these incurable diseases. Let's just hope
this film gets seen by the broader public who would learn much about
the seriousness of psoriasis by watching this engaging film."

InnerState has shown in New York and Washington, DC, and is headed to
cities across the United States, with upcoming screenings scheduled in
Boston, Atlanta, Dallas, Los Angeles, Philadelphia, San Francisco,
Portland (Oregon), Denver, St. Louis, Minneapolis, Chicago and
Pittsburgh. For more information, visit the Psoriasis Cure Now Podcast
page.

Previous podcasts have covered topics including strategies for
treating children with psoriasis, and hand and foot psoriasis. They

are all available free from the Psoriasis Cure Now website and via
iTunes. Psoriasis Cure Now podcasts are made possible by unrestricted
educational grants from Amgen and Genentech, and from contributions

from psoriasis and psoriatic arthritis patients and their loved ones.

randall

unread,

Mar 22, 2007, 3:15:28 AM3/22/07

Hi,

P genes? Maybe

This next one came up yesterday.

http://content.nejm.org/cgi/content/short/356/12/1216

Background Autoimmune and autoinflammatory diseases involve
interactions between genetic risk factors and environmental triggers.
We searched for a gene on chromosome 17p13 that contributes to a group
of epidemiologically associated autoimmune and autoinflammatory
diseases. The group includes various combinations of generalized
vitiligo, autoimmune thyroid disease, latent autoimmune diabetes in
adults, rheumatoid arthritis, psoriasis, pernicious anemia, systemic
lupus erythematosus, and Addison's disease.

Methods We tested 177 single-nucleotide polymorphisms (SNPs) spanning
the 17p13 linkage peak for association with disease and identified a
strong candidate gene. We then sequenced DNA in and around the gene to
identify additional SNPs. We carried out a second round of tests of
association using some of these additional SNPs, thus elucidating the
association with disease in the gene and its extended promoter region
in fine detail.

Results Association analyses resulted in our identifying as a
candidate gene NALP1, which encodes NACHT leucine-rich-repeat protein
1, a regulator of the innate immune system. Fine-scale association
mapping with the use of DNA from affected families and additional SNPs
in and around NALP1 showed an association of specific variants with
vitiligo alone, with an extended autoimmune and autoinflammatory
disease phenotype, or with both. Conditional logistic-regression
analysis of NALP1 SNPs indicated that at least two variants contribute
independently to the risk of disease.

Conclusions DNA sequence variants in the NALP1 region are associated
with the risk of several epidemiologically associated autoimmune and
autoinflammatory diseases, implicating the innate immune system in the
pathogenesis of these disorders.

-------

17q-11 is PSORs2 iirc? mim#602723 ??

I'll look later.

------------------
PSORs-3
http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601454

http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=606636

http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?cmd=entry&id=606636

----

The PPAR's looked more likely. But really knows?

Over expression, under, whatever...

randall...

randall

unread,

Mar 22, 2007, 3:03:43 PM3/22/07

On Mar 21, 11:15 pm, "randall" <ranhu...@aol.com> wrote:
> Hi,
>
>

> This next one came up yesterday.
>
> http://content.nejm.org/cgi/content/short/356/12/1216
>

The speculations regarding NALP1 are following today.

http://www.innovations-report.de/html/berichte/biowissenschaften_chemie/bericht-81309.html

[...]
"What's really exciting for us is that NALP1 hasn't been specifically
implicated in autoimmune diseases before," said Richard Spritz, MD,
director of the Human Medical Genetics Program at UCDHSC and lead
investigator for this study. "Since NALP1 appears to be part of our
body's early-warning system for viral or bacterial attack, this gives
us ideas about how to try to discover the environmental triggers of
these diseases. This finding may also open up new approaches to
treatment, possibly for many different autoimmune diseases."

As a group of approximately 80 disorders that can involve almost any
tissue, organ or system, autoimmune and autoinflammatory diseases
affect 15 million to 25 million people in the United States. In women,
they rank among the top ten causes of death.

Dr. Spritz and his team hope to soon begin organising a clinical trial
of a new treatment for vitiligo, based on their NALP1 discovery.
Spritz foresees research labs using the information from the UCDHSC
study to replicate or test the results in patients with other
autoimmune diseases to see how broad potential applications might be.
His hope is that the gene NALP1 is also found to be involved in
autoimmune and autoinflammatory diseases such as Type 1 diabetes,
Addison's disease, thyroid disease and lupus, among others.

"All diseases are complex, the result of different genes and
environmental risk factors acting together in concert. But if NALP1
turns out to be one of the major genes involved in numerous autoimmune
diseases, and if we can interrupt its negative effects, we may have
the chance to treat many different chronic autoimmune disorders like
vitiligo, lupus and ___psoriasis___ and perhaps eventually eliminate
them altogether," said Dr. Spritz. <end>

----------------

Look at the latest treatment for vitiligo.

Not that it works, it is interesting.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17373978&query_hl=1&itool=pubmed_docsum
Combination of 308-nm xenon chloride excimer laser and topical
calcipotriol in vitiligo.

* Goldinger S,
* Dummer R,
* Schmid P,
* Burg G,
* Seifert B,
* Lauchli S.

Department of Dermatology, University of Zurich, Zurich, Switzerland.

Background A large variety of therapeutic agents are being used for
the treatment of vitiligo, but treatment remains a challenge.
Recently, monochromatic phototherapies such as 311-nm narrowband
ultraviolet B therapy and 308-nm xenon chloride excimer laser have
been reported to be an effective and safe therapeutic option in
children and adult patients with vitiligo. Single reports stipulate
that the addition of topically applied calcipotriol to phototherapy
increases its effectiveness. Objective The purpose of the present
pilot study was to determine if the addition of topical calcipotriol
increases the efficacy of the 308-nm xenon chloride excimer in the
treatment of vitiligo. Methods Ten patients with vitiligo with
essentially bilateral symmetrical lesions were enrolled in this
prospective right/left comparative, single-blinded trial conducted
over a 15-month period. All patients received 308-nm XeCl excimer
laser therapy three times weekly. Calcipotriol ointment (Daivonex(R))
was applied to lesions on one side of the body twice daily. Results
After 24 treatments (8 weeks), nine patients were evaluated. Eight
patients showed evidence of repigmentation on both body sides, with no
significant difference between the body side treated with calcipotriol
and excimer laser and the side treated with excimer laser alone. The
mean repigmentation rate was 22.4% (1- 37%). Conclusion The addition
of calcipotriol ointment to 308-nm xenon chloride excimer laser
phototherapy does not significantly enhance its efficacy. Small
additive effects must be investigated in a larger trial.

PMID: 17373978

-----------------

Young man overcomes P and obstacles in his way,
http://www.clitheroetoday.co.uk/ViewArticle2.aspx?SectionID=9&ArticleID=2138248

----------

randall

JXStern

unread,

Mar 22, 2007, 3:09:54 PM3/22/07

Was: P News 2007

On 22 Mar 2007 12:03:43 -0700, "randall" <ranh...@aol.com> wrote:

...

>The speculations regarding NALP1 are following today.
>
>http://www.innovations-report.de/html/berichte/biowissenschaften_chemie/bericht-81309.html
>
>[...]

>As a group of approximately 80 disorders that can involve almost any
>tissue, organ or system, autoimmune and autoinflammatory diseases
>affect 15 million to 25 million people in the United States. In women,
>they rank among the top ten causes of death.

Betcha "autoinflammatory" includes heart disease and tons of other
symptoms of aging, though aging itself is probably programmed
separately.

randall

unread,

Mar 24, 2007, 12:47:15 AM3/24/07

Hi,

Abstracts today:

The NALP1 gene abstract showed up today.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17377159&query_hl=1&itool=pubmed_docsum
NALP1 in vitiligo-associated multiple autoimmune disease.

* Jin Y,
* Mailloux CM,
* Gowan K,
* Riccardi SL,
* LaBerge G,
* Bennett DC,
* Fain PR,
* Spritz RA.

Human Medical Genetics Program, University of Colorado at Denver and
Health Sciences Center, Aurora, CO 80045, USA.

BACKGROUND: Autoimmune and autoinflammatory diseases involve

interactions between genetic risk factors and environmental triggers.
We searched for a gene on chromosome 17p13 that contributes to a group
of epidemiologically associated autoimmune and autoinflammatory
diseases. The group includes various combinations of generalized
vitiligo, autoimmune thyroid disease, latent autoimmune diabetes in
adults, rheumatoid arthritis, psoriasis, pernicious anemia, systemic

lupus erythematosus, and Addison's disease. METHODS: We tested 177

single-nucleotide polymorphisms (SNPs) spanning the 17p13 linkage peak
for association with disease and identified a strong candidate gene.
We then sequenced DNA in and around the gene to identify additional
SNPs. We carried out a second round of tests of association using some
of these additional SNPs, thus elucidating the association with
disease in the gene and its extended promoter region in fine detail.

RESULTS: Association analyses resulted in our identifying as a

candidate gene NALP1, which encodes NACHT leucine-rich-repeat protein
1, a regulator of the innate immune system. Fine-scale association
mapping with the use of DNA from affected families and additional SNPs
in and around NALP1 showed an association of specific variants with
vitiligo alone, with an extended autoimmune and autoinflammatory
disease phenotype, or with both. Conditional logistic-regression
analysis of NALP1 SNPs indicated that at least two variants contribute

independently to the risk of disease. CONCLUSIONS: DNA sequence

variants in the NALP1 region are associated with the risk of several
epidemiologically associated autoimmune and autoinflammatory diseases,
implicating the innate immune system in the pathogenesis of these

PMID: 17377159

_________________________________________________

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17376209&query_hl=1&itool=pubmed_docsum
Psoriasis treated with ursodeoxycholic acid: three case reports.

* Itoh S,
* Kono M,
* Akimoto T.

Divisions of Hepatology, Rehabilitation and Dermatology, Chiba Central
Medical Center, Chiba, Japan.

We report three Japanese patients with psoriasis vulgaris associated
with nonalcoholic fatty liver disease in which the skin lesions
dramatically resolved after treatment of the fatty liver disease with
ursodeoxycholic acid (UDCA). According to the literature, arachidonic
acid is released from phospholipid by phospholipase A(2) (PLA(2)) and
is a precursor of eicosanoids, including prostaglandins, leucotrienes,
and thromboxanes, which are potent inflammatory mediators. PLA(2)
activity has been reported to be significantly raised in the serum and
skin tissue of patients with psoriasis. UDCA has been reported to
suppress the increased activity of group IIA PLA(2), a secretory low-
molecular-weight PLA(2) (PLA(2)IIA), in HepG2 cells (a human
hepatoblastoma-derived cell line) and in gallbladder and gallbladder
bile samples from patients with cholesterol stones. Thus, UCDA may
improve the skin lesions of patients with psoriasis by suppressing
PLA(2)IIA activity.

PMID: 17376209

http://en.wikipedia.org/wiki/Ursodeoxycholic_acid

Ursodiol

Ursodiol (trade names Actigall, Ursofalk, Urso, Urso Forte) is a bile
acid found in large quantities in bear bile; it also occurs naturally
in human bile in smaller quantities.

The drug reduces cholesterol absorption and is used to dissolve
gallstones in patients who want an alternative to surgery. The drug is
very expensive, however, and if the patient stops taking it, the
gallstones recur. For these reasons, it has not supplanted surgical
treatment by cholecystectomy. It is also the recommended treatment for
Primary biliary cirrhosis, and other cholestatic diseases, and the
primary medicine given to children with biliary atresia.

-----------------

I'm gonna digest that P crud right outa my life! Or something like
that.

-----------------------------------

Hey Zc94! Look at this.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17376430&query_hl=1&itool=pubmed_docsum
ATP non-competitive IGF-1 receptor kinase inhibitors as lead anti-
neoplastic and anti-papilloma agents.

* Steiner L,
* Blum G,
* Friedmann Y,
* Levitzki A.

Unit of Cellular Signaling, Department of Biological Chemistry, The
Alexander Silberman Institute of Life Sciences, The Hebrew University
of Jerusalem, Jerusalem 91904, Israel.

The insulin-like growth factor-1 receptor (IGF-1 receptor) is a
receptor tyrosine kinase, highly homologous to the insulin receptor.
In contrast to the insulin receptor, which is mostly involved in
metabolic pathways, the IGF-1 system plays a pivotal role in normal
and neoplastic cell growth through anti-apoptotic, proliferative and
metastatic pathways. Furthermore, IGF-1 receptor over-activation is
found to correlate with a variety of tumors, such as breast cancer,
prostate cancer, hematological malignancies, colorectal cancer and
other proliferative diseases, such as psoriasis and papilloma. In
addition, accumulating evidence implies that blockade of IGF-1
receptor activity causes reversal of tumor progression in cell lines
as well as in animal tumor models. Because of the central role the
IGF-1 receptor plays in oncogenic maintenance and metastatic
processes, it is a highly appropriate target for anti-cancer agents.
Here we report on a novel substrate-mimic family of IGF-1 receptor
inhibitors. These compounds are tertiary aromatic amines, non-
competitive with ATP and possess high affinity towards the IGF-1
receptor. The most potent compound, SBL02 inhibited the IGF-1 receptor
with an IC(50) of 170 nM in a cell-free kinase assay and was found to
inhibit IGF-1 receptor auto-phosphorylation and substrate
phosphorylation at the low micromolar range in cellular assays. SBL02
also blocks the formation of colonies in soft agar by cancer cells and
inhibits the growth of keratinocytes and of HPV16 immortalized
keratinocytes. This new family of non-ATP competitive, IGF-1 receptor
inhibitors can serve as a lead for the development of anti-cancer,
anti-psoriatic and anti-papilloma agents.

PMID: 17376430

-------------------------------------

Looks interesting to me. How much does it cost?

-------------------------------------------------

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17376017&query_hl=1&itool=pubmed_docsum
An attempt to formulate an evidence-based strategy in the management
of moderate-to-severe psoriasis: a review of the efficacy and safety
of biologics and prebiologic options.

* Leon A,
* Nguyen A,
* Letsinger J,
* Koo J.

University of Miami, Miller School of Medicine, Miami, FL, USA.

Psoriasis is a chronic skin disorder affecting up to 2.5% of the
world's population. Despite the myriad treatment options available,
there is no uniformly accepted therapeutic approach for moderate-to-
severe psoriasis. The objective of this review is to evaluate the
relative efficacy and safety of available therapeutic options and to
formulate general recommendations for the treatment of moderate-to-
severe psoriasis. MEDLINE and Evidence Based Medicine (Cochrane) were
used to perform a comprehensive search of the literature from 1986 to
2006. The most scientifically rigorous clinical trial published in the
literature was selected for Psoriasis Area and Severity Index (PASI
75) comparison. Only information from clinical trials, human subjects
and English language journals are reported in this study. The
percentage of PASI 75 reduction at approximately 12 weeks obtained by
the following treatment options were: Goeckerman and RePUVA, 100%;
calcipotriene plus PUVA, 87%; ciclosporin, 78.2-80.3%; infliximab,
80%; adalimumab 40 mg every other week, 53% and 40 mg/week, 80%; PUVA,
63%; methotrexate, 60%; NB-UVB, 55%; acitretin 52%; etanercept 50 mg
twice weekly, 49% and 25 mg twice weekly, 34%; efalizumab, 31.4%; and
alefacept 21%. Psoriatic treatments with safer profiles compared with
other agents include bath PUVA, Goeckerman and RePUVA. Based on the
literature review of efficacy and safety of biologics and prebiologic
treatment options for moderate-to-severe psoriasis, the risk:benefit
ratio seems most favorable for Goeckerman and RePUVA, followed by
either etanercept or adalimumab.

PMID: 17376017

---------------------------

randall...

randall

unread,

Mar 24, 2007, 1:29:05 PM3/24/07

Hi,

New Mab in testing.

http://sanantonio.bizjournals.com/baltimore/stories/2007/03/19/daily45.html
MedImmune is expanding trials of an experimental drug to see if it
has potential in treating psoriasis.

The Gaithersburg-based company has begun Phase I trials with its drug
MEDI-545 in patients with psoriasis. MedImmune has also asked
regulators for permission to begin trials using the drug as a
treatment for a muscle inflammation disease known as idiopathic
inflammatory myositis.

MedImmune (NASDAQ: MEDI) is already testing the drug in clinical
trails as a possible treatment for lupus.

The company will report on the lupus trials at next month's
International Lupus Consortium in Shanghai, China. It began Phase I
lupus studies last April.

---------------

http://www.medarex.com/cgi-local/item.pl/20051013-767650

[...]
MEDI-545, a fully
human monoclonal antibody (MAb) targeting interferon-alpha.
Preclinical data indicate
that levels of interferon-alpha are elevated in many patients with
active systemic lupus
erythematosus (SLE or lupus) and other autoimmune disorders, and may
be associated with
disease activity. MEDI-545 binds to interferon-alpha and has been
shown to neutralize its
activity in preclinical studies. <sniP>

--------

So its a Mab for IFN and not TNF. I can see JX come up with a cocktail
for that one.

----

What else is in the PiPe?

http://www.pipelinereview.com/joomla/content/view/10569/102/

[...]
The phase II trial (040) of CIMZIA(TM) in psoriasis has demonstrated
strong efficacy in this twelve-week study in the treatment of moderate
to severe chronic plaque psoriasis. A retreatment study (044) is
ongoing with results expected in the third quarter of 2007.

[...]
"We have complete confidence in CIMZIA(TM)'s robust efficacy and
competitive safety", commented Roch Doliveux, Chief Executive Officer,
UCB, "CIMZIATM will be, at launch, the first anti-TNF which is a
PEGylated and Fc-free antibody fragment. We are looking forward to
making this new treatment option available to patients who suffer from
rheumatoid arthritis and Crohn's disease, and will continue our
dialogue with the FDA in order to obtain approval for CIMZIATM in the
US as soon as possible".

-----

Another drug for crohn's and psoriasis and blocks tnf. whoPPee <w>

-------------------------

Its Mab city out there.

How many?
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17379759&query_hl=1&itool=pubmed_docsum
Molecular, Biologic, and Pharmacokinetic Properties of Monoclonal
Antibodies: Impact of These Parameters on Early Clinical Development.

* Mascelli MA,
* Zhou H,
* Sweet R,
* Getsy J,
* Davis HM,
* Graham M,
* Abernethy D.

Centocor Research and Development.

Currently, 14 intact, unconjugated, monoclonal antibodies (Mabs) are
approved for therapeutic use in the United States, and more than 100
Mabs are presently undergoing clinical development or regulatory
review. Mabs are large molecular weight glycoproteins that embody
structural, biochemical, and pharmacologic properties distinct from
other biologics or chemically synthesized compounds. Early therapeutic
Mabs were murine proteins, and clinical testing of these agents
revealed serious immune-mediated toxicities. The side effect profile
of murine Mab therapeutic agents restricted the clinical development
of these agents to indications with high morbidity and/or mortality
(ie, oncology, graft vs host rejection). Advances in genetic
engineering and protein expression technologies resulted in the
development of Mabs composed either predominately (ie, mouse/human
chimeric, "humanized") or completely (ie, "fully human" Mabs) of the
human amino acid sequence. The production of chimeric, humanized, and
fully human Mabs significantly reduced the immune-mediated toxicities
and expanded the utility for these agents in numerous therapeutic
areas, particularly in chronic disorders requiring either long-term
administration (ie, rheumatoid arthritis) or treatment upon the flare
up of disease (Crohn's disease, psoriasis). This review provides an
overview of the molecular, biochemical, and pharmacokinetic properties
and clinical development history of Mabs and details how these factors
currently affect the scope and design of early clinical development
strategies for these drug candidates. Emphasis is placed on the
criteria for selecting appropriate subject populations for phase I
testing of Mabs.

PMID: 17379759

Which Mab is right for YOU?

randall... nothing like some good old drugs without side effects

randall

unread,

Mar 28, 2007, 2:41:54 PM3/28/07

Hi,

A fairly significant percentage of us have or will have RA.

http://www.sciencedaily.com/releases/2007/03/070328073217.htm
A Newly Identified Immunosuppressive Protein In Rheumatoid Arthritis

Science Daily - A complex autoimmune disease, rheumatoid arthritis
(RA) is characterized by chronic inflammation and progressive joint
damage. This process begins with hyperplasia, or excessive increase in
size and thickness, of synovial tissue. Along with provoking cartilage
and bone destruction, this abnormal tissue growth is resistant to
apoptosis, the natural cell death vital to the generation of healthy
new cells.

Decoy receptor 3 (DcR3) is a newly identified member of the tumor
necrosis factor receptor (TNFR) superfamily. A soluble protein, it is
overexpressed in tumor cells, including lung and colon cancers,
gastrointestinal tract tumors, and leukemia. It is also expressed in a
variety of normal tissue--the colon, lung, stomach, spleen, lymph
node, pancreas, and spinal cord. Because rheumatoid synovial cells
share traits with tumor cells--both are resistant to apoptosis, both
proliferate aggressively-- DcR3 might play a role in the destructive
course of RA. To investigate this possibility, researchers at Kobe
University School of Medicine in Japan conducted the first study of
DcR3 expression in RA fibroblast-like synoviocytes (FSL)--cells in the
synovial membrane instrumental to the production of cartilage as well
as synovial fluid. Featured in the April 2007 issue of Arthritis &
Rheumatism their findings expose DcR3 as one of the factors culpable
for RA's hallmark hyperplasia and its crippling consequences.

For their novel study of DcR3, the researchers isolated and cultured
FLS from 19 patients with RA, obtained during total knee replacement
surgery. For comparison, FLS was also extracted in a similar manner
from 14 patients with osteoarthritis (OA). For all samples, expression
of DcR3 in FLS was measured by reverse-transcriptase-polymerase chain
reaction and Western blotting. Then, apoptosis was induced by Fas, a
protein ligand and member of the tumor necrosis factor (TNF) family.
Finally, FLS were incubated with the proinflammatory TNFá prior to Fas-
induced apoptosis, and apoptosis was measured.

DcR3 was expressed in both the RA and OA FLS, with no significant
quantitative differences found between the samples. However, TNFá
increased DcR3 expression in and inhibited Fas-induced apoptosis in RA
FLS, but not in OA FLS.

This study affirms DcR3 as an immunosuppressive agent that actually
protects destructive rheumatoid synovial cells against death. "We
suggest that DcR3 expressed in RA FLS is increased by TNFá, making it
one of the pathologic factors that induces hyperplasia of rheumatoid
synovium," states researcher and author, Dr. Yasushi Miura. "Thus,
strategies aimed at down-regulation of DcR3 in FLS warrant further
investigation as a possible therapeutic approach in RA."

Even in this era of TNF-alpha inhibitors and other powerful drugs,
there are constantly new aspects of biology being found that offer
different forms of treatments for rheumatoid arthritis.

Article: "Decoy Receptor 3 Expressed in Rheumatic Synovial Fibroblasts
Protects the Cells Against Fas-Induced Apoptosis," Shinya Hayashi,
Yasushi Miura, Takayuki Nishiyama, Makoto Mitani, Koji Tateishi,
Yoshitada Sakai, Akira Hashiramoto, Masahiro Kurosaka, Shunichi
Shiozawa, and Minoru Doita, Arthritis & Rheumatism, April 2007; (DOI:
10.1002/art.22494).

------------

Tai Chi for immunity.
http://news.biocompare.com/newsstory.asp?id=175779

-----------

Cure MS. Get pregnant.

http://news.biocompare.com/newsstory.asp?id=175780
Could Estriol Be The Elixir For Multiple Sclerosis? UCLA Researcher's
Promising Pilot Study Moves To Widespread Clinical Trial
3/25/2007

It has long been common knowledge that pregnant women with multiple
sclerosis (MS) experience a sharp drop in the disease's symptoms
during the course of their pregnancy.

Some years back, Dr. Rhonda Voskuhl, director of UCLA's Multiple
Sclerosis Program, and her colleagues discovered the cause. They found
that a female sex hormone called estriol, which is produced during
pregnancy, was responsible for the suppression. Four years ago,
Voskuhl followed that discovery with a pilot study in which 10 non-
pregnant women with MS were given estriol, yielding what she described
as "pretty remarkable" results - an 80 percent drop in inflammatory
lesions in the brain, a hallmark of the disease.

This month, Voskuhl begins a much larger trial of estriol, one that
will involve 150 patients at multiple locations over the next two
years. The prospects, she said, are exciting.

Multiple sclerosis is an autoimmune disease of the central nervous
system that attacks the tissue surrounding the brain's nerve fibers.
This tissue, called myelin, can be thought of as the insulation
wrapped around an electrical wire. When the myelin is damaged, the
nerve's ability to send signals to and from the brain is interfered
with, resulting in symptoms common to MS, including problems with
balance, memory, vision loss and more.

Currently, anti-inflammatory drugs used to treat MS lessen the
symptoms and slow the progression of the disease. But they must be
given by injection daily, weekly or monthly - depending on the drug -
and are expensive, costing between $12,000 to $24,000 a year.

Estriol is a hormone produced by the placenta that is virtually
undetectable until pregnancy, when it progressively increases. It is
thought that its role is to suppress a woman's immune system when she
is pregnant, so that the fetus will not be seen by the body as a
foreign "invader."

"The beauty of estriol is that it can be given as a pill, not a shot,
and also that it's not a new drug; it has decades of safety behind
it," said Voskuhl, who holds the Jack H. Skirball Chair for Multiple
Sclerosis in the UCLA Department of Neurology. For years estriol has
been in widespread use in Europe and Asia as hormone replacement
therapy for women with menopausal symptoms. The fact that the pill
already exists, she said, should dramatically reduce the cost of
treatment.

Most important of all, though, is that the drug potentially provides a
one-two punch against MS, both reducing the ability of immune cells to
attack the brain, as well as making the brain more resistant to damage
if any immune cells do make it through.

"It's a two-pronged approach--an anti-inflammatory prong to reduce the
attacks, but also a neuroprotective prong to make the brain suffer
less damage in case of an attack," said Voskuhl.

In all, seven institutions from around the nation will be involved in
the two-year study. The investigators plan to recruit 150 women who
have not previously been treated for MS. They will be given either
estriol along with Copaxone, an MS drug currently in use, or a placebo
along with Copaxone. "That way, no one will receive less than the
standard of care," Voskuhl said. The team will measure relapse rates
over the course of the trial.

Initial funding of $667,000 for the trial is being provided by the
Southern California Chapter of the National Multiple Sclerosis
Society. The total cost of the trial is expected to be $4.7 million.

For more information about the trial, please contact the UCLA MS
program at (310) 825-7313.

-------------------

70% of drugs come from mother nature
http://www.medicalnewstoday.com/medicalnews.php?newsid=65654&nfid=nl

-----------

How to make a virus
http://www.medicalnewstoday.com/medicalnews.php?newsid=65888&nfid=nl

-----------

Cancer and alcohol links
http://www.medicalnewstoday.com/medicalnews.php?newsid=65779&nfid=nl

---------

D-ribose supplementation for heart cells
http://www.medicalnewstoday.com/medicalnews.php?newsid=65866&nfid=nl

---------

http://news.biocompare.com/newsstory.asp?id=175515

Alnylam And Stanford University Scientists Discover New Role For
MicroRNAs (miRNAs) In T Cell Biology And Immunity
3/23/2007

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi
therapeutics company, announced today publication of a study in the
journal Cell by Alnylam and Stanford University scientists on the role
of miRNAs in immunity. In the pre-clinical study, a specific miRNA,
miR-181a, was shown to play an important role in controlling T cell
responsiveness to antigens by regulating the T cell receptor signaling
pathway. Because the T cell response to antigens is one of the primary
components of certain autoimmune disorders, these findings further
validate miRNAs as disease targets and point to new potential
therapeutic applications for antagomirs, a novel class of
oligonucleotide-based inhibitors of specific miRNAs.
"Our research points to a critical role for miRNAs, specifically
miR-181a, in the regulation of T cell biology," said Dr. Mark Davis
from Stanford University School of Medicine, a senior author of the
publication. "We're excited about this new discovery as it represents
the first clear example of a role for miRNAs in the immune response to
antigens."

"In our study, upward or downward modulation of miR-181a was found to
control certain aspects of T cell development and to regulate T cell
responses to antigens via the T cell receptor signaling pathway," said
Dr. Chang-Zheng Chen, also from Stanford University School of Medicine
and a senior author of the publication.

"Alnylam's research on miRNAs derives from our discovery of
antagomirs, a novel class of oligonucleotide inhibitors of miRNAs.
These reagents have become powerful tools to investigate the role of
miRNAs in biology and disease processes. We are fortunate to
collaborate with some of the leading labs across the world, such as
our colleagues at Stanford, in our efforts to explore therapeutic
opportunities for miRNA antagonists," said Dr. Muthiah Manoharan, Vice
President, Drug Discovery at Alnylam. "Moreover, this new paper in
Cell continues Alnylam's commitment to scientific excellence and our
broad leadership in RNAi research and its translation toward
therapeutics."

T cells play a central and coordinating role in cell-mediated and
acquired immunity. Recognition of both "self" and foreign molecules by
T cells occurs through activation of a cell surface receptor called
the T cell receptor. Activation of T cells through the T cell receptor
involves the complex regulation of multiple biological pathways inside
the cell. miRNAs are a broad class of small RNAs that have been shown
to regulate the expression of a large number of genes in the human
genome through the RNAi pathway, and many of these miRNAs are believed
to be involved in disease processes. Certain miRNAs, including
miR-181a, are known to play a role in B and T cell development, but
their function in antigen recognition is poorly understood. Recently,
Alnylam scientists and collaborators have discovered a new class of
oligonucleotide therapeutics, called antagomirs, that inhibit the
function of specific miRNAs in vitro and in vivo (Krutzfeldt et al.
(2005) Nature 438, 685-689; Esau et al. (2006) Cell Metab., 3, 87-98).

In the current study, increasing expression of miR-181a was found to
increase T cell sensitivity to antigens, while inhibiting miR-181a was
found to decrease the immune response. miR-181a was found to regulate
the responsiveness of the T cell receptor to antigens by the
coordinated down-regulation of a set of phosphatase genes. Inhibiting
miR-181a function with a selective antagomir, antagomir-181a, resulted
in efficient reduction in T cell receptor sensitivity to antigens.
Since abnormal T cell activity toward "self" antigens underscores the
pathology in many autoimmune disorders, antagomirs selective for
miR-181a could define a future therapeutic strategy for the treatment
of these diseases.

About RNA Interference (RNAi)

RNA interference, or RNAi, is a naturally occurring mechanism within
cells for selectively silencing and regulating specific genes. The
discovery of RNAi has been widely acknowledged as a major breakthrough
in biology, and the technology was recognized for its potential broad
impact in medicine with the award of the 2006 Nobel Prize for
Physiology or Medicine. Since many diseases are caused by the
inappropriate activity of specific genes, the ability to silence genes
selectively through RNAi could provide a new way to treat a wide range
of human diseases. RNAi is induced by small, double-stranded RNA
molecules. One method to activate RNAi is with chemically synthesized
small interfering RNAs, or siRNAs, which are double-stranded RNAs that
are targeted to a specific disease-associated gene. The siRNA
molecules are used by the natural RNAi machinery in cells to cause
targeted gene silencing.

About microRNA (miRNA)

RNAi can also be induced by microRNAs, or miRNAs, that occur naturally
within all mammalian cells. The miRNA molecules are encoded by the
cell's own genes, giving rise to small RNA molecules that are similar
in structure to siRNAs. There are believed to be over 250 confirmed
miRNA genes in the human genome and there are many other predicted
miRNAs. miRNAs are thought to work through RNAi to regulate the
activity of an estimated one-third of genes in the genome. The
inappropriate absence or presence of specific miRNA molecules in
various cells has been shown to be associated with specific human
diseases, including cancer and viral infections.

About Alnylam

Alnylam is a biopharmaceutical company developing novel therapeutics
based on RNA interference, or RNAi. The company is applying its
therapeutic expertise in RNAi to address significant medical needs,
many of which cannot effectively be addressed with small molecules or
antibodies, the current major classes of drugs. Alnylam is building a
pipeline of RNAi therapeutics; its lead program is in Phase I human
clinical trials for the treatment of respiratory syncytial virus (RSV)
infection. RSV infects nearly every child at least once by the age of
two and accounts for more than 100,000 hospitalizations annually in
the U.S. pediatric population. RSV infection also poses a great risk
to the elderly and other adults with compromised immune systems. The
company's leadership position in fundamental patents, technology, and
know-how relating to RNAi has enabled it to form major alliances with
leading companies including Merck, Medtronic, Novartis, and Biogen
Idec. The company, founded in 2002, maintains global headquarters in
Cambridge, Massachusetts, and has an additional operating unit in
Kulmbach, Germany. For more information, visit www.alnylam.com.

----------

randall

unread,

Mar 30, 2007, 5:36:55 PM3/30/07

Hi,

Moving ahead or uPstream?

IL-12 Moves to the forefront?

http://en.wikipedia.org/wiki/Interleukin_12
Interleukin 12 (IL-12) is an interleukin that is naturally produced by
macrophages and human B-lymphoblastoid cells (NC-37) in response to
antigenic stimulation.
IL-12 is composed of a bundle of four alpha helices. It is a
heterodimeric cytokine encoded by two separate genes, IL-12A (p35) and
IL-12B (p40). The active heterodimer, and a homodimer of p40 are
formed following protein synthesis.
[...]
L-12 is linked with autoimmunity. Administration of IL-12 to people
suffering from autoimmune diseases was shown to worsen the autoimmune
phenomena. This is believed to be due to its key role in induction of
Th1 immune responses. In contrast, IL-12 gene knock-out in mice or a
treatment of mice with IL-12 specific antibodies ameliorated the
disease.

CNTO1275
http://en.wikipedia.org/wiki/CNTO_1275
&
http://groups.google.com/groups/search?qt_s=1&q=cnto-1275+psoriasis

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17388919&query_hl=2&itool=pubmed_docsum
[...]
Conclusions The IL-12B gene polymorphism conferred a risk for PV in
our Chinese population, although the effect was more minor than that
of HLA-Cw*0602. Cw*0602, KIR2DS1/S2 and MICA-A9 were unlikely to be
risk alleles in our patients with PsA. The other analysed genetic
polymorphisms of cytokine genes do not appear to be associated with
susceptibility to PV and PsA in Chinese patients in Taiwan.

PMID: 17388919

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17357509&query_hl=4&itool=pubmed_docsum
The expression of interleukin-23 (p19/p40) and inteleukin-12 (p35/p40)
in psoriasis skin.

* Chen X,
* Tan Z,
* Yue Q,
* Liu H,
* Liu Z,
* Li J.

Department of Dermatology, Union Hospital, Tongji Medical College,
Huazhong University of Science and Technology', Wuhan 430022, China.

In order to investigate the mRNA expression and function of
interleukin-23 (p19/p40) and interleukin-12 (p35/p40) in the psoriatic
lesion, no-lesion and normal human skin, reverse transcriptase-
polymerase chain reaction (RT-PCR) was used to detect the expression
of IL-23 (p19/p40) and IL-12 (p35/p40). The results showed that the
expression of IL-23p19 mRNA and p40 (IL-12/IL-23) mRNA were higher in
psoriatic lesion than those of non-lesional skin and normal skin. The
levels of IL-23p19 mRNA and p40 (IL-12/IL-23) mRNA were higher in
psoriatic non-lesional skin than normal skin. However, no significant
difference was found in the level of IL-12p35 mRNA among the psoriatic
lesional skin, non-lesional skin and normal skin. It was suggested
that IL-23 might be more important in the pathogenesis of psoriasis
than IL-12.

PMID: 17357509

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17236132&query_hl=4&itool=pubmed_docsum
A large-scale genetic association study confirms IL12B and leads to
the identification of IL23R as psoriasis-risk genes.

Celera, Alameda, CA 94502, USA.

We performed a multitiered, case-control association study of
psoriasis in three independent sample sets of white North American
individuals (1,446 cases and 1,432 controls) with 25,215 genecentric
single-nucleotide polymorphisms (SNPs) and found a highly significant
association with an IL12B 3'-untranslated-region SNP (rs3212227),
confirming the results of a small Japanese study. This SNP was
significant in all three sample sets (odds ratio [OR](common) 0.64,
combined P [Pcomb]=7.85x10(-10)). A Monte Carlo simulation to address
multiple testing suggests that this association is not a type I error.
The coding regions of IL12B were resequenced in 96 individuals with
psoriasis, and 30 additional IL12B-region SNPs were genotyped.
Haplotypes were estimated, and genotype-conditioned analyses
identified a second risk allele (rs6887695) located approximately 60
kb upstream of the IL12B coding region that exhibited association with
psoriasis after adjustment for rs3212227. Together, these two SNPs
mark a common IL12B risk haplotype (OR(common) 1.40,
Pcomb=8.11x10(-9)) and a less frequent protective haplotype
(OR(common) 0.58, Pcomb=5.65x10(-12)), which were statistically
significant in all three studies. Since IL12B encodes the common
IL-12p40 subunit of IL-12 and IL-23, we individually genotyped 17 SNPs
in the genes encoding the other chains of these cytokines (IL12A and
IL23A) and their receptors (IL12RB1, IL12RB2, and IL23R). Haplotype
analyses identified two IL23R missense SNPs that together mark a
common psoriasis-associated haplotype in all three studies (OR(common)
1.44, Pcomb=3.13x10(-6)). Individuals homozygous for both the IL12B
and the IL23R predisposing haplotypes have an increased risk of
disease (OR(common) 1.66, Pcomb=1.33x10(-8)). These data, and the
previous observation that administration of an antibody specific for
the IL-12p40 subunit to patients with psoriasis is highly efficacious,
suggest that these genes play a fundamental role in psoriasis
pathogenesis.

PMID: 17236132

-----------

Atf3 and IL-12B

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16688168&query_hl=3&itool=pubmed_docsum
Systems biology approaches identify ATF3 as a negative regulator of
Toll-like receptor 4.

* Gilchrist M,
* Thorsson V,
* Li B,
* Rust AG,
* Korb M,
* Kennedy K,
* Hai T,
* Bolouri H,
* Aderem A.

Institute for Systems Biology, Seattle, Washington 98103, USA.

The innate immune system is absolutely required for host defence, but,
uncontrolled, it leads to inflammatory disease. This control is
mediated, in part, by cytokines that are secreted by macrophages.
Immune regulation is extraordinarily complex, and can be best
investigated with systems approaches (that is, using computational
tools to predict regulatory networks arising from global, high-
throughput data sets). Here we use cluster analysis of a comprehensive
set of transcriptomic data derived from Toll-like receptor (TLR)-
activated macrophages to identify a prominent group of genes that
appear to be regulated by activating transcription factor 3 (ATF3), a
member of the CREB/ATF family of transcription factors. Network
analysis predicted that ATF3 is part of a transcriptional complex that
also contains members of the nuclear factor (NF)-kappaB family of
transcription factors. Promoter analysis of the putative ATF3-
regulated gene cluster demonstrated an over-representation of closely
apposed ATF3 and NF-kappaB binding sites, which was verified by
chromatin immunoprecipitation and hybridization to a DNA microarray.
This cluster included important cytokines such as interleukin (IL)-6
and IL-12b. ATF3 and Rel (a component of NF-kappaB) were shown to bind
to the regulatory regions of these genes upon macrophage activation. A
kinetic model of Il6 and Il12b messenger RNA expression as a function
of ATF3 and NF-kappaB promoter binding predicted that ATF3 is a
negative regulator of Il6 and Il12b transcription, and this hypothesis
was validated using Atf3-null mice. ATF3 seems to inhibit Il6 and
Il12b transcription by altering chromatin structure, thereby
restricting access to transcription factors. Because ATF3 is itself
induced by lipopolysaccharide, it seems to regulate TLR-stimulated
inflammatory responses as part of a negative-feedback loop.

PMID: 16688168

http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=603148

http://www.leaddiscovery.co.uk/admin%20inflam/files/13085.asp
[...]
Because ATF3 is itself induced by lipopolysaccharide (LPS), it seems
to regulate TLR-stimulated inflammatory responses as part of a
negative-feedback loop.

And this brings up a few hits with TTP (tristetraprolin). Nice. Mice
zinc fingers.

http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=190700

iNOS regulation
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17322004&query_hl=2&itool=pubmed_docsum

TNF and TTP
http://www.medscape.com/viewarticle/459101
Tumor necrosis factor (TNF) has been implicated in the development and
pathogenicity of infectious diseases and autoimmune disorders, such as
septic shock and arthritis. The zinc-finger protein tristetraprolin
(TTP) has been identified as a major regulator of TNF biosynthesis. To
define its intracellular location and examine its regulation of TNF, a
quantitive intracellular staining assay specific for TTP was
developed. We establish for the first time that in peripheral blood
leukocytes, expression of endogenous TTP is confined to the cytoplasm.
Baseline expression of TTP was higher in monocytes than in lymphocytes
or neutrophils. After in vitro incubation with lipopolysaccharide
(LPS), leukocyte TTP levels increased rapidly, peaking after
approximately 2 hours. Monocytes showed the greatest response to LPS
stimulation and lymphocytes the least. <sniP>

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17170118&query_hl=2&itool=pubmed_docsum
Tristetraprolin (TTP)-14-3-3 complex formation protects TTP from
dephosphorylation by protein phosphatase 2a and stabilizes tumor
necrosis factor-alpha mRNA.

* Sun L,
* Stoecklin G,
* Van Way S,
* Hinkovska-Galcheva V,
* Guo RF,
* Anderson P,
* Shanley TP.

Division of Critical Care, Department of Pediatrics, University of
Michigan Medical School, Ann Arbor, Michigan 48109, USA.

Tumor necrosis factor (TNF)-alpha is a major cytokine produced by
alveolar macrophages in response to pathogen-associated molecular
patterns such as lipopolysaccharide. TNF-alpha secretion is regulated
at both transcriptional and post-transcriptional levels. Post-
transcriptional regulation occurs by modulation of TNF-alpha mRNA
stability via the binding of tristetraprolin (TTP) to the adenosine/
uridine-rich elements found in the 3'-untranslated region of the TNF-
alpha transcript. Phosphorylation plays important roles in modulating
mRNA stability, because activation of p38 MAPK by lipopolysaccharide
stabilizes TNF-alpha mRNA. We hypothesized that the protein
phosphatase 2A (PP2A) regulates this signaling pathway. Our results
show that inhibition of PP2A by okadaic acid or small interference RNA
significantly enhanced the stability of TNF-alpha mRNA. This result
was associated with increased phosphorylation of p38 MAPK and MAPK-
activated kinase 2 (MK-2). PP2A inhibition increased TTP
phosphorylation and enhanced complex formation with chaperone protein
14-3-3. TTP physically interacted with PP2A in transfected mammalian
cells. A functional consequence of TTP-14-3-3 complex formation
appeared to be protection of TTP from dephosphorylation by inhibition
of the binding of PP2A to phosphorylated TTP. Mutation of the MK-2
phosphorylation sites of TTP did not influence TNF-alpha adenosine/
uridine-rich element binding and did not alter the increased TNF-alpha
3'-untranslated region-dependent luciferase activity induced by PP2A-
small interference RNA silencing. Our data indicate that, although
phosphorylation stabilizes TNF-alpha mRNA, PP2A regulates the mRNA
stability by modulating the phosphorylation state of members of the
p38/MK-2/TTP pathway.

PMID: 17170118

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17172869&query_hl=2&itool=pubmed_docsum
TIS11D is a candidate pro-apoptotic p53 target gene.

* Jackson RS 2nd,
* Cho YJ,
* Liang P.

Vanderbilt-Ingram Comprehensive Cancer Center, Department of Cancer
Biology, Vanderbilt University Medical Center, Nashville, Tennessee
37232-6840, USA.

A number of target genes for the tumor suppressor, p53, have been
identified, however, the mechanisms that contribute to p53-dependent
apoptosis remain to be fully elucidated. In a comprehensive screen for
p53 target genes by differential display, we have identified TIS11D as
a p53-inducible gene. Induction of TIS11D mRNA was confirmed by
Northern Blot in response to p53 expression. Inducible expression of
TIS11D resulted in inhibition of cell proliferation and apoptosis.
These data suggest TIS11D as a candidate p53 target gene that may be
part of the network of genes responsible for p53-dependent apoptosis.

PMID: 17172869

Does aPPear to be uPstream of a few things in the P pathways..

randall....

randall

unread,

Mar 31, 2007, 10:57:43 AM3/31/07

Hi,

You know those dogs and cats that are kicking off the last few weeks
from
bad pet foods?

Are they loaded with rat poison or what?

What if the contaminate was a drug known to clear psoriasis?

What if it wasn't ever in the pet food to begin with?

Is this six degrees of Kevin's Bacon or what time?

http://news.google.com/news?qt_s=1&tab=gn&ie=UTF-8&q=aminopterin

http://sev.prnewswire.com/biotechnology/20070330/SFF03531032007-1.html

[...]
"We became concerned when Aminopterin was implicated as the toxin in
the recent pet food recall. The clinical pattern did not fit the known
toxicology of Aminopterin," said John A. Zebala, M.D., Ph.D. President
and CEO of Syntrix Biosystems. "We immediately reached out and offered
our expertise to other investigators in the field who had reported
finding the compound in food samples."

[...]
During the period Aminopterin was marketed, the agent was used off-
label to safely treat over 4,000 patients with psoriasis in the United
States, producing dramatic clearing of lesions.(3) The National
Institutes of Health (NIH) has recently awarded Syntrix Biosystems
$800,000 to support the clinical testing of Aminopterin in psoriasis.

Dr. Zebala said, "the exciting and unique clinical properties of
Aminopterin promise to make this the first-line agent for treating
psoriasis, as well as a variety of other human autoimmune diseases
including rheumatoid arthritis, systemic lupus erythematosus,
polymyositis, multiple sclerosis, ulcerative colitis and Crohn's
disease to name a few."

[...]
Dr. Zebala emphasized by saying, "Aminopterin is one of the most
promising new therapeutic drugs in investigational clinical
development for both humans and animals. In order for animals affected
by contaminated pet food to be properly and accurately treated, it is
critical that veterinarians know as soon as possible that Aminopterin
is not the causative agent."

-------------

So? What the heck is this stuff?

http://en.wikipedia.org/wiki/Aminopterin
Aminopterin (4-aminopteroic acid), a 4-amino analog of folic acid, is
an antineoplastic drug with immunosuppressive properties used in
chemotherapy. Aminopterin is a synthetic derivative of pterin.
Aminopterin works as an enzyme inhibitor by competing for the folate
binding site of the enzyme dihydrofolate reductase. Its binding
affinity for dihydrofolate reductase effectively blocks
tetrahydrofolate synthesis. This results in the depletion of
nucleotide precursors and inhibition of DNA, RNA, and protein
synthesis. <sniP>

--------

A folic acid analog? Sounds better then rat poison to me. And it
obviously screws with a pathway that leads to increased psoriasis. But
look at those side effects. PaPa don't Preach, I'm keePin my P! lol

randall.... ratz! Clear em don't kill em!

randall

unread,

Apr 2, 2007, 2:15:32 AM4/2/07

Hi,

This medscape article regarding diet and IBD/crohn's is quite good.

NO fooling.

http://www.medscape.com/viewarticle/553039_1

http://www.medscape.com/viewarticle/553039_2
Introduction
Across every specialty, alternative approaches to conventional
diseases are beginning to take hold. This is certainly no different
for patients suffering from ulcerative colitis and Crohn's disease.
These 2 conditions, collectively referred to as the inflammatory bowel
diseases, have an estimated prevalence of 149 per 100,000 whites, with
increasing, but similar rates in blacks, and lower rates in Hispanics
and Asians.[1]
Despite much effort and research, the etiology of this disease process
continues to remain elusive. Many suspect an immune-mediated process,
and standard therapy includes 5-aminosalicylate derivatives,
corticosteroids, and various immune-modulating drugs (eg, 6-
mercaptopurine, azathioprine, etc). Newer, more selective biologic
agents such as monoclonal antibodies are beginning to emerge as
effective from successful clinical trials.
In spite of these therapies, many turn to alternative medicine to seek
relief from their symptoms. This may be secondary to a variety of
reasons, including undesirable/unwanted medication side effects or
lack or efficacy. Surveys have shown that those with a poorer quality
of life turn to alternative medicine in greater numbers.[2] However, a
poorly regulated industry that profits from the shortcomings of modern
medicine awaits those patients who seek alternative therapies. There
are purported miracle cures for almost any disease, often without
evidence to support their purported effectiveness. However, some forms
of alternative therapies have shown efficacy in clinical studies.
Diet is an especially attractive forum to modulate the inflammatory
process. Dietary factors have been shown to modulate the pathogenesis
of a variety of conditions, including celiac disease, colon cancer,
and diverticulosis, and some believe it may play a role in the
pathogenesis of inflammatory bowel disease. The purpose of this
article is to provide a review of some of what is known about proposed
dietary and nutritional factors and the evidence supporting its effect
on inflammatory bowel disease from various research studies.

http://www.medscape.com/viewarticle/553039_3
Microparticles
There is an abundance of factors that lead some to believe that diet
plays an important role in the etiology of inflammatory bowel disease
(IBD). Experts have observed an increased incidence of IBD in urban
areas, and some believe that this may be due in part to the fact that
urban diets have higher concentrations of so-called microparticles
(such as titanium dioxide and aluminosilicates). These substances are
believed to be inert but play no role in nutrition. It is believed
that these microparticles may combine with other substances in the
intestine (such as bacterial components) and form antigenic particles.
[3] Microparticles have also been associated with other disease
processes such as asthma.[4] The thinking is that these antigens may
activate an immune-mediated inflammatory response.[3] It has been
shown that a microparticle-free diet decreased Crohn's disease
activity.[4]
The discovery of specific antigens, or in this case, microparticles,
is a logical progression from the discovery of the gene encoding for
the NOD2 protein as being associated with the pathogenesis of Crohn's
disease. NOD2 is believed to play a role in the recognition of
bacterial particles and subsequent activation of the inflammation
cascade by the activation of NF-kappa B.[5] It is possible that other
related proteins may be involved in the recognition of other antigenic
substrates, and in this case, microparticles.

http://www.medscape.com/viewarticle/553039_4

http://www.medscape.com/viewarticle/553039_6

http://www.medscape.com/viewarticle/553039_7

http://www.medscape.com/viewarticle/553039_8

The amount of fat in enteral diets has been shown to affect remission
rate. It is also believed that the type of fat may play a role. When a
meta-analysis was performed looking at the rate of remission as
compared to the amount of fat in enteral feedings, it was shown that
fat content and remission rate were inversely related. But it was
predominantly long-chain triglycerides that appeared to have this
adverse effect. When medium-chain triglycerides were added, there was
no noted adverse effect on remission rate.
The determination as to whether a triglyceride is classified as a long
or short chain is based on the number of carbons the fatty acids
contains. Greater than 12 carbons in a fatty acid signifies a long-
chain triglyceride, and between 6 and 12 carbon atoms classifies it as
a medium chain. Medium-chain triglycerides are digested and absorbed
more completely than their long-chain counterparts, and are water
soluble. Medium-chain triglycerides are found in coconut oil, whereas
safflower and soybean oil are good sources of long-chain triglycerides.
[17]
Other small studies have shown that low-fat diets and diets with
medium-chain triglycerides are superior to higher fat diets in the
induction and maintenance of remission.[18,19]
Case control studies have shown that ulcerative colitis may be
associated with an increased intake of monosaturated and
polyunsaturated fats. It has been also shown that omega-6 fatty acids
are positively correlated with IBD, whereas omega-3 fatty acids are
negatively correlated.[3,20] Omega-6 fatty acids are the precursor to
synthesis of arachidonic acid, which is degraded into powerful
mediators of inflammation by phospholipase A2.[14] However, omega-3
fatty acids compete with omega-6 fatty acids in the synthesis pathway
of arachidonic acid, thereby decreasing its synthesis, and
subsequently the synthesis of inflammatory mediators.
Sources of omega-3 fatty acids include fish, fish oil, algae, walnuts,
leafy green vegetables, flax, and canola oils. Sources of omega-6
fatty acids include corn, soy, primrose, sunflower and safflower oils,
red meat, and borage.[21,22] Various studies have shown that
administration of omega-3 fatty acids has a positive effect on IBD.
[3,20,22-25]
http://www.medscape.com/viewarticle/553039_9
High levels of dietary fiber have been shown to decrease the relative
risk for Crohn's disease.[25] In a trinitrobenzenesulfonic acid model
of colitis, dietary fiber was shown to decrease the production of TNF-
alpha and nitric oxide (known mediators of inflammation). It was also
noted that there was a higher concentration of short-chain fatty
acids, which Rodriguez-Cabezas and colleagues[28] conclude may play a
role in both decreasing the production of the certain inflammatory
mediators and also contribute to the repair and regeneration of the
damaged colonic cells. Butyrate and other short-chain fatty acids such
as acetate, propionate, and valerate are created when soluble fibers
are fermented in the intestine. Some believe that the production of
the short-chain fatty acids, which are decreased in colitis, is
important to maintain microbial balance and prevent dysbiosis.[6]
Butyrate is believed to exert anti-inflammatory effects by decreasing
the production of cytokines thought to up-regulate inflammation, such
as IL-6 and IL-8.[50] Additionally, colonic cells use these short-
chain fatty acids (such as butyrate) as their main source of oxidative
fuels. Although butyrate administration does result in improvement,
the studies done on butyrate in ulcerative colitis are conflicting as
to the statistical significance of improvement.[10]
A recent randomized controlled trial comparing Plantago ovata seeds (a
form of dietary fiber whose fermentation in the colon results in the
production of butryrate) to oral mesalamine demonstrated equal
effectiveness in the maintenance of remission in patients with
ulcerative colitis.[49] Two open-labeled trials (one at 4 weeks and
the other at 6 months) have demonstrated clinical improvement in
patients with ulcerative colitis via the administration of germinated
barley foodstuff. Germinated barley foodstuff is believed to exert its
influence by increasing butyrate production, and possibly encouraging
the growth of beneficial bacteria, including Bifidobacterium and
Eubacterium limosum (believed to produce butyrate).[50,51]
http://www.medscape.com/viewarticle/553039_10
Glutamine is sometimes advocated as being beneficial in the management
of inflammation. Although not an essential amino acid, glutamine is
believed to play a role in the maintenance of the colonic mucosal
barrier, and is an energy substrate for colonic cells. It is believed
that altered mucosal permeability can foster translocation of colonic
flora and/or toxins, contributing and/or initiating an inflammatory
response.
However, not all of the studies regarding glutamine show positive
benefit in IBD. When administered in a trinitrobenzenesulfonic acid-
induced colitis model, there was actually a worsening of intestinal
inflammation. Other studies in different models, however, have shown
an improvement. As suggested by Akobeng and colleagues,[28] there may
be an optimal level of glutamine necessary for improvement; alteration
from that level may have deleterious effects.
There are possible reasons why excess glutamine may not serve a
beneficial purpose. It is understood that glutamine up-regulates the
immune system. Glutamine is also a precursor to nitric oxide. Nitric
oxide plays a key role in inflammation and injury and hence may not be
beneficial to patients with IBD.[28,29]

http://www.medscape.com/viewarticle/553039_11
In several models of colitis, including an IL-10 deficient model and
an iodoacetamide-induced model, iron supplementation has been shown to
adversely affect inflammation. It is believed that this is due to the
fact that free radicals are produced through the iron-catalyzed Fenton
reaction. This poses a problem in part because the majority of
ingested iron is not absorbed, and consequently the intestines receive
a large amount of iron substrate.[30,31]
A significant proportion of patients develop iron-deficiency anemia
secondary to blood loss, and hence, if the free radicals are
clinically significant, iron supplementation may worsen inflammation.
A study done by Carrier and colleagues[32] demonstrated that the
supplementation of vitamin E to iron regimens reduced the adverse
effect that iron had on colitis disease activity in a dextran sulfate
sodium-induced colitis model.[32]
In addition to vitamin E (alpha tocopherol), catechins have been shown
to have an anti-inflammatory effect in a trinitrobenzene sulfonic acid-
induced model of ulcerative colitis.[33] Alpha tocopherol is an
antioxidant, which may explain its effectiveness in colitis and also
as a protective role when administered with iron, which is known to
generate free radicals.[6]
Catechins are flavonoids. Flavonoids are noted to have a variety of
functions, including anti-inflammatory, anti-allergic, antiviral, and
anticarcinogenic actions. They are also believed to be antioxidants.
Flavonoids are found in diverse food sources such as citrus fruits,
berries, onions, parsley, legumes, green tea, and red wine.[6] Effects
of catechins that may be beneficial in IBD include antioxidant and
anti-endotoxin effects. Because of noted side effects such as
autoimmune hemolysis, febrile reactions, and urticaria, care must be
exercised when using this product and larger studies are warranted
before this is accepted as a valid alternative therapy for IBD.[6]

http://www.medscape.com/viewarticle/553039_12
1, 25-Dihydrocholecalciferol
1, 25-dihydrocholecalciferol, the active form of vitamin D, has been
shown in an IL-10 knock-out model of ulcerative colitis to reduce
symptoms. This compound has been shown to be immunosuppressant, and
has been shown to positively affect the disease process in a variety
of diseases believed to be mediated by autoimmune processes. While a
definite mechanism has not been fully elucidated, it is believed that
1, 25-dihydrocholecalciferol stimulates the production of transforming
growth factor beta-1 and IL-4. These cytokines may suppress T-cell-
mediated inflammatory activity.[34,35]

http://www.medscape.com/viewarticle/553039_13
Potato Alkaloids
Epidemiologic studies have indicated that the prevalence of IBD is
directly correlated to consumption of fried potato products.
Altered intestinal permeability is believed by some to play a key role
in the initiation and propagation of the inflammatory process. It is
thought that bacterial products or even bacteria themselves may
penetrate this altered epithelial barrier, activating the intestinal
immune system. Potatoes have a high concentration of glycoalkaloids,
specifically alpha-solanine and alpha-chaconine. These molecules
"permeabilize cholesterol-containing membranes" and this is believed
to alter the intestinal epithelial barrier. These glycoalkaloids are
concentrated when potatoes are fried.
These molecules are present in potato as a sort of defense mechanism
for the potato plant, playing a key role in defending the plant
against fungi, bacteria, and parasites. However, these molecules have
been shown to adversely affect the permeability of epithelial cells in
the intestine, and this may aggravate IBD. These compounds have been
shown to adversely affect the intestine permeability in an IL-10-
deficient mice model of colitis, but not in normal mice, suggesting
that those patients with IBD may be predisposed to this adverse effect.
[36]

http://www.medscape.com/viewarticle/553039_20
Conclusion
Physicians may benefit from several sources when questioned by
patients and/or colleagues about various complementary/alternative
approaches to IBD. These include The Cochrane Collaboration (evidence
based reviews on a multitude of topics; www.cochrane.org), Natural
Medicines Comprehensive Database (evidence-based reviews of natural
supplements and medicines; www.naturaldatabase.com), and The Crohn's
and Colitis Foundation of America (www.ccfa.org).
It is also important to advise patients to look carefully at various
manufacturers when choosing a particular supplement/intervention (ie,
probiotics). There is a lack of oversight into the manufacturing and
quality assurance of these supplements. Particular factors that may
lead one to pick one manufacturer over another is their funding of
published research relating to their product, length of time in
business, affiliation with consumer agencies, and previous experience/
outcomes.
As more research is being done regarding complementary/alternative
approaches to a multitude of diseases, we can expect a multitude of
articles and recommendations in the mainstream medical literature. As
randomized trials are few and the evidence is not equivocal, we should
be careful with broad recommendations and endorsements of these
approaches. As we can see, there are a multitude of dietary variables
that show promise as natural ways to affect the inflammatory bowel
disease process. Although more evidence is needed before these become
widely accepted as standard therapy, they represent an exciting and
largely unexplored field in potential therapies for IBD.

randall...

randall

unread,

Apr 2, 2007, 2:58:53 PM4/2/07

Hi,

The new-ish P gene for autoimmune conditions, mentioned in several
posts
in this thread on March 22-23 (posts 43-46) shows up again today, one
day
after april fools. And almost two months after ground hogs day. LOL

http://www.medicalnewstoday.com/medicalnews.php?newsid=66707
Gene Behind Autoimmune Diseases Identified By Researchers

A report in the March 22 issue of the New England Journal of Medicine
reveals that a pinpointed region of chromosome 17, a gene named NALP1,
could be a new target of treatment for autoimmune diseases. This is a
particularly exciting discovery because NALP1, a gene known to control
part of the immune system that serves to alert the body to viral and
bacterial attacks, has not previously been specifically implicated in
autoimmune diseases, affirms the American Autoimmune Related Diseases
Association (AARDA), a national nonprofit patient advocacy
organization. The discovery was the result of collaboration between
St. George University of London, the University of Colorado at Denver
and Health Sciences Center (UCDHSC), and the Barbara Davis Center for
Childhood Disorders.

Why does the body choose the misdirected path of attacking itself, in
an autoimmune process, when it sets out to eliminate invaders, such as
bacteria or viruses, thus resulting in autoimmune diseases--for
example, lupus, multiple sclerosis, rheumatoid arthritis, vitiligo,
thyroiditis (Graves', Hashimoto's), juvenile (type 1) diabetes, or any
one of the more than 100 such diseases?

The findings of this latest research study, which followed 656 persons
from 114 extended families in the United States and the United Kingdom
who had multiple autoimmune diseases, give the researchers a clue as
to why the immune system attacks one of the body's own tissues. "If
the sensor NALP1 is overreactive, it could trigger a response to the
wrong stimulus," said Professor Dorothy Bennett, Professor of Cell
Biology at St. George's University of London, investigator for the UK
arm of the study. She added, "We hope to study exactly how this works
and to learn even more from the other genes that we are working to
identify."

Lead investigator Dr. Richard Spritz, director of the Human Medical
Genetics Program at UCDHSC, was quoted as saying, "Since NALP1 appears

to be part of our body's early-warning system for viral or bacterial
attack, this gives us ideas about how to try to discover the

environmental triggers of these diseases." Dr. Spritz said, "This

finding may also open up new approaches to treatment, possibly for
many different autoimmune diseases."

Dr. Peter Gregerson, director of the Robert S. Boas Center for
Genomics and Human Genetics, Feinstein Institute for Medical Research
in Manhasset, NY, calls the study "provocative." He said, "It raises
the issue of whether this gene might be involved in more common
disorders." He also commented that this research is a good example of
"a successful, family-based approach to gene identification and an
example of how new genes identified that way can raise new connections
among different diseases."

It has been estimated that 50 million Americans are affected by
autoimmune diseases which rank among the top ten causes of death in
women. Recognition of the family connection, as alluded to by Dr.
Gregerson, is important because the ability to develop an autoimmune
disease is determined by a dominant genetic trait that is very common
(20 percent of the population) and may present in families as
different autoimmune diseases within the same family. It is important
for families with members who have autoimmune diseases to mention this
fact when another member of the family is experiencing medical
problems that are difficult to diagnose. "Autoimmune diseases are
often difficult to diagnosis; however, a family history of autoimmune
disease is a major clue" said Virginia Ladd, President of the American
Autoimmune Related Diseases Association.

About AARDA

American Autoimmune Related Diseases Association (AARDA) is the
nation's only non-profit organization dedicated to bringing a national
focus to autoimmunity as a category of disease and a major women's
health issue, and promoting a collaborative research effort in order
to find better treatments and a cure for all autoimmune diseases. For
more information, please visit http://www.aarda.org.

American Autoimmune Related Diseases Association (AARDA)
22100 Gratiot Avenue
Eastpointe, MI 48021-2227
United States
http://www.aarda.org

========================================

And a reposting of the abstract,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17377159&query_hl=1&itool=pubmed_docsum

I don't think this one was posted before,

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17349957&query_hl=1&itool=pubmed_docsum
Reconstituted NALP1 inflammasome reveals two-step mechanism of
caspase-1 activation.

* Faustin B,
* Lartigue L,
* Bruey JM,
* Luciano F,
* Sergienko E,
* Bailly-Maitre B,
* Volkmann N,
* Hanein D,
* Rouiller I,
* Reed JC.

Burnham Institute for Medical Research, La Jolla, CA 92037, USA.

Interleukin (IL)-1beta maturation is accomplished by caspase-1-
mediated proteolysis, an essential element of innate immunity. NLRs
constitute a recently recognized family of caspase-1-activating
proteins, which contain a nucleotide-binding oligomerization domain
and leucine-rich repeat (LRR) domains and which assemble into
multiprotein complexes to create caspase-1-activating platforms called
"inflammasomes." Using purified recombinant proteins, we have
reconstituted the NALP1 inflammasome and have characterized the
requirements for inflammasome assembly and caspase-1 activation.
Oligomerization of NALP1 and activation of caspase-1 occur via a two-
step mechanism, requiring microbial product, muramyl-dipeptide, a
component of peptidoglycan, followed by ribonucleoside triphosphates.
Caspase-1 activation by NALP1 does not require but is enhanced by
adaptor protein ASC. The findings provide the biochemical basis for
understanding how inflammasome assembly and function are regulated,
and shed light on NALP1 as a direct sensor of bacterial components in
host defense against pathogens.

PMID: 17349957

Or this one,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17164409&query_hl=1&itool=pubmed_docsum
Inflammasome Components NALP 1 and 3 Show Distinct but Separate
Expression Profiles in Human Tissues, Suggesting a Site-specific Role
in the Inflammatory Response.

* Kummer JA,
* Broekhuizen R,
* Everett H,
* Agostini L,
* Kuijk L,
* Martinon F,
* van Bruggen R,
* Tschopp J.

Department of Pathology (JAK,RB) and Department of Immunology (LK),
University Medical Center Utrecht, Utrecht, The Netherlands; and
Department of Biochemistry, University of Lausanne, BIL Biomedical
Research Center, Epalinges, Switzerland (HE,LA,FM,RVB,JT).

Several autoinflammatory disorders such as Muckle-Wells syndrome are
characterized by mutations in the NALP3/cryopyrin gene. NALP3 and
NALP1 proteins can assemble to inflammasomes that activate caspase-1,
resulting in the processing of the pro-inflammatory cytokines IL-1beta
and IL-18. The present study was designed to determine which cells and
tissues express NALP1 and NALP3. Monoclonal antibodies were developed
and their use revealed distinct distribution profiles of NALP1 and
NALP3. Granulocytes, monocytes (very weakly), dendritic cells, B and T
cells all express NALP1 and NALP3. Highest levels of NALP1 are found
in T cells and Langerhans cells. Furthermore NALP1 is present in
glandular epithelial structures, such as stomach, gut, lung, and,
surprisingly, in neurons and testis. In contrast to NALP1, NALP3 shows
a more restricted tissue distribution with expression mainly in non-
keratinizing epithelia in the oropharynx, esophagus and ectocervix.
Moreover, NALP3 expression is found in the urothelial layer in the
bladder. Likewise a difference in subcellular distribution between
NALP1 and NALP3 is observed, since NALP1 is mainly localized in the
nucleus while NALP3 is predominantly cytoplasmic. We propose that the
presence of NALP3 in epithelial cells lining the oral and genital
tract allows the rapid sensing of invading pathogens, thereby
triggering an innate immune response.

PMID: 17164409

And look at the keyword in this one,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17077693&query_hl=1&itool=pubmed_docsum
The impact of endogenous triggers on trauma-associated inflammation.

* Zedler S,
* Faist E.

Klinikum Grosshadern, Ludwig-Maximilians-University of Munich,
Department of Surgery, Munich, Germany.

PURPOSE OF REVIEW: Inflammation immediately starting after trauma is a
consequence of an efficient host defense system that is not only
capable of sensing exogenous and pathogen-derived danger signals, but
also endogenous, multifunctional alarm signals, which both can
initiate an inflammatory response. RECENT FINDINGS: Even in the
absence of infection, Toll-like receptors play an important role in
inflammation via recognition of host-derived, endogenous 'damage
signals' like heat shock proteins and 'alarmins' such as the nuclear
protein high-mobility group box protein 1, which are presented as a
result of tissue trauma. In addition to the Toll-like receptors, a
number of other receptors are involved in the host inflammatory
response, including the new family of nucleotide oligomerization
domain-like receptors capable of sensing the presence of danger
signals in the cytoplasm. Important links occur between the Toll-like
receptors as key inducers of the pro-forms of interleukin-1beta and
interleukin-18 and the activation of certain nucleotide
oligomerization domain-like receptors, resulting in inflammasome
formation--an essential process leading to the secretion of these
proinflammatory cytokines. SUMMARY: In addition to improved insights
into the regulation of traumatic inflammation and the etiology of the
systemic inflammatory response syndrome, some endogenous immune
triggers seem to have the potential to serve as novel biomarkers in
predicting post-traumatic complications.

PMID: 17077693

========================

WE have endogenous coming out our yin/yang's around this group. And
others for
that matter.

http://groups.google.com/groups/search?qt_s=1&q=endogenous+psoriasis

Over 140 hits for our group alone.

And web hits are over 300,000.
http://www.google.com/search?qt_s=1&q=endogenous%20psoriasis&sa=N&tab=gw

Yet my concern has been LPS and TLR-4.

And keyword LPS takes it down 80%,
http://www.google.com/search?hl=en&q=endogenous+psoriasis+lps&btnG=Search

And Tlr-4 takes it down as much or more,
http://www.google.com/search?hl=en&q=endogenous+psoriasis+lps+tlr-4&btnG=Search

When NALP-1 gets factored against these items. I wonder what we'll
see?

More then I expected,
http://www.google.com/search?hl=en&q=endogenous+psoriasis+lps+tlr-4+nalp1&btnG=Search

And widening this out by backing out P and endogenous,
http://www.google.com/search?hl=en&q=lps+tlr-4+nalp1&btnG=Search

First hit works.
http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=609364

And a search of Nalp1 in OMIM gives us 18 hits. The first one,
http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=606636

To,
http://www.ncbi.nlm.nih.gov/Omim/getmap.cgi?l606636

&
http://www.ncbi.nlm.nih.gov/mapview/maps.cgi?taxid=9606&CHR=17&maps=genes-r,pheno,morbid,genec&R1=on&query=NUP88&VERBOSE=ON&ZOOM=3

PSOR2 is on Chromosome 17 at 17q iirc.

I'll find it,
http://www.ncbi.nlm.nih.gov/mapview/maps.cgi?taxid=9606&chr=17

Nope it's at 17q25
http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=602723

http://www.ncbi.nlm.nih.gov/Omim/getmap.cgi?l602723

http://www.ncbi.nlm.nih.gov/mapview/maps.cgi?taxid=9606&CHR=17&maps=genes-r,pheno,morbid,genec&R1=on&query=PSORS2&VERBOSE=ON&ZOOM=3

http://www.ncbi.nlm.nih.gov/mapview/maps.cgi?TAXID=9606&CHR=17&MAPS=genes-r,pheno,morbid,genec[4166.00%3A4314.50]&QUERY=PSORS2&CMD=TXT#4

And back in a circle to all the psors,
http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=177900

Can't forget caspase1,
http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=147678

P is a HLA and MHC thingy. Thats for sure.

randall... find that P gene. The game is a foot....

randall

unread,

Apr 4, 2007, 3:32:21 AM4/4/07

Hi,

http://news.biocompare.com/newsstory.asp?id=176031

Researchers Identify Key Protein In Immune Response To Malaria And TB
3/27/2007

Source: Wellcome Trust

An international team of researchers has identified a key protein
involved in the immune system's response to malaria, tuberculosis (TB)
and a number of other infectious diseases. The insights suggest
possible new therapies to tackle these major global diseases.

Professor Luke O'Neill from Trinity College Dublin, Ireland,
identified the protein in 2001. The protein, known as Mal, alerts the
immune system to respond against invading bacteria. Now, Professor
Adrian Hill from the Wellcome Trust Centre for Human Genetics,
University of Oxford, UK, has shown that there are two variants of Mal
in humans and that the combination of these variants determines how
the immune system responds.

The results of the study, funded by the Wellcome Trust, Science
Foundation Ireland, Irish Health Research Board and the Agency for
Science, Technology and Research, Singapore, are published in the
April edition of Nature Genetics this week.

"Mal is in effect an alarm system for the immune system," explains
Professor O'Neill. "When the body is infected with the malaria
parasite or other germs, a set of sensors called 'toll-like
receptors' (TLRs) lock onto the intruder. TLRs relay the detection via
Mal, which wakes up the immune system to mobilise and defend us."

However, working with patients in Kenya, the Gambia, Vietnam and the
UK, Professor Hill and his team showed that there are two common
variants of the protein, one which allows the immune system to work
normally, the other resulting in too strong a stimulation. A person
will carry a combination of two copies of the protein, one from the
mother and one from the father.

"If you have the overactive type, you are twice as likely to succumb
to infection because your immune system goes into overdrive, often
leading to severe forms of the disease, in a manner akin to 'friendly
fire'," explains Professor Hill, a Wellcome Trust Principal Research
Fellow. "Similarly, if you have two copies of the less active form,
the body does not fight the infection and you get the disease. The
optimum situation is to have one copy of each variant, giving a
balanced system, sufficient to mount a response, but not overly
activating."

The researchers found that having the overactive Mal doubled the risk
of disease, with a four times greater risk of severe malaria in some
populations. Malaria and TB account for over five million deaths per
year in the developing world, particularly amongst children.

"We hope that a drug that modulates the balance of Mal variants might
prevent disease in those who are at greater risk," says Professor
O'Neill. "Our next step is to work towards developing such drugs."

The research has been welcomed by Dr Mark Walport, Director of the
Wellcome Trust, which funds research into diseases of the developing
world such as malaria and TB, mainly through its major overseas
programmes.

"Malaria and TB present a major challenge to the health of people in
the developing world," says Dr Walport. "Particularly given the recent
rise in the number of cases of drug-resistant strains, it is essential
that we understand how the immune system responds to infection if we
are to develop novel treatments."

The researchers also believe that the findings may provide a valuable
insight into how dysfunctional immune systems can lead to non-
infectious diseases, specifically autoimmune diseases such as type 1
diabetes and rheumatoid arthritis.

===========================

http://news.biocompare.com/newsstory.asp?id=176595

Omega-3 Fatty Acids Affect Risk Of Depression, Inflammation
3/29/2007

Source: Ohio State University
A new study suggests that people whose diets contain dramatically more
of one kind of polyunsaturated fatty acid than another may be at
greater risk for both clinical depression and certain inflammatory
diseases.

The report, published online this week in the journal Psychosomatic
Medicine, suggests that we need to balance out our intake of omega-6
and omega-3 fatty acids. The current typical American diet contains 20
times more omega-6 than omega-3, a ratio that researchers say should
be lowered to 4-to-1, or even 2-to-1.
This is the most recent in a long series of experiments Ohio State
University researchers have conducted on the links between
psychological stress and immunity. The addition of dietary questions
to studies that have previously focused solely on emotional and
biochemical markers may yield important new clues about the immune
system.
"In this study, we're looking at the intersection of behavior, immune
function and diet. In past experiments, we concentrated only on the
first two," explained Jan Kiecolt-Glaser, professor of psychiatry and
psychology at Ohio State and lead author on the paper.
"It now appears that diet is a very important variable in the equation
as to how people respond to depression and stress."
The study, conducted in OSU's Institute for Behavioral Medicine
Research, focused on a group of 43 middle-aged to elderly men and
women, nearly half of which were the caregiver spouses of people with
Alzheimer's or other dementias. By including caregivers who typically
report greater stress and more depression than similar adults who are
not caregiving, the researchers could look at how depression and diet
might interact to affect inflammation.
Blood samples were drawn from each person in the study and tested for
interleukin-6 (IL-6), tumor necrosis factor -alpha (TNF-alpha ) and
the receptor molecule for IL-6. Participants also completed a survey
questionnaire that gauged their level of depression.
The analysis showed that participants who had much more omega-6 --
compared to omega-3 -- fatty acids, and who also were reporting more
symptoms of depression, had much higher levels of IL-6 and TNF-alpha,
two cytokines which enhance inflammation.
"The data suggest that higher depression and a poorer diet in terms of
omega-3 can work together to promote inflammation. Other researchers
have shown that clinically depressed people -- those with more severe
depression -- often have lower omega-3 levels in their blood, and
several studies have shown that supplementing diets with omega-3
improves depression," Kiecolt-Glaser said, although the reason isn't
clear.
"People who are depressed don't eat well, or it might be that there is
something about depression that affects how well people process such
foods."
In recent years, research has shown that an increase in omega-3 fatty
acids in the diet has specific health benefits, especially in patients
with depression, cardiovascular disease and inflammatory and
autoimmune diseases.
Martha Belury, an associate professor of human nutrition,
endocrinology, diabetes & metabolism at Ohio State and co-author of
the study, said the design of the study was important.
"We looked at people who were experiencing real depression, not those
whose depression arose as a part of some experiment, and we could
clearly see a relationship between lower omega-3 fatty acids and
certain markers of depression and inflammation."
Belury said that current recommendations allow up to two servings each
week of cold-water fish - the best source of omega-3 - such as salmon
or trout. This would not apply to pregnant women, she said, where
concerns are greater about the heavy metal contamination such fish
might contain. Omega-3 is also available as nutritional supplements
"This study has shown that even in people who did not take
supplements, maybe just a little bit more omega-3, could help reduce
their markers for both stress and depression," Belury said.
"The important message for consumers is that they don't have to take
mega-doses of omega-3 to have some impact. It might not take a whole
lot to have a significant clinical impact," Belury said.
The researchers are now starting a larger, more comprehensive
randomized and controlled trial of omega-3 in adults between the ages
of 50 and 80 in hopes of testing the questions raised in this pilot
study.

------------

randall..

Brett

unread,

Apr 4, 2007, 11:17:22 AM4/4/07

Here's a page that compares the ratio of Omega 6 to Omega 3 in many
different oils. Even olive oil works out to be 13:1 in favour of Omega 6.
http://efaeducation.nih.gov/sig/esstable.html

Maybe that's why megadoses of fish oil have helped my condition so much,
because it has helped balance the ratio which has kept the inflammatory
response way down.

Brett

"randall" <ranh...@aol.com> wrote in message
news:1175671941.0...@n76g2000hsh.googlegroups.com...

Skeats

unread,

Apr 4, 2007, 2:28:46 PM4/4/07

"randall" <ranh...@aol.com> wrote in message
news:1175671941.0...@n76g2000hsh.googlegroups.com...

Did you notice this on Medscape.
Apologies if you have noted it previously!

.........Comparison of Clinical and Pharmacokinetic Profiles of Etanercept
25 mg
Twice Weekly and 50 mg Once Weekly in Patients with Psoriasis
The ability to administer a single injection of etanercept 50 mg once
weekly could potentially increase patient compliance with the treatment
regimen.
Br J Dermatol 156(1) 2007
http://mp.medscape.com/cgi-bin1/DM/y/eBMJv0ELEpu0Dzo0ITJO0Ee

Skeats

randall

unread,

Apr 5, 2007, 1:15:29 PM4/5/07

On Apr 4, 11:28 am, "Skeats" <anythingg...@anythinggoesagain.co.uk>
wrote:

<sniP>

>
> Did you notice this on Medscape.
> Apologies if you have noted it previously!

Nope. But thanks for putting it in this thread. :)

>
> .........Comparison of Clinical and Pharmacokinetic Profiles of Etanercept
> 25 mg
> Twice Weekly and 50 mg Once Weekly in Patients with Psoriasis
> The ability to administer a single injection of etanercept 50 mg once
> weekly could potentially increase patient compliance with the treatment
> regimen.
> Br J Dermatol 156(1) 2007

http://mp.medscape.com/cgi-bin1/DM/y/eBMJv0ELEpu0Dzo0ITJO0Ee

> Skeats

============

P News today:

http://sev.prnewswire.com/health-care-hospitals/20070404/SFW03104042007-1.html
Video: Psoriasis Foundation Seeks Congressional Co-Sponsors for
Landmark Bill

PORTLAND, Ore., April 4 /PRNewswire-USNewswire/ -- On behalf of
millions of Americans with psoriasis, the National Psoriasis
Foundation is calling on the public to support the first-ever
comprehensive psoriasis legislation introduced in Congress.

To view the Multimedia News Release, go to:

http://www.prnewswire.com/mnr/psoriasis/27667/

The Psoriasis and Psoriatic Arthritis Research, Cure and Care Act
(PPARCCA) of 2007, also known as H.R. 1188, was introduced in the U.S.
House of Representatives in February by Rep. David Wu, D-Ore.-1st,
with bipartisan support. The bill, spearheaded by the Psoriasis
Foundation, calls on the federal government to increase its investment
in psoriasis research and to improve patient access to treatment.

In February, the National Psoriasis Foundation and 100 volunteers
traveled to Washington, D.C., to ask their members of Congress to
support the bill. The accompanying video, produced by the Psoriasis
Foundation, captures the emotional impact of the disease and the
empowering experience of going to Capitol Hill. <sniP>

------------------------

We need more treg's to turn off immunity when it's done doing it's
job.

A definite area of interest for us.

http://www.signaling-gateway.org/update/updates/200704/nri2058.html
Regulatory T cells: WASP helps TReg cells sting their prey

Wiskott-Aldrich syndrome protein (WASP) plays a controversial but
important role in the development and function of regulatory T cells.

Wiskott-Aldrich syndrome (WAS) is a primary immunodeficiency resulting
from defective expression of the WAS protein (WASP). Up to 70% of
patients with WAS also develop some form of autoimmune disease. Given
the role of naturally occurring CD4+CD25+ regulatory T (TReg) cells in
preventing autoimmunity, three new studies have examined the role of
WASP in the development and function of TReg cells. The three groups
agree that WASP has an important role in TReg cells, but they propose
slightly different explanations for its effects.

Both Humblet-Baron et al. and Marangoni et al. showed that WASP is not
required for the normal thymic development of TReg cells, whereas
Maillard et al. found decreased numbers of TReg cells in the thymus of
Wasp-/- mice, as well as in the spleen and lymph nodes. Marangoni et
al. next showed that Wasp-/- TReg cells had a decreased capacity to
suppress the proliferation of both wild-type and Wasp-/- effector T
cells in vitro. Maillard et al. obtained similar in vitro results and
further showed that, in contrast to wild-type TReg cells, Wasp-/- TReg
cells could not prevent the induction of colitis by the adoptive
transfer of wild-type effector T cells in vivo.

Therefore, Marangoni et al. and Maillard et al. both conclude that
WASP deficiency abrogates the suppressive activity of TReg cells, and
Maillard et al. also propose that the decreased production of TReg
cells has a role. The defect in the suppressive activity observed for
Wasp-/- TReg cells was shown to result partly from a defect in the
production of transforming growth factor-beta (Marangoni et al.) or
interleukin-10 (IL-10) (Maillard et al.).

However, Humblet-Baron et al. showed that wild-type and Wasp-/- TReg
cells mediated equivalent suppression of Wasp-/- effector T cells in
vitro, but that the number of Wasp-/- TReg cells in peripheral
lymphoid compartments was decreased. On the basis of three independent
in vivo mouse models, they propose that WASP deficiency decreases the
competitive fitness of TReg cells, rather than their function. For
example, when chimeric bone marrow containing a mixture of wild-type
and Wasp-/- cells was transplanted into lethally irradiated Wasp-/-
mice, there was a preferential expansion of wild-type compared with
Wasp-/- TReg-cell populations. The failure of adoptively transferred
Wasp-/- TReg cells to engraft in wild-type hosts (Marangoni et al.)
and their defective homing to peripheral lymphoid organs (Maillard et
al.) also lend support to the idea that Wasp-/- TReg cells have
decreased fitness.

Finally, all three groups considered the potential contribution of
changes in effector T cells to the decreased activity of TReg cells in
Wasp-/- mice. Wasp-/- effector T cells were not as effectively
suppressed as wild-type effector T cells by wild-type TReg cells
(Marangoni et al.), and both Marangoni et al. and Maillard et al.
showed that the addition of exogenous IL-2 could partially rescue the
suppression defect of Wasp-/- TReg cells. Humblet-Baron et al. agree
that the decreased competitive fitness of Wasp-/- TReg cells could be
exacerbated by decreased production of IL-2 by effector T cells in
Wasp-/- mice, although this does not explain the decreased fitness of
Wasp-/- TReg cells in Wasp+/- female mice.

-----------------

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17363300&query_hl=4&itool=pubmed_DocSum

PMID: 17363300

-----------------

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17368474&query_hl=4&itool=pubmed_docsum
A CFSE based assay for measuring CD4(+)CD25(+) regulatory T cell
mediated suppression of auto-antigen specific and polyclonal T cell
responses.

* Venken K,
* Thewissen M,
* Hellings N,
* Somers V,
* Hensen K,
* Rummens JL,
* Stinissen P.

Hasselt University, Biomedisch Onderzoeksinstituut and Transnationale
Universiteit Limburg, School of Life Sciences, Diepenbeek, Belgium.

CD4(+)CD25(+) regulatory T cells (Tregs) are considered to play a key
role as suppressors of immune mediated reactions. The analysis of Treg
function in patients with autoimmune, allergic or oncogenic diseases
has emerged over the past years. In the present study we describe a
CFSE based protocol to measure Treg mediated suppression of CD4(+) T
cells. Measuring Treg suppressive capacity towards proliferation of
anti-CD3 Ab stimulated CD4(+)CD25(-) T cells in coculture experiments
by means of a CFSE based and a classical [(3)H]thymidine incorporation
assay gave similar results, provided that CD4(+)CD25(+) T cells were
anergic. However, when CD4(+)CD25(+) T cells proliferated upon
mitogenic stimulation, data obtained by the CFSE assay allowed the
detection of a significant Treg suppression whereas this was clearly
underestimated using the [(3)H]thymidine assay. In addition, an
indirect CFSE based method was developed to analyze antigen specific
responses of total CD4(+) T cells and Treg depleted CD4(+) T cells
(i.e. CD4(+)CD25(-) T cells). Our results indicate that, in healthy
individuals, CD4(+) T cell responses against the multiple sclerosis
(MS) auto-antigens, myelin basic protein (MBP) and myelin
oligodendrocyte glycoprotein (MOG), were increased in Treg depleted
CD4(+) T cells as compared to total CD4(+) T cells. Our initial data
suggest that Tregs in MS patients show an impaired suppression of
myelin reactive T cells when compared to healthy controls. Moreover,
this experimental setup permits the measurement of cytokine production
of the antigen proliferated CFSE(low) T cells by additional flow
cytometric analyses. In conclusion, the described CFSE based Treg
suppression assay is a valuable tool to study suppressor T cells in
(auto)immune disorders.

PMID: 17368474

-----------

randall..... to treg or flake, that is the question...

JXStern

unread,

Apr 5, 2007, 1:50:31 PM4/5/07

On 5 Apr 2007 10:15:29 -0700, "randall" <ranh...@aol.com> wrote:

>PORTLAND, Ore., April 4 /PRNewswire-USNewswire/ -- On behalf of
>millions of Americans with psoriasis, the National Psoriasis
>Foundation is calling on the public to support the first-ever
>comprehensive psoriasis legislation introduced in Congress.

If they outlaw psoriasis, only outlaws will have psoriasis.

randall

unread,

Apr 5, 2007, 8:07:30 PM4/5/07

On Apr 5, 10:50 am, JXStern <JXSternChange...@gte.net> wrote:

> On 5 Apr 2007 10:15:29 -0700, "randall" <ranhu...@aol.com> wrote:
>
> >PORTLAND, Ore., April 4 /PRNewswire-USNewswire/ -- On behalf of
> >millions of Americans with psoriasis, the National Psoriasis
> >Foundation is calling on the public to support the first-ever
> >comprehensive psoriasis legislation introduced in Congress.
>
> If they outlaw psoriasis, only outlaws will have psoriasis.
>
> J.

If Sheriff Treg comes to the rescue, there won't be any P outlaws.

Or at least we'd like to think. LOL

Lets see if we can find him or any of his dePuties....

NOw don't go shooting them. LOL

We be burnin:
http://en.wikipedia.org/wiki/I_Shot_the_Sheriff

Is he here somewhere?

http://www.nimr.mrc.ac.uk/molimm/stockinger/th17/

blow up of Th17 diagram:
http://www.nimr.mrc.ac.uk/molimm/stockinger/th17/image/

http://www.nimr.mrc.ac.uk/molimm/stockinger/
http://www.nimr.mrc.ac.uk/molimm/stockinger/tcell_reg/
http://www.nimr.mrc.ac.uk/molimm/stockinger/memory/

Their abstract:

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=16473830
TGFbeta in the context of an inflammatory cytokine milieu supports de
novo differentiation of IL-17-producing T cells.

Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B.

Division of Molecular Immunology, MRC National Institute for Medical
Research, Mill Hill, London NW7 1AA, United Kingdom.

We describe de novo generation of IL-17-producing T cells from naive
CD4 T cells, induced in cocultures of naive CD4 T cells and naturally
occurring CD4+ CD25+ T cells (Treg) in the presence of TLR3, TLR4, or
TLR9 stimuli. Treg can be substituted by TGFbeta1, which, together
with the proinflammatory cytokine IL-6, supports the differentiation
of IL-17-producing T cells, a process that is amplified by IL-1beta
and TNFalpha. We could not detect a role for IL-23 in the
differentiation of IL-17-producing T cells but confirmed its
importance for their survival and expansion. Transcription factors
GATA-3 and T-bet, as well as its target Hlx, are absent in IL-17-
producing T cells, and they do not express the negative regulator for
TGFbeta signaling, Smad7. Our data indicate that, in the presence of
IL-6, TGFbeta1 subverts Th1 and Th2 differentiation for the generation
of IL-17-producing T cells.

Publication Types:

* Research Support, N.I.H., Extramural
* Research Support, Non-U.S. Gov't

PMID: 16473830

I'm treg'ed out.

(((((((((((((((((((((((((((())))))))))))))))))))))))

Wheat kicks arse on some of US. Want to know of a virus that may kicks
its behind?

www.newscientist.com/

Billions at risk from wheat super-blight

"This thing has immense potential for social and human destruction."
Startling words - but spoken by the father of the Green Revolution,
Nobel laureate Norman Borlaug, they are not easily dismissed.

An infection is coming, and almost no one has heard about it. This
infection isn't going to give you flu, or TB. In fact, it isn't
interested in you at all. It is after the wheat plants that feed more
people than any other single food source on the planet. And because of
cutbacks in international research, we aren't prepared. The famines
that were banished by the advent of disease-resistant crops in the
Green Revolution of the 1960s could return, Borlaug told New
Scientist.

The disease is Ug99, a virulent strain of black stem rust fungus
(Puccinia graminis), discovered in Uganda in 1999. Since the Green
Revolution, farmers everywhere have grown wheat varieties that resist
stem rust, but Ug99 has evolved to take advantage of those varieties,
and almost no wheat crops anywhere are resistant to it.

The strain has spread slowly across east Africa, but in January this
year spores blew across to Yemen, and north into Sudan (see Map).
Scientists who have tracked similar airborne spores in this part of
the world say it will now blow into Egypt, Turkey and the Middle East,
and on to India, lands where a billion people depend on wheat.

There is hope: this week scientists are assessing the first Ug99-
resistant varieties of wheat that might be used for crops. However, it
will take another five to eight years to breed up enough seed to plant
all our wheat fields.

The threat couldn't have come at a worse time. Consumption has
outstripped production in six of the last seven years, and stocks are
at their lowest since 1972. Wheat prices jumped 14 per cent last year.

Black stem rust itself is nothing new. It has been a major blight on
wheat production since the rise of agriculture, and the Romans even
prayed to a stem rust god, Robigus. It can reduce a field of ripening
grain to a dead, tangled mass, and vast outbreaks regularly used to
rip through wheat regions. The last to hit the North American
breadbasket, in 1954, wiped out 40 per cent of the crop. In the cold
war both the US and the Soviet Union stockpiled stem rust spores as a
biological weapon.

After the 1954 epidemic, Borlaug began work in Mexico on developing
wheat that resisted stem rust. The project grew into the International
Maize and Wheat Improvement Center, known by its Spanish acronym
CIMMYT. The rust-resistant, high-yielding wheat it developed banished
chronic hunger in much of the world, ended stem rust outbreaks, and
won Borlaug the Nobel peace prize in 1970.

Yet once again Borlaug - now 93 and fighting cancer - is leading the
charge against his old enemy. When Ug99 turned up in Kenya in 2002, he
sounded the alarm. "Too many years had gone by and no one was taking
Ug99 seriously," he says. He blames complacency, and the dismantling
of training and wheat testing programmes, after 40 years without
outbreaks.

Now a Global Rust Initiative (GRI) is under way at CIMMYT. It's head,
Rick Ward, blames the delay on cuts, starting in the 1980s, in
CIMMYT's funding for routine monitoring and maintenance of crops and
pests.

"CIMMYT was slow to detect the extent of susceptibility to Ug99
[because] it didn't have the scientific eyes and ears on the ground
any more," says Chris Dowswell of CIMMYT. "Once it did, it had to
start a laborious fund-raising campaign to respond."

Ward is now being promised adequate support as fears grow in rich
wheat-growing countries, but meanwhile Ug99 has got worse. It was
first noticed because it started appearing on wheat previously
protected by a gene complex called Sr31, the backbone of stem rust
resistance in most wheat farmed worldwide. Then last year it acquired
the ability to defeat another widely used complex, Sr24. "Of the 50
genes we know for resistance to stem rust, only 10 work even partially
against Ug99," says Ward. Those are present in less than 1 per cent of
the crop.

The first line of defence is fungicide, but the poor farmers who stand
to lose most from the blight generally cannot afford it, or don't have
the equipment or know-how to apply it. CIMMYT is considering "fire
brigade" spray teams armed with cheap, generic fungicides in poor
areas. However, they will be competing with the rich for fungicide,
and depending on where Ug99 strikes, stocks could be limited.

Even rich countries face problems. The US has been fighting soybean
rust with fungicide ever since spores blew in on hurricane Ivan in
2004. If Ug99 arrives as well, the US could be in trouble because it
doesn't make enough fungicide for both crops. Kitty Cardwell of the US
Department of Agriculture says there might be enough if the US fights
Ug99 the same way as it is tackling soya rust: spotting outbreaks with
a fast DNA-based field test and posting the results on an interactive
website (www.sbrusa.net), so farmers spray only when danger looms.
Ultimately, says Ward, the only real answer "is to get new, resistant
varieties out there".

CIMMYT has been working on this by taking countries' top-yielding
varieties and crossing them with wheat from its seed collections that
does resist Ug99. For two years now the crosses have been tested for
resistance at field stations in Njoro, Kenya, and in Ethiopia, where
it is safe to release Ug99 as it is already there. Resistant strains
are sent back to CIMMYT in Mexico and assessed for yield and other
qualities, then sent out again for further tests. Resistant lines are
now being grown on 27 plots in Nepal, India, Afghanistan and Pakistan.

So far so good, but the real challenge is multiplying up enough
resistant seed so that if Ug99 hits, there will be enough to plant the
next crop. This takes time - and it will only happen if the new
resistant varieties match or exceed existing yields. Nor is it an
exact science. No one knows why wheat that looks good in Mexico might
grow as well in Egypt, say, but fail in China unless it is crossed
with a local variety.

There is nothing for it but to do the tests, says Ravi Singh, the
GRI's chief wheat pathologist. The resistant lines must be just as
good as the ones people are growing now, he says, or farmers won't use
them, and government-owned seed companies that dominate the wheat
industry in developing countries won't sell them, no matter what new
disease the scientists say is coming.

Singh calculates that if he can get countries to devote 3 to 5 per
cent of their wheat-growing area to resistant varieties, the seed
harvest will be enough to plant the whole country with resistant wheat
if Ug99 hits.

So it's a race, and who wins depends on what Ug99 does now. Stem rust
can arrive in a new area and lurk for years before it gets the right
conditions for an outbreak. "It won't suddenly explode everywhere. It
will be like a moving storm," says Dowswell.

However, Ug99 has another ace up its sleeve. The spores blowing in the
wind now are from the asexual stage that grows on wheat. If any blow
onto the leaves of its other host, the barberry bush (Berberis
vulgaris), they will change into the sexual form and swap genes with
whatever other stem rusts they find. Barberry is native to west Asia.
"As if it wasn't challenging enough breeding varieties that resist
this thing," laments Ward. "All I know is that what blows into Iran
will not be the same as what blows out."

What's more, Ug99 will find agriculture has changed to its liking in
the decades stem rust has been away. "Forty years ago most wheat
wasn't irrigated and heavily fertilised," says Borlaug. Now, thanks to
the Green Revolution he helped bring about, it is. That means modern
wheat fields are a damper, denser thicket of stems, where dew can
linger till noon - just right for fungus.

Another worry is that travel has exploded in the past 40 years. There
have now been several documented cases of travellers carrying rust
spores on their clothing. Some fear Ug99 will hitchhike as much as it
flies - and its spread need not be innocent. New Scientist has learned
that the US Department of Homeland Security met in March to discuss
the possibility that someone could transport Ug99 deliberately.

Even at 93, Borlaug is looking to the long term. Eventually,
scientists will have to create wheat with a wide spectrum of
resistances. The genes may be hiding in other grains and grasses. "Why
has rice had no rusts for millions of years?" he asks.

For now, Borlaug says, we have to rely on fungicides, wheat breeding
and luck. "We're moving as fast as we can now, but we started three
years too late," he says. "We'd better have some good luck.
Governments think this is still small and local, but these things
build up."

================

Does your guy lighten uP after LOVE?

Newscientist.com

Clubbers who take the "love drug" ecstasy really might be "loved up".
Studies in rats suggest the drug causes a brain surge of oxytocin -
the hormone that helps bond couples, as well as mothers to their
babies.

Earlier research found increased oxytocin in the blood of people who
had taken ecstasy. However, many drugs increase blood oxytocin without
raising it in the brain - something thought necessary for any "pro-
social" effects.

Iain McGregor at the University of Sydney in Australia, and his
colleagues studied the effects of ecstasy in rats, which, like people,
become more sociable on the drug. "It's very characteristic behaviour.
They lie next to each other and chill out," McGregor says.

The team gave the rats the equivalent of two to three ecstasy tablets
in an adult human and found that the drug activated oxytocin-
containing neurons in an area of their brains called the hypothalamus.
When they gave the rats a drug that blocked brain receptors for
oxytocin, the increased sociability almost disappeared.

Why it didn't disappear entirely isn't clear. It could be that the
dose of the receptor blocker was too low, or that other brain
chemicals, such as dopamine, are also involved in triggering the
sociable behaviour, McGregor says.
"Sensual, not sexual"

The finding ties in with reports from people on ecstasy about how they
feel, McGregor points out. Rodent studies have shown a massive surge
of oxytocin after orgasm in males. "It's interesting that guys on
ecstasy feel more sensual than sexual," McGregor says. "It could be
that raising oxytocin levels puts them in that sort of post-orgasmic
state where they're actually not very good at performing sexually but
they feel really good about the person they're with."

McGregor's team now plan to investigate the levels of oxytocin in
rats' brains after they've taken MDMA, and to see which parts of the
brain in particular are affected.

They suspect that the oxytocin release might be implicated not only in
the pro-social effects of ecstasy but also in the reinforcing effects.
There is much research to be done on how drugs of abuse affect
oxytocin in the brain, says McGregor. "What we know at the moment
could be written on the back of a postage stamp."

----------------

Wasn't Susan or someone all over the hormone thing a week or two ago?

Prolactin wasn't it?

Then the oxytocin/prolactin connection to P is worth hooking uP isn't
it? Or iirc,
didn't we do it? And in this thread no less?

Let's try again then?

http://www.creationofman.net/chapter3/chapter3_5.html

Then let's review, (hey there it is)
http://groups.google.com/group/alt.support.skin-diseases.psoriasis/msg/8ee06bd9af2c3f9c?&q=prolactin+psoriasis
(you need to go over half way down this link to get to the prolactin
parts)

A full review of prolactin in the group,
http://groups.google.com/groups/search?qt_s=1&q=prolactin+psoriasis

------------

Where is this going? LOL

randall... hormones!

JXStern

unread,

Apr 5, 2007, 9:12:09 PM4/5/07

On 5 Apr 2007 17:07:30 -0700, "randall" <ranh...@aol.com> wrote:

>On Apr 5, 10:50 am, JXStern <JXSternChange...@gte.net> wrote:
>> On 5 Apr 2007 10:15:29 -0700, "randall" <ranhu...@aol.com> wrote:
>>
>> >PORTLAND, Ore., April 4 /PRNewswire-USNewswire/ -- On behalf of
>> >millions of Americans with psoriasis, the National Psoriasis
>> >Foundation is calling on the public to support the first-ever
>> >comprehensive psoriasis legislation introduced in Congress.
>>
>> If they outlaw psoriasis, only outlaws will have psoriasis.
>>
>> J.
>
>If Sheriff Treg comes to the rescue, there won't be any P outlaws.

OK, I messed up the line, it should be:

If psoriasis is outlawed, only outlaws will have psoriasis.

There.

But I didn't shoot no deputy.

randall

unread,

Apr 6, 2007, 3:30:13 PM4/6/07

On Apr 5, 6:12 pm, JXStern <JXSternChange...@gte.net> wrote:

> On 5 Apr 2007 17:07:30 -0700, "randall" <ranhu...@aol.com> wrote:
>
> >On Apr 5, 10:50 am, JXStern <JXSternChange...@gte.net> wrote:
> >> On 5 Apr 2007 10:15:29 -0700, "randall" <ranhu...@aol.com> wrote:
>
> >> >PORTLAND, Ore., April 4 /PRNewswire-USNewswire/ -- On behalf of
> >> >millions of Americans with psoriasis, the National Psoriasis
> >> >Foundation is calling on the public to support the first-ever
> >> >comprehensive psoriasis legislation introduced in Congress.
>
> >> If they outlaw psoriasis, only outlaws will have psoriasis.
>
> >> J.
>
> >If Sheriff Treg comes to the rescue, there won't be any P outlaws.
>
> OK, I messed up the line, it should be:

OK great. Now I realize my mind reading gene is also imPaired.

>
> If psoriasis is outlawed, only outlaws will have psoriasis.
>
> There.
>
> But I didn't shoot no deputy.
>
> J.

Shoot! No one gets shot. Nature or nurture, it all goes back to a
gene thing, for
us anyway.

OK, but you did do the IGF-1 gene and dog post.

http://www.sciam.com/article.cfm?articleId=C2DB4FF2-E7F2-99DF-3971247AD8E5B1A8&chanId=sa013&modsrc=most_popular

And IGF-1 has been around this group,
http://groups.google.com/groups/search?q=igf1+psoriasis&qt_s=Search

At least that's been in the news.

And we know why exercise is so darn imPortant,
http://www.telegraph.co.uk/health/main.jhtml?view=DETAILS&grid=&xml=/health/2007/04/04/hbrain104.xml

[...]
When IGF-1 reaches the brain, it acts on the cells that release
neurotransmitters, the chemicals responsible for communication. It
triggers an increase in production of brain-derived neurotrophic
factor or BDNF, which promotes the growth of new nerve cells and which
Harvard psychiatrist, John Ratey, has nicknamed "Miracle-Gro for the
brain".
advertisement

As new brain cells are created, they form pathways and links, as we
learn new facts and skills. The greater level of BDNF you have, the
more new nerve cells you can produce and the greater the number of
building blocks available to you to extend your learning capacity. But
if levels fall, it can work in reverse. Those born with a faulty
variant of the gene responsible for the production of BDNF have
trouble with recall and creating new memories.

Using an MRI scanner, the Columbia researchers led by Professor Scott
Small examined a living brain before and after exercise and, for the
first time, were able to see neurogenesis effectively in action.

Those most likely to benefit from the finding are victims of
degenerative brain disorders such as Alzheimer's, and the next step
will be to use this information to create an exercise regime
specifically tailored to preventing age-related memory loss.

Professor Bruce Lynn, from University College London, welcomes the new
findings. He recalls similar findings being presented in the 1960s -
and then ignored by the scientific community. Even five years ago, he
says, there were only half a dozen papers on the topic; yet now it has
become a very active area for research, as it has become abundantly
clear that those who remain physically active stay cognitively fit,
too.

"The big question however," says Prof Lynn, "is what is the link? It
is not obvious why exercise has this effect on the brain. Growth
factors are important but blood flow to the brain is not relevant.
Some people suggest increased oxygen is crucial but our blood is
always saturated with oxygen unless we're in the Himalayas - or,
ironically, exercising.

"What type of exercise you choose seems to matter: aerobics works, but
you don't get the same results from strength training. However, when
you are strength training - using weights - you see big increases in
the production of IGF-1."

At the University of Birmingham, Professor Asker Jeukendrup, a
specialist in exercise metabolism, confirms there is a lot of evidence
that physical activity helps brain development. He thinks there is
some truth to the theory that suggests improving blood supply and
therefore fuel to the brain is important.

"You don't need to do much to get an effect," he says. "Studies have
already shown that just 20 minutes walking - not even particularly
briskly - will reduce degeneration of the brain and improve learning
ability. Yet many people are still below that threshold. And, of
course, other studies show that the more you do, the better it gets."
<sniP>

-----------------

Maybe if they worked this chimp like crazy his brain would become
human?
http://www.newscientist.com/blog/shortsharpscience/2007/03/great-ape-on-trial.html?DCMP=NLC-nletter&nsref=sblog_greatape

But even with more IFG-1 his genes are only going to be 96% of ours.

So, while he may become a genius ape, he'd still be a moron of a
human?

I'm only giving a flying fig to find a thread that unties the P
genes....after all? Right?

This lawsuit clears up the rights to a new drug that may help to
understand the IGF-1
pathways, anyway.
http://www.bioworld.com/servlet/com.accumedia.web.Dispatcher?next=bioWorldHeadlines_article&forceid=42889

And I can hardly wait to find out what directions Susan's treatments
take after her last
doctor visit.

Hormones look like an xlnt area for a JX cocktail... I'd be all for
LOW dose FAE's
with a host of herbs and things that mimic hormones..

Lets find an article on hormones and IGF-1,

Here's a good one.
http://www.rocklintoday.com/news/templates/diabetes_information.asp?articleid=4939&zoneid=53

To improve body composition and achieve optimal health, balancing your
hormones are critical to short- and long-term success.

There are seven main hormones involved. Insulin, the biggest culprit,
was discussed last month.

IGF-1 is the only dependable indicator of bioavailable
growth hormone in the human body. In a healthy person, IGF-1 levels
are 100 times insulin levels. When there is ample supply of IGF-1,
manufactured and released by the liver, there is less need for
insulin.

In healthy individuals, insulin levels are very low between meals, in
unhealthy people, insulin will be high because IGF-1 is low. Exercise
has a powerful effect on increasing growth hormone, and therefore
IGF-1 levels.

Cortisol is secreted with perceived stress. In
prehistoric times, cortisol increased blood sugar to physically help
the stressed individual fight or flee; insulin was not needed for the
blood sugar rise because a physical response was necessary.

Today, however, most stress is mental; cortisol increases
blood sugar, which raises insulin, thereby increasing fat storage.
With middle age and obesity, DHEA drops, leading to lower IGF-1
levels, more insulin and more fat.

Androgens (androstenedione, DHEA testosterone, and
possibly progesterone) are the anti-fat hormones. They oppose
cortisol and insulin. When androgens are optimal, as in adolescence,
the tendency to get fat is less likely.

Androgens, reaching their peaks in early adulthood for
both males and females, decline slightly each year after 25. Obesity
is caused by increased body insulin and cortisol with a fall in
androgens.

Estrogen can contribute to obesity in some females when
hormonal levels are higher than normal, which can raise insulin and
lower androgens. One example is the estrogen-induced weight gain from
birth control pills. When estrogen levels are high, however, IGF-1
release is inhibited.

Thyroid optimal function is critical to metabolism. Make
sure that your thyroid is operating efficiently, or losing fat will be
an uphill battle.

Epinephrine is necessary to activate cortisol and thyroid
receptors to maintain normal metabolism. Epinephrine deficiency may
result from hypochlorhydria (insufficient stomach HCl), leading to
poor disassembly of proteins, and a deficiency of available amino
acids such as phenylalanine or tyrosine, necessary for production of
epinephrine.

The second cause of epinephrine deficiency is shortages of
vitamins and co-factors, necessary for its biosynthesis.

----------------------

OK, i know i'm quoting a NMD.... like i'm over those rants ok?

randall... time to exercise more then the brain? Walk for 20 minutes!

randall

unread,

Apr 18, 2007, 1:48:50 PM4/18/07

Hi,

OK, i'm starting to work on the Stirling Strauss theory for P.
See: Acrylamide calcium protease/ Psoriasis (threads)

http://www.lbl.gov/Publications/Currents/Archive/Mar-21-2003.html

(a little more then half way down the page to:)

[...]

How a single gene makes different forms
of a protein as they are needed

By Paul Preuss

John Conboy of Berkeley Lab's Life Sciences Division and his
colleagues recently found the mechanism that switches on and off a
part of the gene for protein 4.1R.

Protein 4.1R is essential to the strength and flexibility of red blood
cells, because it binds together other proteins in cell membranes. The
switch that controls its binding ability shows how critical
alternative gene splicing can be for cell development.

Developmental strategy

The precursors of red blood cells begin as stem cells in the bone
marrow and pass through several distinct stages on their way to
maturity.

Early on they are packed with ribosomes, molecular machines that
manufacture proteins including oxygen-carrying hemoglobin, which will
eventually take up almost all the space inside the cell. Shortly
before leaving the bone marrow they eject their nuclei, and soon
afterward their ribosome networks dissolve. What's left are the
supple, disk-shaped red cells that constitute half the volume of the
blood.

What makes the membranes of mature red cells tough and flexible are
"skeletal" proteins like actin and spectrin. Protein 4.1R is the clasp
that links them together.

But actin-spectrin linkages would interfere with cell development, so
early differentiating cells produce an altered form of 4.1R that can't
bind spectrin and actin.

A switch in time

To form the messenger RNA (mRNA) that specifies the order of amino
acids in a finished protein, noncoding introns have to be discarded
from the gene's DNA sequence and its coding exons spliced together.

While many genes are hard-wired to express a single mRNA product, many
others can generate multiple mRNAs. These alternative splicings occur
when one or more exons are spliced in or clipped out of the messenger
RNA.

"When a tissue is differentiating, many changes in gene activity are
occurring," Conboy says. "Many researchers have focused on which genes
are being turned on and off, but alternative splicing in individual
genes may be just as important."

Conboy has studied the gene for protein 4.1R since his days as a
postdoctoral fellow at the University of California at San Francisco.
With some 240,000 base pairs, the 4.1R gene is much larger than the
average human gene, and several of its two dozen exons are subject to
alternative splicing.

Recently Conboy and his colleagues zeroed in on the exon labeled 16.
Exon 16 is suppressed while the red cell is developing but must be
switched on in the mature cell. "The result of a failure to make this
switch is an unstable red cell membrane."

The importance of CE16

Much of exon 16 consists of a sequence well conserved by evolution.
Approximately 40 nucleotides long and designated CE16, it has a
special function: it is a splicing silencer that, when activated,
prevents exon 16 from being recognized by the spliceosome - what
Conboy calls the "big protein machine" inside the cell nucleus that
edits and assembles messenger RNA.

When CE16 is turned on, the mRNA does not include information from
exon 16. Instead it specifies a form of the protein that cannot bind
spectrin and actin.

When CE16 is turned off, exon 16 is recognized and spliced into mRNA.
The resulting protein has a functioning binding domain, essential in
mature red blood cells.

Minigenes and mutations pinpoint a protein

Instead of working with the entire large 4.1R gene, Conboy and his
colleagues constructed an artificial "minigene" with only three exons,
including exon 16. They manipulated its nucleotide sequences and
observed the results in cells grown in vitro.

In some mutations, the researchers replaced the entire CE16 silencer
region with a neutral sequence. With the original sequence missing,
exon 16 was expressed efficiently, confirming that CE16 is needed to
prevent the splicing of the exon into mRNA.

Other mutations of just four or five nucleotides identified what turns
the silencer on and off: a spliceosome protein, hnRNP A1, which binds
directly to the CE16 silencer and prevents splicing of exon 16 into
the mRNA.

Levels of hnRNP A1 are high during the early stages of red blood cell
differentiation, but as the cells mature, levels decrease
dramatically. The effect is to inactivate the CE16 silencer and allow
exon 16 splicing.

In turn this allows synthesis of 4.1R proteins with functional
spectrin-actin binding domains - just when they are needed to produce
cells with tough, flexible membranes.

The results make it clear that a single gene's exons play multiple
roles in biology.

"The most obvious role for DNA sequences in the past was that they
specify the amino-acid sequences in the proteins they encode," Conboy
says. "Now we know that nucleotide sequences also play an important
role in regulating the decision to splice the exons in which they
reside."

Conboy's colleagues on this work were Victor Hou, now at Children's
Hospital Oakland; Mark Koury of the Department of Medicine, Vanderbilt
University; Adrian Krainer of Cold Spring Harbor; Akila Mayeda of the
University of Miami School of Medicine; Michael Wu of UC Berkeley;
Chris Turck of UC San Francisco; and Robert Lersch, Sherry Gee, Julie
Ponthier, and Annie J. Lo of the splicing research team at Berkeley
Lab.

More information about alternative splicing of the 4.1R gene is
available at http://www.lbl.gov/Science-Articles/Archive/LSD-single-gene.html.

--------------

Do a pubmed: [ protein 4.1r glutamate ]

WhooPs forgot to do it. LOL

--------------

I'll have to finish this line of inquiry later.

((((((((((((((((((((((((((())))))))))))))))))))))))))))))))))))))))))

P NEWS from the last week:::

http://news.biocompare.com/newsstory.asp?id=178324

Microbes Start Immune Response By Sneaking Inside Cells
4/16/2007

Immune cells that are the body's front-line defense don't necessarily
rest quietly until invading bacteria lock onto receptors on their
outside skins and rouse them to action, as previously thought. In a
new paper, University of Michigan scientists describe their findings
that bacteria can barge inside these guard cells and independently
initiate a powerful immune response.

The study, published online ahead of print in the April issue of the
journal Immunity and accompanied by a special commentary, adds
important new details to an emerging picture of how the body
recognizes invading bacteria and responds. The work of the U-M team
and researchers elsewhere - now taking place in laboratory animal
studies - offers a different way of thinking about how best to design
future human vaccines, as well as drugs that could more precisely
target the body's inflammatory response in rheumatoid arthritis and
some other autoimmune diseases.

"In our study, the presence of bacterial microbes inside the cell is
what triggers the immune response. That creates a new perspective for
developing new drugs," says senior author Gabriel Nunez, M.D., the
Paul H. de Kruif professor of pathology at the U-M Medical School and
a member of the U-M Comprehensive Cancer Center.

For years, scientists have believed that when bacteria invade the
body, they set off alarms in the immune system by interacting with
receptors on a cell's surface. But, now new studies are revealing that
bacteria can also plunge inside immune system cells and trigger the
immune response there. In the new study, Nunez' team sheds light on
one major pathway in which this process occurs.

When invading bacteria enter immune system cells, a protein called
cryopyrin, present in the fluid inside the cells, responds and
activates a key pathogen-fighting molecule, Nunez' team reported last
year in Nature. Cryopyrin is implicated in the development of several
inflammatory syndromes characterized by recurrent fever, skin rash and
arthritis.

Cryopyrin triggers a key enzyme involved in the body's inflammatory
response, capsase-1, which in turn causes production of IL-1beta, a
powerful molecule which signals the immune system to attack pathogens
and induces fever to help the body fend off infection. IL-1beta plays
an important role, too, in excessive immune system activity in
inflammatory diseases.

The researchers report in the new paper how cryopyrin is activated to
start the process. In experiments that exposed mouse immune cells
called macrophages to bacteria, Thirumala-Devi Kanneganti, Ph.D., a U-
M research investigator in pathology, and Mohamed Lamkanfi, Ph. D, a U-
M research fellow, the study's co-first authors, find that cryopyrin's
call to action inside the cells occurs without requiring a well-known
set of cell-surface receptors called Toll-like receptors or TLRs. "We
prove that these TLRs are not required to activate cryopyrin. That is
a major step," says Nunez.

Instead, bacteria were able to enter the cells through a pore in the
cell membrane, and stimulate the cryopyrin-initiated immune response
without activating TLRs. The researchers discovered that a protein
called pannexin-1 creates the pore, like a devious undersea diver
drilling a hole in a ship hull.

The team's work joins a growing body of research revealing the
importance of recently discovered receptors such as cryopyrin inside
cells, known collectively as NOD-like receptors. Knowledge about NOD-
like receptors is moving forward rapidly and will contribute to a
fuller understanding of the human immune system, say the U-M
researchers.

-----------------

This looks like good info: Are fats fate for P skin? Getting the
pathway straight.
http://www.medicalnewstoday.com/medicalnews.php?newsid=67089&nfid=nl

[...]
"Previously we didn't know what molecule in the capillaries
facilitated the capture of chylomicrons and facilitated the
interaction with lipoprotein lipase," said Dr. Stephen Young, study
author and investigator at the David Geffen School of Medicine at
UCLA. "We think that we've found the missing piece of the puzzle."

Investigators discovered that a protein called
glycosylphosphatidylinositol-anchored high-density lipoprotein-binding
protein 1 (GPIHBP1) may be the missing link.

Scientists found that mice deficient in GPIHBP1 develop very high
triglyceride levels, even on a normal diet, demonstrating that fats in
the bloodstream are not readily metabolized in the absence of GPIHBP1.

Laboratory tests confirmed that GPIHBP1-deficient mice had much higher
levels of chylomicrons in the bloodstream than normal mice. The
GPIHBP1-deficient mice had grossly milky plasma, reflecting very large
amounts of triglycerides in the blood.

"These findings indicate a defect in the breakdown of chylomicrons in
mice that don't have GPIHBP1," Beigneux said.

Investigators predicted that if GPIHBP1 were involved in the
processing of chylomicrons in the bloodstream, then the protein would
be made by endothelial cells of capillaries, where the breakdown of
triglycerides takes place. Indeed, microscopy showed that GPIHBP1 is
expressed highly and exclusively on the endothelial cells of
capillaries of heart, adipose tissue and skeletal muscle.

Interestingly, scientists found that this protein was absent from the
brain, which mainly uses glucose for energy.

"These differences suggest that endothelial cells may play an active
role in regulating the delivery of lipid nutrients to different
tissues," Beigneux said.

Experiments with cultured cells revealed that GPIHBP1 binds both
chylomicrons and lipoprotein lipase, suggesting GPIHBP1 is a key
platform for the processing of chylomicrons.

The next step, according to investigators, will be to determine if
GPIHBP1 provides the only binding site for chylomicrons and
lipoprotein lipase within capillaries. In addition, investigators
would like to define the molecular basis for how GPIHBP1 binds to
chylomicron particles.

---------------------

Syndrome-X rhyme?

Sugar, sugar on my cell, tell me if it's cancer or autoimmune time!
http://www.medicalnewstoday.com/medicalnews.php?newsid=67406&nfid=nl

New Role For Sugars: Research Shows Connections Between Sugar
Modifications In Cells And Cancer

In a ground-breaking study published in the top journal, Cell, Dr.
James Dennis, senior investigator at the Samuel Lunenfeld Research
Institute at Mount Sinai Hospital, has discovered a new role for
sugars on proteins.

Every cell in the human body is controlled by signaling networks that
are responsive to external stimuli. The stimuli are received by
protein receptors on the cell surface. These proteins act as
interpreters for cells, receiving messages from the outside and then
instructing the cells to divide or to move.

Most of the important proteins that decorate the outside of human
cells have complex sugars attached to them. Researchers at the Samuel
Lunenfeld Research Institute have known that changes in these sugars
are often associated with diseases such as cancer, diabetes and
autoimmune diseases such as Multiple Sclerosis.

"Our research shows that the sugar composition of these receptor
proteins controlled the amount of time the protein was available to
interact with the external messages, in effect, changing the
likelihood that a receptor could be activated," states Dr. Dennis.
"This explains how cells can adapt in their nutrient environment.
However, when this normal adaptation becomes imbalanced, cancer cells
can grow and promote metastasis."

Dr. Dennis' team continues to research the effects of changing the
sugars associated with the key proteins that act as receptors for
hormones and growth factors. These are the same types of proteins that
are targeted by a new generation of anti-cancer drugs such as
Herceptin (trastuzumab).

"These findings may lead to a new class of drug treatments as well as
strategies to improve the effectiveness of existing anti-receptor
drugs," states Dr. Jim Woodgett, Director of Research, Samuel
Lunenfeld Research Institute.

-------------------

http://www.medicalnewstoday.com/medicalnews.php?newsid=67781&nfid=nl

How Do The Rules Of Immunity Change During Chronic Infections?

After a viral infection, a small percentage of the T cells generated
to kill virus-infected cells remain on guard to establish long-term
immunity. These so-called memory T cells, which derive from a family
of immune cells known as CD8 T cells, engage in a self-renewal process
that is essential to their persistence. This ongoing process ensures
effective protection against any repeat infection by the same virus,
even decades later.

But not all infections are equal. While most viral infections are
cleared from the body within a few days or weeks, some infections,
such as HIV or hepatitis C infections, become chronic. Some studies
have suggested that the virus-specific CD8 T cells generated during a
chronic infection may not develop the same characteristics as the CD8
T cells that persist after an acute infection.

Now, scientists at The Wistar Institute have found that the CD8 T
cells generated to fight a chronic infection operate under an entirely
different maintenance scheme than do the CD8 T cells that become
memory T cells following an acute infection, becoming wholly dependent
upon the presence of virus for their continuation. Details of the
study will appear in the April 16 issue of The Journal of Experimental
Medicine, published online April 9.

In addition, the CD8 T cells maintained during chronic infections
establish a distinct pattern of cell division that creates a rapid
turnover of cells, a characteristic that could be manipulated to
design new therapeutic options for chronic infections, says E. John
Wherry, Ph.D., senior author on the study and an assistant professor
in the Immunology Program at Wistar.

"It appears the immune system responds to viral infections with two
very different cell types," Wherry says. "In one case, when virus is
completely cleared, you have a memory T cell capable of self-renewal.
But during chronic infection, you have a totally different type of T
cell that is not governed by the same pathways and mechanisms."

Understanding how the body's immune response operates during chronic
infections, and why it fails to clear these infections, could help
scientists design more effective therapies to fight chronic infections
and certain types of tumors, says Wherry.

In previous studies, Wherry had shown that chronically stimulated CD8
T cells were unable to undergo the slow, steady self-renewal process
used by the CD8 T cells that persist as memory T cells after an acute
infection. In addition, his studies showed that CD8 T cells associated
with chronic infections responded poorly to IL-7 and IL-15, growth
factors needed to maintain memory T cells after an acute infection. He
theorized that prolonged exposure to the virus might prevent the
development of normal memory T cells.

To test his theory, Wherry and his group infected mice with a virus
that simulates a chronic infection. The scientists then treated the
mice to clear the virus from their systems. When the virus was
cleared, the CD8 T cells that had partial function also disappeared.
By not going through the normal process of self-renewal, the
disappearing T cells left the mice with no long-term immunity.

"The findings suggest that we're caught in an immunological catch-22
with chronic infections," Wherry says. "The persistence of the virus
is inactivating the T cells, yet the T cells are now dependent on the
persisting virus for their maintenance."

The study also showed that over a four-week period, the CD8 T cells
generated to fight the virus had divided five to six times, yet the
number of these T cells remained relatively stable. Wherry says this
observation suggests that either a very small subset of the cells are
recruited to divide or that the virus-driven division of this T cell
population is accompanied by extensive cell death.

Though these questions remain to be answered, the findings have
implications for developing treatments for patients with chronic
infections, Wherry says. "The results suggest that the rate of
proliferation or cell death could perhaps be modulated to alter the
size or quality of virus-specific CD8 T cell populations during
persisting infections."

The lead author on the study is Haina Shin at The Wistar Institute.
Shawn D. Blackburn, also at Wistar, is a co-author, as is Joseph N.
Blattman of the Fred Hutchinson Cancer Research Center in Seattle. The
research was supported by grants from the National Institutes of
Health, the Commonwealth Universal Research Enhancement Program of the
Pennsylvania Department of Health, and The Wistar Institute.

The Wistar Institute is an international leader in biomedical
research, with special expertise in cancer research and vaccine
development. Founded in 1892 as the first independent nonprofit
biomedical research institute in the country, Wistar has long held the
prestigious Cancer Center designation from the National Cancer
Institute. Discoveries at Wistar have led to the creation of the
rubella vaccine that eradicated the disease in the U.S., rabies
vaccines used worldwide, and a new rotavirus vaccine approved in 2006.
Wistar scientists have also identified many cancer genes and developed
monoclonal antibodies and other important research tools. Today,
Wistar is home to eminent melanoma researchers and pioneering
scientists working on experimental vaccines against flu, HIV, and
other diseases. The Institute works actively to transfer its
inventions to the commercial sector to ensure that research advances
move from the laboratory to the clinic as quickly as possible. The
Wistar Institute: Today's Discoveries Tomorrow's Cures. On the web at
http://www.wistar.org.

--------------

http://www.medicalnewstoday.com/medicalnews.php?newsid=67508&nfid=nl

Scripps Research Study Shows Humans And Plants Share Common Regulatory
Pathway - Could Shine New Light On Human Immune Response To Infection

The study was published in an advance online edition of the
Proceedings of the National Academy of Sciences during the week of
April 9, 2007.

The study provides new evidence that Nod1, a member of the Nod-like
Receptor (NLR) protein family, is activated by the protein SGT1, which
also activates Resistance (R) proteins in plants; R proteins protect
plants from various pathogens. The study also confirms structural
similarities between the Nod1 protein, which plays a pivotal role in
the innate immune system's recognition and response to bacterial
infection and members of the R protein family.

"There has been a great deal of speculation that R proteins and Nod1
are related, but our study provides the first direct link between
plants and humans," said Richard Ulevitch, the Scripps Research
scientist whose laboratory conducted the study. "Plants have Nod-like
receptors and similar immune responses to bacteria and other pathogens-
the R proteins evolved to counteract these pathogenic effects. Our
study provides a new perspective on the Nod1 pathway in mammalian
cells as well as the value of drawing on plant studies of R protein
pathways to better understand the pathogen recognition functions of
these proteins."

The Nod proteins recognize invasive bacteria, specifically distinct
substructures found in Gram-negative and Gram-positive organisms. Once
activated, Nod1 produces a number of responses that include activation
of intracellular signaling pathways, cytokine production and apoptosis
or programmed cell death. Despite the fact that various models of Nod1
activation have been described, little has been known about other
proteins that might affect the protein's activation. In contrast, a
number of additional proteins have been linked to the activation
pathways of the R protein in plants.

"The NLR family has clear links to human disease," Ulevitch said. "Out
of the more than 20 proteins in the NLR family, several mutations are
linked to diseases that involve chronic inflammation or autoimmune
consequences. Up to now, there has been a limited understanding of the
regulatory pathways of Nod1. By identifying SGT1 as a positive
regulatory protein, our study offers new insights into the entire
family."

SGT1 is a protein found in yeasts, plants, and mammals in both the
nucleus and the cytosol. It functions in several biological processes
through interaction with different multi-protein complexes. A large
body of evidence also suggests that the protein plays a role in
regulating pathogen resistance in plants. Various genetic studies have
identified SGT1 as a crucial component for pathogen resistance in
plants through regulation of expression and activities of some R
proteins

Although there is a significant genetic crossover between plants and
mammals, very little is known about this common human-plant regulatory
pathway. Ulevitch speculated that certain protein regulatory
structures might exist in both plants and humans simply because they
do the same thing in much the same way.

"In reality," he said, "there are only so many ways to accomplish
related biological responses."

The study also showed that a heat shock protein, HSP90, helped
stabilize Nod1.

"Inhibiting HSP90 resulted in a significant reduction of Nod1 protein
levels," Ulevitch said. "That clearly suggests that this protein plays
a key role in stabilizing Nod1 and protecting it from degradation. In
contrast, turning off SGT1 did not alter levels of Nod1."

In an earlier study, Ulevitch's laboratory reported that Nod1 also
interacted with the COP9 complex, a multiprotein complex that is known
to play a role in a number of development pathways in plants and that
has a mammalian counterpart. This interaction, Ulevitch noted,
provides a second link between Nod1 and plant R protein pathways.

"The association of Nod1 with SGT1 and the COP9 complex suggests that
one possible role of SGT1 could be to target resistance-regulating
proteins for degradation," he added. "In this hypothesis, the target
protein would be a negative regulator of immune responses."

Future studies, Ulevitch said, will focus on the extensive literature
that exists describing the R protein dependent immunity in plants to
better understand human NLR pathways, especially those dependent on
Nod1.

--------------

Is p simply a gene thing? With fat in the fire who knows?

http://www.medicalnewstoday.com/medicalnews.php?newsid=67543&nfid=nl

Study Finds Dietary Fat Interacts With Genes

Research published in the Journal of Molecular Medicine examines how
calories from fat, carbohydrate, and protein might interact with genes
to affect body mass index (BMI), or body weight-for-height, and risk
of obesity among adults in the Framingham Heart Study. Jose Ordovas,
PhD, director of the Nutrition and Genomics Laboratory at the Jean
Mayer US Department of Agriculture Human Nutrition Research Center on
Aging (USDA HNRCA) at Tufts University, and colleagues analyzed
several common gene variants known as single nucleotide polymorphisms
(SNPs) of the apolipoprotein A5 gene (APOA5), which produces a protein
(APOA5) involved in the metabolism of fats in the body. For 13 percent
of people in the study with a specific SNP (-1131T>C), dietary fat
intake was not significantly associated with BMI and risk of obesity.

We observed an interaction between APOA5 and dietary fat intake, but
we did not see an interaction between APOA5 and carbohydrate or
protein intake for any genetic variants of APOA5," says Ordovas, who
is corresponding author of the study.

"For most people in this study, eating more fat was related to a
higher BMI. However, for people with a specific SNP (-1131T>C), fat
intake was not significantly related to BMI. This contradicts results
for most of the study population, where high dietary fat intake was
related to obesity," explains Ordovas, who is also a professor at the
Friedman School of Nutrition Science and Policy at Tufts. "These
results were true despite a person's age, sex, physical activity
status, or the amount of total calories consumed."

Ordovas notes that a high fat intake may potentially have health
ramifications other than increased weight. However, in terms of
weight, "It seems there might be a lucky few - in this study, 13
percent - who can eat any combination of food and maintain a healthy
BMI. Whether they eat cheesecake or four pieces of whole wheat bread
will not make a difference in their body weight if the foods have the
same amount of calories.

"We have all known people that do not watch what they eat, but usually
don't see any effect on their weight," says Ordovas. "This is the
first study that enables us to identify this segment of the population
using information on this gene.

"This does not mean that it is impossible for people with the specific
SNP (-1131T>C) to become obese," Ordovas continues. "While exact
components of the diet may not be as critical to maintaining a healthy
weight, excessive calories over time can still contribute to obesity.
Also, since the specific SNP does not interact with carbohydrate or
protein, and does not affect BMI when interacting with fat, it may be
more problematic for people in this group to lose weight through
dietary changes if they do, in fact, become obese. Our findings
demonstrate that although genetics help to determine our risk of
obesity, dietary and lifestyle habits are also important to consider."

Ordovas determined that the interaction between the specific SNP
(-1131T>C) and dietary fat was strongest for monounsaturated fatty
acids (MUFAs), found in foods such as olive oil and canola oil. People
with the specific SNP who consumed 11 percent or more of total
calories as MUFAs had a lower likelihood of obesity. "Basically, it
appeared that the interaction of the specific SNP with MUFAs was the
reason that fat intake did not affect BMI for this group," says
Ordovas. "This interaction between APOA5 and dietary MUFA intake may
explain why the Mediterranean diet, which is rich in MUFAs, is not
generally associated with an increase in body weight. However, more
studies are needed to confirm this.

"At this point, everyone is encouraged to follow current guidelines
that recommend a well-balanced, healthful diet in order to maintain a
healthy BMI and to reduce risk of certain diseases. But we study
nutrigenomics with the idea that we can pinpoint people who may be at
higher risk for certain conditions like cardiovascular disease,
allowing these individuals to proactively alter the way nutrition
affects their genes," says Ordovas. "Once we are able to do this, we
may develop several sets of guidelines for the public, based upon a
person's genotype."

Ordovas concludes that, "The problems of obesity are complex and there
is variability among people. This study contributes to our knowledge
of how APOA5 works and adds to our understanding of genetics and
dietary interventions."

------------------------

Darn now i've got to go back and do the plastic fantastic for p skin
thingy.

randall.... i'm burning out here. I"ve done six posts in two hours!

randall

unread,

Apr 22, 2007, 7:28:44 PM4/22/07

Hi,

OK, i've been taxing my grey cells for cooked fats. So the odyssey
goes.
Still those cells are sugar fired and our skin is ruled by arachidonic
acids etc.

On march 22-23rd (posts 43, 44 and 46 of this thread) and april 2nd
(post 52 of this thread)
a new gene (NALP1) with relevance for Psoriasis was examined.

Lets hang with it for awhile longer.

NALP-1 and autoimmune questions, vitiligo gene connections,
http://news.biocompare.com/newsstory.asp?id=177935

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17164409&query_hl=1&itool=pubmed_docsum

Inflammasome Components NALP 1 and 3 Show Distinct but Separate

Expression Profiles in Human Tissues Suggesting a Site-specific Role
in the Inflammatory Response.

* Kummer JA,
* Broekhuizen R,
* Everett H,
* Agostini L,
* Kuijk L,
* Martinon F,
* van Bruggen R,
* Tschopp J.

Dept. of Biochemistry, Ch. des Boveresses 155, CH-1066 Epalinges,
Switzerland. jurg.t...@unil.ch.

resulting in the processing of pro-inflammatory cytokines IL-1beta and

IL-18. The present study was designed to determine which cells and
tissues express NALP1 and NALP3. Monoclonal antibodies were developed
and their use revealed distinct distribution profiles of NALP1 and

NALP3. Granulocytes, monocytes (very weakly), dendritic cells, and B

and T cells all express NALP1 and NALP3. Highest levels of NALP1 are

found in T cells and Langerhans cells. Furthermore, NALP1 is present
in glandular epithelial structures such as stomach, gut, lung, and,

surprisingly, in neurons and testis. In contrast to NALP1, NALP3 shows
a more restricted tissue distribution with expression mainly in non-

keratinizing epithelia in the oropharynx, esophagus, and ectocervix.

Moreover, NALP3 expression is found in the urothelial layer in the

bladder. Likewise, a difference in subcellular distribution between
NALP1 and NALP3 is observed because NALP1 is localized mainly in the
nucleus, whereas NALP3 is predominantly cytoplasmic. We propose that

the presence of NALP3 in epithelial cells lining the oral and genital

tracts allows the rapid sensing of invading pathogens, thereby

triggering an innate immune response.

PMID: 17164409

-------------------

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17442855&query_hl=1&itool=pubmed_docsum

Caspase-1 inflammasomes in infection and inflammation.

* Lamkanfi M,
* Kanneganti TD,
* Franchi L,
* Nunez G.

Department of Pathology and Comprehensive Cancer Center, University of
Michigan Medical School, Ann Arbor, Michigan, USA.

Nucleotide-binding and oligomerization domain-like receptors (NLRs)
constitute a family of germline-encoded pattern-recognition receptors,
which allow the host to respond rapidly to a wide variety of
pathogenic microorganisms. Here, we discuss recent advances in the
study of a subset of NLRs, which control the activation of caspase-1
through the assembly of large protein complexes, inflammasomes. The
NALP1b inflammasome recognizes anthrax lethal toxin, and flagellin
from Salmonella and Legionella induces assembly of the Ipaf
inflammasome. Cryopyrin/NALP3 mediates caspase-1 activation in
response to a wide variety of bacterial ligands, imidazoquinolines,
dsRNA, and the endogenous danger signal uric acid. The importance of
these cytosolic receptors in immune regulation is underscored by the
identification of mutations in cryopyrin/NALP3, which are genetically
linked to human autoinflammatory disorders.

PMID: 17442855

---------

And the last article had this cryopyrin thing going for it. So lets go
with it for P.

http://groups.google.com/groups/search?qt_s=1&q=Cryopyrin+psoriasis

http://groups.google.com/groups/search?q=nalp+psoriasis&qt_s=Search

http://groups.google.com/groups/search?q=caspase+psoriasis&qt_s=Search
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17433728&query_hl=1&itool=pubmed_docsum
Pannexin-1-Mediated Recognition of Bacterial Molecules Activates the
Cryopyrin Inflammasome Independent of Toll-like Receptor Signaling.

* Kanneganti TD,
* Lamkanfi M,
* Kim YG,
* Chen G,
* Park JH,
* Franchi L,
* Vandenabeele P,
* Nunez G.

Department of Pathology, Comprehensive Cancer Center, University of

Michigan Medical School, Ann Arbor, Michigan 48109, USA.

Cryopyrin is essential for caspase-1 activation triggered by Toll-like
receptor (TLR) ligands in the presence of adenosine triphosphate
(ATP). However, the events linking bacterial products and ATP to
cryopyrin remain unclear. Here we demonstrate that cryopyrin-mediated
caspase-1 activation proceeds independently of TLR signaling, thus
dissociating caspase-1 activation and IL-1beta secretion. Instead,
caspase-1 activation required pannexin-1, a hemichannel protein that
interacts with the P2X(7) receptor. Direct cytosolic delivery of
multiple bacterial products including lipopolysaccharide, but not
flagellin, induced caspase-1 activation via cryopyrin in the absence
of pannexin-1 activity or ATP stimulation. However, unlike Ipaf-
dependent caspase-1 activation, stimulation of the pannexin-1-
cryopyrin pathway by several intracellular bacteria was independent of
a functional bacterial type III secretion system. These results
provide evidence for cytosolic delivery and sensing of bacterial
molecules as a unifying model for caspase-1 activation and position
pannexin-1 as a mechanistic link between bacterial stimuli and the
cryopyrin inflammasome.

PMID: 17433728

Does this take TLr-4 and LPS out of the equation or add to it?

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16953978&query_hl=1&itool=pubmed_docsum
NALP3: a key player in caspase-1 activation.

* Sutterwala FS,
* Ogura Y,
* Zamboni DS,
* Roy CR,
* Flavell RA.

Section of Immunobiology, Yale University School of Medicine, New
Haven, Connecticut 06520, USA.

The NLR (NACHT-LRR) family of proteins have been implicated in the
regulation of immune responses and cell death pathways. Some NLR
family members can form multiprotein complexes, called inflammasomes,
involved in the activation of pro-inflammatory caspases. Mutations in
the NALP3/CIAS1/cryopyrin gene, a member of the NLR family, are linked
to three auto-inflammatory disorders: Muckle-Wells syndrome, familial
cold auto-inflammatory syndrome and neonatal-onset multisystem
inflammatory disease. NALP3 along with the adaptor molecule ASC
activates caspase-1 in response to a wide variety of stimuli. Here we
review recent findings on the biology of NALP3 suggesting that it has
functions beyond that of pathogen recognition.

PMID: 16953978

Caspase: http://en.wikipedia.org/wiki/Caspase

http://www.google.com/search?hl=en&q=caspase-14+psoriasis&btnG=Search

http://www.google.com/search?hl=en&q=caspase-14+psoriasis+lps&btnG=Search

http://www.google.com/search?hl=en&q=caspase-14+psoriasis+lps+tlr&btnG=Search

http://www.google.com/search?hl=en&q=caspase-14+psoriasis+lps+tlr+il-18&btnG=Search

Pubmed:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Search&db=PubMed&term=caspase+psoriasis&tool=QuerySuggestion

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Search&db=PubMed&term=psoriasis+il%2D18&tool=QuerySuggestion

CGRP and P,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Search&db=PubMed&term=psoriasis+cgrp&tool=QuerySuggestion

-----------

randall...it's a p gene, know what I mean?

randall

unread,

May 2, 2007, 8:13:45 PM5/2/07

Hi,

Time for the Beaver to steP aside?

http://www.earthtimes.org/articles/show/news_press_release,98853.shtml

PORTLAND, Ore., May 2 /PRNewswire/ -- The National Psoriasis
Foundation announced today that CariDee English, winner of Cycle 7 of
America's Next Top Model(R), has signed as spokesperson for the
nonprofit organization.

CariDee, who developed psoriasis at the age of 5, openly discussed her
disease on the television show that aired in late 2006. As a teenager,
psoriasis covered nearly 70 percent of her body. She spent years
gathering information and trying various treatments. Her psoriasis
persisted but so did CariDee. She maintained an optimistic outlook and
the intense belief that modeling is what she was born to do. After
hard-won acceptance of the disease, and visits to three different
dermatologists to find a treatment that works for her, she is living
her dream.

As a youngster, CariDee says she felt "cursed" with psoriasis. She
experienced taunts and embarrassment. Today, her "curse" is her cause.

"Psoriasis awareness is very important to me. I want others with the
disease to know they are not alone. I want to inspire them to live
their dreams," she said.

CariDee will participate in various events over the next year,
including the National Psoriasis Foundation(R) 2007 National
Conference in Las Vegas, Nev., Aug. 17-18.

"This is a very exciting opportunity for us," said Gail Zimmerman,
president and CEO of the Psoriasis Foundation. "Many people with
psoriasis are reluctant to talk about it. As a model whose success is
dependent on outward appearance, it's courageous of CariDee to step up
and speak out about psoriasis."

About psoriasis <sniP>

===========

http://www.laboratorytalk.com/news/ill/ill100.html

Beadchips in German genetic research project

Scientists will genotype 8000 patients and controls using Illumina's
Infinium BeadChips to investigate genetic variations to better
understand underlying causes of 25 complex diseases

Germany's National Genome Research Network (NGFN) has selected
Illumina's Infinium HumanCNV370-Duo, HumanHap300-Duo, and HumanHap550
BeadChips to conduct one of the world's largest genetic research
projects to date. Diseases to be studied using Illumina's tools
include several mental health diseases such as Bipolar disease and
Schizophrenia, in addition to Parkinson's disease, Alzheimer's
disease, alcohol addiction, inflammatory bowel disease, and psoriasis.

'Genome-wide association studies will provide the life science
community with genetic maps for some of the most complex diseases,'
said Professor Stefan Schreiber of the University of Kiel.

'The National Genome Research Network aims to drive this analysis to a
meta-level above single (indication) phenotypes and thus understand
genetic risk as an overarching susceptibility for general processes
like inflammation, degeneration, or cancer'.

Researchers at the NGFN will compare patients' data with the data of
healthy individuals to identify genetic variations and differences
associated with the diseases, ultimately aiding in the development of
better treatment options.

============

http://www.americanchronicle.com/articles/viewArticle.asp?articleID=25293
US Health Freedom On Verge Of Collapse
Bill Haymin
April 25, 2007

By Byron J. Richards, CCN

April 25, 2007

NewsWithViews.com

A new attack against health freedom, drug safety, and dietary
supplements was launched last week by Senator Edward Kennedy (D-MA)
with major support from Michael Enzi (R-WY). It is called the Food and
Drug Administration Revitalization Act (S1082). This legislation was
planned over the past few years working hand-in-glove with the FDA's
dysfunctional management and legal team - meaning this legislation was
written for the profits of Big Pharma and Big Biotech AT THE EXPENSE
OF SAFETY AND HUMAN HEALTH.

S1082 is a Trojan Horse bill that pretends to address safety issues.
Unbelievably, the bill turns the FDA into a drug development company
that will expose Americans to new and dangerous biological drugs that
have little testing to prove safety or effectiveness. And to top it
off, the bill gives broad new regulatory powers to the FDA that can be
used to frivolously attack dietary supplements and forward the FDA
management's anti-American globalization agenda.

<sniP>

-----------

http://www.wellnessresources.com/news/050207.php

Call the Capitol toll-free: 800-828-0498, 800-459-1887, or
800-614-2803
S1082 Update - Tuesday's Activity
Fight Erupts on Senate Floor

Senators Bribed by Big Pharma vs. Senators Not Bought Off

By Byron J. Richards, CCN
May 2, 2007

As the Senate continues to debate the Big Pharma-friendly sweeping
reform of the FDA a new problem for Big Pharma?s prize Senators has
erupted and quickly turned into confrontation on the floor of the
Senate. At stake is at least 10 billion dollars per year in exorbitant
Big Pharma profits. In one corner is Big Pharma-puppet Orrin Hatch (R-
UT), representing the Kennedy/Enzi drug cartel. In the other corner is
a majority of Senators lead by Byron Dorgan (D-ND).

At issue is an amendment that Dorgan has added to S1082, one that is
vehemently opposed by the authors of the bill and by the White House.
Dorgan?s amendment calls for Americans to be able to purchase
prescription drugs from other countries. This would bring to an end
the Big Pharma price-fixing scam that has Americans paying at least
twice as much for the same drugs. Hatch unsuccessfully pleaded with
Dorgan (while attacking him) to withdraw the amendment. Bush is
threatening to veto the entire bill if the Dorgan amendment is part of
the legislation. <sniP>

==================

randall

unread,

May 6, 2007, 7:23:30 PM5/6/07

Hi,

Is the cure for P in outersPace?

http://www.sfgate.com/cgi-bin/article.cgi?file=/chronicle/archive/2007/05/06/ING9GPK9UJ1.DTL

Let's see now. Some protein crystal gizmo grone in ostersPace is gonna
cost what? LOL

---------------

This NAD+ thing has gotten me really excited.

Certainly gives new credence to GOT MILK...

I'm starving for some help from milk, seeing as how arachidonic acid
is in there as well. <g>

If this means longer life and more quality with less P, then what's
not to like?

http://www.google.com/search?hl=en&q=nicotinamide+riboside+nad+milk&btnG=Google+Search

--------

Maybe uwe had stumbled on to this pathway? We'll most likely never
know the truth.

But so what?

Real science works for me and time will tell!!

randall..looking at 100 and P free? keep Praying!

randall

unread,

May 7, 2007, 7:16:07 PM5/7/07

On May 6, 4:23 pm, randall <ranhu...@aol.com> wrote:
> Hi,
>
> Is the cure for P in outersPace?
>

> http://www.sfgate.com/cgi-bin/article.cgi?file=/chronicle/archive/200...

>
> Let's see now. Some protein crystal gizmo grone in ostersPace is gonna
> cost what? LOL
>
> ---------------
>
> This NAD+ thing has gotten me really excited.
>
> Certainly gives new credence to GOT MILK...
>
> I'm starving for some help from milk, seeing as how arachidonic acid
> is in there as well. <g>
>
> If this means longer life and more quality with less P, then what's
> not to like?
>
> http://www.google.com/search?hl=en&q=nicotinamide+riboside+nad+milk
>

> --------
>
> Maybe uwe had stumbled on to this pathway? We'll most likely never
> know the truth.
>
> But so what?
>
> Real science works for me and time will tell!!
>
> randall..looking at 100 and P free? keep Praying!

Hi,

As to your last post a few minutes ago.

Kibitz?

http://paulchesne.com/KibitzNovember06.jpg

__________________

And trying to stay in the same vein with the last few days.

This next excerpt was taken from
http://www.technologyinvestor.com/

Who took it from the New York times.
http://www.nytimes.com/2007/05/06/magazine/06dialogue-t.html?ref=health
(has a video link if you'd rather watch this interview)

------------
(excerpted from NY Times:)

How can I live forever? The New York Times interviewed two medical
scientists (Lenny Guarente and Robert N. Butler) about how the body
ages and the research on trying to extend our healthy life span. Sad
answer from long article: There are no magic bullets, except the
obvious lead a healthy life (no smoking), with decent exercise and
restrict your calorie intake. Excerpt:

NYTimes: Have you identified genes that can extend health and life
span?

GUARENTE: The genes we study counteract aging. First we studied yeast
cells, and it took us eight years to identify a gene called SIR2,
which protects the cells from damage during the aging process. Then we
did a similar experiment in a more complex critter, the roundworm, and
what was remarkable is, we identified the same gene. That told us that
this type of gene is performing an antiaging function broadly in
nature.

Do humans have this gene?

GUARENTE: There's one gene in our genome, SIRT1, that would be a dead
ringer for this one - the technical term is ortholog - but we also
have six other genes that have a related sequence to this. They're
called sirtuins, and they're all going to play a role, but I think the
dead ringer is undoubtedly the most important based on experiments
that have been done.

You assert a fairly radical concept: that these longevity genes have
the power to keep the body supercharged and maintaining its natural
repair activities regardless of age. Does that mean we could live,
what, another 20, 30 years? Fifty?

GUARENTE: We think the sirtuin genes are there to recognize lack of
food or other stressful situations and to spring into action to create
a physiology that will promote longevity. The evolutionary value is
that in times of stress - food scarcity, for example - this gene would
slow down the aging process and keep you alive longer, so that when
times are better, you could reproduce.

But how long would the gene work? Maybe it only operates temporarily?

GUARENTE: We can gauge this by asking what happens in rodents on a
calorie-restricted diet, which mimics food scarcity and activates the
SIR2 gene. Do they live forever? No. They live up to 50 percent
longer. So in a perfect world, one would hope that we could live 50
percent longer than the current expected life span.

In our lifetimes, could this happen?

GUARENTE: I think one can expect perhaps another decade of robust
health.

ROBERT BUTLER: A lot of it comes down to our willingness in this
country to make an investment in the biology of aging. Historically,
we've devoted our energies and money to studying one disease at a
time. At the same time, we have neglected targeting the underlying
risk factor of aging.

Are you saying that aging itself leads to disease?

BUTLER: Why does 50 percent of all cancer occur after 65? Why does 80
percent occur after age 50? As we age, there are changes at the
cellular molecular level that predispose us to disease and disability.
But so far, no government, no foundation, no corporation anywhere in
the world has fully embraced the importance of longevity science. If
we could target aging, that would have an impact on diseases.

What do you mean "target" aging?

GUARENTE: Slow down aging in the same way that calorie restriction
slows down aging. Bob makes an important point about diseases and
aging. I believe that the two are intertwined and experimentally this
has been demonstrated by using modern strains of mice that have been
genetically altered to get specific diseases - for example,
neurodegenerative diseases or cancer, or cardiovascular disease or
diabetes - and to see whether calorie restriction will either postpone
or prevent these diseases. The general finding is that calorie
restriction forestalls many of these diseases. The hypothesis is that
if one could activate the sirtuin genes - not by a calorie-restricted
diet but pharmacologically - then this would have an impact on the
diseases of aging.

How close are we to such a drug being available?

GUARENTE: Ten, maybe 15 years. I think the drugs that aim at sirtuins,
for example, will be tested initially for a particular disease, say,
diabetes. And it will turn out that the drugs have broader benefits
than one initially imagined.

------------

Why did it take this long to find this sexy secret?

To Sir2 with LOVE or Kibitz?

A Dr. Leonard Guarente post from Nov. 17, 2001 to the psoriasis
newsgroup (PNG)

http://groups.google.com/groups/search?qt_s=1&q=guarente+psoriasis

--------

And what about PPAR's? It's not like this haPPened just yesterday.

Evetsm felt that they were a cure for syndrome X as well as psoriasis.

Who can forget how many times they were hashed over in this PNG?

Try 64 posts for evestm alone!
http://groups.google.com/groups/search?qt_s=1&q=ppar+evetsm

And with that post from 2001, that sPace odyssey of fat lipids isn't
over for psoriatics.

randall... not in a heartbeat anyway.... someday

randall

unread,

May 10, 2007, 12:31:08 PM5/10/07

Hi,

A newer more imProved biological in our/your future?

http://www.biopharma-reporter.com/news/ng.asp?n=76427-abbott-biologic-drugs-psoriasis-autoimmune-disorders
Abbott's novel psoriasis biologic shows promise

By Katrina Megget

10/05/2007 - Abbott has announced it is "very excited" with its novel
psoriasis treatment in Phase II trials.

According to Abbott, the drug ABT-874 stands apart from other biologic
drugs that treat psoriasis because it is the first treatment to target
a part of the inflammatory response not addressed in other therapies.

While other drugs, such as Humira (adalimumab), bind to tumour
necrosis factor-alpha, ABT-874, a fully human monoclonal antibody, has
a novel mechanism whereby it targets and neutralizes interleukin-12
and interleukin-23, two proteins involved in the inflammatory
response.

According to the firm, nine out of 10 patients with moderate to severe
psoriasis in four of five dosing groups achieved 75 per cent
improvement in symptoms after 12 weeks. This was compared to three per
cent improvement of patients that received the placebo.

In addition, more than half of the 180 patients that took part in the
trial achieved a 90 per cent improvement, the firm reported.

"It's the best clearance results than anything we have seen out there
to date," Abbott spokeswoman Tracy Sorrentino told BioPharma-
Reporter.com.

Described as "promising", ABT-874 will go on to Phase III trials later
this year, though Sorrentino said it was "too early" to say how the
drug would perform in the market or what peak sales would be if it was
approved.

Psoriasis is a chronic autoimmune disease causing red, raised areas of
skin covered with flaky white scales which can often affect the self-
esteem of sufferers.

Biologic drugs already on the market for the treatment of psoriasis
include Amevive (alefacept), the first biologic treatment approved for
treating moderate to severe psoriasis, Enbrel (etanercept), and
Raptiva (efalizumab). Remicade (infliximab) and Humira (adalimumab)
are used in the treatment of psoriasis arthritis, rheumatoid arthritis
and Crohn's disease.

The development of biologic drugs reflects a shift in the
understanding of autoimmune disorders, such as rheumatoid arthritis,
Crohn's disease and psoriasis. They target the cause of the problem
rather than just relieving the symptoms, as was the case with earlier
treatments.

These drugs account for almost 20 per cent of all dollars spent on
drugs in the US with an expected rise to 25 per cent by 2008,
according to biologicdrugreport.com.

Already, 14 biologic drugs have been approved in the US and in other
countries and more than 70 are in late stage clinical trial with over
1000 in preclinical development.

The Phase II results will be presented next week at the Society for
Investigative Dermatology annual meeting in Los Angeles.

====================

More on ABT-874
http://www.medicalnewstoday.com/medicalnews.php?newsid=69923

=====================

As I mentioned Treg cells in my last nitwit post, I shall google them
as WELL.

And oh looky.
http://www.pharmalive.com/News/index.cfm?articleid=439027&categoryid=36%2C61

[...]
At the Keystone Symposium on Regulatory T Cells held February in
Vancouver, British Columbia, Hollis-Eden reported data demonstrating
HE3286 also produced a dramatic benefit in rodent models of both
initial-onset and established rheumatoid arthritis. Potential
mechanisms of action for HE3286 in this indication include regulation
of NF-kappaB and increasing the production of regulatory T cells, or
Treg cells. Treg cells play a key role in keeping the immune system
from attacking the body itself, and are being cited increasingly in
the medical literature as therapeutic targets in a range of diseases
and disorders beyond autoimmune conditions. Hollis-Eden anticipates
potentially filing an IND for HE3286 later this year in rheumatoid
arthritis. The Phase I trial program planned for metabolic disorders
with HE3286 may also support a Phase II study of the compound in the
indication of rheumatoid arthritis.

As reported in February at the American Society for Clinical
Oncology's Prostate Cancer Symposium, HE3235 has demonstrated
impressive activity in preclinical models of hormone driven prostate
and breast cancer. In a unique approach that may translate into first-
in-class treatments for hormone sensitive cancers, Hollis-Eden is
developing HE3235 as an orally active therapy to block the ability of
tumors to use estrogen and other adrenal hormones to grow. In addition
to further profiling HE3235 in preclinical cancer models, Hollis-Eden
has begun scaling up the manufacturing process in anticipation of
conducting IND-enabling toxicology studies. Assuming results of these
activities are successful, the Company anticipates filing an IND for
HE3235 in early 2008.

"Following years of committed effort, focused on the scientific
exploration of our proprietary class of adrenal steroid hormones,
Hollis-Eden is at an exciting and potentially rewarding stage of
development," stated Richard B. Hollis, Chairman and Chief Executive
Officer. "Through our exploration, we have made breakthrough
discoveries on our founding scientific mission of defining the
biological role and function of the most abundant human hormone -
dehydroepiandrosterone, or DHEA. Among these discoveries is that the
beneficial activities long believed to be associated with DHEA are not
attributable to DHEA itself but rather to the metabolic conversions
produced by its chemical transformation in the body. Our mission,
which we have never lost sight of, or focus on, has been to uncover
the chemical structures of these adrenal steroid hormones, to
determine which particular functions they regulate, and to apply the
principles of medicinal chemistry to confer pharmaceutically useful
characteristics to these naturally occurring molecules. <sniP>

=============

Another hallmark of P is ROS production.
http://en.wikipedia.org/wiki/Reactive_oxygen_species

Quite awhile back (2003) a protein called LAT (linker for activation)
was posted in this group.
http://groups.google.com/groups/search?qt_s=1&q=lat+protein+psoriasis

Can we get this linker to link uP with Ai conditions? More so then Hg?
LOL

And what about ROS and iNOS?

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17339448&query_hl=11&itool=pubmed_docsum
Kinetic proofreading of ligand-FcepsilonRI interactions may persist
beyond LAT phosphorylation.

* Torigoe C,
* Faeder JR,
* Oliver JM,
* Goldstein B.

Department of Chemistry and Chemical Biology, Cornell University,
Ithaca, NY 14853, USA.

Cells may discriminate among ligands with different dwell times for
receptor binding through a mechanism called kinetic proofreading in
which the formation of an activated receptor complex requires a
progression of events that is aborted if the ligand dissociates before
completion. This mechanism explains how, at equivalent levels of
receptor occupancy, a rapidly dissociating ligand can be less
effective than a more slowly dissociating analog at generating distal
cellular responses. Simple mathematical models predict that kinetic
proofreading is limited to the initial complex; once the signal passes
to second messengers, the dwell time no longer regulates the signal.
This suggests that an assay for kinetic proofreading might be used to
determine which activation events occur within the initial signaling
complex. In signaling through the high affinity IgE receptor
FcepsilonRI, the transmembrane adaptor called linker for activation of
T cells (LAT) is thought to nucleate a distinct secondary complex.
Experiments in which the concentrations of two ligands with different
dwell times are adjusted to equalize the level of LAT phosphorylation
in rat basophilic leukemia 2H3 cells show that Erk2 phosphorylation,
intracellular Ca(2+), and degranulation exhibit kinetic proofreading
downstream of LAT phosphorylation. These results suggest that ligand-
bound FcepsilonRI and LAT form a complex that is required for
effective signal transmission.

PMID: 17339448

And as this may be a rich area for exPloration,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17339328&query_hl=11&itool=pubmed_docsum
Novel Role for Mitochondria: Protein Kinase C{theta}-Dependent
Oxidative Signaling Organelles in Activation-Induced T-Cell Death.

* Kaminski M,
* Kiessling M,
* Suss D,
* Krammer PH,
* Gulow K.

Tumor Immunology Program, German Cancer Research Center (DKFZ), Im
Neuenheimer Feld 280, 69120 Heidelberg, Germany. k.gu...@dkfz.de.

Reactive oxygen species (ROS) play a key role in regulation of
activation-induced T-cell death (AICD) by induction of CD95L
expression. However, the molecular source and the signaling steps
necessary for ROS production are largely unknown. Here, we show that
the proximal T-cell receptor-signaling machinery, including ZAP70
(zeta chain-associated protein kinase 70), LAT (linker of activated T
cells), SLP76 (SH2 domain-containing leukocyte protein of 76 kDa),
PLCgamma1 (phospholipase Cgamma1), and PKCtheta (protein kinase
Ctheta), are crucial for ROS production. PKCtheta is translocated to
the mitochondria. By using cells depleted of mitochondrial DNA, we
identified the mitochondria as the source of activation-induced ROS.
Inhibition of mitochondrial electron transport complex I assembly by
small interfering RNA (siRNA)-mediated knockdown of the chaperone
NDUFAF1 resulted in a block of ROS production. Complex I-derived ROS
are converted into a hydrogen peroxide signal by the mitochondrial
superoxide dismutase. This signal is essential for CD95L expression,
as inhibition of complex I assembly by NDUFAF1-specific siRNA prevents
AICD. Similar results were obtained when metformin, an antidiabetic
drug and mild complex I inhibitor, was used. Thus, we demonstrate for
the first time that PKCtheta-dependent ROS generation by mitochondrial
complex I is essential for AICD.

PMID: 17339328

=======================================

randall... what about the iNOS?? Give it a day to sink in.

JXStern

unread,

May 10, 2007, 3:02:34 PM5/10/07

Sounds complementary to CNTO 1275.

And Enbrel/Humira/Remicade.

Cocktails!

(but won't happen soon, cuz they'd have to do full set of separate
trials for the combinations ... and it'd be a brave doctor and a rich
patient who would try it in the field, cuz no insurance company on the
planet is going to pay for it without approval!)

Thanks Randall for the posting!

ps - what was the MOA for CNTO 1275, il-10?
googling ...
CNTO 1275 is an antagonist to interleukins 12 and 23
oh dingleberries, it's the SAME as ABT-274.
OK, cocktails will be intra-vendor, Humira+274, Remicade+1275.

(was: P News 2007)

Message has been deleted

randall

unread,

May 10, 2007, 8:51:50 PM5/10/07

On May 10, 12:08 pm, Susan <neverm...@nomail.com> wrote:
> x-no-archive: yes
>

> JXStern wrote:
> >>A newer more imProved biological in our/your future?
>

> >>http://www.biopharma-reporter.com/news/ng.asp?n=76427-abbott-biologic...

> >>Abbott's novel psoriasis biologic shows promise
>
> >>By Katrina Megget
>
> >>10/05/2007 - Abbott has announced it is "very excited" with its novel
> >>psoriasis treatment in Phase II trials.
>

> Have I lost a year? This is dated *October* 2007.
>
> Susan
>
>
Nope, your fine as usual.

European dating?

Their 10/5/2007 is 5/10/2007 for us?

Their month comes before the day, ours is the opposite, day before the
month.

At least we both agree on the year.

What year is it btw?

Year of the pig after Feb. 18th, 2007?

http://en.wikipedia.org/wiki/Chinese_New_Year

randall... our lucky year?

randall

unread,

May 11, 2007, 1:21:41 PM5/11/07

On May 10, 5:51 pm, randall <ranhu...@aol.com> wrote:
> On May 10, 12:08 pm, Susan <neverm...@nomail.com> wrote:
>
> > x-no-archive: yes
>
> > JXStern wrote:
> > >>A newer more imProved biological in our/your future?
>
> > >>http://www.biopharma-reporter.com/news/ng.asp?n=76427-abbott-biologic...
> > >>Abbott's novel psoriasis biologic shows promise
>
> > >>By Katrina Megget
>
> > >>10/05/2007 - Abbott has announced it is "very excited" with its novel
> > >>psoriasis treatment in Phase II trials.
>
> > Have I lost a year? This is dated *October* 2007.
>
> > Susan
>
> Nope, your fine as usual.
>
> European dating?
>
> Their 10/5/2007 is 5/10/2007 for us?
>
> Their month comes before the day, ours is the opposite, day before the
> month.

Whoops. You do know what I meant? Theirs has the day first.

Back to P NEWS?

OK.... Some say wheaties is the breakfast of chamPions.

What about for psoriatics? We've heard 16% to 32% and beyond are
affected in a non celiac sort of way by the gluten protein.

What is this protein and how does it work?
http://www.celiac.com/st_prod.html?p_prodid=8

Here's a woman who rose like a phoenix from her wheaty demise,
http://www.wallowacountychieftain.info/main.asp?SectionID=9&SubSectionID=61&ArticleID=13005&TM=62244.83

[...]
Wheat intolerance, on the other hand, tends to be a delayed reaction
(two or three days later) of gastro-intestinal problems, stomach
bloating and cramping, headache, memory loss, depression, mouth
ulcers, eczema, psoriasis, food cravings, tiredness and chronic
fatigue.

[...]
Had not Summers known someone previously with a wheat allergy and had
he not mentioned it to her, she might never have felt better. "I don't
know how much longer it would have taken me to figure it out."

Zscheile has been on the Elimination diet and has continued to educate
herself as to all the different forms of wheat-byproducts that find
their way into foods. "You can't ever assume, unless it's fresh whole
foods, without reading the label."

Nevertheless, the process of reading food labels and seeking out whole
foods has helped her to improve her diet. "It really encourages you to
eat healthier," she said of her gluten-free diet.
<sniP>

-----------

But does any of this with the excePtion of P make sense for the
psoriatic?

Are we so strong that all systems with the exception of the skin are
bullet proof?
That doesn't seem to make sense, unless psoriasis is the ultimate
compensatory
mechanism. Psoriasis saps up headaches and all other ills and dumps it
in the skin???
To hard to believe? Then look at this. Stirling Strauss says that his
program
hasn't found a single person who hasn't cleared with his diet/program
that
eliminates wheat, fried foods (acrylamides), calcium ions/proteases?

But how many of us will win the P skin game? He says all of us! But
then
admits that a bad diet will lead to flake city post haste.

--------------
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17263812&query_hl=7&itool=pubmed_docsum
Palmoplantar pustulosis and gluten sensitivity: a study of serum
antibodies against gliadin and tissue transglutaminase, the duodenal
mucosa and effects of gluten-free diet.

* Michaelsson G,
* Kristjansson G,
* Pihl Lundin I,
* Hagforsen E.

Departments of Dermatology and Gastroenterology, Medical Sciences,
University Hospital, Uppsala, Sweden.

Background Palmoplantar pustulosis (PPP) is a chronic inflammatory
disease affecting mainly smoking women. Some patients also have
psoriasis. A subgroup of patients with psoriasis has been shown to
have silent gluten sensitivity with relevance for their psoriasis.
Nothing is known about gluten sensitivity in PPP. Objectives To find
out whether any patients with PPP are gluten-sensitive and whether
this might be relevant for the PPP activity. Patients and methods One
hundred and twenty-three patients (113 women) with PPP participated.
Screening for IgA antibodies against gliadin and tissue
transglutaminase (tTG) was performed, the duodenal mucosa in patients
with and without these antibodies was studied and the effect of a
gluten-free diet (GFD) was followed up. Results Twenty-two patients
(18%) had IgA antibodies against gliadin and nine of 94 (10%) against
tTG. Twelve patients with antibodies and 11 without underwent gastro-
duodenoscopy. Four displayed villous atrophy, whereas all other
specimens were judged as essentially normal at routine staining.
However, with immunohistochemistry, the numbers of CD3+ and CD8+
lymphocytes in the epithelium were found to be increased in patients
with any type of antibody, although they were most numerous in those
with both types of antibodies. Seven of 123 patients (6%) had coeliac
disease (three previously diagnosed). Patients with antibodies who
adhered to the GFD displayed total or nearly total clearance of the
skin lesions and normalization of the antibody levels. Conclusions
Patients with PPP should be screened for antibodies against gliadin
and tTG. Those with antibodies can be much improved on a GFD
regardless of the degree of mucosal abnormalities.

PMID: 17263812

Only a few psoriatics (18%) had the IgA antibodies in this recent
study.

Is there something else in there that may be causal?
-----

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17475890&query_hl=4&itool=pubmed_docsum
Immune cross-reactivity in celiac disease: anti-gliadin antibodies
bind to neuronal synapsin I.

* Alaedini A,
* Okamoto H,
* Briani C,
* Wollenberg K,
* Shill HA,
* Bushara KO,
* Sander HW,
* Green PH,
* Hallett M,
* Latov N.

Department of Neurology and Neuroscience, Cornell University, New
York, NY 10021.

Celiac disease is an immune-mediated disorder triggered by ingestion
of wheat gliadin and related proteins in genetically susceptible
individuals. In addition to the characteristic enteropathy, celiac
disease is associated with various extraintestinal manifestations,
including neurologic complications such as neuropathy, ataxia,
seizures, and neurobehavioral changes. The cause of the neurologic
manifestations is unknown, but autoimmunity resulting from molecular
mimicry between gliadin and nervous system proteins has been proposed
to play a role. In this study, we sought to investigate the immune
reactivity of the anti-gliadin Ab response toward neural proteins. We
characterized the binding of affinity-purified anti-gliadin Abs from
immunized animals to brain proteins by one- and two-dimensional gel
electrophoresis, immunoblotting, and peptide mass mapping. The major
immunoreactive protein was identified as synapsin I. Anti-gliadin Abs
from patients with celiac disease also bound to the protein. Such
cross-reactivity may provide clues into the pathogenic mechanism of
the neurologic deficits that are associated with gluten sensitivity.

PMID: 17475890

Where is the enteropathy for psoriasis here,
http://en.wikipedia.org/wiki/Gluten-sensitive_enteropathy

Is it simply the leaky gut (permeable Gi tract) that is at issue as
Stirling states?
But even alcohol creates a leaky gut, along with a myriad of foods and
things
that go down the pie hole.
http://en.wikipedia.org/wiki/Leaky_gut

If its only a leaky gut, then is stirling off track or does his diet
shore up the
gut holes from everything but wheat?

What if your lower bowel is a friendly environ for alkaline bugs?

Candida,
http://en.wikipedia.org/wiki/Candidiasis

[...]
internal (hormonal or other physiological changes) disturbances can
perturb the normal flora, constituting lactic acid bacteria, such as
lactobacilli, and an overgrowth of yeast can result in noticeable
symptoms. <sniP>

-----------------

With the exception of the WIT KIT, i've never found a faster and
easier way to re-acidify the colon with lactobacilli and diet.

http://www.thewholewhey.com/Item10.htm
---------------

Once the holes are plugged you can eat wheat and your psoriasis won't
come back
till you drill more holes or re-alkalize your colon and invite back in
the boorish Candida bugs.
Simply by __alkalizing__ your colon it's enough to skew yourself back
towards a Th1 profile.
Acidification will bring you back towards a neutral Th0 state and
allow for Th2 and tregs
to enter the picture and block extreme Ai (autoimmunity) or I.M.I.Ds
(immune mediated
inflammatory diseases)

http://en.wikipedia.org/wiki/T_helper_cell
http://www.iir.suite.dk/IIR/03Th/Th.htm

If the lacti loving acidifying bugs aren't working the tregs take the
hit and IL-10 levels go down
and there's little to stop psoriasis without biological usage and
endless goops and steroid
tweaking's.

The answer so to speak is right under our nostrils inside of us. If
your not
willing to re-acidify the colon, plan on a life time of funky monkey
plaque-ish
skin.

But if Stirling is right. Take out the breakfast of chamPions (wheat)
and let us
know how you fare.

Who knows? If your in that 18% realm you'll be helped for sure.

If you in the other 82% and get help we really want to know.

randall...

Message has been deleted

randall

unread,

May 11, 2007, 2:26:57 PM5/11/07

On May 11, 10:35 am, Susan <neverm...@nomail.com> wrote:
> x-no-archive: yes
>

> Top posting because I don't want to respond point by point...
>
> I don't recall if I discussed this here, but in researching my adrenal
> problems, I've learned that higher insulin levels suppress our cortisol
> synthesis, or our ability to produce our endogenous anti inflammatories.
> Insulin also reduces our cortisol binding globulin, thereby preventing
> the delivery of cortisol to our cells. The cells then start signaling
> for more cortisol, so ACTH is released, unleashing an inflammatory cascade.
>
> Since fat, unlike protein and carbs, does not stimulate insulin nor
> glucagon, and healthy fats from olives, nuts and fish have anti
> inflammatory properties, a case could be made for a high fat, adequate
> protein (due to protein loss via skin and steroids) and low carb diet
> for optimal dietary results. Even if P stays the same, your arteries
> will thank you!
>
> YMMV, as always.
>
> Susan

OK. I'm middle posting because, when I think of the space taken up by
images and video i'm not worried about moore's law smacking in to
quantum
mechanics,
http://en.wikipedia.org/wiki/Moores_law
http://en.wikipedia.org/wiki/Quantum_mechanics

Or am I putting the day before the month again?

Back to your new found knowledge of endocrine functions,
http://en.wikipedia.org/wiki/Endocrine

Keto diets have been mentioned more then a few times
http://groups.google.com/groups/search?qt_s=1&q=ketogenic+psoriasis
http://en.wikipedia.org/wiki/Ketogenic

How would your IDEAL P diet differ from the run of the mill ketogenic
one?

randall

> >http://www.wallowacountychieftain.info/main.asp?SectionID=9&SubSectio...

> >http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&...

Message has been deleted

Brett

unread,

May 11, 2007, 4:30:38 PM5/11/07

Personally, I've never been afraid of trying the higher fat approach, as at
one time I was incorporating lots of avocados, coconut and coconut oil,
olive oil, organic butter, and of course, fatty fish and fish oils. I'm not
sure exactly why I began cutting out some of the fats, but as I've posted a
few times, I've mainly become a fishetarian (if there is such a word). : )

One thing I didn't do is to go on the low carb approach because I truly
believe that complex carbs are needed in adequate amounts for proper brain
and bodily functions, and especially if a person is leading an active
lifestyle. I've tried to figure out the percentage of my daily caloric
intake, and I've calculated it now to be roughly 55% carbs, 30% fat, and 15%
protein, varying slightly from day to day, and I'm down to 1% coverage even
with carbs being my highest percentage of calories.

I truly think it's the type of carbs, fat, and protein a person ingests,
rather than the percentage, that ends up being either anti or
pro-inflammatory in the body. There are so many variables with our
condition, that all I can say is to stick with what works best for you.

Brett

"Susan" <neve...@nomail.com> wrote in message
news:5ajs6lF...@mid.individual.net...
> x-no-archive: yes

>
> randall wrote:
>
>> How would your IDEAL P diet differ from the run of the mill ketogenic
>> one?
>>
>

> My IDEAL diet for those with or without P would differ from standard
> ketogenics by relying on only grass fed meat and dairy and wild caught
> fish. I also tend to eat lower fat as a total % of my diet's calories,
> 50% fat, with about a third of that saturated. And organic produce.
>
> Susan

Message has been deleted

Brett

unread,

May 11, 2007, 6:29:05 PM5/11/07

I'm just here to post what works for me. But I will say that when it comes
to your statement about endurance athletes able to compete on low carb
diets, well that I have to reply to.
I've been long distance running now for approximately 10 years, and in that
time have never met one competitor that's performed well on a low carb diet.
Even the coach of Lance Armstrong had this to say about low carb diets for
athletes, and yes, I do realize he's mentioning high protein instead of high
fat.
http://www.boosman.com/blog/2004/08/lance_armstrongs_coach_on_carb.html All
I'm trying to say is that from my own personal experience and that of other
successful athletes, a higher carb diet is a necessity for performing well.
If you aren't active and burning the fuel you ingest on a daily basis, then
maybe the lower carb approach would be fine.

Brett

"Susan" <neve...@nomail.com> wrote in message

news:5ak556F...@mid.individual.net...
> x-no-archive: yes

>
> Brett wrote:
>
>> One thing I didn't do is to go on the low carb approach because I truly
>> believe that complex carbs are needed in adequate amounts for proper
>> brain and bodily functions, and especially if a person is leading an
>> active lifestyle.
>

> First of all, the term "complex carbs" has lost all meaning in this
> discussion, since we now know that many complex carbs are worse for you
> than table sugar. White flour and potatoes, for example. Emphasis these
> days is placed upon nutrient dense vs. calorie dense, insulin gush
> inducing carbs.
>
> Second, the human brain and body have abolutely no requirement for dietary
> carbohydrate. The brain needs a small amount of glucose per day, but it
> prefers and runs better on ketones when they are present. Glucose is
> manufactured from protein meals, so there's no need to eat carbohydrates
> to meet the requirement of the brain.
>
> Endurance athletes are able to compete on low carb diets, so you probably
> could, too, after adaptation. One trick used by body builders is to eat a
> ketogenic diet, but fuel workouts with Dextrose drinks to fuel the workout
> but not remain in the bloodstream.

>
> I've tried to figure out the percentage of my daily caloric
>> intake, and I've calculated it now to be roughly 55% carbs, 30% fat, and
>> 15% protein, varying slightly from day to day, and I'm down to 1%
>> coverage even with carbs being my highest percentage of calories.
>

> 55% carbs means you're promoting inflammation, but if you're happy with
> the way things are going for you, who's to argue?

>
>>
>> I truly think it's the type of carbs, fat, and protein a person ingests,
>> rather than the percentage, that ends up being either anti or
>> pro-inflammatory in the body. There are so many variables with our
>> condition, that all I can say is to stick with what works best for you.
>

> It's both. Since insulin is proven to inhibit steroidogenesis and CBG,
> and promotes inflammatory cytokines, there's little argument to be made
> against it.
>
> I pay very careful attention to eating/buying grass fed meat and dairy and
> wild fish, and lots of colorful, leafy veggies while avoiding starches
> pretty much completely. By volume, my diet has boatloads of carbs, just
> not by calorie count.
>
> Susan

Message has been deleted

randall

unread,

May 14, 2007, 1:07:39 PM5/14/07

On May 11, 4:41 pm, Susan <neverm...@nomail.com> wrote:
> x-no-archive: yes

I would think that the Kenyans hit the wall sooner and rely on fat
burning to carry them thru? They look rail thin to begin with.

http://www.marathonandbeyond.com/choices/latta.htm
http://www.cartoonstock.com/lowres/dco0074l.jpg

Then again is this 20 mile hit the wall rule the only rule? Can you
hit it sooner?
http://david.ziegler.ws/running/tips/the-wall

You hit the wall and how long till the fat burner
kicks in? If the kenyans are thinner then wouldn't they
hit the wall sooner?

This guy looks rail thin,
http://www.nctimes.com/content/articles/2006/01/16/sports/amateur/11506192152.jpg

They all do,
http://images.google.com/images?svnum=10&um=1&hl=en&q=+marathon+kenyans&btnG=Search+Images

These are the guys are they not? That win then long haul races more
often then not?

Could a keto diet be their secret?

And what about the bicycle guys? Is the key to them testosterone?

When do they hit the wall?

randall.... simply doesn't know. But wants to!

>
> Brett wrote:
> > I'm just here to post what works for me. But I will say that when it comes
> > to your statement about endurance athletes able to compete on low carb
> > diets, well that I have to reply to.
> > I've been long distance running now for approximately 10 years, and in that
> > time have never met one competitor that's performed well on a low carb diet.
> > Even the coach of Lance Armstrong had this to say about low carb diets for
> > athletes, and yes, I do realize he's mentioning high protein instead of high
> > fat.
> >http://www.boosman.com/blog/2004/08/lance_armstrongs_coach_on_carb.html All
> > I'm trying to say is that from my own personal experience and that of other
> > successful athletes, a higher carb diet is a necessity for performing well.
> > If you aren't active and burning the fuel you ingest on a daily basis, then
> > maybe the lower carb approach would be fine.
>

> Brett, I'm not questioning your personal experience, nor telling you
> what to do for your athletic performance. I know that most endurance
> athletes believe they need to eat high carb to perform, but lots of
> folks believe things about nutrition that aren't true:
>
> Metabolism. 1983 Aug;32(8):769-76. Related Articles, Links
>
> The human metabolic response to chronic ketosis without caloric
> restriction: preservation of submaximal exercise capability with
> reduced carbohydrate oxidation.
>
> Phinney SD, Bistrian BR, Evans WJ, Gervino E, Blackburn GL.
>
> To study the effect of chronic ketosis on exercise performance in
> endurance-trained humans, five well-trained cyclists were fed a
> eucaloric balanced diet (EBD) for one week providing 35-50 kcal/kg/d,
> 1.75 g protein/kg/d and the remainder of kilocalories as two-thirds
> carbohydrate (CHO) and one-third fat. This was followed by four weeks
> of a eucaloric ketogenic diet (EKD), isocaloric and isonitrogenous
> with the EBD but providing less than 20 g CHO daily. Both diets were
> appropriately supplemented to meet the recommended daily allowances
> for vitamins and minerals. Pedal ergometer testing of maximal oxygen
> uptake (VO2max) was unchanged between the control week (EBD-1) and
> week 3 of the ketogenic diet (EKD-3). The mean ergometer endurance
> time for continuous exercise to exhaustion (ENDUR) at 62%-64% of
> VO2max was 147 minutes at EBD-1 and 151 minutes at EKD-4. The ENDUR
> steady-state RQ dropped from 0.83 to 0.72 (P less than 0.01) from
> EBD-1 to EKD-4. In agreement with this were a three-fold drop in
> glucose oxidation (from 15.1 to 5.1 mg/kg/min, P less than 0.05) and a
> four-fold reduction in muscle glycogen use (0.61 to 0.13 mmol/kg/min,
> P less than 0.01). Neither clinical nor biochemical evidence of
> hypoglycemia was observed during ENDUR at EKD-4. These results
> indicate that aerobic endurance exercise by well-trained cyclists was
> not compromised by four weeks of ketosis. This was accomplished by a
> dramatic physiologic adaptation that conserved limited carbohydrate
> stores (both glucose and muscle glycogen) and made fat the predominant
> muscle substrate at this submaximal power level.
>
> PMID: 6865776 [PubMed - indexed for MEDLINE]

randall

unread,

May 14, 2007, 1:17:04 PM5/14/07

Hi,

I've preached about the Th1 skew of p for quite some time now.

With this Th1 skew your more prone to Ai (autoimmunity).

With a Th2 skew, the other side of this teeter totter, you prone to
cancer.

This article became available the last few days, and got me thinking.

http://www.medicalnewstoday.com/medicalnews.php?newsid=70323
Molecule That Destroys Bone Also Protects It, New Research Shows

An immune system component that is a primary cause of bone destruction
and inflammation in autoimmune diseases such as rheumatoid arthritis
actually protects bone in the oral cavity from infectious pathogens
that play a major role in periodontal disease in humans, research at
the University at Buffalo has shown.

The component, IL-17, was recognized only in the past 18 months to be
a primary cause of bone destruction and inflammation in autoimmune
diseases. Therapies that target IL-17 or its cellular receptor
currently are being developed.

However, a UB molecular biologist has discovered that, in contrast to
its action in rheumatoid arthritis(RA), IL-17 actually protects bone
in the oral cavity from infectious pathogens such as Porphyromonas
gingivalis, a bacterium that plays a major role in most periodontal
disease in humans.

The research findings appear in the current (May) issue of the journal
Blood.

Sarah L. Gaffen, Ph.D., associate professor of oral biology in the UB
School of Dental Medicine and associate professor of microbiology and
immunology in the UB School of Medicine and Biomedical Sciences, is
senior author. Jeffrey J. Yu, a medical student and doctoral candidate
who is a researcher working in Gaffen's lab, is first author.

Gaffen and colleagues conducted the research in mice bred to have no
receptors for IL-17. Other researchers had shown previously, using
rats and mice as animal models, that blocking the receptor for IL-17
could be an effective therapy for RA and possibly for other autoimmune
diseases such as multiple sclerosis, colitis, psoriasis and lupus.

The effects of an IL-17 deficiency in periodontal disease, however,
were unknown, so Gaffen's lab set out to investigate.

"I predicted these mice without the IL-17 receptor were going to be
protected from periodontal bone loss, just like they're protected from
arthritic bone loss," Gaffen said. "In fact, we got the opposite
result. The mice without IL-17 were much more susceptible to bone loss
caused by periodontal disease, compared to normal mice.

"What's the difference between an autoimmune disease like RA and
periodontal disease" Periodontal disease is an infectious disease, and
as with most infectious diseases, white blood cells of the innate
immune system called neutrophils play a critical role in fighting
infections. In fact, humans with neutrophil defects usually lose all
their teeth by the time they are 20 due to severe periodontal disease.

"It turns out that IL-17 is really important in regulating neutrophils
by causing other cells in the vicinity to recruit these infection
fighters to the infection site," Gaffen said.

IL-17 is a cytokine, a protein hormone made by "T helper" cells of the
immune system that stimulate immunity. Gaffen noted that until
recently, immunologists believed there were only two major types of "T
helper" cells -- TH1 and TH2 -- which were believed to be responsible
for nearly all immune system activities.

"This paradigm underwent a sea change in 2005 with the discovery of a
new type of T cell that produces IL-17, now called TH-17," she said.
"We know now that almost all autoimmune diseases, at least in the
mouse model, are caused by TH-17 cells. This new information has
forced scientists to revise completely how they view their favorite
disease. Everyone now has to rethink the causative mechanism."

Gaffen said IL-17 likely would be toxic if given systemically, so it
may not be a therapeutic candidate to increase immunity. But
inhibitors of IL-17 are considered important targets for drugs to
treat autoimmune diseases such as RA and psoriasis.

On the down side, however, this new finding indicates that inhibiting
IL-17 too much could put people taking such a drug at risk for
opportunistic infections such as periodontal disease and tuberculosis,
she noted.

"Developing knowledge about the molecules that contribute to host
defense versus pathology is very important for gaining a fundamental
understanding of the immune system," Gaffen said, "but also because
the consequences of therapies that target these cytokines need to be
understood."

--------------------

So? Are the bugs in our mouths recruiting IL-17 and adding to Ai
(autoimmunity)?

--------

Lets go over IL-17.

We've only had six hits directly to the group,
http://groups.google.com/groups/search?qt_s=1&q=il-17+psoriasis

Neither Th1 or Th2,
http://www.nature.com/ni/journal/v6/n11/abs/ni1105-1069.html
TH-17: a giant step from TH1 and TH2
Thomas A Wynn
Thomas A. Wynn is at the National Institute of Allergy and Infectious
Diseases, National Institutes of Health, Bethesda, Maryland 20892,
USA. twynn @niaid.nih.gov
CD4+ T cells have been classically separated into two dominant
effector populations: T helper types 1 and 2. Two new studies suggest
that T cells producing interleukin 17 constitute a previously unknown
lineage of CD4+ T cells.

===================================

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=16616472
Expanding the effector CD4 T-cell repertoire: the Th17 lineage.

* Harrington LE,
* Mangan PR,
* Weaver CT.

Department of Pathology, University of Alabama at Birmingham, 845 19th
Street South, Birmingham, AL 35294, USA.
The Th1/Th2 paradigm has provided the framework for understanding CD4
T-cell biology and the interplay between innate and adaptive immunity
for almost two decades. Recent studies have defined a previously
unknown arm of the CD4 T-cell effector response--the Th17 lineage--
that promises to change our understanding of immune regulation, immune
pathogenesis and host defense. The factors that specify
differentiation of IL-17-producing effector T-cells from naive T-cell
precursors are being rapidly discovered and are providing insights
into mechanisms by which signals from cells of the innate immune
system guide alternative pathways of Th1, Th2 or Th17 development.

PMID: 16616472

------------------
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Search&db=PubMed&term=th%2D17&tool=QuerySuggestion

-------------

http://www.ebioscience.com/ebioscience/whatsnew/Th17.htm

IL-17 Biology
Interleukin-17 (IL-17) is a CD4+ T cell-derived cytokine that promotes
inflammatory responses and is correlated with rheumatoid arthritis,
asthma, multiple sclerosis, psoriasis, and transplant rejection. The
cDNA encoding human IL-17 was isolated from a library of CD4+ T cells;
the encoded protein exhibits 72 percent amino acid identity with
HVS13 , an open reading frame from a T lymphotropic Herpesvirus
saimiri, and 63 percent with mouse CTLA-8. Human IL-17 exists as
glycosylated 20-30 kD homodimers. High levels of IL-17 homodimer are
produced by activated peripheral blood CD4+ T-cells. IL-17 enhances
expression of the intracellular adhesion molecule-1 (ICAM-1) in human
fibroblasts. Human IL-17 also stimulates epithelial, endothelial, or
fibroblastic cells to secrete IL-6, IL-8, G-CSF, and PGE2. In the
presence of human IL-17, fibroblasts can sustain the proliferation of
CD34+ hematopoietic progenitors and induce maturation into
neutrophils. Mouse, rat, and human IL-17 can induce IL-6 secretion in
mouse stromal cells, indicating that all homologs can recognize the
mouse IL-17 receptor.

--------------

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17372020&query_hl=3&itool=pubmed_docsum
Oncostatin M secreted by skin infiltrating T lymphocytes is a potent
keratinocyte activator involved in skin inflammation.

* Boniface K,Diveu C,Morel F,Pedretti N,Froger J,Ravon E,Garcia
M,Venereau E,Preisser L,Guignouard E,Guillet G,Dagregorio G,Pene
J,Moles JP,Yssel H,Chevalier S,Bernard FX,Gascan H,Lecron JC.

UPRES-EA 3806, Centre Hospitalier de l'Universite de Poitiers,
Poitiers, France.

Cutaneous inflammatory diseases such as psoriasis vulgaris and atopic
dermatitis are associated with altered keratinocyte function, as well
as with a particular cytokine production profile of skin-infiltrating
T lymphocytes. In this study we show that normal human epidermal
keratinocytes express a functional type II oncostatin-M (OSM) receptor
(OSMR) consisting of the gp130 and OSMRbeta components, but not the
type I OSMR. The type II OSMR is expressed in skin lesions from both
psoriatic patients and those with atopic dermatitis. Its ligand, OSM,
induces via the recruitment of the STAT3 and MAP kinase pathways a
gene expression profile in primary keratinocytes and in a
reconstituted epidermis that is characteristic of proinflammatory and
innate immune responses. Moreover, OSM is a potent stimulator of
keratinocyte migration in vitro and increases the thickness of a
reconstituted epidermis. OSM transcripts are enhanced in both
psoriatic and atopic dermatitic skin as compared with healthy skin and
mirror the enhanced production of OSM by T cells isolated from
diseased lesions. Results from a microarray analysis comparing the
gene-modulating effects of OSM with those of 33 different cytokines
indicate that OSM is a potent keratinocyte activator similar to TNF-
alpha, IL-1, IL-17, and IL-22 and that it acts in synergy with the
latter cytokines in the induction of S100A7 and beta-defensin 2
expression, characteristic of psoriatic skin. Taken together, these
results demonstrate that OSM and its receptor play an important role
in cutaneous inflammatory responses in general and that the specific
effects of OSM are associated with distinct inflammatory diseases
depending on the cytokine environment.

PMID: 17372020

There are a handful of IL-17 hits for keyword: psoria* (14 hits)

For IL-17 as the only keyword we pick up 740 abstracts,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Search&db=PubMed&term=il%2D17&tool=QuerySuggestion

If you keyword: Treg* with IL-17, as psoriatics have low levels of
treg's, we pick up
11 key clues.

----------

This area seems to be the key to finding the psoriasis genes most
responsible for our condition.

randall... with understanding a cure will come. At what cost and side
effects?

randall

unread,

May 18, 2007, 1:41:47 PM5/18/07

Hi,

Will a treg cure for psoriasis be a local topical? Some cancer cures
have a cream
called imiquimod (aldara) that simply causes a Th1 skew right in the
place where it's rubbed in. Imagine that, if you rubbed this in
right around your psoriasis, you'd have a huge flare going on.
As it causes TNF. The same stuff that biologicals block.

But Cancer is a Th2 condition and needs a Th1 skew to go back towards
normal....So rub a dub dub and your cancer is chewed up by TNF, the
same stuff that flares our hides 24/7...

Here's this wonder cream for cancer.
http://en.wikipedia.org/wiki/Imiquimod

While trying to explain Th1 and Th2 i've mentioned this cream many
times.

There is a teeter totter to immunity, but with a hitch. As mentioned
in the last
post to this thread we have Th17 (IL-17) to figure in to the mix. So,
I guess
we have to think about a three way or four way teeter totter. LOL

Like a gyroscoPe on steroids.

And psoriasis genetics has over weighted two sides skewing us
towards a Th1 paradigm. How do we balance this thing without spinning
out
of control??

With Tregs (T regulatory cells) in this mix it's getting more
complicated.

Will we have our Th2/Th17 cream to rub in to our plaques that raise
Tregs
and stops or slows inflammation?

Let's move on with it.

http://www.signaling-gateway.org/update/updates/200705/nri2078.html
Regulatory T cells (Tregs) in autoimmunity

During autoimmune disease, effector T cells at acute sites of
inflammation produce high levels of tumor necrosis factor (TNF) and
cytokines such as interleukin 6 (IL-6) that impede their suppression
by regulatory T cells.

Forkhead box P3 (FOXP3)+CD4+CD25+ regulatory T (TReg) cells have an
important role in limiting autoimmune tissue damage. However, the
origin and function of TReg cells at the site of inflammation during
autoimmune disease are still unclear. Kuchroo and colleagues tracked
autoantigen-specific T cells during the course of experimental
autoimmune encephalomyelitis (EAE), a mouse model of multiple
sclerosis, and found that although autoantigen-specific TReg cells
accumulated at the site of inflammation, they did not prevent the
onset of disease.
Using a standard immunization protocol with a myelin oligodendrocyte
glycoprotein (MOG) peptide (MOG35-55), EAE was induced in mice in
which the expression of FOXP3 is linked to the expression of green
fluorescent protein (GFP). The proportion of FOXP3+ TReg cells (GFP+)
and effector T cells (GFP-) in the central nervous system (CNS; the
site of inflammation) was then assessed. The authors showed that the
percentage of GFP- T cells increased in the CNS approximately 3 days
before the peak of the disease and rapidly declined at the start of
recovery. By contrast, the number of GFP+ T cells in the CNS, which
can be detected as early as day 10 after the induction of EAE, did not
contract after the peak of the disease, but increased fivefold during
the onset of remission. GFP+ T cells in the CNS expressed higher
levels of surface receptors that are associated with the recruitment
of TReg cells to inflammatory sites, compared with GFP+ T cells in the
lymph nodes and spleen. Furthermore, autoantigen-specific GFP+ T cells
were stained in the draining lymph nodes and spleen with MOG35-55/IAb
(MHC class II) tetramers. These data indicate that autoantigen-
specific TReg cells expand in the periphery and readily accumulate in
the CNS during autoimmune disease.

Because TReg cells are present at the site of inflammation during the
peak of the disease, the authors next examined the function of these
autoantigen-specific TReg cells during this time. TReg cells isolated
from the CNS at the peak of the disease suppressed the in vitro-
proliferation of MOG-specific effector T cells isolated from the
spleen, but not of those isolated from the CNS. CNS-derived effector T
cells were shown to produce higher amounts of interleukin-6 (IL-6) and
tumour-necrosis factor (TNF) than cells from the spleen.
Interestingly, the addition of IL-6 and TNF to the in vitro co-
cultures completely prevented the suppression of spleen-derived T
cells by TReg cells, indicating that the cytokine milieu at the site
of inflammation might determine the ability of TReg cells to control
autoimmunity at the peak of disease.

Therefore, the treatment of autoimmune disease with regulatory T cells
generated ex vivo might need to be accompanied by the control of local
tissue inflammation.

by Olive Leavy

References:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17384649&query_hl=2&itool=pubmed_docsum
Myelin-specific regulatory T cells accumulate in the CNS but fail to
control autoimmune inflammation.

* Korn T,
* Reddy J,
* Gao W,
* Bettelli E,
* Awasthi A,
* Petersen TR,
* Backstrom BT,
* Sobel RA,
* Wucherpfennig KW,
* Strom TB,
* Oukka M,
* Kuchroo VK.

Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard
Medical School, Boston, Massachusetts 02115, USA.

Treatment with ex vivo-generated regulatory T cells (T-reg) has been
regarded as a potentially attractive therapeutic approach for
autoimmune diseases. However, the dynamics and function of T-reg in
autoimmunity are not well understood. Thus, we developed Foxp3gfp
knock-in (Foxp3gfp.KI) mice and myelin oligodendrocyte glycoprotein
(MOG)(35-55)/IA(b) (MHC class II) tetramers to track autoantigen-
specific effector T cells (T-eff) and T-reg in vivo during
experimental autoimmune encephalomyelitis (EAE), an animal model for
multiple sclerosis. MOG tetramer-reactive, Foxp3(+) T-reg expanded in
the peripheral lymphoid compartment and readily accumulated in the
central nervous system (CNS), but did not prevent the onset of
disease. Foxp3(+) T cells isolated from the CNS were effective in
suppressing naive MOG-specific T cells, but failed to control CNS-
derived encephalitogenic T-eff that secreted interleukin (IL)-6 and
tumor necrosis factor (TNF). Our data suggest that in order for
CD4(+)Foxp3(+) T-reg to effectively control autoimmune reactions in
the target organ, it may also be necessary to control tissue
inflammation.

PMID: 17384649

===================================

search:: treg's and th17 (7 hits)

Here's one,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17433650&query_hl=1&itool=pubmed_docsum
Differentiation and function of Th17 T cells.

* Stockinger B,
* Veldhoen M.

Division of Molecular Immunology, The MRC National Institute for
Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, United
Kingdom.
IL-17-producing T cells have recently been classified as a new
effector T-cell subset, termed Th17, which is distinct from Th1, Th2
and Treg subsets. There has been much progress in the past year,
leading to identification of the molecular mechanisms that drive
differentiation of Th17 T cells. This has helped to clarify many
aspects of their role in host defense as well as in autoimmunity.
Nevertheless, many intriguing questions remain to be answered
regarding the regulation of Th17-mediated responses as well as their
interactions with the other T-cell subsets. Furthermore, the role of
pathogens and pathogen-derived molecules in influencing effector T-
cell polarization needs to be re-evaluated in the light of the
differentiation conditions that favor Th17 T-cell responses.

PMID: 17433650

------------

Il-2 constrains th-17
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17363300&query_hl=1&itool=pubmed_docsum
Interleukin-2 signaling via STAT5 constrains T helper 17 cell
generation.

PMID: 17363300

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17328715&query_hl=1&itool=pubmed_docsum
The role of T helper 17 (Th17) and regulatory T cells (Treg) in human
organ transplantation and autoimmune disease.

* Afzali B,
* Lombardi G,
* Lechler RI,
* Lord GM.

Department of Nephrology and Transplantation, King's College London,
Guy's and St Thomas' Hospital, UK.
Uncommitted (naive) murine CD4+ T helper cells (Thp) can be induced to
differentiate towards T helper 1 (Th1), Th2, Th17 and regulatory
(Treg) phenotypes according to the local cytokine milieu. This can be
demonstrated most readily both in vitro and in vivo in murine CD4+ T
cells. The presence of interleukin (IL)-12 [signalling through signal
transduction and activator of transcription (STAT)-4] skews towards
Th1, IL-4 (signalling through STAT-6) towards Th2, transforming growth
factor (TGF)-beta towards Treg and IL-6 and TGF-beta towards Th17. The
committed cells are characterized by expression of specific
transcription factors, T-bet for Th1, GATA-3 for Th2, forkhead box P3
(FoxP3) for Tregs and RORgammat for Th17 cells. Recently, it has been
demonstrated that the skewing of murine Thp towards Th17 and Treg is
mutually exclusive. Although human Thp can also be skewed towards Th1
and Th2 phenotypes there is as yet no direct evidence for the
existence of discrete Th17 cells in humans nor of mutually
antagonistic development of Th17 cells and Tregs. There is
considerable evidence, however, both in humans and in mice for the
importance of interferon (IFN)-gamma and IL-17 in the development and
progression of inflammatory and autoimmune diseases (AD).
Unexpectedly, some models of autoimmunity thought traditionally to be
solely Th1-dependent have been demonstrated subsequently to have a non-
redundant requirement for Th17 cells, notably experimental allergic
encephalomyelitis and collagen-induced arthritis. In contrast, Tregs
have anti-inflammatory properties and can cause quiescence of
autoimmune diseases and prolongation of transplant function. As a
result, it can be proposed that skewing of responses towards Th17 or
Th1 and away from Treg may be responsible for the development and/or
progression of AD or acute transplant rejection in humans. Blocking
critical cytokines in vivo, notably IL-6, may result in a shift from a
Th17 towards a regulatory phenotype and induce quiescence of AD or
prevent transplant rejection. In this paper we review Th17/IL-17 and
Treg biology and expand on this hypothesis.

PMID: 17328715

* http://www.ingentaconnect.com/bsc/cei/2007/00000148/00000001/art00003
* http://openurl.ingenta.com/content?genre=article&issn=0009-9104&volume=148&issue=1&spage=32&epage=46
* http://dx.doi.org/10.1111/j.1365-2249.2007.03356.x

---------

TGF
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17137775&query_hl=1&itool=pubmed_docsum
Transforming growth factor-beta: innately bipolar.

* Wahl SM.

Oral Infection and Immunity Branch, National Institute of Dental and
Craniofacial Research (NIDCR), National Institutes of Health (NIH),
Bethesda, MD 20892-4352, USA. smw...@dir.nidcr.nih.gov
Widely heralded for depressing ongoing immune responses, renewed
interest in the proficiency by which transforming growth factor beta
(TGF-beta) not only engages but also might drive an over-reactive
innate response highlights its bipolar nature. Although coordination
of the development and function of Treg, in addition to direct
inhibition of cellular activation, are prominent pathways by which TGF-
beta controls adaptive immunity, paradoxically TGF-beta appears
instrumental in initiation of host responses to invasion through
recruitment and activation of immune cells and persuasion of Th17
lineage commitment. Nevertheless, true to its manic-depressive
behavior, new evidence links TGF-beta with depression of innate cells,
including NK cells, and by way of a potential bridge between mast
cells and Treg. Disruption of the tenuous balance between these
opposing actions of TGF-beta underlies immunopathogenicity.

PMID: 17137775

For research going along with PMID: 17372020 in the last post to this
thread.

http://en.wikipedia.org/wiki/Oncostatin_M

http://www.nature.com/icb/journal/v85/n2/full/7100032a.html

http://www.nature.com/icb/journal/v85/n2/full/7100035a.html

-------------------------
===============================================

Here are the abstracts for the last week that stand out in one way or
another.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17498449&query_hl=1&itool=pubmed_docsum
Increase of intracellular methylglyoxal levels as a mode of action of
retinoids against psoriasis.

* Namazi MR.

PMID: 17498449

And the explanation:

http://dermatology.cdlib.org/132/letters/retinoids/namazi.html

---------------

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17498423&query_hl=1&itool=pubmed_docsum
Unraveling the paradoxes of HIV-associated psoriasis: a review of T-
cell subsets and cytokine profiles.

* Fife DJ,
* Waller JM,
* Jeffes EW,
* Koo JY.

UC Irvine Department of Dermatology, USA.
HIV-associated psoriasis appears paradoxical, being a T-cell mediated
disease in the face of decreasing T-cell counts. Furthermore,
psoriasis is generally mediated by type-1 cytokines, whereas in HIV,
type-2 cytokines tend to predominate. How can one have psoriasis in
the essentially Th2 environment of HIV? The details and pertinent
research regarding T cell subsets and cytokine profiles in psoriasis,
HIV, and HIV-associated psoriasis were reviewed. It appears that both
in the presence and absence of HIV infection, psoriasis is largely
mediated by memory CD8 T cells, and that IFN-gamma secreted by these
cells and others is of key importance. Studying psoriasis in a model
such as HIV in which certain elements of the immune system are
stripped away or altered may help us better understand the pathogenic
mechanisms and potential treatment targets for psoriasis vulgaris.

PMID: 17498423

If we assume the hiv patient is on meds then it must be iatrogenic?
But still a paradox.

----------

Poor digestion or metabolism of fats?

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17497039&query_hl=1&itool=pubmed_docsum
Accumulation of oxidized low-density lipoprotein in psoriatic skin and
changes of plasma lipid levels in psoriatic patients.

* Tekin NS,
* Tekin IO,
* Barut F,
* Sipahi EY.

Department of Dermatology, Faculty of Medicine, Zonguldak Karaelmas
University, Kozlu, 67600 Zonguldak, Turkey.
Background. Psoriasis is a chronic inflammatory skin disease
characterized by an accelerated turnover of epidermal cells and an
incomplete differentiation in epidermis with lesion. However, the
exact etiology of psoriasis is unknown. Abnormalities in essential
fatty acid metabolism, free radical generation, lipid peroxidation,
and release of lymphokines have been proposed. Objective. Our purpose
was to evaluate the plasma lipids and oxidized low-density lipoprotein
accumulation in psoriatic skin lesion in order to ascertain the
possible participation of oxidative stress and oxidative modification
of lipids in pathogenesis of psoriasis. Methods. The study group
included 84 patients with psoriasis, and 40 sex- and age-matched
healthy volunteers. Blood lipid profile was determined. Psoriatic and
nonlesional skin samples of psoriatic patients were evaluated for the
presence of oxidized low-density lipoprotein by using an immune-
fluorescent staining method. Results. The mean levels of lipids (total
cholesterol, triglyceride, and LDL cholesterol) in patients with
psoriasis were found to be significantly higher than those of healthy
subjects. Psoriatic skins were shown positive oxidized low-density
lipoprotein staining. There was no staining in nonlesional skin
samples of the same individuals. Conclusion. Lipid peroxidation
mediated by free radicals is believed to be one of the important
causes of cell membrane destruction and cell damage. This study shows
for the first time the accumulation of oxidized low-density
lipoprotein in psoriatic skin lesion. We believe that accumulation of
ox-LDL in psoriatic skin may have an important role in the immune-
inflammatory events that result in progressive skin damage.

PMID: 17497039

We aren't fat heads. We're fat skins with some ROS going on.

Is this why a low fat diet works for psoriasis? Less fat means less
ROS and hence
less psoriasis?

------------------

The MOA of FAE's rears it's lovely head.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17495961&query_hl=1&itool=pubmed_docsum
Dimethylfumarate Specifically Inhibits the Mitogen and Stress-
Activated Kinases 1 and 2 (MSK1/2): Possible Role for its Anti-
Psoriatic Effect.

* Gesser B,
* Johansen C,
* Rasmussen MK,
* Funding AT,
* Otkjaer K,
* Kjellerup RB,
* Kragballe K,
* Iversen L.

1Department of Dermatology, Aarhus University Hospital, Aarhus,
Denmark.
The p38 mitogen-activated protein kinase (MAPK) signaling pathway,
which regulates the activity of different transcriptions factors
including NF-kappaB, is activated in lesional psoriatic skin. The
purpose of this study was to investigate the effect of fumaric acid
esters (FAEs) on the p38 MAPK and the downstream kinases mitogen- and
stress-activated protein kinase (MSK)1 and 2 in cultured human
keratinocytes. Cell cultures were incubated with dimethylfumarate
(DMF), methylhydrogenfumarate (MHF), or fumaric acid (FA) and then
stimulated with IL-1beta before kinase activation was determined by
Western blotting. A significant inhibition of both MSK1 and 2
activations was seen after preincubation with DMF and stimulation with
IL-1beta, whereas MHF and FA had no effect. In addition, DMF decreased
phosphorylation of NF-kappaB/p65 (Ser276), which is known to be
transactivated by MSK1. Furthermore, incubation with DMF before
stimulation with IL-1beta resulted in a significant decrease in NF-
kappaB binding to the IL-8 kappaB and the IL-20 kappaB-binding sites
as well as a subsequent decrease in IL-8 and IL-20 mRNA expression.
Our results suggest that DMF specifically inhibits MSK1 and 2
activations and subsequently inhibits NF-kappaB-induced gene-
transcriptions, which are believed to be important in the pathogenesis
of psoriasis. These effects of DMF explain the anti-psoriatic effect
of FAEs.Journal of Investigative Dermatology advance online
publication, 10 May 2007; doi:10.1038/sj.jid.5700859.

PMID: 17495961

--------------

What comes first? The LDL fats in the skin or lack of oxygen?
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17495954&query_hl=1&itool=pubmed_docsum
Upregulation of Hypoxia-Inducible Factors in Normal and Psoriatic
Skin.

* Rosenberger C,
* Solovan C,
* Rosenberger AD,
* Jinping L,
* Treudler R,
* Frei U,
* Eckardt KU,
* Brown LF.

1Nephrology and Medical Intensive Care, Charite Universitatsmedizin,
Virchow Campus, Berlin, Germany.
Angiogenesis induced by vascular endothelial growth factor (VEGF)
plays an important role in psoriasis. Hypoxic adaptation is conferred
through hypoxia-inducible transcription factors (HIFs). VEGF and its
receptor Flt-1 are HIF target genes. Growth factors and inflammatory
cytokines activate the phosphoinositol-3 kinase pathway, and via
activated protein kinase B (phospho-Akt) augment HIF activity. Here,
we demonstrate that the major oxygen-dependent HIF isoforms are
strongly upregulated in psoriatic skin: HIF-1alpha mainly in the
epidermis, in an expression pattern similar to VEGF mRNA; HIF-2alpha
in both the epidermis and in capillary endothelial cells of the
dermis. In contrast, normal human skin shows low expression of HIF-
alpha proteins, with the exception of hair follicles, and glands,
which strongly express HIF-1alpha. In normal human skin, phospho-Akt
appeared in the basal epidermal layer, in hair follicles, and in
dermal glands. In contrast, in psoriasis, phospho-Akt expression was
low in the epidermis, but markedly enhanced in the dermal capillaries
and in surrounding interstitial/inflammatory cells. Our data suggest
that hypoxia initiates a potentially self-perpetuating cycle involving
HIF, VEGF, and Akt activation, which could drive physiologic growth of
hair follicles and skin glands. Furthermore, such a cycle may exist in
psoriasis in dermal capillaries and contribute to disease
progression.Journal of Investigative Dermatology advance online
publication, 10 May 2007; doi:10.1038/sj.jid.5700874.

PMID: 17495954

================================

randall... may your days be sunny and clear...

randall

unread,

May 20, 2007, 4:25:33 PM5/20/07

Hi,

This next article is hoPeful. The gut scientists are finally on the
right path or so we hope.
That which is in us, living symbiotically controls more then we KNOW.
Or at least more then they know. The last two posts, may 14 & 18th
dealt
with a NEW Th17 aka-il-17, also had unKNOWNs to the science world
till now.
The microbes in the gut (Gi tract) seemingly more important then meds
from without, lead to health or disease for autoimmune conditions or
so all this NEW SCIEnCE is leading us to believe.

These increasingly aware scientists may even pass me up one of these
days.

But I doubt it. LOL

Till they can change the microbiota of the gut to their/our advantage,
i'm ahead of them. <w>

There was one guy with a IL-10 raising bug for the colon reported a
few years back.

I'll have to see what he's up to again. Still that worked in a
straight Th1/Th2 paradigm,
maybe not with Th17?

When will we learn the truth here?

Untill then,

http://www.sciencenews.org/articles/20070519/bob9.asp
Our Microbes, Ourselves
How bacterial communities in the body influence human health

[...]

Investigations of the human microbiota could also shed light on
complex skin conditions such as psoriasis and eczema. At present, most
researchers consider psoriasis to be caused by the immune system gone
awry. But because human skin is home to a complex ecosystem of mostly
unidentified bacteria, Martin Blaser, a microbiologist at the New York
University School of Medicine, suggests that microbes are involved.
"The field of investigative dermatology has almost completely ignored
the role of microbes," he says.

To demonstrate the complexity of the skin's microbiota, Blaser's group
analyzed skin swabs taken from the inner forearms of six healthy
people. Reporting in the Feb. 20 Proceedings of the National Academy
of Sciences, the researchers identified 182 species of bacteria. Each
person showed a unique microbial makeup-only four species of bacteria
were found in all six participants, and each participant carried an
average of 48 species. The results offer a first glimpse of the
diverse array of microbial species inhabiting healthy skin, Blaser
says.

The researchers resampled four of the participants 8 to 10 months
later and found many of the microbes previously identified along with
65 new bacterial species. All the volunteers had retained some of
their previous microbial residents and had acquired new ones. The
result suggests that each individual's skin harbors both a core set of
microbes and a group of transient members.

Blaser's lab is now examining people with psoriasis to see whether
there's a microbial signature for the skin disease.

However, identifying individual species may be irrelevant in some
cases of disease caused by microbial communities. "It might not matter
who is there but rather what the collective is doing," says Relman.

For instance, he's found that some people with severe gum disease
harbor an abundance of hydrogen-consuming microbes called methanogens.
Related to bacteria but properly classified as archaea, methanogens
live in the deep gaps between gums and teeth.

But not everyone with severe gum disease hosts methanogens. Other
people's afflicted mouths instead support large populations of
hydrogen-consuming bacteria called treponemes.

Hydrogen is a by-product of fermentation in oxygen-deprived
environments, such as the tooth-gum gaps, and it also limits growth
among hydrogen-producing microbes. Relman says that through a behavior
called syntropy, the hydrogen-consuming microbes-whether methanogens
or treponemes-work together with the other microbes to stabilize the
microbial community and keep it going.

Similarly, Gordon's group found that two common species of gut
microbes work together to boost fat storage in germ-free mice (SN:
6/17/06, p. 373: Available to subscribers at
http://www.sciencenews.org/articles/20060617/fob5.asp).

These observations reinforce the notion that to develop new <sniP>

==================================================

WELL, most of the article deals with flora in us and not on us. That
within stoPs the sin without or so we hoPe without a doubt? <w>

Nevertheless, we've seen links recently that oral flora may be a
trigger.
Or indirectly thru their endotoxins?

So oral flora -> LPS (endotoxin)-> Th1 skew + p genes = a life
time of craP.

Or further down the Gi tract LPS and the same thing? Take your pick.

Enough for now....we'll be shouting and not pouting when it's gone!

(((((((((((((((((((((((((((((((((((((((((((())))))))))))))))))))))))))))))))))))))))))

To rehash the last two posts.

http://www.rxpgnews.com/research/Molecule-that-destroys-bone-also-protects-it-new-research-shows_29868.shtml

[...]

IL-17 is a cytokine, a protein hormone made by T helper cells of the
immune system that stimulate immunity. Gaffen noted that until
recently, immunologists believed there were only two major types of T
helper cells -- TH1 and TH2 -- which were believed to be responsible
for nearly all immune system activities.

This paradigm underwent a sea change in 2005 with the discovery of a
new type of T cell that produces IL-17, now called TH-17, she said. We
know now that almost all autoimmune diseases, at least in the mouse
model, are caused by TH-17 cells. This new information has forced
scientists to revise completely how they view their favorite disease.
Everyone now has to rethink the causative mechanism.

Developing knowledge about the molecules that contribute to host
defense versus pathology is very important for gaining a fundamental
understanding of the immune system, Gaffen said, but also because the
consequences of therapies that target these cytokines need to be
understood.

<end>

_______________________________________

I don't know about you, but would you give uP dental bone mass for
clear skin?

This Th1/Th2 teeter totter just got more comPlicated as stated in the
last two
posts.

I guess you can see i'm hooked on it now. LOL

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17504655&query_hl=1&itool=pubmed_docsum
Changing paradigms in the immunological science of allergy.

* Goetzl EJ.

Department of Medicine, University of California, Room UB8B, UC Box
0711, 533 Parnassus Avenue at 4th Avenue, San Francisco, CA
94143-0711, USA. edward...@ucsf.edu

The nonallergic roles of mast cells in infections and immune tolerance
recently have been elucidated more fully at mechanistic levels. Mast
cells that have been activated by contact with microbial surfaces
secrete chemotactic mediators capable of attracting leukocytes through
blood vessels permeabilized by other mediators. In the setting of
allograft transplantation, regulatory CD4 T cells promote tolerance
both by direct immunosuppressive effects and by releasing interleukin
(IL)-9 that attracts and stimulates differentiation of mast cells with
the capacity to induce local tolerance. For the first time in over 20
years, two new subclasses of CD4 T cells have been identified that
have major immune functions. The first are T-helper interleukin-17
(T(H)17) cells, which mediate acute and chronic inflammation in
recurring exacerbations of autoimmune diseases, and the second are
sets of adaptive regulatory T cells, which control CD4 effector T
cells and other immune effector cells by secreting transforming growth
factor-beta or IL-10.

PMID: 17504655

As reported recently and not so recently, some of us have been taking
glucosamine. And then this post by Manfred came out the last few days
concerning N-acetylglucosamine (GlcNAc) and MS was posted here.

Letting that cat out of the bag for the 9th time.

Is there something in this for us?

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=14507305&query_hl=4&itool=pubmed_docsum
Immunobiological effects of glucosamine in vitro.

* Forchhammer L,
* Thorn M,
* Met O,
* Gad M,
* Weidner MS,
* Claesson MH.

Department of Medical Anatomy, The Panum Institute, The University of
Copenhagen, Denmark.

Glucosamine (GlcN) and N-acetyl-d-glucosamine (GlcNAc) were assayed in
vitro for their effects on proliferation, cytotoxicity and cytokine
secretion in primary and secondary mixed lymphocyte cultures (MLCs).
In addition, we studied the effect of GlcN and GlcNAc on the
proliferation of purified CD4+ T cells exposed to immobilized anti-CD3
antibody. The present data show that GlcN, but not GlcNAc, inhibits
CD4+ T-cell proliferation, the generation of alloreactive cytotoxic T
lymphocytes (CTLs) and the secretion of interferon-gamma (IFN-gamma)
and interleukin-5 (IL-5) in primary MLC. In secondary T helper-2 (Th2)-
polarized MLC, GlcN, but not GlcNAc, inhibits IL-4 and IL-5 secretion,
whereas no effect was found on IFN-gamma secretion in Th1-polarized
MLC. Dendritic cells treated with GlcN showed a 75-80% decreased
capacity for antigen cross-presentation and allostimulation. In
cellular bioassays, GlcN was shown to inhibit the stimulatory activity
of IL-4 and IL-2, as well as the cytotoxic activity of tumour necrosis
factor-alpha (TNF-alpha). In conclusion, GlcN suppresses unprimed T-
cell responses by interfering with antigen-presenting cell functions
and by a direct inhibitory effect on T-cell proliferation. In
addition, GlcN inhibits the secretion of cytokines in antigen-
stimulated unprimed T cells and primed Th2-polarized cells.

PMID: 14507305

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=15585841&query_hl=4&itool=pubmed_docsum
N-acetylglucosaminyltransferase V (Mgat5)-mediated N-glycosylation
negatively regulates Th1 cytokine production by T cells.

* Morgan R,
* Gao G,
* Pawling J,
* Dennis JW,
* Demetriou M,
* Li B.

Department of Antibacterials, Immunology, and Cancer, Pfizer Global
Research and Development, Groton, CT 06340, USA.

The differentiation of naive CD4(+) T cells into either
proinflammatory Th1 or proallergic Th2 cells strongly influences
autoimmunity, allergy, and tumor immune surveillance. We previously
demonstrated that beta1,6GlcNAc-branched complex-type (N-
acetylglucosaminyltransferase V (Mgat5)) N-glycans on TCR are bound to
galectins, an interaction that reduces TCR signaling by opposing
agonist-induced TCR clustering at the immune synapse. Mgat5(-/-) mice
display late-onset spontaneous autoimmune disease and enhanced
resistance to tumor progression and metastasis. In this study we
examined the role of beta1,6GlcNAc N-glycan expression in Th1/Th2
cytokine production and differentiation. beta1,6GlcNAc N-glycan
expression is enhanced by TCR stimulation independent of cell division
and declines at the end of the stimulation cycle. Anti-CD3-activated
splenocytes and naive T cells from Mgat5(-/-) mice produce more IFN-
gamma and less IL-4 compared with wild-type cells, the latter
resulting in the loss of IL-4-dependent down-regulation of IL-4Ralpha.
Swainsonine, an inhibitor of Golgi alpha-mannosidase II, blocked
beta1,6GlcNAc N-glycan expression and caused a similar increase in IFN-
gamma production by T cells from humans and mice, but no additional
enhancement in Mgat5(-/-) T cells. Mgat5 deficiency did not alter IFN-
gamma/IL-4 production by polarized Th1 cells, but caused an
approximately 10-fold increase in IFN-gamma production by polarized
Th2 cells. These data indicate that negative regulation of TCR
signaling by beta1,6GlcNAc N-glycans promotes development of Th2 over
Th1 responses, enhances polarization of Th2 cells, and suggests a
mechanism for the increased autoimmune disease susceptibility observed
in Mgat5(-/-) mice.

PMID: 15585841

What does this mean?

Well. In the old Th1 th2 paradigm it looks good.

With the new Th17 (il17) paradigm, who knows.

Try taking some
http://www.easycart.net/BeyondACenturyInc./Glucosamine_Chondroitin_Etc.html#7374

And let us know how you do. Or let me know.

-----------------------------------

randall.... Lets have fun and get clear in the process!

randall

unread,

May 27, 2007, 1:57:44 PM5/27/07

Hi,

Do psoriatics have one GENE to few? Wouldn't that
be a twist? Instead of looking for THE *p* GENE we should
be wondering if we have enough FCGR3B genes.

Certainly to few of these puPPies leads to SLE (luPus)?

http://www.medicalnewstoday.com/medicalnews.php?newsid=71973
Genes Add Up Risk Of Autoimmune Disease
Geneticists have identified a link between the number of copies of a
specific gene an individual has and their susceptibility to autoimmune
diseases like lupus. Research using DNA has revealed that people who
have a below average number of copies of a gene, known as FCGR3B, have
an increased risk of developing diseases caused when the body's immune
system attacks its own tissue.

The research by Professor Tim Aitman of the Medical Research Council
Clinical Sciences Centre at Imperial College London, and colleagues,
is published in Nature Genetics.

Professor Aitman explains the team's research discovery:

''The variations in DNA that people carry contribute to observable
characteristics like height, weight and skin colour. Genetic
variations have similar effects on individual susceptibility to
disease. In this research our team focused on structural differences
in the genome and set out to determine whether the number of copies of
a particular gene a person has influences their chances of developing
an autoimmune disease. We discovered that not only does the number of
copies of a gene you have influence your chances of disease but that
this kind of structural variation in the genome could be driving
evolution of human weaknesses for infection and inflammation.'' The
team studied DNA from two groups of people living in the UK and
France. They discovered that people who have a comparatively low
number of FCGR3B genes are more likely to suffer from autoimmune
diseases like lupus (systemic lupus erythematosus) that affect the
whole body. The same link was not found to autoimmune conditions
affecting just one organ such as Addisons' disease, which damages the
adrenal gland, or Graves' disease, which attacks the thyroid.

Human genome research increasingly provides evidence that individuals
vary in the number of copies of genes present in each of their
genomes. Professor Aitman concludes:

''Our discovery highlights the importance of gene copy number
variation, that is differences in the number of copies of a specific
gene a person carries, in genetic predisposition to common human
diseases. The next step is to find out whether genes that are closely
related to this susceptibility gene, FCGR3B, also vary in copy number
and predispose to similar diseases.''

The research team hopes to achieve these aims by studying the genomes
of individual people to find out if there is any correlation between
gene copy number and patterns of disease presentation or responses to
specific treatments.

Medical Research Council
www.mrc.ac.uk

Let's ihoP it,
http://www.ihop-net.org/UniPub/iHOP/gs/88164.html

[...]
FCGR3B is the Fc fragment of IgG, low affinity IIIb, receptor
(CD16b)

AKA's---CD16, CD16b, CD16B, CD16b antigen, FCG3, Fc-gamma RIII, Fc-
gamma RIIIb, Fc-gamma RIII-beta, FCGR3, FcR-10, FcRIII, FcRIIIb,
IGFR3, IgG Fc receptor III-1, Low affinity immunoglobulin gamma Fc
region receptor III-B precursor
<sniP>
&
Pubmed it,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Search&db=PubMed&term=FCGR3B&tool=QuerySuggestion

Look at #10. Do we have more oral connections this week? LOL

This should take some time. So let's move on.

For keywords sake:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15245367
Characterization of human FCGR3B*02 (HNA-1b, NA2) cDNAs and IMGT
standardized description of FCGR3B alleles.

* Bertrand G,
* Duprat E,
* Lefranc MP,
* Marti J,
* Coste J.

Laboratoire R & D, Agents Transmissibles par transfusion,
Etablissement Francais du Sang Pyrenees-Mediterranee, Montpellier,
France.

The low-affinity Fc gamma receptor IIIb (Fc gamma RIIIb and CD16b) is
constituted by a unique FCGR3B polypeptide chain that comprises two
extracellular immunoglobulin-like domains, and is expressed as a
glycosylphosphatidyl inositol-anchored receptor on the neutrophils.
The FCGR3B chain bears allotypes that define the human neutrophil
antigen-1 (HNA-1 and NA) system involved in major post-transfusional
reactions. FCGR3B is highly homologous to FCGR3A, which is expressed
as a transmembrane receptor on natural killer cells and monocytes/
macrophages. Its transcription products were not yet fully
characterized. In the present work, we sequenced FCGR3B cDNAs with
complete 3' untranslated region from purified granulocytes of HNA-1b/
HNA-1b (NA2/NA2) genotyped donors. We characterized two FCGR3B cDNAs
of different lengths corresponding to two polyadenylation sites. This
result was corroborated by data raised by serial analysis of gene
expression (SAGE). FCGR3B allele polymorphisms, from this article
[FCGR3B*02 (HNA-1b, NA2)] and from the literature, are described for
the first time according to the IMGT standardized nomenclature and to
the IMGT unique numbering for C-LIKE-DOMAIN (http://imgt.cines.fr).
These rules, described in the IMGT Scientific chart, are based on the
IMGT-ONTOLOGY concepts. IMGT allele alignments and IMGT Collier de
Perles graphical two-dimensional representations are provided for the
two Ig-like domains (or C-LIKE-DOMAINs) [D1] and [D2] of FCGR3B*02.
The standardized description of FCGR3B allele polymorphisms was
approved by the IMGT Nomenclature Committee (IMGT-NC) and is freely
available in IMGT repertoire at IMGT, http://imgt.cines.fr.

PMID: 15245367

Now we'll move on.

But a pubmed search of IGg and gliadin may turn uP a clue.

Is it all a simPle wheat thing like stirling imPlicated?

Nah...

---------

Caspase-14 and Skin Health
http://www.news-medical.net/?id=25379

& a pubmed to go with it,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17515931&query_hl=19&itool=pubmed_docsum
Caspase-14 protects against epidermal UVB photodamage and water loss.

* Denecker G,
* Hoste E,
* Gilbert B,
* Hochepied T,
* Ovaere P,
* Lippens S,
* Van den Broecke C,
* Van Damme P,
* D'Herde K,
* Hachem JP,
* Borgonie G,
* Presland RB,
* Schoonjans L,
* Libert C,
* Vandekerckhove J,
* Gevaert K,
* Vandenabeele P,
* Declercq W.

[1] Department for Molecular Biomedical Research, VIB, Technologie
Park 927, B-9052, Ghent, Belgium. [2] Department of Molecular Biology,
Ghent University, Technologie Park 927, B-9052, Ghent, Belgium.

Caspase-14 belongs to a conserved family of aspartate-specific
proteinases. Its expression is restricted almost exclusively to the
suprabasal layers of the epidermis and the hair follicles. Moreover,
the proteolytic activation of caspase-14 is associated with stratum
corneum formation, implicating caspase-14 in terminal keratinocyte
differentiation and cornification. Here, we show that the skin of
caspase-14-deficient mice was shiny and lichenified, indicating an
altered stratum-corneum composition. Caspase-14-deficient epidermis
contained significantly more alveolar keratohyalin F-granules, the
profilaggrin stores. Accordingly, caspase-14-deficient epidermis is
characterized by an altered profilaggrin processing pattern and we
show that recombinant caspase-14 can directly cleave profilaggrin in
vitro. Caspase-14-deficient epidermis is characterized by reduced skin-
hydration levels and increased water loss. In view of the important
role of filaggrin in the structure and moisturization of the skin, the
knockout phenotype could be explained by an aberrant processing of
filaggrin. Importantly, the skin of caspase-14-deficient mice was
highly sensitive to the formation of cyclobutane pyrimidine dimers
after UVB irradiation, leading to increased levels of UVB-induced
apoptosis. Removal of the stratum corneum indicate that caspase-14
controls the UVB scavenging capacity of the stratum corneum.

PMID: 17515931

Would uPregulation of caspase-14 protect against to few FCGR3B's?

NAh!

Let's move on to global warming.

Is it good or bad for P? LOL
-----------

http://lfpress.ca/newsstand/News/Local/2007/05/27/4211599-sun.html

[...]
Pollution, said London researcher Lina Dagnino, who studies the
formation of skin cancers, contains chemicals with "oxidative agents,"
which are known to "co-operate with UV to make things worse and cause
cancer."

A link has been found between oxidative agents in creams to control
psoriasis that actually increase susceptibility to cancer, she said.

Such agents can be found in a wide variety of chemicals in poor-
quality air, said Dagnino, an associate professor of physiology,
pharmacology and obstetrics at the University of Western Ontario.

While skin cancer accounts for one-third of all cancers, Dagnino said,
a good prognosis can result from early detection and treatment. "Very
few people die from it," she said.

Research into the combination of ultraviolet radiation and pollution
is in its infancy, she conceded. "This is something we are just
starting to look at."

Besides chemicals and fine particles that sweep across the region,
stagnant, ground-level ozone on smog days also magnifies ultraviolet
radiation. <sniP>

-------------

Understading Ai
http://news.biocompare.com/newsstory.asp?id=183290
Scientists Develop Method To Track Immune System Enzyme In Live
Animals
5/17/2007
Scientists supported by the National Institute of Arthritis and
Musculoskeletal and Skin Diseases (NIAMS) at the National Institutes
of Health have created two mouse strains that will permit researchers
to trace, in a live animal, the activity of an enzyme believed to play
a crucial role both in the normal immune response as well as
autoimmunity and B cell tumor development. Their report appears in the
Journal of Experimental Medicine.

The enzyme, known as activation-induced cytidine deaminase or AID
(which has no relation to the AIDS virus), is expressed by B cells,
which are produced in the bone marrow and are responsible for making
antibodies that attack foreign invaders such as viruses and bacteria.
The enzyme enables the cells to respond with precision to the almost
limitless types of invaders the body may encounter. Unfortunately, it
also has a down side.

B cells constantly scan the body for foreign invaders, explains Rafael
Casellas, Ph.D., an investigator in NIAMS' Molecular Immunology and
Inflammation Branch and lead author of the paper. As B cells encounter
foreign antigens from viruses, bacteria or allergens, they migrate to
germinal centers - specialized microenvironments in tonsils, spleen
and lymph nodes. Within germinal centers, B cells divide extensively
and express the AID enzyme, which causes random mutations and
recombination in the cells' immunoglobulin (antibody) genes. For the
most part, these genetic changes are beneficial because they enable B
lymphocytes to attack and stop the invader. In some cases, however,
AID-dependent alterations in the genetic material of B cells can also
lead to unwanted results such as autoimmunity and development of B
cell tumors, as in the case of Burkitt lymphoma.

"It becomes crucial that we comprehend how AID is regulated during the
normal immune response as well as in tumorigenesis and autoimmunity,"
says Casellas. The problem with understanding how AID is regulated or
deregulated is that there has not been an easy way to visualize the
enzyme's action in a living animal - until now.

To address this issue, Dr. Casellas and his colleagues created
transgenic mice that had a green fluorescent protein derived from
jellyfish fused to the AID enzyme. In these transgenic animals, B
cells express the tagged enzyme during the immune response. In a
second mouse strain, Casellas and coworkers expressed permanently a
yellow fluorescent protein in the progeny of germinal center B cells.
"Thanks to these new mouse models, we can track in live animals
whenever the AID enzyme is active as well as the result of that
activity," says Casellas. Scientists can also cross these new mouse
strains with mice predisposed to B-cell tumors or autoimmunity to see
differences in enzyme expression in health and disease.

NIAMS Director Stephen I. Katz. M.D., Ph.D., believes these new tools
have great potential to help solve some mysteries of the immune
system, such as the causes of B-cell tumors and autoimmunity. "The
better we understand these problems," he says, "the closer we come to
better treatments for them and eventually, perhaps, ways to prevent
them."

---------------

Since i'm taking ALA and ALC (alcar) right now. This next one is
helPful.
Lipoic Acid Explored As Anti-Aging Compound
5/17/2007
Source: Oregon State University

Researchers said today they have identified the mechanism of action of
lipoic acid, a remarkable compound that in animal experiments appears
to slow down the process of aging, improve blood flow, enhance immune
function and perform many other functions.

The findings, discussed at the "Diet and Optimum Health" conference
sponsored by the Linus Pauling Institute at Oregon State University,
shed light on how this micronutrient might perform such a wide range
of beneficial functions.

"The evidence suggests that lipoic acid is actually a low-level
stressor that turns on the basic cellular defenses of the body,
including some of those that naturally decline with age," said Tory
Hagen, an LPI researcher and associate professor of biochemistry and
biophysics at OSU. "In particular, it tends to restore levels of
glutathione, a protective antioxidant and detoxification compound, to
those of a young animal. It also acts as a strong anti-inflammatory
agent, which is relevant to many degenerative diseases."

Researchers at LPI are studying vitamins, dietary approaches and
micronutrients that may be implicated in the aging or degenerative
disease process, and say that lipoic acid appears to be one of those
with the most compelling promise. It's normally found at low levels in
green leafy vegetables, but can also be taken as a supplement.

According to Hagen, research on the natural processes of aging, and
steps that could slow it or improve health until near the end of life,
are of growing importance.

"We're coming into the middle of an aging epidemic in the country," he
said. "In a short time more than 70 million Americans will be over 65.
This is partly because of the Baby Boom, but also people are living
longer, being saved with antibiotics and other medical treatments. In
any case, it will be an unprecedented number of elderly people in this
nation."

The goal of LPI research, Hagen said, is to address issues of
"healthspan," not just lifespan - meaning the ability to live a long
life with comparatively good health and vigor, free of degenerative
disease, until very near death. The best mechanisms to accomplish
that, scientists say, have everything to do with diet, exercise,
healthy lifestyle habits and micronutrient intake.

At the moment, Hagen said, that's not the way things appear to be
headed - diabetes is skyrocketing, about 50 percent of people over 65
have high blood pressure, heart disease often leads to permanent
disability, and almost half of the elderly people in America have
malnutrition that is easily preventable.

No single intervention can address all of these issues, Hagen said,
but one that scientists keep coming back to is lipoic acid.

"Our studies have shown that mice supplemented with lipoic acid have a
cognitive ability, behavior, and genetic expression of almost 100
detoxification and antioxidant genes that are comparable to that of
young animals," Hagen said. "They aren't just living longer, they are
living better - and that's the goal we're after."

What the OSU researchers now believe is that the role of lipoic acid
is not so much a direct one to benefit cells, but rather an indirect
aid that "kick starts" declining function in cells and helps them
recover the functions that came more easily and naturally in young
animals.

In various effects, lipoic acid appears to help restore a cellular
"signaling" process that tends to break down in older blood vessels.
It reduces mitochondrial decay in cells, which is closely linked to
the symptoms of aging. With age, glutathione levels naturally decline,
making older animals more susceptible to both free radicals and other
environmental toxins - but lipoic acid can restore glutathione
function to near normal. And the expression and function of other
genes seems to come back to life.

"We never really expected such a surprising range of benefits from one
compound," Hagen said. "This is really unprecedented, and we're pretty
excited about it."

Many other presentations have been made at this conference on the role
of diet, lifestyle and micronutrients in health and degenerative
disease, including cancer, heart disease, neurological diseases and
aging.

The conference is organized every two years by OSU's Linus Pauling
Institute, and attracts leading experts from around the world in these
research fields.

=====================

This one should have went with the last one in this thread regarding
Th-17.

It made a point or two.

http://www.expresspharmaonline.com/20070531/research01.shtml

[...]
Topical cortico steriods like Betamethasone, Beclomethasone,
Mometasone, Clobetasol, Hydrocor-tisone can be used to treat
psoriasis. However, the mechanism of the anti-inflammatory activity of
the topical steroids, in general, is unclear. "Corticosteroids are
thought to act by the induction of phospholipase A2 inhibitory
proteins, collectively called lipocortins. It is postulated that these
proteins control the biosynthesis of potent mediators of inflammation
such as prostaglandins and leukotrienes by inhibiting the release of
their common precursor, arachidonic acid. Arachidonic acid is released
from membrane phospholipids by phospholipase A2,"
[...]
Lupin is amongst the companies which are ardently pursuing derma
research. It has in its kitty a novel anti-psoriasis compound called
Desoris which acts by enhancing IL-10. "Two exploratory studies were
conducted to evaluate the efficacy and safety of this herbal oral
formulation for the treatment in patients with chronic stable plaque
type of psoriasis," informs Arora. In the first study (open, non-
comparative), out of 22 completed patients 11 patients showed
Psoriasis Area and Severity Index (PASI) score reduction by 100
percent and 10 patients showed more than 75 percent reduction in PASI
score. In the second study (double blind, randomised and parallel),
treatment "LLL 3348" was effective in reducing PASI score by 75
percent in eight out of 26 subjects. "Further, there were no
significant adverse effects of the drug observed during clinical, ECG,
and laboratory investigations evaluations when post-treatment means
were compared with pre-treatment means," avers Arora.

Lupin has recently also announced a collaboration project with
Department of Science and Technology (DST) for the clinical
development of its psoriasis projects. The collaboration will support
the extended Phase I and Phase II trials of LL-4218, a pure compound
derived from an herbal source, for the treatment of chronic stable
plaque type of psoriasis. The project is expected to be completed in
two years.
----------

Randall.... sun's out! must move on...

randall

unread,

May 29, 2007, 12:40:49 PM5/29/07

Hi,

Vitamin D doctor receives Linus Pauling award.
http://www.medicalnewstoday.com/medicalnews.php?newsid=72309

------------------------------------

ABSTRACTS:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17530646&query_hl=1&itool=pubmed_docsum
TNF polymorphisms in psoriasis: Association of psoriatic arthritis
with the promoter polymorphism TNF*-857 independent of the PSORS1 risk
allele.

* Reich K,
* Huffmeier U,
* Konig IR,
* Lascorz J,
* Lohmann J,
* Wendler J,
* Traupe H,
* Mossner R,
* Reis A,
* Burkhardt H.

Georg-August-University Gottingen, Gottingen, Germany.

OBJECTIVE: Single-nucleotide polymorphisms (SNPs) of the tumor
necrosis factor gene TNF at positions -238 and -308 have been
associated with psoriasis vulgaris and psoriatic arthritis (PsA). The
strong linkage disequilibrium (LD) at chromosome region 6p21, a region
known to harbor risk factors for psoriasis susceptibility (PSORS1)
other than just SNPs of the TNF gene, renders the interpretation of
these findings difficult. The aim of this study was to analyze several
SNPs of the TNF gene and its neighboring LTA gene for independent and
dependent carriage of the PSORS1 risk allele. METHODS: SNPs in the
promoter of the TNF (-238G/A, -308G/A, -857C/T, and -1031T/C), LTA
(+252A/G), TNLFRSF1A (+36A/G), and TNLFRSF1B (+676T/G) genes were
genotyped in 375 psoriasis patients, 375 PsA patients, and 376
controls. The Trp- Trp-Cys-Cys haplotype of the CCHCR1 gene
(CCHCR1*WWCC) was used as an estimate of the risk allele PSORS1.
RESULTS: Whereas we were able to confirm the previously described
strong association of allele TNF*-238A with psoriasis, our study
revealed that this association was completely dependent on carriage of
the PSORS1 risk allele. For PsA, but not psoriasis vulgaris without
joint involvement, a strong association with the allele TNF*-857T
(odds ratio 1.956 [95% confidence interval 1.334-2.881]; corrected P =
0.0025) was also detected in patients negative for the PSORS1 risk
allele. CONCLUSION: Our results indicate that there are genetic
differences between psoriasis vulgaris patients with and without joint
manifestations. While the previously reported association between
TNF*-238A and psoriasis seems to primarily reflect LD with PSORS1,
TNF*-857T may represent a risk factor for PsA that is independent of
the PSORS1 allele.

PMID: 17530646

----------------

http://www.medicalnewstoday.com/medicalnews.php?newsid=71793&nfid=nl
Positive Clinical Data On CC-10004 Confirms Potential As Novel Oral
Approach To Treating Inflammatory Diseases

Celgene Corporation (Nasdaq: CELG) announced its plans to advance the
development of leading oral anti-inflammatory candidates across a
broad range of inflammatory diseases. CC-10004 (apremilast), an oral
TNF antagonist and anti-inflammatory agent has demonstrated
significant activity and an excellent side effect profile in a placebo
controlled proof-of-mechanism trial in psoriasis.

The multicenter, randomized, double blind, placebo-controlled Phase II
study achieved the primary endpoint after 12 weeks of treatment with
24% of patients receiving CC-10004 twice daily achieving a PASI-75
score compared to 10% of those receiving placebo. The Psoriasis Area
and Severity Index (PASI) is a standard measurement of response
utilized to assess improvement in patients with moderate to severe
psoriasis. In addition, 57% of patients receiving CC-10004 twice daily
achieved a PASI-50 compared to 23% of those receiving placebo. Most
importantly, patients receiving CC-10004 continued to improve over
time.

"The data from the Phase II study in patients with moderate-to-severe
psoriasis are clinically and statistically significant compared with
placebo. In addition, patients continued to improve throughout the 12
week treatment regimen with an oral therapy that has a good side
effect profile addressing an unmet medical need," said Alice Gottlieb,
M.D., Ph.D., Dermatologist in Chief and Chair, Department of
Dermatology of Tufts-New England Medical Center. "The PASI-90 response
of 14% for CC-10004 is comparable to Enbrel dosed at 25 mg twice
weekly."

Based on these results, Celgene is accelerating clinical and
regulatory strategies for CC-10004 in psoriasis, psoriatic arthritis,
rheumatoid arthritis and other inflammatory diseases. The Company is
also initiating development plans to advance CC-11050 and other
compounds from this class of oral TNF alpha inhibitors, as potential
novel oral therapies for chronic inflammatory diseases.

"CC-10004 is a unique oral therapy that demonstrates reasonable
efficacy and favorable safety profile in a moderate to severe
psoriasis setting. The drug is clearly working," said Kim Papp, M.D.,
Ph.D., Assistant Clinical Professor of Medicine at the University of
Western Ontario, Canada and a principle investigator of the Phase II
study.

Adverse side effects in patients receiving CC-10004 were mild and well
tolerated. Overall, the percentage of patients who reported at least
one adverse event in the CC-10004 twice daily arm (54%) was equivalent
to that experienced with the placebo arm of the study (60%).

"These positive results validate the potential of our oral class of
anti- inflammatory compounds," said Sol J. Barer, Ph.D., Chairman and
Chief Executive Officer of Celgene Corporation. "We plan to evaluate
multiple opportunities across a broad range of debilitating
inflammatory diseases where there are limited effective oral treatment
options for these devastating conditions."

About the Phase II Study

This Phase II study was a multicenter, randomized, double blind,
placebo- controlled, parallel-group, dose comparison efficacy study in
260 patients with moderate-to-severe plaque-type psoriasis who were
candidates for systemic therapy. Patients who participated in this
study were required to have a minimum of a 6-month history of moderate-
to-severe plaque-type psoriasis prior to enrollment.

About Chronic Inflammatory Diseases

[...]

About CC-10004

CC-10004 is a member of a proprietary pipeline of novel small
molecules with anti-inflammatory activities that inhibit the
production of multiple proinflammatory mediators including, PDE-4, TNF-
alpha, interleukin-2 (IL-2), interferon-gamma, leukotrienes, and
nitric oxide synthase. CC-10004 is our lead investigational drug in
this class of anti-inflammatory compounds. Based on promising results
from proof-of-mechanism studies, Celgene is accelerating the
evaluation of clinical and regulatory strategies around the
development of CC-10004 and other anti-inflammatory agents into
clinical trials designed to determine their potential across a broad
range of debilitating inflammatory diseases.

About Celgene

Celgene Corporation, headquartered in Summit, New Jersey, is an
integrated global biopharmaceutical company engaged primarily in the
discovery, development and commercialization of novel therapies for
the treatment of cancer and inflammatory diseases through gene and
protein regulation. For more information, please visit the Company's
website at http://www.celgene.com.

This release contains certain forward-looking statements which involve
known and unknown risks, delays, uncertainties and other factors not
under the Company's control, which may cause actual results,
performance or achievements of the Company to be materially different
from the results, performance or other expectations implied by these
forward-looking statements. These factors include results of current
or pending research and development activities, actions by the FDA and
other regulatory authorities, and those factors detailed in the
Company's filings with the Securities and Exchange Commission such as
Form 10-K, 10-Q and 8-K reports.

Celgene Corporation
http://www.celgene.com

((((((((((((((((((((((((((((((((((()))))))))))))))))))))))))))))))

http://www.medicalnewstoday.com/medicalnews.php?newsid=71679&nfid=nl
Understanding Of Metabolic System Helped By Transplanting Human Gut
Bugs Into Mice

Bugs found in the guts of humans, which play an important part in
people's metabolic makeup, have been transplanted into mice to further
understanding of the human and animal metabolic system, reveals a new
study in the journal Molecular Systems Biology.

Bugs in the gut are known as gut microbes and they live symbiotically
in human and animal bodies. The new study involved understanding the
major role that gut microbes have in determining how the body absorbs
fat and digests fibre, and their effects on metabolic pathways in the
body. The researchers, from Imperial College London and Nestle
Research Center, Lausanne, Switzerland, found that microbes affect the
way fats are absorbed and metabolised, by affecting bile acids. Bile
acids are made by the liver to allow emulsification of fats in the
upper gut. The researchers found that gut microbes can change how
effective this emulsification process is because they metabolise bile
acids.

The bile acids are also hormonal regulators which change the way fat
is processed in the liver, so changes made by gut microbes to bile
acid metabolism can affect this internal process.

The scientists also explored how microbes break down fibre in the
lower gut. Certain microbes allow dietary fibre to be digested and the
more effective these microbes are, the more calories are absorbed from
the diet.

Different people have different types of gut microbes living inside
them and abnormalities in some types have recently been linked to
diseases such as diabetes and obesity. The scientists believe that
transplanting the bugs found in humans into mice will enable better
understanding of gut microbes' effects, good and bad, and help them to
develop better treatments (including probiotics and functional foods)
for a wide range of conditions.

Professor Jeremy Nicholson, one of the lead authors of the paper from
the Department of Biomolecular Medicine at Imperial College London,
said: "Humans carry around 1.5kg of bacteria inside of us - that's the
same sort of weight as your liver, so they have a big metabolic effect
on our bodies. By transplanting human gut microbes into mice,
scientists from Nestle Research Center, Lausanne were able to make
them partially human from a metabolic point of view, because we made
their biochemistry more like ours. This makes studies on mice much
more relevant to human problems.

"We found that the humanised mice had very different metabolic
profiles to normal mice with respect to the metabolism of fats and in
future we might be able to modify their metabolism using probiotics,
like those found in some natural yoghurts. This gives us a new way of
studying the beneficial effects of probiotics and functional foods and
understanding what they do to our "friendly" bacteria. Our new
approach allows us to explore which bugs are doing what in metabolic
terms, to identify which bugs which might be causing chronic health
problems, and investigate what effects different foods and probiotics
can have on improving overall health," he added.

(((((((((((((((((((((((((((())))))))))))))))))))))))))))))

Cut out the salt
http://www.medicalnewstoday.com/medicalnews.php?newsid=71845&nfid=nl
Gastric Ulcer Bug Virulence Increased By Salt

Scientists have identified yet another risk from a high-salt diet.
High concentrations of salt in the stomach appear to induce gene
activity in the ulcer-causing bacterium Helicobacter pylori, making it
more virulent and increasing the likelihood of an infected person
developing a severe gastric disease.

"Apparently the stomach pathogen H. pylori closely monitors the diets
of those people whom it infects. Epidemiological evidence has long
implied that there is a connection between H. pylori and the
composition of the human diet. This is especially true for diets rich
in salt," says Hanan Gancz, of the Uniformed Services University of
the Health Sciences in Bethesda, Maryland, who presented the research
at the 107th General Meeting of the American Society for Microbiology
in Toronto.

H. pylori is a spiral-shaped bacterium that can live in the acidic
environment of the stomach and duodenum which is the section of
intestine below the stomach. It is the most common cause of ulcers of
the stomach and duodenum, accounting for up to 90% of duodenal ulcers
and up to 80% of gastric ulcers. Infection with H. pylori also causes
gastritis, and infected persons also have a 2- to 6-fold increased
risk of developing mucosa-associated lymphoid tissue (MALT) lymphoma,
and gastric cancer compared with uninfected counterparts.

H. pylori infection is common in the United States and is most often
found in persons from lower income groups and older adults. About 20%
of persons less than 40 years of age and about 50% of persons over 60
years of age are infected. Most infected people do not have symptoms
and only a small percentage go on to develop disease.

Previous research has focused on the affects diet has on the stomach
environment where H. pylori resides, but until now scientists have
overlooked the response of the microorganism specifically to these
dietary queues. Working from the epidemiological evidence that H.
pylori infection combined with a high-salt diet results in an
increased incidence of severe gastric maladies, Gancz and colleagues
decided to look at the direct effect a high concentration of salt had
on both the growth and gene expression of the bacterium.

"We noted that H. pylori growth rate shows a sharp decline at high
salt concentrations. Moreover, bacterial cells exposed to increased
salt exhibited striking morphological changes: cells became elongated
and formed long chains," says Gancz. "We conclude that H. pylori
exposed to high levels of salt in vitro exhibit a defect in cell
division."

They also discovered transciption of two genes responsible for the
virulence of the bacterium was increased during high-salt conditions.

"The altered expression patterns of some virulence genes may partially
explain the increased disease risk that is associated with a high salt
diet in H. pylori infected individuals," says Gancz.

==================================

Researchers Investigate Impact Of Lifestyle On GI Health
http://www.medicalnewstoday.com/medicalnews.php?newsid=71754&nfid=nl

==================================

New Data On The Probiotic Strain Bifantis

http://www.medicalnewstoday.com/medicalnews.php?newsid=72300&nfid=nl

[...]
This study represents some of the latest work assessing the link
between diet involving probiotics and certain autoimmune diseases.

In the second study, mice were fed Bifantis and then exposed to
Salmonella, a common bacteria associated with a form of food
poisoning.
Animals that received Bifantis showed dramatically increased numbers
of
certain immune cells that control the immune system's response to
harmful pathogens, in this case Salmonella. Bifantis also increased
the
numbers of T-regulatory cells in the body, in effect limiting the
concentrations of certain signals essential to inflammation, such as
cytokines. <sniP>

=====================

Natural Immune-Control System May Aid Treatment Of Autoimmune Disease
And Tissue
Rejection
http://www.medicalnewstoday.com/medicalnews.php?newsid=71426&nfid=nl

The immune system's ability to police itself may offer a new method of
arresting the cells responsible for autoimmune diseases such as
multiple sclerosis and for the rejection of transplanted organs and
tissues, scientists at Dana-Farber Cancer Institute report in a study
in the May issue of the journal Immunity, available online.

Because the technique utilizes the body's own mechanism for
controlling
the immune system, it may prove more effective and less prone to side
effects than current therapies, which take a less direct approach, the
study authors indicate. Although the research was done in mouse cells,
it is likely to apply to humans because of strong similarities between
mouse and human immune cells.

"We found that when we block a key interaction between two
types of immune system cells, one of those types -- which is often
associated with autoimmune disease and tissue rejection -- is attacked
and dies," says senior author Harvey Cantor, MD, of Dana-Farber. "The
fact that this approach uses the body's natural system for regulating
the immune response encourages us that it can be the basis of an
effective therapy for a variety of immunological conditions."

Autoimmune disease and tissue rejection pose a complex
challenge to scientists. Both problems result from an attack by immune
system cells -- which are trained to detect and destroy infected or
diseased tissue -- on parts of the body where it isn't wanted. In the
case of rejection, they recognize transplanted tissue as foreign and
mount an assault on it. In autoimmune diseases, they attack the body's
own tissue as through it were foreign.

Conventional therapies for these conditions can have serious
drawbacks. Many of them rely on natural substances called antibodies,
which wedge inside "receptors" on immune system T cells. The coupling
blindfolds T cells to the presence of foreign or diseased tissue,
blunting their ability to spark an immune attack.

Antibody-based treatments fall short for a variety of reasons:
the antibodies often fail to fit securely inside T cells receptors, so
the immune response is only slightly reduced; or the antibodies
succeed
in blocking the receptor, but that inadvertently causes the T cells to
launch a more ferocious attack. In other cases, antibodies work too
well, suppressing the entire immune system, rather than just a portion
of it, leaving patients susceptible to dangerous infections.

To overcome these problems, researchers have tried to harness
the body's natural system for quieting the immune response. One
intriguing approach involves the immune system's "natural killer," or
NK, cells. Scientists have long known that some NK cells can kill a
class of T cells -- known as CD4 T cells -- that have been activated
to
fight infection, but that NK cells are often restrained from doing so.

Cantor and his colleagues theorized that when a tiny hook, or
ligand, called Qa-1-Qdm on activated CD4 T cells latches onto the
NKG2A
receptor on NK cells, the T cells are protected from destruction. To
test this, they produced activated T cells that either lacked the
Qa-1-Qdm receptor or had a faulty version of it, preventing them from
binding to the NKG2A receptor. The result was that the T cells became
vulnerable to attack from a set of NK cells. Using an antibody to
block
the connection between Qa-1-Qdm and NKG2A had the same result.

"Our findings suggest that it is possible to use antibodies to
trigger the body's own mechanism for suppressing the immune response,"
Cantor remarks. "The results serve as a proof of principle that this
approach can be applied to the treatment of conditions characterized
by
an excessive or unwanted immune response."

While the work was done with mouse cells, the Qa-1-Qdm ligand
has the same shape and structure in human and mouse T cells, raising
hopes that the approach will prove effective in humans as well, adds
Cantor, who is also a professor of pathology at Harvard Medical
School.

======================================

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17529885&query_hl=1&itool=pubmed_docsum
CYP2S1 Gene Polymorphisms in a Korean Population.

* Jang YJ,
* Cha EY,
* Kim WY,
* Park SW,
* Shon JH,
* Lee SS,
* Shin JG.

>From the *Department of Pharmacology; daggerPharmacogenomics Research
Center; and double daggerDepartment of Dermatology, Inje University
College of Medicine, Gaegum-dong, Jin-gu, Busan, Korea.

Cytochrome P450 2S1 (CYP2S1) is a drug-metabolizing enzyme that shows
interindividual variations in response to treatments for psoriasis and
is regarded as a putative prognostic marker for colorectal cancer
treatment. To gain insight into the genetic basis for the
interindividual variations, CYP2S1 gene polymorphisms were analyzed in
Korean subjects. Using direct sequencing of the CYP2S1 gene, 12
genetic variations, which included the two novel nonsynonymous
mutations CYP2S1 S61N (0.3%) and CYP2S1 L230R (0.8%), were identified
in 50 Korean subjects. Homology modeling predicted the location of the
L230R change to be near two conserved alpha-helices in the hood of the
substrate-binding site. Linkage disequilibrium (LD) analysis with
seven common CYP2S1 variations showed two discrete LD blocks in CYP2S1
gene and consequently a limited number of haplotypes. Although the
importance of novel CYP2S1 variants and haplotypes remains to be
discovered, CYP2S1 polymorphisms would provide useful information on
interindividual variations with respect to CYP2S1 function, which
facilitates drug response predictions and disease prognosis.

PMID: 17529885
---------------------------

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17523932&query_hl=1&itool=pubmed_docsum
Lack of effect of oral selenite on p53 associated gene expression
during TL01 therapy of psoriasis patients.

* Desilva B,
* Beckett GJ,
* McLean S,
* Arthur JR,
* Hunter JA,
* Norval M,
* McKenzie RC.

Department of Dermatology, University of Edinburgh, Edinburgh, UK.

Selenium (Se) has protective properties against ultraviolet (UV)-
induced changes in skin cells in vitro but little is known about such
activity in human subjects. In the present study, seven patients with
psoriasis ingested 400 mug of sodium selenite daily during a 4 week
course of whole-body narrow-band UVB (TL01) therapy while six more
psoriasis patients, similarly irradiated, ingested a placebo. Skin
biopsies, collected at the start and end of the phototherapy were
analysed for phosphorylated p53, Fas, Bcl-2, Bax and oxidized
guaninosine, and for numbers of Langerhans and sunburn cells.
Following the TL01 therapy, no significant difference was observed for
any of these markers when the Se group was compared with the placebo
group of patients, although p53 and Bcl-2 expression decreased in the
Se supplemented group.

PMID: 17523932

--------------------

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17526178&query_hl=1&itool=pubmed_docsum
[Clinical observation on effect of compound E-bei ointment in treating
plaque psoriasis]
[Article in Chinese]

* Song P,
* Yan ZF,
* Xu X.

Guang' anmen Hospital, China Academy of Chinese Medical Sciences,
Beijing. song_...@hotmail.com

OBJECTIVE: To observe the efficacy oand safety of Compound E-Bei
ointment (CEBO) in treating plaque psoriasis. METHODS: Adopting block-
randomized, open, positive Western medicine and placebo parallel group
controlled method, a total of 120 enrolled patients were administered
orally with Saoxuan Pill, and randomized into three groups
respectively treated with external application of CEBO, Daivonex, or
vehicle control twice a day for 4 weeks. The changes of erythema,
infiltration, scaly eruption, pruritus and the area of lesion were
evaluated, the safety and the initiating time of symptom improvement
(ITSI) were observed as well. RESULTS: Observation on local lesion
showed that the scores of erythema, infiltration, scaly eruption,
pruritus were significantly improved in difference between the CEBO
group and the Daivonex group (P < 0.01). But in the placebo control
group, significant improvement was only shown in scaly eruption scores
(P < 0.01), so, the improvement in skin lesion in the placebo group
was significantly inferior to that in the other two groups (P < 0.01).
The ITSI of pruritus was shorter in CEBO group than that in the
Daivonex group and the placebo group (P < 0.01), but that of other
symptoms showed insignificant difference between the CEBO group and
the Daivonex group, as for comparing in ITSI of erythema,
infiltration, scaly eruption and pruritus, it was significantly
shorter in the CEBO group and Daivonex group than that in the placebo
group respectively (P < 0.01). The occurrence of adverse events in the
CEBO group had insignificant difference to that in the Daivonex group,
but the recurrence rate in the former was significantly lower than
that in the latter (P < 0.05). CONCLUSION: CEBO can effectively
improve the symptoms of skin lesion in patients with plaque psoriasis,
the clinical efficacy is not inferior to that of positive Western
medicine.

PMID: 17526178

I wonder what this ointment has in it?
http://www.google.com/search?hl=en&q=Compound+E-Bei+psoriasis&btnG=Search

I''m still wondering. LOL

randall

JXStern

unread,

May 29, 2007, 6:19:46 PM5/29/07

On 27 May 2007 10:57:44 -0700, randall <ranh...@aol.com> wrote:

>Do psoriatics have one GENE to few? Wouldn't that
>be a twist? Instead of looking for THE *p* GENE we should
>be wondering if we have enough FCGR3B genes.

...

Very interesting, just wanted to say.

If it's true, might just be possible to do something about it, supply
the missing protein, or even promote the body to make more itself.

randall

unread,

May 30, 2007, 2:18:44 PM5/30/07

On May 29, 3:19 pm, JXStern <JXSternChange...@gte.net> wrote:

> On 27 May 2007 10:57:44 -0700, randall <ranhu...@aol.com> wrote:
>
> >Do psoriatics have one GENE to few? Wouldn't that
> >be a twist? Instead of looking for THE *p* GENE we should
> >be wondering if we have enough FCGR3B genes.
>
> ...
>
> Very interesting, just wanted to say.
>
> If it's true, might just be possible to do something about it, supply
> the missing protein, or even promote the body to make more itself.
>
> J.

I'm still Pondering a low dose Naltrexone + MTX + phentermine JX-P
tyPe cocktail.

Since my demeanor demands firstly, do NO harm, i'm conjecturing
a nearly homeopathic preparation with extra ethanol and fruit juice.
LOL

I've got black berries coming out my ying yang already! May gray has
been nice and mild so far this year. Can only wonder how i'll fare for
june
gloom. The P shakes are quite tasty and sans alcohol. <g>

Just saw this on the newsgroup:
http://www.newstarget.com/021875.html
Soap nuts used for P???

What are these nuts? Are they the same as bitter melon?
Nope
http://en.wikipedia.org/wiki/Sapindus
http://en.wikipedia.org/wiki/Bitter_melon

I've never been able to eat enough bitter melon (Momordica charantia)
to get any results.

But wait, here's a pill,
http://www.viable-herbal.com/singles/herbs/s124.htm

So, another low dose product to add in to the JX cocktail?

OOO'k already--- but there may be a hormesis effect with some combo of
these!
http://en.wikipedia.org/wiki/Hormesis

And back to science. Be my guest,
http://www.ncbi.nlm.nih.gov/gquery/gquery.fcgi?term=FCGR3B

I love the entrez search engine,
http://en.wikipedia.org/wiki/Entrez

I just don't use it enough to find the ultimate P JX cocktail, yet!

randall.... keePing on clicking-- pass the cocktail! BERRY good!

JXStern

unread,

May 31, 2007, 11:26:22 AM5/31/07

On 30 May 2007 11:18:44 -0700, randall <ranh...@aol.com> wrote:

>I'm still Pondering a low dose Naltrexone + MTX + phentermine JX-P
>tyPe cocktail.
>
>Since my demeanor demands firstly, do NO harm, i'm conjecturing
>a nearly homeopathic preparation with extra ethanol and fruit juice.
>LOL
>
>I've got black berries coming out my ying yang already! May gray has
>been nice and mild so far this year. Can only wonder how i'll fare for
>june gloom. The P shakes are quite tasty and sans alcohol. <g>

I don't know about those.

But if you want to try something your own self, I recommend ...
horseradish! Use it like and WITH turmeric, about half a teaspoon of
bottled (in the frig section) horseradish twice a day.

My diet is so tailored I have yet to verify what the horseradish alone
is doing, but I suspect it blocks some more cox pathways. In fact,
you want my current spicey cocktail:

* turmeric - about 3g twice a day
* onion - about 2 oz chopped twice a day
* horseradish - about 3g (half a teaspoon) twice a day
* 81mg baby aspirin - twice a day
* grape seed extract - 50mg capsule 3x a day or more (mild
antihistamine, also antioxidant)
* selenium - 100mg twice a day

The cox-blocking spices need to be taken more than once a day, the
aspirin has to be a small dose so as not to encourage bleeding, I also
take 500mg evening primrose oil and keep it as far from the aspirin as
possible, last I checked my nails would go bad again if I stopped the
EPO, even with the spices helping elsewhere.

Anyway, if you could find time to mix in the horseradish to your
various experiments, I'd appreciate the effort and hearing about the
results.

randall

unread,

May 31, 2007, 12:19:45 PM5/31/07

On May 31, 8:26 am, JXStern <JXSternChange...@gte.net> wrote:

> On 30 May 2007 11:18:44 -0700, randall <ranhu...@aol.com> wrote:
>
> >I'm still Pondering a low dose Naltrexone + MTX + phentermine JX-P
> >tyPe cocktail.
>
> >Since my demeanor demands firstly, do NO harm, i'm conjecturing
> >a nearly homeopathic preparation with extra ethanol and fruit juice.
> >LOL
>
> >I've got black berries coming out my ying yang already! May gray has
> >been nice and mild so far this year. Can only wonder how i'll fare for
> >june gloom. The P shakes are quite tasty and sans alcohol. <g>
>
> I don't know about those.

They only taste good and help me to avoid a worse diet? lol

>
> But if you want to try something your own self, I recommend ...
> horseradish! Use it like and WITH turmeric, about half a teaspoon of
> bottled (in the frig section) horseradish twice a day.

I'll try it. I wonder if a half teaspoon will overpower my sweet whey
shake?
I could add a little extra molasses to cut it? But i've put green
onions,
garlic, carrots and all sorts of veggies in these power shakes.

>
> My diet is so tailored I have yet to verify what the horseradish alone
> is doing, but I suspect it blocks some more cox pathways. In fact,
> you want my current spicey cocktail:
>
> * turmeric - about 3g twice a day
> * onion - about 2 oz chopped twice a day
> * horseradish - about 3g (half a teaspoon) twice a day
> * 81mg baby aspirin - twice a day
> * grape seed extract - 50mg capsule 3x a day or more (mild
> antihistamine, also antioxidant)
> * selenium - 100mg twice a day

I take the selenium already. Unsuccessfully tried the aspirin in the
past. Even smaller amounts seemingly doesn't help at all.
I'm all over the green onions for the most part and even using them
in shakes.

>
> The cox-blocking spices need to be taken more than once a day, the
> aspirin has to be a small dose so as not to encourage bleeding, I also
> take 500mg evening primrose oil and keep it as far from the aspirin as
> possible, last I checked my nails would go bad again if I stopped the
> EPO, even with the spices helping elsewhere.

I've started to clean my mouth more often as a result of recent posts
with
tongue scraping and salt water gargles. That type of thing and 2x a
day.
Also baking soda pushed gently down in to the gums to neutralize
pockets of bacteria.

>
> Anyway, if you could find time to mix in the horseradish to your
> various experiments, I'd appreciate the effort and hearing about the
> results.

Since i've recently started gone back with alcar/ala i'll add it
with a keen eye as i've already made very positive headway in
short order. Legs are nearly clear enough to get away with
sock less sandals. :)

randall... elbows aren't so hot :(

>
> J.

randall

unread,

May 31, 2007, 12:52:00 PM5/31/07

Hi,

BEYOND the Biologics!
http://www.biopharma-reporter.com/news/ng.asp?n=76971-ucb-psoriasis-biologic-tnf-alpha
31/05/2007 - New research presented yesterday has revealed that a new
class of biologic drug may bring new relief to those suffering from
the skin condition psoriasis.

Cimziatin (certolizumab pegol) is the world's first PEGylated, Fc-free
anti-tumour necrosis factor (TNF). Unlike other anti-TNF drugs
currently available, its Fc-free nature means that it avoids potential
cellular cytotoxicity, said its developers, UCB. Incidentally, UCB is
also developing cimziatin for indications in Crohn's disease and
rheumatoid arthritis.

The first study involving patients treated with the investigational
drug demonstrated that subcutaneous regimens of both the 200mg and
400mg liquid formulations significantly reduced the redness, thickness
and scaliness of psoriasis lesions compared with placebo, according to
data shown to attendees of the European Academy of Dermatology and
Venereology (EADV) Annual Meeting.

"The results... suggest that it has the potential for further
development into a valuable new treatment option for this difficult-to-
treat disease," said Professor Jean-Paul Ortonne, Department of
Dermatology, Hospital LÀrchet, Nice, France.

[...]

Current treatments include drugs that target the pathophysiological
effects of TNF-alpha, which is a cytokine that plays a key role in
mediating pathological inflammation, and when produced in excess in
the body, is implicated in a wide variety of diseases, including
psoriasis.

UCB is not alone in its quest to develop a new treatment for this skin
ailment. Earlier this month Abbott has announced it is "very excited"
with its novel psoriasis treatment, from results in Phase II trials.

While other drugs, such as the currently available Humira
(adalimumab), as well as UCB's cimziatin, bind to TNF-alpha, Abbott's
investigational compound ABT-874, a fully human monoclonal antibody,
is touted as having a novel mechanism whereby it targets and
neutralises interleukin-12 and interleukin-23, two proteins involved
in the inflammatory response.

In addition, more than half of the 180 patients that took part in the
trial achieved a 90 per cent improvement, the firm reported.

"It's the best clearance results than anything we have seen out there
to date," Abbott spokeswoman Tracy Sorrentino told BioPharma-

Reporter.com in an earlier interview.

------------------

=======================================

A MAJOR new player in the psoriasis pathways! HOT off pubmed
abstracts!

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17533487&query_hl=27&itool=pubmed_docsum
Expression of allograft inflammatory factor-1 in inflammatory skin
disorders.

* Orsmark C,
* Skoog T,
* Jeskanen L,
* Kere J,
* Saarialho-Kere U.

Department of Biosciences and Nutrition, Karolinska Institutet.

Allograft inflammatory factor-1 (AIF-1) is an evolutionarily
conserved, inflammatory protein produced by activated macrophages
during chronic transplant rejection and in inflammatory brain lesions.
Since T-cell-mediated inflammation is common to various dermatoses and
nothing is known about AIF-1 in skin, we studied its protein
expression at the tissue level and regulation in monocytic cell lines
by various agents. Using immunohistochemistry, we found that AIF-1 is
expressed at low levels in normal skin, but is highly upregulated in
various inflammatory skin disorders, such as psoriasis, lichen planus,
graft-versus-host disease and mycosis fungoides. The main cell types
expressing AIF-1 in affected skin are macrophages and Langerhans'
cells. We also show by real-time PCR that AIF-1 mRNA levels in
monocytic THP-1 and U937 cell lines are significantly upregulated by
retinoic acid as well as a number of cytokines. We conclude that AIF-1
may mediate survival and pro-inflammatory properties of macrophages in
skin diseases.

PMID: 17533487

AIF-1 is on chromosome 6p21.3?
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=retrieve&dopt=graphics&list_uids=199

Psors1 is located in the same place isn't it?

--------

Yes it is.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17530646&query_hl=42&itool=pubmed_docsum

Georg-August-University Gottingen, Gottingen, Germany.

PMID: 17530646

------

And another one for TNF and psors1.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17530646&query_hl=25&itool=pubmed_docsum

Georg-August-University Gottingen, Gottingen, Germany.

PMID: 17530646

-----------------------------

Lets find some more info on AIF1...

http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601833
*601833
ALLOGRAFT INFLAMMATORY FACTOR 1; AIF1

Alternative titles; symbols
INTERFERON RESPONSE TRANSCRIPT 1; IRT1
<sniP>

----------------------------------------
And here comes 59 hits:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Search&db=PubMed&term=Allograft+inflammatory+factor%2D1+%28AIF%2D1%29+&tool=QuerySuggestion

This one says it all. IL-10 blocks the effects of AIF-1.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17394154&query_hl=27&itool=pubmed_docsum

[...]
The expression of inducible nitric oxide synthase (iNOS), tumor
necrosis factor (TNF)-alpha, and caspase 9 in the 40% grafts were
upregulated after reperfusion, whereas the augmentation could be
suppressed by the administration of IL-10. Finally, IL-10 culture
could block AIF-1-mediated NO production and downregulate the
expression of iNOS and TNF-alpha in a macrophage cell line. In
conclusion, IL-10 rescued the small-for-size liver grafts by its
antiinflammatory properties, through inhibition of AIF-1 mediated
proinflammatory and proapoptotic activities of the macrophages during
the early period after ischemia/reperfusion.

PMID: 17394154

--------------------------

Since psoriatics are short in the IL-10 department, it makes sense why
we flare like we do.
How much does AIF-1 skew us towards a Th1 profile is a biggie.

Does the SHGC-132025 gene factor in here? You scientist out there must
get all over this one..

WE want to be CLEAR every day every way....

ChoP choP.... :)

======================================================

------------------------------------------------------

Back to wheat to honor Stirling who put more then a little effort in
to his
program. Which he says keeps him clear...

#1 is his anti-gliadin (NO WHEAT) program.

--------------

Wheat does not cause translocation (read-leaky guts) of gliadin
proteins??
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17477542&query_hl=13&itool=pubmed_docsum
Intestinal Translocation Capabilities of Wheat Allergens Using the
Caco-2 Cell Line.

* Bodinier M,
* Legoux MA,
* Pineau F,
* Triballeau S,
* Segain JP,
* Brossard C,
* Denery-Papini S.

INRA, Research Unit on Biopolymeres, Interactions et Assemblages
(BIA), and INRA, Universite de Nantes, UMR 1280, Research Unit on
Physiologie des adaptations nutritionnelles (PHAN), rue de la
Geraudiere, B.P. 71627, F44316 Nantes, France.

Because intestinal absorption of food protein can trigger an allergic
reaction, the effect of wheat proteins on intestinal epithelial cell
permeability was evaluated and the abilities of these proteins in
native or pepsin-hydrolyzed state to cross the epithelial cell
monolayer were compared. Enterocytic monolayers were established by
culturing Caco-2 cells, a model of enterocytes, on permeable supports
that separate the apical and basal compartments. Proteins were added
into the apical compartment, and the transepithelial resistance (TER)
was measured; proteins that crossed the cell monolayer were detected
in the basal medium by ELISA. Wheat proteins did not alter the cell
monolayer. TER and Caco-2 cell viability were conserved, and the
passage of dextran was prevented. Native and pepsin-hydrolyzed forms
of omega5-gliadin and lipid transfer proteins were detected in the
basal medium. The results suggest that these two major allergens in
food allergy to wheat were able to cross the cell monolayer by the
transcellular route. Keywords: Allergy; Caco-2; crossing; intestinal
barrier; LTP; omega5-gliadins; wheat proteins.

PMID: 17477542

------------

But it does cause translocation in this abstract!

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16456012&query_hl=13&itool=pubmed_docsum
Gliadin stimulation of murine macrophage inflammatory gene expression
and intestinal permeability are MyD88-dependent: role of the innate
immune response in Celiac disease.

* Thomas KE,
* Sapone A,
* Fasano A,
* Vogel SN.

Department of Microbiology and Immunology, University of Maryland
School of Medicine, Baltimore, 21201, USA.

Recent studies have demonstrated the importance of TLR signaling in
intestinal homeostasis. Celiac disease (CD) is an autoimmune
enteropathy triggered in susceptible individuals by the ingestion of
gliadin-containing grains. In this study, we sought to test the
hypothesis that gliadin initiates this response by stimulating the
innate immune response to increase intestinal permeability and by up-
regulating macrophage proinflammatory gene expression and cytokine
production. To this end, intestinal permeability and the release of
zonulin (an endogenous mediator of gut permeability) in vitro, as well
as proinflammatory gene expression and cytokine release by primary
murine macrophage cultures, were measured. Gliadin and its peptide
derivatives, 33-mer and p31-43, were found to be potent inducers of
both a zonulin-dependent increase in intestinal permeability and
macrophage proinflammatory gene expression and cytokine secretion.
Gliadin-induced zonulin release, increased intestinal permeability,
and cytokine production were dependent on myeloid differentiation
factor 88 (MyD88), a key adapter molecule in the TLR/IL-1R signaling
pathways, but were neither TLR2- nor TLR4-dependent. Our data support
the following model for the innate immune response to gliadin in the
initiation of CD. Gliadin interaction with the intestinal epithelium
increases intestinal permeability through the MyD88-dependent release
of zonulin that, in turn, enables paracellular translocation of
gliadin and its subsequent interaction with macrophages within the
intestinal submucosa. There, the interaction of gliadin with
macrophages elicits a MyD88-dependent proinflammatory cytokine milieu
that facilitates the interaction of T cells with APCs, leading
ultimately to the Ag-specific adaptive immune response seen in
patients with CD.

PMID: 16456012

-----------
===============================================

This next one is key. I've tried taking 750 mg.s of L-Glutamine to
negative results a few times.
And cruiser has sparked exlnt results with histidine iirc.

((((((((((((((((((((((((((())))))))))))))))))))))))))))

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17357151&query_hl=17&itool=pubmed_docsum

Inhibition of glutamine transport into mitochondria protects
astrocytes from ammonia toxicity.

* Pichili VB,
* Rao KV,
* Jayakumar AR,
* Norenberg MD.

Department of Pathology, University of Miami School of Medicine,
Miami, Florida.

Hepatic encephalopathy (HE) is a major neurological complication that
occurs in the setting of severe liver failure. Ammonia is a key
neurotoxin implicated in this condition, and astrocytes are the
principal neural cells histopathologically and functionally affected.
Although the mechanism by which ammonia causes astrocyte dysfunction
is incompletely understood, glutamine, a by-product of ammonia
metabolism, has been strongly implicated in many of the deleterious
effects of ammonia on astrocytes. Inhibiting mitochondrial glutamine
hydrolysis in astrocytes mitigates many of the toxic effects of
ammonia, suggesting the involvement of mitochondrial glutamine
metabolism in the mechanism of ammonia neurotoxicity. To determine
whether mitochondriaare indeed the organelle where glutamine exerts
its toxic effects, we examined the effect of L-histidine, an inhibitor
of mitochondrial glutamine transport, on ammonia-mediated astrocyte
defects. Treatment of cultured astrocytes with L-histidine completely
blocked or significantly attenuated ammonia-induced reactive oxygen
species production, cell swelling, mitochondrial permeability
transition, and loss of ATP. These findings implicate mitochondrial
glutamine transport in the mechanism of ammonia neurotoxicity. (c)
2007 Wiley-Liss, Inc.

PMID: 17357151

(((((((((((((((((((((()))))))))))))))))))))))))))))))))

randall... having a wonderful day....

randall

unread,

Jun 1, 2007, 2:39:15 AM6/1/07

On May 31, 8:26 am, JXStern <JXSternChange...@gte.net> wrote:

>
> Anyway, if you could find time to mix in the horseradish to your
> various experiments, I'd appreciate the effort and hearing about the
> results.
>
> J.

Before I hit the smart and final, i'll see what bang for the buck to
expect.

http://en.wikipedia.org/wiki/Allyl_isothiocyanate

[...]
Allyl isothiocyanate is the chemical compound responsible for the
pungent taste of mustard, horseradish and wasabi. It is a colorless to
pale yellow liquid that is slightly soluble in water, but well soluble
in most organic solvents.

Allyl isothiocyanate itself does not occur in the mustard seed.
Instead, when ground mustard seeds are mixed with water, vinegar, or
other liquids or when they are chewed, a chemical reaction between the
enzyme myrosinase and a glucosinolate known as sinigrin from the seeds
of black mustard (Brassica nigra) or brown Indian mustard (Brassica
juncea) leads to the production of allyl isothiocyanate.<sniP>

------------------

For additional considerations:
http://en.wikipedia.org/wiki/Brassica_juncea

--------------

http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17097904&itool=pubmed_docsum
Allyl isothiocyanate (AITC) and phenyl isothiocyanate (PITC) inhibit
tumour-specific angiogenesis by downregulating nitric oxide (NO) and
tumour necrosis factor-alpha (TNF-alpha) production.

* Thejass P,
* Kuttan G.

Department of Immunology, Amala Cancer Research Centre, Amala Nagar,
Thrissur, Kerala 680 555, India.

Angiogenesis, a crucial step in the growth and metastasis of cancers,
is initiated with vasodilation mediated by nitric oxide (NO). The pro-
inflammatory cytokine, tumour necrosis factor-alpha (TNF-alpha), is a
mediator of nitric oxide synthesis. We analyzed the effect of allyl
isothiocyanate (AITC) and phenyl isothiocyanate (PITC) on serum NO as
well as TNF-alpha level during angiogenesis. In vivo antiangiogenic
activity was studied using B16F-10 melanoma cell-induced capillary
formation in C57BL/6 mice. Intraperitoneal administration of AITC and
PITC at a concentration of 25 microg/dose/animal significantly
inhibited tumour-directed capillary formation. Treatment of AITC and
PITC significantly downregulated serum NO as well as TNF-alpha level
in angiogenesis-induced animals compared to untreated control animals.
The in vitro antiangiogenic study, using rat aortic ring assay, showed
that both AITC and PITC at non-toxic concentrations inhibited the
production of proangiogenic factors from B16F-10 melanoma cells which
was evident with the inhibition of microvessel outgrowth from aortic
rings. Both AITC and PITC significantly inhibited sodium nitroprusside
as well as TNF-alpha-induced microvessel outgrowth from rat aortic
ring. Administration of AITC and PITC also significantly reduced NO
and TNF-alpha production by LPS-stimulated macrophages both in vivo as
well as in vitro. Bio-assay using serum of angiogenesis-induced
animals and supernatant from LPS-stimulated macrophages clearly
confirmed the downregulatory action of AITC and PITC on TNF-alpha
production. These results clearly demonstrated that AITC and PITC
inhibited tumour-specific angiogenesis by downregulating NO and TNF-
alpha production.

PMID: 17097904

-----------------

Keywords: allyl isothiocyanate tnf

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Search&db=PubMed&term=allyl+isothiocyanate+tnf&tool=QuerySuggestion

Keywords: allyl isothiocyanate curcumin

http://www.google.com/search?hl=en&q=allyl+isothiocyanate+curcumin&btnG=Google+Search

--------------
Keyword search:
allyl isothiocyanate Brassica+juncea

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Search&db=PubMed&term=allyl+isothiocyanate+Brassica+juncea&tool=QuerySuggestion

---------------------

randall... doesn't seem to be a bad bet for my $

JXStern

unread,

Jun 1, 2007, 11:41:04 AM6/1/07

On Thu, 31 May 2007 23:39:15 -0700, randall <ranh...@aol.com> wrote:

>Before I hit the smart and final, i'll see what bang for the buck to
>expect.

Just on the shelves, S&F has big jars of horseradish cheap, but with
lots of preservatives. All the markets carry the Silver Springs stuff
in either branded or generic jars, about $2.99 for eight ounces, and
very inconsistent in the strength of its flavor - don't know if that
corresponds to effectiveness, but it probably does. Surprisingly,
about half the local markets do carry the raw root, at prices from $4
to $6/pound. Watch out for the extra ingredients, they make it hot by
adding acid, and of course hot horseradish will blow your head off!
Plain, grated root might not be bad at all.

>
>http://en.wikipedia.org/wiki/Allyl_isothiocyanate
>
>[...]
>Allyl isothiocyanate is the chemical compound responsible for the
>pungent taste of mustard, horseradish and wasabi. It is a colorless to
>pale yellow liquid that is slightly soluble in water, but well soluble
>in most organic solvents.

Randall, you're a gem!

Oddly enough, I have mustard filed in a category of
makes-things-worse. Of course, it must (!) have other components too.

>Allyl isothiocyanate itself does not occur in the mustard seed.
>Instead, when ground mustard seeds are mixed with water, vinegar, or
>other liquids or when they are chewed, a chemical reaction between the
>enzyme myrosinase and a glucosinolate known as sinigrin from the seeds
>of black mustard (Brassica nigra) or brown Indian mustard (Brassica
>juncea) leads to the production of allyl isothiocyanate.<sniP>

Sounds like garlic in those regards.

But, does that mean you have to prepare the horseradish that way too?

>http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17097904&itool=pubmed_docsum
>Allyl isothiocyanate (AITC) and phenyl isothiocyanate (PITC) inhibit
>tumour-specific angiogenesis by downregulating nitric oxide (NO) and
>tumour necrosis factor-alpha (TNF-alpha) production.

And there we are! Well, perhaps, perhaps.

Would still want to know more about just where in the cascade this
happens.

randall

unread,

Jun 2, 2007, 3:43:06 AM6/2/07

On Jun 1, 8:41 am, JXStern <JXSternChange...@gte.net> wrote:

You mean a smashing good time? I'll find a link below.

>
> >http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?db=pubmed&cmd=Retrieve...

> >Allyl isothiocyanate (AITC) and phenyl isothiocyanate (PITC) inhibit
> >tumour-specific angiogenesis by downregulating nitric oxide (NO) and
> >tumour necrosis factor-alpha (TNF-alpha) production.
>
> And there we are! Well, perhaps, perhaps.
>
> Would still want to know more about just where in the cascade this
> happens.

Search me! Gut, liver or skin take your pick. A case could
be made for in situ, (in our case in plaque U) lol
http://en.wikipedia.org/wiki/In_situ
Then again it may go systemic from a more remote area
and migrate? If P is a compensatory condition
then the skin is a dumPing ground.

Which for Stirling Strauss would mean, wheat-> gut
permeability--> TNF--> migration to the skin and
--> interference of calcium ions (calmodulin) , protease
and acrylamides..(fried or cooked foods containing n-6's)
------> = psoriasis...

Which I would counter with where does the P genes
operate and how do we down regulate them?
IL-10 and uPregulation of TREGs being the goal
via Th-17. And down regulation of TNF and
arachidonic acid cascades..
http://en.wikipedia.org/wiki/Arachidonic
http://en.wikipedia.org/wiki/Tumor_necrosis_factor-alpha

[...]
The human TNF gene (TNFA) was cloned in 1985.[6] It maps to chromosome
6p21.3, spans about 3 kb and contains 4 exons. The last exon codes for
more than 80% of the secreted protein.[7] The 3' UTR of TNF alpha
contains an ARE. <sniP>

(randall note: AIF-1 is a new inflammatory player and found on 6p21.3
according to the last article
in this thread, may 31st)

>
> J.

As to smashing uP some garlic or horseradish,

http://groups.google.com/groups/search?q=sinigrin+glycoside+sugar+allyl+isothiocyanate&qt_s=Search

http://www.botanical.com/botanical/mgmh/h/horrad38.html

If I was serious i'd cultivate the *real* wasabi and kalawalla (aka-
cotochupa) for that matter.

http://en.wikipedia.org/wiki/Wasabi

And calaguala,
http://en.wikipedia.org/wiki/Calaguala
Huh?
http://en.wikipedia.org/wiki/Callawalla

Interesting to say the least.

------------------------------

Lets face it, i'm back on a testosterone triP instead.

http://groups.google.com/groups/search?qt_s=1&q=alcar+testosterone+

So ALCAR is a good deal,
http://www.medscape.com/viewarticle/473414

Hey J! I didn't know this stuff. I had to find out the HARD way.
LOL :)

Got to love that acetyl L-carnitine and alpha lipoic acid.

Will I totally clear uP with some dose of nicotinamide riboside?
http://groups.google.com/groups/search?qt_s=1&q=nicotinamide+riboside+psoriasis

randall.... hard and clear! just another P triP in OZ

JXStern

unread,

Jun 2, 2007, 1:54:57 PM6/2/07

On Sat, 02 Jun 2007 00:43:06 -0700, randall <ranh...@aol.com> wrote:

>> Would still want to know more about just where in the cascade this
>> happens.
>
>Search me! Gut, liver or skin take your pick. A case could
>be made for in situ, (in our case in plaque U) lol
>http://en.wikipedia.org/wiki/In_situ
>Then again it may go systemic from a more remote area
>and migrate? If P is a compensatory condition
>then the skin is a dumPing ground.

I meant where in the EFA metabolism, not where in the body, though
that's a good question, too.

>As to smashing uP some garlic or horseradish,
>
>http://groups.google.com/groups/search?q=sinigrin+glycoside+sugar+allyl+isothiocyanate&qt_s=Search
>
>http://www.botanical.com/botanical/mgmh/h/horrad38.html

Hmm, suggests that yes, the flavor and presumably the active
ingredient is produced by smashing with water ... and then apparently
oxidizes over time and loses strength.

Also suggests you can plant pieces of the root!

>Lets face it, i'm back on a testosterone triP instead.
>
>http://groups.google.com/groups/search?qt_s=1&q=alcar+testosterone+
>
>So ALCAR is a good deal,
>http://www.medscape.com/viewarticle/473414
>
>Hey J! I didn't know this stuff. I had to find out the HARD way.
>LOL :)
>
>Got to love that acetyl L-carnitine and alpha lipoic acid.

I tried just a little ALA couple of years ago, and it made me feel
giddy, I see they (still) have it at TJ's pretty cheap. The AL-C
seems a bit pricey at Whole Foods, looks cheaper various places on the
web.

I will try this again at some point, I'm getting to the age where a
little extra testosterone might be a good thing, the hair already
being thin on top anyway! But (knock on wood - no pun intended) I seem
to be getting some slow clearing with my current spice cocktail, don't
want to mess with it. Any clearing is a Big Deal for me!

Mostly wish I knew wtf was really going on with any of these spices.
Maybe if I just tripled the dosage I'd be clear in a week, hey?

randall

unread,

Jun 2, 2007, 8:43:01 PM6/2/07

On Jun 2, 10:54 am, JXStern <JXSternChange...@gte.net> wrote:
> On Sat, 02 Jun 2007 00:43:06 -0700, randall <ranhu...@aol.com> wrote:

<sniP>

>
> I meant where in the EFA metabolism, not where in the body, though
> that's a good question, too.

My first choice is still in situ. If we duplicate these pathways in a
petri
dish we're still a million miles from reality.
Even by sticking it the body you have a dozen or more enzymes at work
and countless genes.

>
> >As to smashing uP some garlic or horseradish,
>

> >http://groups.google.com/groups/search?q=sinigrin+glycoside+sugar+all...

>
> >http://www.botanical.com/botanical/mgmh/h/horrad38.html
>
> Hmm, suggests that yes, the flavor and presumably the active
> ingredient is produced by smashing with water ... and then apparently
> oxidizes over time and loses strength.

Once again, we're looking at enzymes at a key part of the process.
Duplicating the reaction in the body is a huge craP shoot.

>
> Also suggests you can plant pieces of the root!
>
> >Lets face it, i'm back on a testosterone triP instead.
>
> >http://groups.google.com/groups/search?qt_s=1&q=alcar+testosterone+
>
> >So ALCAR is a good deal,
> >http://www.medscape.com/viewarticle/473414
>
> >Hey J! I didn't know this stuff. I had to find out the HARD way.
> >LOL :)
>
> >Got to love that acetyl L-carnitine and alpha lipoic acid.
>
> I tried just a little ALA couple of years ago, and it made me feel
> giddy, I see they (still) have it at TJ's pretty cheap.

I did some trials with ala as well. NO luck then without the alc.

> The AL-C
> seems a bit pricey at Whole Foods, looks cheaper various places on the
> web.

Try beyond a century,
http://www.beyondacenturyonline.com/
Go to shop online and enter your product or term in the search box.

>
> I will try this again at some point, I'm getting to the age where a
> little extra testosterone might be a good thing, the hair already
> being thin on top anyway!

"I hold the world but as the world, Gratiano; A stage where every man
must play a part, And mine is a sad one" William Shakespeare

>But (knock on wood - no pun intended) I seem
> to be getting some slow clearing with my current spice cocktail, don't
> want to mess with it. Any clearing is a Big Deal for me!

Empirical works for me. A lead is a lead and I trust your plaques not
to lie. :)

>
> Mostly wish I knew wtf was really going on with any of these spices.
> Maybe if I just tripled the dosage I'd be clear in a week, hey?

Why not try?

randall
>
> J.

JXStern

unread,

Jun 2, 2007, 8:54:09 PM6/2/07

On Sat, 02 Jun 2007 17:43:01 -0700, randall <ranh...@aol.com> wrote:

>> Mostly wish I knew wtf was really going on with any of these spices.
>> Maybe if I just tripled the dosage I'd be clear in a week, hey?
>
>Why not try?

I can't get myself to sign the release form.

randall

unread,

Jun 6, 2007, 2:40:24 PM6/6/07

Hi,

To much spice/herbs in those last posts?

How about a testosterone fueled post?

OK,

http://en.wikipedia.org/wiki/Testosterone

&
http://www.vrp.com/graphics/Fig.3.GIF

What's new?

http://www.docguide.com/news/content.nsf/news/852571020057CCF6852572F100646E22
TORONTO, CANADA -- June 5, 2007 -- Decreased vitamin D levels are
linked to shorter telomeres, the end pieces of DNA, according to a
study presented here at the 89th annual meeting of the Endocrine
Society (ENDO).

The study used data from the TwinsUK cohort to assess if there was a
relationship between vitamin D levels and length of telomeres, said
lead investigator John Brent Richards, MD, MSc, postdoctoral fellow,
King's College, London, United Kingdom.

Dr. Richards noted that telomeres shorten in length with each cell
cycle and have been demonstrated to degrade when exposed to
inflammation. He explained that vitamin D is thought to inhibit a pro-
inflammatory response. <sniP>

--------------

Keep that testosterone at normal levels for a LONG life. <w>
http://www.signonsandiego.com/uniontrib/20070606/news_7m6hormone.html

------------

Let's pubmed it and find out for sure.

Psor women have less testosterone,
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=12898883&ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

[...]
The testosterone levels and LH/FSH ratio were significantly lower in
the psoriatic group. The triglyceride concentrations were
significantly higher in the patients, and this phenomenon was not
related to their body mass.

PMID: 12898883

----------

Here's a counterintuitive study,
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=2311285&ordinalpos=13&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

---------

Hormones explain a higher percentage of females with autoimunne
conditions
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=10870028&ordinalpos=14&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

Hasn't Susan gone to great efforts to correct iatrogenic damages to
her hormone levels?

Yes and still fighting the good fight to achieve homeostasis.
-----------

What if the Leaky gut theory is right? And LPS does have some effects?
What would endotoxins (LpS) do to testosterone levels?
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17187183&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

DisruPtion sounds right...

----

Let's recaP what's been said in the past.
http://groups.google.com/groups/search?qt_s=1&q=testosterone+psoriasis

Hey? I forgot we had these conversations.

------------------------------------------------------------------------------------
================================================

Since, i've gone back on ALCAR (ALC and ALA) plus other suPPlements
i've noticed marked clearings and now I"m going to add in choline and
other supplements to try and turbo the effects.

Will some of these raise testosterone levels? I'm not taking DHEA or
pregnenolone, but may at some point.

Let's go back to a recent article I found interesting, as i'm the
first
one to flare due to arachidonic acid.

http://www.expresspharmaonline.com/20070531/research01.shtml

proteins, collectively called ____lipocortins.____ It is postulated

that these proteins control the biosynthesis of potent mediators of
inflammation such as prostaglandins and leukotrienes by inhibiting the

release of their common precursor, arachidonic acid (AA). Arachidonic

acid is released from membrane phospholipids by phospholipase A2,"

avers Saxena.

<sniP>

---------------

OK. So lipocortins block the AA inflammation action.

And in which case psoriatics clear up.

Lets look:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=1692066
Lipocortins are major substrates for protein kinase C (Pkc) in
extracts of human neutrophils.

* Stoehr SJ,
* Smolen JE,
* Suchard SJ.

Department of Pediatric Hematology/Oncology, University of Michigan
Medical Center, Ann Arbor 48109.

We have identified two major proteins in human neutrophils that are
phosphorylated in vitro by protein kinase C (PKC) as lipocortins III
and a fragment of a lipocortin-like 68-kDa protein. In electroporated
cells, the 68-kDa protein was phosphorylated during stimulation of the
cells with either FMLP or PMA. Lipocortins are of interest because of
their Ca2(+)- and phospholipid-dependent actin binding properties and
ability to inhibit phospholipase A2. Two crude fractions of enzymes
and proteins exposed to [gamma-32]PATP in the presence of Ca2+, Mg2+,
phosphatidylserine and 1,2-oleoyl-acetyl-rac-glycerol were analyzed by
gel electrophoresis and autoradiography. A number of proteins in a
detergent-free fraction, including proteins at 36 and 32 kDa, were
phosphorylated in the presence of these cofactors. In contrast, only
two major proteins (35 and 32 kDa) were phosphorylated in a detergent-
extracted fraction. Phosphorylation of the 36, 35, and 32 kDa proteins
required the presence of Ca2+, Mg2+, and phosphatidylserine in our
soluble fraction and detergent extract, indicating PKC-dependent
phosphorylation. The 32-kDa protein phosphorylated in both the soluble
fraction and detergent extract was identified as lipocortin III by
immunoprecipitation with a cross-reactive antibody that recognized
lipocortin I and comparison of cyanogen bromide (CNBr) cleavage
patterns of this protein with a lipocortin III standard. The 68-kDa
protein was identified as a lipocortin VI-like protein by
immunoprecipitation with anti-calelectrin. Additionally, the CNBr
cleavage pattern of the 68-kDa protein was similar to that of the 36-
kDa protein phosphorylated in our soluble fraction. Autoradiograms of
the 68- and 36-kDa fragments immunoprecipitated from our soluble
fraction with anticalelectrin and cleaved with CNBr showed that both
of these proteins were phosphorylated in this sample. Because
phosphorylation is known to change the functional characteristics of
the lipocortins, the potential exists to link PKC and lipocortins in
neutrophils to regulation of granulemembrane interactions or mediation
of inflammation.

PMID: 1692066

PKC and P:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Search&db=PubMed&term=pkc+psoriasis&tool=QuerySuggestion

----

Pkc and lipocortin:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Search&db=PubMed&term=pkc+lipocortin&tool=QuerySuggestion

And look at all of them:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Search&db=PubMed&term=lipocortins&tool=QuerySuggestion

------------

Try some keyword searches on lipocortin: TNF, arachidonic, n-3, scraf
etc
Here's a good one,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17215481&query_hl=18&itool=pubmed_docsum
Annexin 1: the new face of an old molecule.

* Lim LH,
* Pervaiz S.

Department of Physiology, Yong Loo Lin School of Medicine, National
University of Singapore, Singapore 117597.

The annexin superfamily consists of 13 calcium or calcium and
phospholipid binding proteins with a significant degree of biological
and structural homology (40-60%). First described in the late 1970s
and subsequently referred to as macrocortin, renocortin, lipomodulin,
lipocortin-1, and more recently Annexin 1, this 37 kDa calcium and
phospholipid binding protein is a strong inhibitor of glucocorticoid-
induced eicosanoid synthesis and PLA2. Recent interest in the
biological activity of this intriguing molecule has unraveled
important functional attributes of Annexin 1 in a variety of
inflammatory pathways, on cell proliferation machinery, in the
regulation of cell death signaling, in phagocytic clearance of
apoptosing cells, and most importantly in the process of
carcinogenesis. Here we attempt to present a short review on these
diverse biological activities of an interesting and important
molecule, which could be a potential target for novel therapeutic
intervention in a host of disease states.

PMID: 17215481

And another,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17470426&query_hl=17&itool=pubmed_docsum
Role of scarf and its target proteins in epidermal calcium
homeostasis.

* Hwang J,
* Kalinin A,
* Hwang M,
* Anderson DE,
* Kim MJ,
* Stojadinovic O,
* Tomic-Canic M,
* Lee SH,
* Morasso MI.

NIAMS, Developmental Skin Biology Unit, National Institutes of Health,
Bethesda, MD 20892.

The novel Ca++-binding protein, Scarf (skin calmodulin-related factor)
belongs to the calmodulin-like protein family and is expressed in the
differentiated layers of the epidermis. To determine the roles of
Scarf during stratification, we set out to identify the binding target
proteins by affinity chromatography and subsequent analysis by mass
spectrometry. Several binding factors including 14-3-3s, annexins,
calreticulin, ERp72, and nucleolin were identified, and their
interactions with Scarf were corroborated by co-immunoprecipitation
and co-localization analysis. In order to further understand the
functions of Scarf in epidermis in vivo, we altered the epidermal Ca++
gradient by acute barrier disruption. The change in expression levels
of Scarf and its binding target proteins were determined by
immunohistochemistry and western blot analysis. The expression of
Scarf, annexins, calreticulin and ERp72 are upregulated by Ca++
gradient disruption whereas the expression of 14-3-3s and nucleolin is
reduced. Since annexins, calreticulin and ERp72 have been implicated
in Ca++-induced cellular trafficking including the secretion of
lamellar bodies and Ca++ homeostasis, we propose that the interaction
of Scarf with these proteins might be crucial in the process of
barrier restoration. On the other hand, down-regulation of 14-3-3s and
nucleolin potentially is involved in the process of keratinocyte
differentiation and growth inhibition. The calcium-dependent
localization and upregulation of Scarf and its binding target proteins
were studied in mouse keratinocytes treated with ionomycin and during
the wound healing process. We found increased expression and nuclear
presence of Scarf in epidermis of the wound edge 4 and 7 days post
wounding, entailing Scarf's role in barrier restoration. Our results
suggest that Scarf plays a critical role as a Ca++ sensor, potentially
regulating the function of its binding target proteins in a Ca++-
dependent manner in the process of restoration of epidermal Ca++
gradient as well as during epidermal barrier formation.

PMID: 17470426

----

We can't forget the granddaddy keyword: Psoriasis + lipocortin
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Search&db=PubMed&term=lipocortin+psoriasis&tool=QuerySuggestion

--------------

Let's get back to biologicals,
http://en.wikipedia.org/wiki/Etanercept

[...]
Etanercept is made from the combination of two naturally occurring
soluble human 75-kilodalton TNF receptors linked to an Fc portion of
an IgG1. The effect is an artificially engineered dimeric fusion
protein.

<sniP>

------------

Anti-tnf is cool. What is tnf-alpha?
http://en.wikipedia.org/wiki/Tumor_necrosis_factor-alpha

[...]
Gene

The human TNF gene (TNFA) was cloned in 1985.[6] It maps to chromosome
6p21.3, spans about 3 kb and contains 4 exons. The last exon codes for
more than 80% of the secreted protein.[7] The 3' UTR of TNF alpha
contains an ARE. <sniP>

-----

So, they use human and mice Fc to block to much TNF-a?

See:
http://en.wikipedia.org/wiki/Infliximab

----

All the anti-tnf biologicals do something to slow TNF without blocking
all of it.
We do need some to kill the real culprits beyond the simple autoimmune
fictions.

-------------

Let's run lipocortin and Fc on pubmed:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Search&db=PubMed&term=lipocortin+fc&tool=QuerySuggestion

-----------
=====================================

While i've seen exlnt help from IP6, It's time to expand my trials. I
still
rely on the basic sweet whey to slow gut permeability and endotoxin
translocation. :)

This next phase is aimed at the hormones and cellular components.

--------------------

randall.... shutting down the p pathways

randall

unread,

Jun 7, 2007, 4:45:08 PM6/7/07

Hi,

Did you get anything out of yesterdays, testosterone and vitamin D3
post?

Moving around in the sun with naked skin to do it's D3 thing will keep
that
testosterone in the zone and you'll live longer.....

Just forget about your psoriasis and live longer with a smile and a...
<w>

Don't let your thinking stoP you....

Think = stink.... move and groove in the rays on sunny days already..

=============================

Next: BACK to the FUTURE... genes and autoimmunity in the NEWs

-----

Down Under wonder's--- link seven diseases. Is P one of them?

Crohn's and diabetes are they close enough to P to yield target rich
research???

Will Seven COME Eleven or will we craP OUT???

http://www.tuscaloosanews.com/apps/pbcs.dll/article?AID=/20070607/ZNYT04/706070356/1002/NEWS04
Researchers Detect Variations in DNA That Underlie Seven Common
Diseases

Applying a new genomic technique to a large group of patients,
researchers in Britain have detected DNA variations that underlie
seven common diseases, discovering unexpected links between them.

The variations pinpoint biological pathways underlying each of the
diseases, and researchers hope that as the pathways are analyzed, new
drugs and treatments will emerge.

The seven common diseases are bipolar disorder, coronary artery
disease, Crohn's disease, hypertension, rheumatoid arthritis, and Type
1 and Type 2 diabetes.

Unveiling the complex genetics of common diseases was the promised
payoff of the $3 billion human genome project, completed in 2003, but
progress was slow until the recent development of devices that in a
single operation can read the DNA sequence at up to 500,000 points
across an individual's genome. With the devices, called chips,
researchers can compare large numbers of patients with healthy
individuals, looking for points of differences in their genomes that
may be associated with disease.

The approach is known as whole genome association, and studies on Type
2 diabetes, heart disease and breast cancer have been reported within
the last few weeks. Those and the new study, which was financed by the
Wellcome Trust of London, demonstrate the power and reliability of the
whole genome association method, which stands in contrast to the many
uncorroborated claims of disease genes made previously.

"It's now absolutely clear that this is a new dawn in the genetics of
common human diseases," said Peter Donnelly, a statistical geneticist
at Oxford University who was chairman of the consortium of 50
institutions involved in the Wellcome Trust study.

The consortium compared 2,000 patients with each disease from across
Britain with 3,000 healthy individuals as controls, half of whom were
born in a single week in 1958. The consortium's findings are published
in today's Nature, along with reports from two groups that largely
confirm the consortium's genomic hits in independent patient groups
suffering from Crohn's disease and Type 1 diabetes.

The consortium discovered some 24 variants strongly linked to disease,
about half of which have been found already by other groups and half
of which are new.

Among its most interesting findings is that genetic variants close to
a gene known as PTPN2 are associated with both Crohn's disease and
Type 1 diabetes. The link may be that both are autoimmune diseases and
that the gene helps regulate the immune system. Researchers hope that
analysis of the gene's operations may produce a treatment for the two
diseases.

The consortium also found a genetic variant on chromosome 7 that
carries a high risk of rheumatoid arthritis for women, but none for
men. Very few such variants are known in diseases common to both
sexes, Dr. Donnelly said.

Anne Bowcock, a geneticist at the Washington University School of
Medicine in St. Louis, said the Wellcome Trust study was a "tour de
force" that established how large-scale studies should be conducted.

Marie Nierras, an official of the Juvenile Diabetes Research
Foundation, which supported the companion study of Type 1 diabetes,
said the research was "a significant advance that identifies
additional pathways that need to be looked at."

Dr. Kari Stefansson, chief executive of DeCode Genetics, an Icelandic
company that has dominated the search for common disease genes until
the arrival of the whole genome association method, said the Wellcome
Trust study was "a large body of work, done by very good people" but
that it "hadn't come up with any big discovery."

Dr. Stefansson said the study had been delayed because of problems
with the Affymetrix chip it used, and would have had greater impact in
the fast-moving field if it had appeared several months earlier.

In the course of screening for any geographically related genetic
bias, the Wellcome Trust researchers discovered a southeast-to-
northwest gradient across Britain composed of 13 genes. The genes were
probably under natural selection in the people who became the island's
first inhabitants.

One of the genes, which arose among Europe's first cattle herders
5,000 years ago, enables people to drink milk in adulthood, an ability
known as lactose tolerance. The other genes, the researchers
speculate, may confer resistance to former scourges like pellagra,
tuberculosis and leprosy.

Another possible source of statistical bias relates to race. The
Wellcome Trust consortium asked their 17,000 subjects to identify
their race, then genetically tested them and excluded 153 people who
had non-European ancestry. The procedure is necessary because whole
genome association studies look for small differences between patients
and controls, which can be confounded by the genetic differences
between races.

The Wellcome Trust's findings apply to populations of European descent
and need to be verified in other races. Geneticists do not yet know
what proportion of the genetic variants associated with common disease
will be found in all races, but hope the overall biology will be much
the same.

"The genetics gives us a whole new foothold into the biology of
disease," Dr. Donnelly said. "If you find a variant in one population
you might learn a lot about that disease which is relevant to the
disease in other populations."

Because whole genome association studies work only in people of a
single race, researchers are concerned that follow-up studies should
then be done in other races. "I think everyone is committed to make
sure that is the case," said Mark Daly, a geneticist at Massachusetts
General Hospital.

--------------

Crohn's and P have many charateristics in common and Anne Bowcock
knows P like nobody else. I'm sure she's working on PTPN2 or at least
looking at it like me right now.

NO WAY dude your an idiot and she's a freaking genius....

She has your dna in her tissue bank...

Well? Thats true.. LOL

----

I guess a quick look at PTPN2 is warranted:
http://www.ncbi.nlm.nih.gov/gquery/gquery.fcgi?term=ptpn2

I see that ptpn1 was identified as a diabetes agent in 2004,
http://www.ncbi.nlm.nih.gov/gquery/gquery.fcgi?term=ptpn1

You know, we've had some Protein-tyrosine phosphatase posts in the
psoriasis newsgroup under ptpn22.
http://groups.google.com/groups/search?qt_s=1&q=Protein-tyrosine+phosphatase+ptpn22+psoriasis

And on the web,
http://www.google.com/search?tab=gw&q=Protein-tyrosine%20phosphatase%20ptpn22%20psoriasis

And a lack of helP here,
http://www.nature.com/jid/journal/v125/n2/full/5603497a.html

PTPN22 isn't already on the suspect list for autoimmunity. Or is it?

Nice link.. I should look at those tables next time...

Geez... what a wiz..yes? no? and I don't KNOW...

We do know a huge linkage with crohn's and type II diabetes is the
ptpn2 gene. NOW

Why psoriasis wasn't in the mix in this one is a glaring question in
my mind....

Why?

Who cares? LOL

I do... the schiz'd out, I want a P cure NOW... man...

==================================

This DNA thing is ramPing uP like nobodies business. Dr. Watson has
his on dvd now!

Will it be a best seller? And what about Sherlock and Crick? Ones a
hit and the
other a genius? <w>

http://www.medicalnewstoday.com/medicalnews.php?newsid=72751

------

And stem cell magic is closer to a reality as some future form of
treatment.

IN ten years it may be the ultimate cure for psoriasis!

http://www.abc.net.au/science/news/stories/2007/1944796.htm?health
&
http://presszoom.com/story_133677.html

----------

===============================

OK, ok already... i'm in the zone now...

Need to feed the skin with vitamin D3. Must get naked under the
uvb's.... what a tonic!

Full sPectrum or not, here i COME. lol

randall.... someone has to run the sun trials with a wink and a gin....

JXStern

unread,

Jun 7, 2007, 6:05:57 PM6/7/07

On Thu, 07 Jun 2007 13:45:08 -0700, randall <ranh...@aol.com> wrote:

>randall.... someone has to run the sun trials with a wink and a gin....

I've been running my sun trials for years now, with the full knowledge
that the day it cures psoriasis will also be the day it causes skin
cancer.

Brett

unread,

Jun 7, 2007, 7:39:39 PM6/7/07

I'll take all the benefits of the sun any day over the so called cancer
risks. This is a pretty good article about sunlight and skin cancer, with a
number of links to check out and read.
http://homeschoolmath.blogspot.com/2006/07/sunlight.html

Brett

"JXStern" <JXSternC...@gte.net> wrote in message
news:780h63hh66e87pfb3...@4ax.com...

randall

unread,

Jun 8, 2007, 5:51:16 PM6/8/07

On Jun 7, 4:39 pm, "Brett" <brettd...@telus.net> wrote:
> I'll take all the benefits of the sun any day over the so called cancer
> risks. This is a pretty good article about sunlight and skin cancer, with a
> number of links to check out and read.http://homeschoolmath.blogspot.com/2006/07/sunlight.html
>
> Brett
>

> "JXStern" <JXSternChange...@gte.net> wrote in message
>
> news:780h63hh66e87pfb3...@4ax.com...

>
> > On Thu, 07 Jun 2007 13:45:08 -0700, randall <ranhu...@aol.com> wrote:
>
> >>randall.... someone has to run the sun trials with a wink and a gin....
>
> > I've been running my sun trials for years now, with the full knowledge
> > that the day it cures psoriasis will also be the day it causes skin
> > cancer.
>
> > J.

If the numbers of psoriasis topical skin cancers was one sided it
would show uP
in the figures. Other then the occasional psoriatic piping uP over
their experience
with it, I don't see a increase.

Check this one out:
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17553037&ordinalpos=3&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
The challenge of follow-up in narrowband ultraviolet B phototherapy.
Diffey BL, Farr PM.

Department of Medical Physics, Newcastle General Hospital, Newcastle
upon Tyne NE4 6BE, U.K.

Background The use of narrowband ultraviolet (UV) B phototherapy to
treat psoriasis and other disorders has increased markedly since the
TL-01 lamps were introduced in the 1980s. While broadband UVB
phototherapy has generally been considered to be a relatively safe
treatment, some concern has been raised about the potential increased
skin cancer risk with narrowband UVB. Objectives The likelihood of a
patient who is free of nonmelanoma skin cancer (NMSC) at the start of
phototherapy developing a malignancy after a certain follow-up period
will be dependent not only on the carcinogenic potential of the
treatment but also on the age-conditional probability of natural
occurrence. We were interested to explore the potential difficulty of
designing studies to separate these two events. Methods Mathematical
models were developed that combined age-conditional probabilities of
developing NMSC due to natural causes with the risk of inducing these
cancers from narrowband UVB phototherapy in order to estimate the
excess number of cancers resulting from this therapeutic intervention
in a cohort of patients. Results Within-department studies will be
most unlikely to demonstrate that the number of NMSCs observed in
follow-up studies is significantly different from that expected in an
untreated population, even for a follow-up period of 20 years.
Conclusions Determination of the carcinogenic potential associated
with narrowband UVB will require large multicentre studies typically
involving several thousand new patients per year and followed up for
10 years or more.

PMID: 17553037

If we assume the nb-uvb's are more carcinogenic then full spectrum
rays,
http://en.wikipedia.org/wiki/Carcinogen
Then you'd expect the numbers to be glaring on the side of new cases.

My father a late onset psoriatic had a small carcinoma successfully
removed a few
years ago.

And it would seem to me that a diet high in omega-6's would contribute
more to
skin cancer then sunlight in general.

Or I would also suspect cancers from iatrogenesis (as a result of
treatments) before
sunshine as the sole contributing factor.
http://en.wikipedia.org/wiki/Iatrogenesis

((((((((((((((((((((((((((((((((((((((()))))))))))))))))))))))))))))))))))))))))))))))

Other abstracts from the last few days:::

It would be nice to know how this one came out,
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17553044&ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
Consecutive use of different biological therapies in the treatment of
psoriasis.
Costanzo A, Papoutsaki M, Mazzotta A, Chimenti S.

Department of Dermatology, University of Rome 'Tor Vergata', Viale
Oxford 81, 00133 Rome, Italy.

PMID: 17553044

-----

I'd love to see a well designed trial of low dose therapies on mild to
moderate psoriatics.

And include FAE's and varied topicals in this trial... Plus JX's
cocktails... :)

The NIH can send us a few million to construct it....

So much for dreaming out loud. lol

We can even make it double blind. Wear a sack over your head when out
in the sun.

Back to genes?

OK!

----------------------------------

http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17554368&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
Polymorphisms in Interleukin-15 Gene on Chromosome 4q31.2 Are
Associated with Psoriasis Vulgaris in Chinese Population.
Zhang XJ, Yan KL, Wang ZM, Yang S, Zhang GL, Fan X, Xiao FL, Gao M,
Cui Y, Wang PG, Sun LD, Zhang KY, Wang B, Wang DZ, Xu SJ, Huang W, Liu
JJ.

Through a series of linkage analyses in a large Chinese family cohort
of psoriasis, we previously identified and confirmed a non-HLA
psoriasis linkage locus PSORS9 within a small region at 4q31.2-32.1.
Within the critical region of the PSORS9 locus, IL-15 has been long
recognized as a strong candidate gene for psoriasis. In this study, we
investigated the association between IL-15 genetic polymorphisms and
psoriasis in a large Chinese sample. Highly significant evidence for
association was identified at a single-nucleotide polymorphism (SNP)
(g.96516A --> T) within the 3'-untranslated region (UTR) of the IL-15
gene (P=0.00006, after correction for multiple testing). Haplotype
analysis using the SNPs within the 3'UTR region also provided strong
supporting evidence for association (P=0.00005), where we identified a
haplotype of the 3'UTR region of IL-15 associated with increased risk
to psoriasis (odds ratio=1.65). This association was also supported by
the results of our expression activity analyses, where we demonstrated
that the identified risk haplotype is associated with an increased
activity of IL-15. Therefore, we provided early evidence for the
important role of IL-15 genetic variants in the pathogenesis of
psoriasis, probably by increasing interleukin production and
inflammation in the lesions of psoriasis.Journal of Investigative
Dermatology advance online publication, 31 May 2007; doi:10.1038/
sj.jid.5700896.

PMID: 17554368

Psors9:
http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=607857

And of course psors1:
http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=177900

-------

Whats a polymorphism?
http://en.wikipedia.org/wiki/Polymorphism_%28biology%29

Been awhile since biology class? LOL
http://en.wikipedia.org/wiki/Haplotype

Lets check IL-15,

http://en.wikipedia.org/wiki/Interleukin_15

It's a stub. So try IL-2,
http://en.wikipedia.org/wiki/Interleukin_2
and plain old interleukin,
http://en.wikipedia.org/wiki/Interleukin

--------------

Back to psors9
http://www.genizon.com/html/content.asp?node=22

[...]
Genizon BioSciences has completed a genome-wide association study in
its Psoriasis program using 500 trios from the QFP. Genotyping was
performed in collaboration with Perlegen Sciences using the Quebec LD
Map (QLDM) which is based upon the genetic structure of the QFP. The
QLDM consists of approximately 81,000 SNP markers whose density varies
as the LD, or genetic sharing, varies across the genome in the QFP.
Genizon's study resulted in the identification of more than 16 loci
with haplotypes (combinations of SNPs) that significantly increase the
risk of developing psoriasis. Several novel disease gene signals were
identified and two known loci associated with psoriasis were
confirmed: PSORS1,a disease locus in the HLA region on chromosome 6
that has repeatedly been observed in other studies, and PSORS9, a
locus on chromosome 4 that has previously been reported several times.
<sniP>

------------

=====================================

So much for all this mumbo jumbo.

How about a trial of television radiation effects on psoriatics?

Lost of exercise and brain waves being a salient factor on the long
(time) side of
the curve. LOL

randall...

randall

unread,

Jun 9, 2007, 1:49:11 PM6/9/07

Hi,

Since, current trials are pointing at vitamin D, sunshine and exercise
in the context of disease, let's continue with it.

Metaphorically, are we meant to touch the sun?

Do Psoriatics suffer from the Icarus syndrome?
http://en.wikipedia.org/wiki/Icarus_(mythology)
Will the light melt our wings or clear our hides?

Sunshine, exercise, fresh air and a diet riPe with omega-3's seems to
be the best doctor for all of us.
http://www.newstarget.com/021892.html

Here is ONE GLARING caveat:
Sunshine is fine, unless you have the braf GENE mutation,
http://www.eurekalert.org/pub_releases/2007-06/uonc-see060807.php

BRAF is not your buddy,
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17516929&ordinalpos=10&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
&
http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=PubMed&list_uids=15289355&dopt=Abstract
&
http://www.google.com/search?hl=en&q=braf+mutation&btnG=Search

We're racing towards individual medicines for our funky genes,
http://www.biopharma-reporter.com/news/ng.asp?n=76949-exelixis-imclone-systems-personalised-medicine-breast-cancer-american-association-of-cancer

STILL, even with these funked out genes, one would hope, that a Th1
skew would brew the
interleukins required to provide TNF for cell lysis to occur.
http://en.wikipedia.org/wiki/Lysis

With the cancerous cells simply being chewed up by TNF, you don't
develop
cancer.

BUT, what haPPens if you do get cancer?

What about sun, fun and diet then???

It seems more necessary then ever provided you want to watch the sun
go round.

http://www.signonsandiego.com/news/health/20070609-9999-7m9cancer.html

=========================

randall... move it or lose it, the sun is fun!

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