Alps Checkpoint

[Trudi Miranda]

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Autoimmune lymphoproliferative syndrome (ALPS) is an inherited non-malignant and non-infectious lymphoproliferative syndrome caused by mutations in genes affecting the extrinsic apoptotic pathway (FAS, FASL, CASP10). The resulting FAS-mediated apoptosis defect accounts for the expansion and accumulation of autoreactive (double-negative) T cells leading to cytopenias, splenomegaly, lymphadenopathy, autoimmune disorders, and risk of lymphoma. However, there are other monogenetic disorders known as ALPS-like syndromes that can be clinically similar to ALPS but are genetically and biologically different, such as observed in patients with immune checkpoint deficiencies, particularly cytotoxic T-lymphocyte antigen 4 (CTLA-4) insufficiency and lipopolysaccharide-responsive beige-like anchor protein LRBA deficiency. CTLA-4 insufficiency is caused by heterozygous mutations in CTLA-4, an essential negative immune regulator that is constitutively expressed on regulatory T (Treg) cells. Mutations in CTLA-4 affect CTLA-4 binding to CD80-CD86 costimulatory molecules, CTLA-4 homodimerization, or CTLA-4 intracellular vesicle trafficking upon cell activation. Abnormal CTLA-4 trafficking is also observed in patients with LRBA deficiency, a syndrome caused by biallelic mutations in LRBA that abolishes the LRBA protein expression. Both immune checkpoint deficiencies are biologically characterized by low levels of CTLA-4 protein on the cell surface of Tregs, accounting for the autoimmune manifestations observed in CTLA4-insufficient and LRBA-deficient patients. In addition, both immune checkpoint deficiencies present with an overlapping but heterogeneous clinical picture despite the difference in inheritance and penetrance. In this review, we describe the most prominent clinical features of ALPS, CTLA-4 insufficiency and LRBA deficiency, emphasizing their corresponding biological mechanisms. We also provide some clinical and laboratory approaches to diagnose these three rare immune disorders, together with therapeutic strategies that have worked best at improving prognosis and quality life of patients.

About this very famous checkpoint that is a dream of many cyclist to ride up there at least once in the live:

Build 1876 with an altitude of 2642m is it today the 5th highest mountain pass road in the Alps. It was 1911 the first mountain pass in the Alps that was part of the Tour de France. It was part of a 366km stage from Chamonix to Grenoble. At the south side of the top tunnel you find a monument that remembers to Henri Desgrange, the founder of the Tour de France.

This year I had the opportunity to join the vet team for La Grande Odysse, a long-distance staged dogsled race that travels through the French Alps. I was very excited to work on a staged race for the first time, which is very different from the Quest, and I was also lured by the promise of French food and little French villages tucked into the Alps.

I arrived in France at the beginning of January. There are four different races that take place during La Grande Odysse - a long distance race, a mid distance race, and two shorter races that only last 3 days each. Every day the mushers, race officials, logistics team and vet team travel to a different village to set up the stage, which involves making a start and finish chute, musher parking, and a small mobile veterinary hospital. The mushers drive smaller teams - 10 dogs for the long distance racers, 8 dogs for the mid-distance racers, as opposed to the 14 dogs that Quest mushers drive - and because they're not camping overnight, their sleds are astonishingly light. It typically take teams between 3-6 hours to complete a stage, and once the teams complete a stage, the dogs hang out at their dog truck rather than camping in straw on the gangline.

One of the big differences between La Grande Odysse (LGO) and other races I have worked on was the array of diagnostic equipment we had available. Because we reached every checkpoint by road, we were able to set up a small mobile hospital at each checkpoint with an x-ray, ultrasound and blood chemistry analyzers. While the bread and butter of sled dogs vets are lameness and diarrhea, which usually don't require diagnostic equipment to diagnose or manage, these tools were very useful for the more unusual cases that presented. One of the most dangerous conditions that can occur in sled dogs is myopathy, a condition where diffuse, widespread breakdown of muscle tissue releases proteins that can cause kidney failure and sudden death. The clinical signs of this disease are distressingly subtle - a dog may begin to pull less hard, or adopt an unusual gait, or may collapse in the harness but spring back up again within a few minutes and scream to start moving again. Often there will be a characteristic coffee-brown urine that helps point you towards the correct diagnosis, but we're not always lucky enough to catch that sign. On LGO this year we had a dog who came in weak and reluctant to get up from laying down, but the musher had not noticed any brown urine. When we ran his bloodwork we found a severe elevation in his creatinine kinase, an enzyme that acts as a biomarker for muscle damage. This told us that the dog had myopathy and could potentially go into a life-threatening crisis if not treated, so we started him on high rates of iv fluids to help protect his kidneys and flush out the damaging proteins, and the dog recovered uneventfully.

The weather added a challenge to the LGO that I hadn't anticipated. While the weather conditions overall were much warmer than what Quest veterinarians experience (I think our all-time low was -15 C on top of Mont Cenis), we didn't have the infrastructure available on northern dogsled races. Having heated checkpoints on the Yukon Quest and other northern races is critical when temperatures can drop to -40 C or below, but in the more hospitable weather of the LGO our checkpoints were unheated, 3-walled tents that we would erect and take down each day. This made it very challenging to keep iv fluids and iv medications from freezing. I had a small pharmacy of various injectable medications tucked into the internal pockets of my parka, and we would try to keep iv fluids thawed on the dashboards of our vans. Administering iv fluids to dogs was hugely challenging, as the fluids would try to freeze in the administration line, and we would have to take advantage of supplies we had and the generosity of people around us with various forms of heat to keep the fluids running.

The vets on the LGO were incredibly smart and generous with their knowledge, the mushers were good humoured and devoted to their dogs, the dogs were strong and brave and silly and adorable, and the Alps were breathtaking. But I missed the rhythm of the races up here - the punishing frenzy of the first 48 hours of the Quest contrasting with the quiet moments between teams arriving when you can walk through the dogyard and spy on a dog you were worried about to make sure they're wagging their tail and eating well. I am incredibly grateful to head veterinarian Dr. Yannick Klein as well as the entire La Grande Odysse race organization for allowing me to come and learn from them. I'm heading up to Dawson to work on the Percy again in March, and can't wait to be out in the dogyard again.

I remember a "Choose Your Own Adventure"-style novel whose title I cannot remember. I read it sometime between 2010 and 2016 (throwing darts at a memory board). It is an English title, and I believe it was a paperback with a red car on the cover. It had a few black and white line images, I believe, but was otherwise text. Second-person narration seems most likely from what I recall.

It starts off as a race in the Italian Alps, with you and your (female?) partner barely reaching a checkpoint in time. A man at a desk writes down some stuff and waves you off next. A good portion of the book revolves around finishing the race.

Another portion of the plot involves choices that lead to your kidnapping, you being the son of a wealthy figure. Escaping/evading capture makes up another major portion of the book. One possible way you get captured is a scruffy man offering to "go on a walk" with you, and you don't refuse because of his gun holster announcing itself silently.

"Going somewhere, my young friend?" comes a voice. The speaker is a man with unruly blond hair. It looks like a wig, but you're not sure. Your attention is drawn to his left foot. The heel on the boot is thicker than the other foot.

"I think you had better come with me," he says as you notice a small black revolver in his right hand. He does not smile.Suddenly the fog clears. He is the man on the moped you saw in Paris! But did that even happen? Or was it all a dream? The gun, however, is real enough.

There are magnets that pull us through life. People, places, and narratives that we adorn with magical meaning, with or without intention, to give our reality a semblance of direction, a sense of purpose. The biggest beacons become our gods, our meccas and icons, shaping our finite lifelines into a semblance of destiny.

The Maratonas has everything one would hope for in a European cycling event. Epic climbs and descents on buttery smooth roads, distance options from 37km to 138km, and a reputation of being well organized, now that it is in its 40th annual race. Add to it the great Italian culture (and food!), and the one-of-a-kind love for life of the Italian people, one would be hard pressed to not have a near-religious experience here. 8,000+ other riders agree, making it a sell out event once more.

Back at the hotel, I was out of options, and decided to just go rent any bike I could find in the 20 minutes before all the stores closed (race day was at 5am the next morning). But as the elevator opened, there was a young man who also had a brand new bike and the same Di2 shifters, and he gracefully lent me his cable. What an angel! He and his brother grew up in Vienna, and now lived in California, the flipside of my life journey. Then as we chatted, we figured out that his girlfriend was a new intern at adidas that I had just met the previous week! Such a small world.

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