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Today, I’ll tell you the truth about the most common myths about hair. And stay tuned until the end of this episode for the question of the day if you answer it correctly, you’ll have a chance to win a free skincare product! Hello I’m Dr. Neal Schultz pause And welcome to DermTV. There’s just as much misinformation flying around about hair as there is about skincare. So today I’ll tell you six of the worst myths about your hair. Let’s get started! Myth 1 Hereditary hair loss is caused by maternal genes!.

Actually, the heredity of hair loss is very confusing and complex and not nearly as simple as just being inherited from mom. I’m sure you can blame a lot of stuff on your mom, but no longer can you blame your hair loss on her! Myth 2 If you shampoo less often, your scalp will gradually produce less oil. In fact, if you shampoo less often, you’re hair and scalp will be dirtier and more oily as the oils accumulate and trap more dirt. The only thing that regulates oil production is your level of.

Male hormone in your blood. Period. End of story. Nothing else affects oil production in your scalp or skin. Myth 3 If you wax long enough the hair will stop growing. If stopping unwanted hair were only that easy! Actually, if you wax long enough, you’ll get more and more ingrown hairs Which is neither very attractive nor fun Especially when they’re painful! Myth 4 Hair loss is caused by clogs in scalp pores The reality is that hair loss may be aggravated by uncontrolled dandruff, which may increase hair loss,.

But has nothing to do with clogged pores. Myth 5 Frequent hair cutting makes hair grow faster. The only thing that I know that makes scalp hair grow faster is finasteride, also known as Propecia, which is used by men to stimulate hair growth. Bimatoprost, known as Latisse, can cause eyelashes to grow faster, but is much too expensive to consider for scalp hair even if ongoing studies do demonstrate that it works. And last but not least, myth 6 Frequent Shampooing Makes Hair Fall Out Shampooing will only make hairs fall out which are ready to fall out.

And would have fallen out in the next day or two by themselves even if you didn’t shampoo. Gentle and normal shampooing never affects normal hairs adversely. So there you have it. Six of the biggest myths about hair and where they all fall short. And in future DermTV episodes, I’ll share some more! Now for today’s skincare trivia! Answer today’s question correctly and you’ll be entered in a drawing to win a free skincare product! Submit your answer at DermTV Dot Com Slash Trivia, within three days of this episode’s airing.

How to Diagnose Severity of Genetic Under Eye Bags to Choose Fillers or Surgery

Considering lower blepharoplasty for genetic eyebags. Would fillers be a better option because of my age My mom says she had eyebags even as a child. Now she is 50 and trying to get a lower blepharoplasty, since they have worsened in the last few years. I also have had eyebags as long and I can remember and I would like to get treated. I also have chronic allergies, which make them worse. Would a blepharoplasty be the best course of action for me, or would fillers be a good choice for my age and type of eyebags I’d rather get a lower bleph, because that.

Will be permanent. But again, my age is a factor. Thank you for your question! You submitted photos as well as a very good history of your mom at the age of 50 having eyebags looking for a blepharoplasty and your question is whether or not to have the blepharoplasty within the context of you having allergies or whether because of your age, is it better to do fillers. So I can tell you that as a practicing oculofacial plastic surgeon for 20 years, I have operated on people as young as 14 for bags under the eyes. You are certainly accurate that it runs.

In families, it’s genetics. I have operated on 3 generations in the same family. And I would suggest to you that there are some key important factors that help you make this decision. The first factor of course is how prominent are the bags. Although in your photo, it appears that they are relatively prominent, lighting and other factors can impact how 3dimensional the bags are. If the bags are very subtle, then you are talking about maybe being able to camouflage with a filler like Restylane of hyaluronic acid. But if the bags.

Are more prominent and when you look up, they bulge forward and are very prominent, then certainly you can consider a lower eyelid blepharoplasty. In a younger person like yourself, I would typically do a transconjunctival blepharoplasty. I’m assuming that you understand that you have lower eyelid fat prolapse so we won’t get into the details of what that is. In addition, as far as the allergies are concerned, allergies accumulate a lot of fluid in the eye area. Management of allergies is very important when you are considering rejuvenation of the lower eyelids. if your eyes are itchy, if you have watery eyes, if you need eye drops,.

Those things should be managed. If you need to take antihistamines, take the antihistamines. Allergies can still affect the appearance of your under eye area. When puffiness is removed, I tell most of my patients who are in similar situation as yourself, once we reduce the bags, even if you have allergies, it would typically won’t look as puffy than when you did have the fat pockets there. So chances are, you would probably be best served when doing a blepharoplasty as opposed to having a filler. But again, as I mentioned, 3deminsionality is something that can only be appreciated in a physical.

Examination. Skin quality with allergies is an also an issue so you also have to think about good topical skin care. Sometimes people with chronic allergies and they rub their eyes a lot, the skin become somewhat irregular and it kind of ages in appearance and we would routinely do something like plateletrich plasma injection as well as the use of fractional CO2 laser. Again, that’s more of a physical exam that requires actually contact. So I think that as your mother is doing her research, it will be good for you to tag alone.

And have a consultation. You are young, I recently did a facelift and eyes on a mother and daughter and they actually supported each other very nicely during their healing process and so it’s something that might be worth considering when you do your consultation. But most importantly, understanding what level of the fat prolapse you have and deciding if it’s beyond a certain level, you’re probably best served with having the lower eyelid blepharoplasty. So I wish you the best of luck, I hope that was helpful and thank you for your question!.

Ionic Detox VS helps clear up a skin rash.

Ok, well, I guess I’m going to tell you the story of Aaron Fisher part 2. We’ve been working with Aaron Fisher out in Lancaster Pennsylvania for a little over a year now the Ionic Detox and we’ve actually seen some pretty amazing results. His rash he’s been dealing with from the yeast and toxins in his body have actually gone about 60 percent away. He’s got new skin. His skin is softer and smoother and he absolutely loves the results he is seeing, so it has sped up the ability of our herbs probably a good 40. It’s a phenomenal product.

Define Urticaria What is Urticaria Urticaria Definition What is Hives

What is Urticaria or Hives Find out more at besturticariacure Urticaria or hives is a kind of skin rash notable for pale red, raised, itchy bumps! Hives might also cause a burning or stinging sensation! Hives are frequently caused by allergic reactions! Most cases of hives lasting less than six weeks are the result of an allergic trigger. Chronic urticaria is rarely due to an allergy Which lasts longer than six weeks. The majority of chronic hives cases have an unknown idiopathic cause! Acute viral infection is another common cause of acute urticaria viral exanthem!.

Less common causes of hives include friction, pressure, exercises and sunlight! Wheals from urticaria can appear anywhere on the surface of the skin! Whether the trigger is allergic or not, a complex release of inflammatory mediators including histamine from cutaneous mast cells results in fluid leakage from blood vessels. Wheals may be pinpoint in size, or several inches in diameter! Acute urticaria is defined as the presence of evanescent wheals which completely resolve within six weeks! Chronic urticaria is defined as the presence of evanescent wheals which persist for greater than six weeks!.

Cure for Boils Natural Ayurvedic Home Remedies

Have you ever suffered from boils Yes, then here’s an info capsule. Boils are caused by deep bacterial infection of hair follicles. They can occur on any part of the body that has hair follicles. They are usually harmless and tend to heal within a few weeks. Boils start as small, red, painful nodules and gradually increase in size to haunt you. Some people are physiologically more susceptible to develop boils because they tend to be staph carriers. The bacteria cause boils when they enter the skin. Boils are generally not contagious.

But the bacteria that cause boils certainly are. Moreover, people with diabetes, low immunity, poor hygiene, poor nutrition, or longterm illnesses are more prone to this problem. I will now tell you about some home remedies that will help cure boils naturally. For the first home remedy. Take some black seeds and boil them in some water. Grind them along with a little water to get a paste like this. And apply it on the affected area twice daily. The next home remedy to treat boils. Take about a handful of neem leaves.

And grind them to form a paste like this. And apply it on the effected area. Alternately, you can also boil 15g neem leaves in about 500 ml water until the quantity of water reduces to onethird. For this another home remedy that can be used to bring a boil to the head and reduce inflammation and swelling use a bread poultice. For this, you need to soak a bread in hot milk or water and apply it as a poultice on the effected area. Now some tips to help your boils heal faster.

How to Remove Dark Circles

Hi Friends Welcome to Priyanka’s beauty and masala mantra today’s tip is related to dark circles most of us are fed up of their dark circle I have small and simple home remedy for you so let me tell how to vanish your dark circles for that we need we will take grated cucumber grate it propely Aleo vero, it is easily available in shop or market many people use it nowadays cut it from middle take out the inner gel portion from it and with that add 12 tsp of honey.

Mix is properly Aleo vera gel is thick in its original so smash it properly so that it mix well now the paste is ready apply it all over and under your eyes and leave for 15 mins and after 15 min mins wash it off with cold water Do it for almost 1 month it is very effective if possible apply it twice a day morning and eveing If it is not possible in morning because of work in evening wash off your eyes and apply this paste leave for 15 mins.

Demystifying Medicine 2014 Itching pruritus Mechanisms, Diseases, and Treatment

Gtgt I THINK WE’LL BEGIN. SO TODAY WE’RE GOING TO HAVE A DISCUSSION AND PRESENTATION ON A VERY BROAD PROBLEM. EVERYBODY AT ONE TIME OR ANOTHER HAS HAD AN ITCH. SO I’VE ALWAYS BEEN INTERESTED IN THE ORIGIN OF WORDS, SO I LOOKED UP THIS AND WHAT I FOUND, YES. DO YOU KNOW WHAT BRIDGE THAT IS YOU DON’T DO YOU KNOW THAT’S THE MOST FAMOUS BRIDGE IN THE WORLD. THAT’S THE BROOKLYN BRIDGE. IF YOU EVER GO TO NEW YORK, YOU SHOULD WALK ACROSS THE BROOKLYN BRIDGE, PREFERABLY WITH A DATE.

BECAUSE IT’S TRULY ONE OF THE MORE ROMANTIC EXPERIENCES. AND IT DOESN’T COST A PENNY. AND THER ARE TWO VERY NICE RESTAURANTS. NOW WHY WE WOULD PUT UP A BRIDGE FOR SOMETHING LIKE THIS IT’S BECAUSE THIS WHOLE COURSE IS SORT OF A LOGO, AND THE IDEA THAT WHAT WE’RE TRYING TO DO IS TO CONNECT SCIENCE AND MEDICINE, SORT OF BASIC REDUCTION IN MOLECULAR CELLULAR, ETCETERA, ETCETERA. THE SORT OF STUFF THAT GOES ON ALL AROUND US HERE. AND THERE’S A BIG GAP. MOST PEOPLE KNOW A LOT ABOUT ONE.

THING KNOW LITTLE ABOUT THE DISEASES, AND OFTEN THE REVERSE IS TRUE. SO WHAT WE TRY TO DO HERE IS TO SORT OF TAKE MAJOR HEALTH PROBLEMS AND TAKE ADVANTAGE OF THE EXTRAORDINARY FACULTY ON BOTH SIDES OF THE BRIDGE. NOW THESE GENTLEMEN WHOSE PICTURE WERE THERE, THOSE DAYS YOU COULD WALK ACROSS THE CATWALK WHILE THEY WERE BUILDING IT AND LADIES USED TO GO ACROSS LONG GOWNS AND HAVE THEIR PICTURE TAKEN. SYMBOLICALLY WE’RE DOING THE SAME THING WITH LONG GOWNS BUT WE’RE OUT ON A CATWALK. SO THE IDEA IS TO LEARN AS MUCH.

AS YOU CAN. THIS ISN’T A MEDICAL SCHOOL RECTOR WHERE YOU’RE GOING TO BE QUIZZED. YOU’RE ENCOURAGED TO INTERRUPT AND AT THE END ASK QUESTIONS AND DON’T HESITATE. BEST PROFESSOR I EVER HAD TOLD ME THAT THE PERSON WHO DOESN’T ASK THE FOOLISH QUESTION IS THE FOOL. SO I LOOKED U THE ORIGIN OF THE WORD PRURITUS AND ITCHING. PRURITUS IS LATIN AND I COULDN’T FIND OUT WHAT IT MEANS IN LATIN. BUT IN OLD ENGLISH, THEY INTRODUCED THE WORLD ITCHING. WHAT IT MEANT WAS AN URGE. SO IT’S AN URGE TO SCRATCH BUT.

WE USE IT FAR MORE OFTEN IN TERMS OF I’M ITCHING TO GO SEE THE BROOKLYN DODGERS PLAY AGAIN OR WHATEVER YOU’RE ITCHING TO DO. SO IT’S AN URGE TO DO SOMETHING OR WANT SOMETHING BUT IT’S INTERESTING THAT ITCHING HAS ITS ORIGIN IN URGE AND FOR PATIENTS ITCHING IS LINKED TO THE URGE TO SCRATCH AND TO RELIEVE THE SENSATION. SO WE WHENEVER POSSIBLE BEGIN BY PRESENTING A LIVE PATIENT WHO KINDLY COMES AND BRIEFLY EXPLAINS WHAT THE NATURE OF THEIR ILLNESS IS AS RELATED TO THIS TOPIC. AND SEVERAL YEARS AGO, ONE OF.

THE POST DOCS SAID THAT’S ONE OF THE GREAT THINGS ABOUT THE CHORUS BECAUSE IT PUTS A HUMAN FACE ON THE DISEASE. IT DOESN’T MATTER IF YOU’RE A MOLECULAR BIOLOGIST OR SURGEON, IT’S STILL THE SAME. SO WE’RE FORTUNATE THAT MARK IS A PHYSICIAN AND PART OF THE GROUP HERE AT THE NIH. AND HE’S BEEN KIND ENOUGH TO BRING ONE OF HIS PATIENTS WHO HE IS GOING TO BRIEFLY INTERVIEW AND YOU CAN ASK QUESTIONS. AND THIS IS A GENTLEMAN WHO HAS A DISEASE WHICH IS CHARACTERIZED BY RATHER SEVERE ITCHING.

Gtgt IF I COULD ASK MR. WEAVER TO COME UP. WHILE HE’S COMING UP, THE DISEASE THAT MR. WEAVER HAS IS CALLED PRIMARY DAILY CIRRHOSIS. ITCHING IS A PREDOMINANT FEATURE OF IT. IN FACT, 20 YEARS AGO, 2030 YEARS AGO, ITCHING WAS PROBABLY ONE OF THE PREDOMINANT PRESENTING SYMPTOMS OCCURRING IN ABOUT TWO THIRDS OF INDIVIDUALS. FATIGUE IS THE OTHER COMMON SYMPTOM PRESENT IN THIS CONDITION. SO I’LL LET HIM TELL YOU A LITTLE ABOUT HIS SYMPTOMS. SO, COULD YOU TELL US WHEN YOU FIRST STARTED TO EXPERIENCE SYMPTOMS RELATED TO YOUR.

CONDITION. gtgt INDISCERNIBLE. AT THE BEGINNING MY INDISCERNIBLE. gtgt OKAY. WAS YOUR ITCHING WORSE IN THE MORNING OR THE EVENING OR IT WAS NOT DIFFERENT. gtgt THE SAME ALL DAY LONG. gtgt THE SAME ALL DAY LONG. AND WHEN YOU ITCH, DID YOU ITCH ENOUGH TO BREAK THE SKIN gtgt NO. gtgt BUT YOU ALSO COMPLAINED OF SOMETHING ELSE AS WELL ON YOUR SKIN. YOU NOTICE YOUR SKIN CHANGING. gtgt YES. gtgt SO THE SKIN WAS ALSO CHANGING COLOR, WAS GETTING DARKER AND ALSO GETTING A LITTLE THICKER. gtgt RIGHT. gtgt CAN YOU TELL US A LITTLE BIT.

ABOUT HOW SEVERE THE ITCHING WAS. gtgt WELL HE’S SAYING THAT BETWEEN 101, IT WAS ABOUT 8. THAT WOULD BE THE GOAL FOR ITCHING. gtgt AS YOU CAN WELL IMAGINE WE DON’T HAVE VERY GOOD SCALES TO MEASURE ITCHING, SO IT’S MOSTLY SUBJECTIVE WHAT PATIENTS REPORT. SO WHAT HE’S SAYING IS THAT ON A SCALE OF ZERO TO 10, EVEN HIS OWN INTERNAL SCALE HE REPORTS IT BEING AN 8. SO FAIRLY BAD FOR HIM. DID YOU WANT TO SAY SOMETHING. gtgt I THINK THAT THE INDISCERNIBLE HELPED HIM BIG TIME.

WHEN I BROUGHT HIM IN 2007 INDISCERNIBLE RIGHT HERE WITH ME ON A STABLE CONDITION INDISCERNIBLE THE TREATMENT HE’S BEEN OFFERED AND GIVEN. I THINK THAT’S MAKING A BIG DIFFERENCE. I GUESS THAT’S WHY WE ARE HERE TO SHOW THAT HIM AND PEOPLE IN THE CLINIC ARE DOING A JOB THAT IS REALLY HELPING. AND HE’S THE PROOF. HE’S THE LIVING PROOF. gtgt SO MAYBE WE COULD TALK A LITTLE BIT, DOES ANYONE HAVE ANY QUESTIONS DO YOU MIND SHOWING. SO YOU CAN SEE HERE WHERE HIS SKIN’S A LITTLE DARKER.

IF YOU’RE UP CLOSE YOU COULD SEE WHAT WE CALL INDISCERNIBLE WHERE THE SKIN BECOMES THICKENED, MORE LIKE ELEPHANT SKIN ESPECIALLY IF YOU RUB YOUR HAND ON IT. SO IT’S A REACTIVE CHANGE. ANYONE HAVE QUESTIONS ABOUT THE COME DIGOXIN YOU WOULD LIKE TO KNOW YES. gtgt INDISCERNIBLE gtgt SO THEY WOULD LIKE TO KNOW HOW DEBILITATING IT WAS, HOW MUCH DID IT AFFECT YOUR LIFE, THE ITCHING. gtgt HE WAS. gtgt CAN HE TELL US IN WHAT WAY gtgt I HAVE COME TO MY ARMS ALL THE TIME SCRATCHING. gtgt DID IT AFFECT HIS SLEEP, HIS.

WORK. gtgt AT NIGHTTIME SLEEPING, YES, IT WAS A PROBLEM BACK THEN IN 2007. gtgt OKAY. gtgt INDISCERNIBLE. gtgt THAT’S ALSO VERY CHARACTERISTIC THE WARM WEATHER WOULD MAKE IT WORSE. WERE THERE ANY DO DIETARY COMPONENTS. DID FOOD MAKE IT WORSE. gtgt NO. gtgt IT’S ALSO CHARACTERISTIC. IT’S NOT AFFECTED BY FOOD. NO, HE’S NEVER BEEN JAUNDICED. ANY OTHER QUESTIONS ABOUT CHARACTER OR EXACERBATING FACTORS OF HIS PRURITUS WAS THERE ANYTHING YOU COULD DO TO MAKE IT BETTER gtgt THE COLD. gtgt THE COLD. WE’LL TALK ABOUT SOME THING THAT.

WE TRIED TO MAKE IT BETTER. I DON’T WANT TO, YOU KNOW, TAKE, STEAL HIS THUNDER BUT WE’LL TELL YOU WHAT HE DID TO TRY TO MAKE IT BETTER. WHAT HE HAS IS ASSOCIATED ASSOCIATED WITH THIS IS DUE TO ELEVATED BECAUSE OF THE CONDITION THAT HE HAS DUE TO TCELL MEDIATED DESTRUCTION OF THE INTRALOBULAR. THIS IS THE CONDITION THAT HE HAS. SO THE NURSE APPROACH THAT WE TOOK WAS TO USE A CALLED COLE AND THE YOU ARE DOSE IS TO START AT FOUR GRAMS AND TRY.

TO WORK UP TO 16 GRAMS. SO WE TRIED HIM WITH COLE STY MEAN. CAN YOU ASK HIM TO TELL US WHETHER THE COLE STY MEAN HELPED. THESE WERE THE PACKETS THAT WERE LIKE SAND THAT WE GAVE HIM. THIS IS WHAT IT’S LIKE. gtgt YES, IT DID. gtgt DID IT HELP HIS SYMPTOMS. gtgt YES, IT DID. gtgt BUT THERE WAS A PROBLEM THAT HE EXPERIENCED, RIGHT KIDNEY. gtgt I HAVE INDISCERNIBLE SEVERAL TIMES. gtgt THAT’S CHARACTERISTIC OF THE COLE STY MEAN, IT MAKES ONE CONSTIPATED AND LIMITS THE AMOUNT OF DOSE YOU CAN GIVE TO.

PATIENTS. ALSO IT’S REALLY LIKE DRINKING SAND. IT’S NOT VERY PALATABLE. THE MOST HE COULD TOLERATE WAS 8 GRAMS SO TWO PACKETS. SO WE HAD TO TRY DIFFERENT STRATEGIES BECAUSE THAT WASN’T WORKING. SO THE NEXT THING WE TRIED WAS A DRUG CALLED AND THAT WAS THE SECOND DRUG WE TRIED. NOW DID THAT HELP YOU gtgt I DON’T REMEMBER. THIS WAS SEVERAL YEARS AGO. gtgt I’LL AT THE YOU, WE TRIED 150 MILLIGRAMS TWICE A DAY AND THAT HAD NO EFFECT WHATSOEVER. SO THE NEXT DRUG IN THE.

ALGORITHM THAT WE GO THROUGH WAS, WELL WITH REGARDS TO THE PATHOGENESIS OF THIS CONDITION I’VE ALLUDED THAT PERHAPS ELEVATED IN THE SKINS PARTICULARLY AN IRRITATION OF THE NERVE ENDINGS COULD BE A PARTICULAR EXPLANATION TO WHY PATIENTS GET ITCHING. THE SECOND EXPLANATION IS THAT PERHAPS THERE’S OVERSTIMULATION OF OPIOID RECEPTORS. SO ONE STRATEGY WAS TO USE OPIOID ANTAGONISTS. SO WE TRIED AN ORAL ONE CALLED AND INITIALLY STARTED HIM ON 25 MILLIGRAMS AND THEN INCREASED IT TO 50 MILLIGRAMS. NOW DID THE MAL TREXONE HELP YOU gtgt YES, IT DID.

SO THAT WAS THE ONE DRUG THAT ACTUALLY GAVE HIM THE MOST IMPROVEMENT. BECAUSE OF THAT WE ACTUALLY PUSHED THE DOSE UP TO 75 MILLIGRAMS. AND HE IS TAKING THAT FOR ABOUT FIVE OR SIX YEARS. AND IT’S ONLY WITHIN THE LAST YEAR THAT WE DISCONTINUED IT. AND THE REASON FOR DISCONTINUING IT WAS BECAUSE HIS SYMPTOMS BEGAN TO IMPROVE. HE COMPLAINED OF LESS ITCHING. AND ALSO HE’S TAKING MANY OTHER MEDICATIONS AND HE’S BEGINNING TO HAVE DRUG INTERACTIONS. SO WE ACTUALLY STOPPED THAT. AND THEN HE WAS PUT ON PREDNISONE.

NOW PREDNISONE IS NOT THE STANDARD THERAPY FOR THE CONDITION THAT HE HAS. THE STANDARD THERAPY IS BUT HE WASN’T RESPONDING TO IT. HIS LIVER BIOPSY WAS ALREADY CONSISTENT WITH THE DIAGNOSIS OF BILLIARY CIRRHOSIS BUT SOME PATIENTS MAY HAVE AN OVERLAPPED CONDITION WHERE THEY HAVE AUTOIMMUNE BILLIARY OBSTRUCTION. WE PUT HIM ON THAT THINKING THIS MAY HELP BECAUSE HE WAS IMPROVING BUT HE WAS STILL SYMPTOMATIC. WE PUT HIM ON PREDNISONE 10 MILLIGRAMS FOR A PERIOD OF TWO YEARS. CAN YOU TELL US IF THE PREDNISONE HELPED gtgt IT INDISCERNIBLE MY.

APPETITE TO BEGIN WITH. IT WAS MUCH BETTER. gtgt THAT’S ALSO TYPICAL OF PREDNISONE, IT MAKES PEOPLE INCREASE THEIR APPETITE, GAIN WEIGHT BUT THERE ARE OTHER SIDE EFFECTS. AND WE TRIED THEM FOR A PERIOD OF TWO YEARS. AND HIS LIVER BIO CHEMISTRY DID NOT IMPROVE MUCH ON IT. SO WE ACTUALLY DECIDED TO STOP IT BECAUSE OF HE WASN’T GETTING MUCH BENEFIT AND THERE WERE A LOT OF SIDE EFFECTS ASSOCIATED WITH IT SO WE DISCONTINUED IT. SO RIGHT NOW HE’S ONLY ON COLIC ACID AND HIS ITCHING HE.

SAYS IS MUCH BETTER. DOES ANYBODY HAVE ANY QUESTIONS THEY WOULD LIKE TO ASK ABOUT THE THERAPEUTIC APPROACH OR ANYTHING ELSE ABOUT HIS CONDITION BEFORE WE TURN IT OVER TO DR. ARIAS. gtgt SO IF WE USE OBJECTIVE MEASURES, THOSE MINIMAL IMPROVEMENTS FROM THE MEDICATIONS. TYPICALLY WITH THESE DRUGS WHAT YOU SEE IS NORMALIZATION OR SIGNIFICANT IMPROVEMENT IN THE AL KIND PHOSPHATASE THE TWO BLURRY ENZYMES. HE HAD MAYBE ABOUT A 2030 IMPROVEMENT WHICH IS NOT MUCH. ALSO HIS SEAMPLE MINOR TRANSFERASE OR DID NOT IMPROVE SIGNIFICANTLY. THEY’RE STILL ELEVATED.

HE ALSO HAD TWO LIVER BIOPSIES WHICH CONTINUED TO SHOW BILE DUCT LOSS AND BILE DUCT DESTRUCTION. SO ALL THE OBJECTIVE DATA SUGGESTS THAT THERE’S NOT MUCH IMPROVEMENT WITH THESE. SUBJECTIVELY THOUGH HE DOES REPORT IMPROVEMENT IN HIS SYMPTOMS. gtgt OKAY. ALL RIGHT, THANK YOU VERY VERY MUCH. gtgt SO I’M GOING TO TALK FOR A BRIEF WHILE ABOUT THIS PROBLEM OF ITCHING AND LIVER DISEASE AND SOME OF THE THINGS I’LL MENTION I’LL REFER BACK TO THE PATIENT WHO PRESENTED MANY OF THE FEATURES. AND THEM MARK HOON IS GOING TO.

SPEAK. MARK IS A TENURE TRACK INVESTIGATOR AT NIDCR. HE GOT A PH.D. IN BIO CHEMISTRY AT THE UNIVERSITY OF LEEDS. CAME TO THE NIH IN 1992 AND HAS DONE EXTRAORDINARILY INTERESTING WORK ON THE PROBLEM OF TAPES. THERE’S A REMARKABLE ARTICLE IN SCIENCE WHICH WE PUT UP ON THE WEBSITE THAT YOU CAN REFER TO ON THE CIRCUITRY FOR ITCH RESPONSE IN MICE THAT WAS PUBLISHED IN 2013. BY THE WAY, ALL THE POWER POINTS, BACKGROUND AND EVERYTHING ELSE ARE AVAILABLE TO YOU HOPEFULLY BEFORE EACH SESSION ON OUR WEBSITE.

OKAY. SO I’VE GOT A DISCLAIMER BECAUSE MUCH OF THE DATA THAT I’M GOING TO SHOW YOU IS FROM THE GROUP OF WHO IS AT THE ACADEMIC MEDICAL CENTER IN AMSTERDAM. AND THE TWO KEY REFERENCES ON THE BOTTOM OF THIS SLIDE AND THEY ARE ALSO ON THE WEBSITE PAPERS. HE WAS A FELLOW WITH US MANY MOONS AGO AT ALBERT EINSTEIN AND ONE OF THE THING WE WERE THINKING ABOUT IS WHAT CAUSES THIS ITCHING WHICH CAN BECOME EXTREMELY SEVERE IN PEOPLE WITH LIVER DISEASE. AND WE MADE A FEW OBSERVATIONS.

AND THAT HAS SORT OF PEAKED MY INTEREST THROUGH THE YEARS AND FOLLOWED THROUGH BUT MOSTLY THE DATA I’M GOING TO SHOW YOU. I’M GOING TO TALK A LITTLE BIT ABOUT THE SIGNS, THE SYMPTOMS, WHO GETS ITCHING WITH LIVER DISEASE. SOME CLINICAL OBSERVATIONS WILL POINT TOWARD POSSIBLE MECHANISMS, THAT’S THE BIRDS BUSINESS. THE CURRENT TREATMENT HAS BEEN DISCUSSED A LITTLE BIT. WE’LL COMMENT ABOUT IT. MECHANISMS, OLD AND NEW. AND SOME NEW THERAPEUTIC CONSIDERATIONS. AND THEN MARK HOON IS GOING TO DISCUSS IN MORE DETAIL THE NEUROBIOLOGY OF ITCHING. NOW, PRURITUS AND LIVER DISEASE.

ITCHING IS QUITE VARIED. AND AS IS POINTED OUT, IT’S KIND OF SUBJECTIVE. BUT IN MANY DISEASES, INCLUDING THIS ONE, PRIMARY BILLIARY CIRRHOSIS, THE ITCHING CAN BE REALLY SEVERE. NOW THE PATIENT HAS THOSE SIGNIFICANT PRURITUS, AND AS YOU COULD SEE THE SCRATCHING AND A LOT OF THE SECONDARY CHANGES MEAN IT’S BEEN GOING ON FOR A LONG TIME. BUT EVEN PATIENTS WHERE IT’S INFINITELY WORSE. THERE’S ONE PATIENT REPORTED IN THE LITERATURE WITH LIVER DISEASE WHO WOULD NOT HAVE HAD A LIVER TRANSPLANT FOR THE DISEASE AT LEAST AT THAT TIME.

IT WAS SO DISRUPTIVE THAT A LIVER TRANSPLANT WAS ACTUALLY PERFORMED THROUGH THE PROCESS. SO THE PRURITUS CAN BE SEVERE. IT’S USUALLY AT NIGHT. PEOPLE OFTEN DESCRIBE IT LIKE AN ANIMAL UNDER THEIR SKIN AND THEY KIND OF DIG SO THEY EXCORIATE, MEANING THEY HAVE LOCAL BLEEDING. AND THEY GET RELIEF WITH RUBBING AND MEDICATIONS HELP A LITTLE BIT NOT MUCH. MOST ITCHING DOESN’T INVOLVE THE PALMS AND THE SOLES OF YOUR FEET BUT ITCHING IN SEVERE LIVER DISEASE CAN AND THAT’S A REAL DISABILITY. IT’S UNAFFECTED BY SLEEP. PEOPLE WHO ARE EXHAUSTED FALL.

ASLEEP AND STILL CONTINUE TO ITCH. SO WHO GETS IT WELL, NOT EVERYBODY WITH LIVER DISEASE. THAT’S WHY I ASKED THIS PATIENT IF HE WAS EVER JAUNDICED BECAUSE THIS IS PRECISELY THE CIRCUMSTANCE UNDER WHICH THE ITCHING IS SEVERE. THIS IS A VERY IMPORTANT CLINICAL OBSERVATION. I’LL EXPLAIN WHY. SO WHEN PEOPLE HAVE CONVENTIONAL HEPATITIS, ACUTE HEPATITIS, ABC, ETCETERA, ETCETERA, PRURITUS IS NOT USUALLY A PART OF THAT PICTURE. AT LEAST NOT A SIGNIFICANT ONE. AND PEOPLE ARE DEEPLY JAUNDICED DUE TO A COMPLETE OBSTRUCTION OF THE BILE DUCT, SAY CANCER OF THE.

PANCREAS OR SOMETHING. IT’S A COMPLETE OBSTRUCTION. ITCHING IS USUALLY NOT PRESENT AND IF IT IS, IT’S VERY MILD. SO WHEN DOES IT OCCUR. IT OCCURS IN DISEASES WHERE THERE’S INCOMPLETE BILLIARY OBSTRUCTION. NOW, THE BILLIARY TREE STARTS WAY UP AT THE HEPATOCYTES WITH THE SMALL BRANCHES WHICH THEN COME TOGETHER AND ULTIMATELY INFORM THE COMMON BILE DUCT THAT THEIR LIVER IS BILE INTO THE INTESTINE. THAT TREE CAN BE AFFECTED BY DIFFERENT DISEASES THAT PARTIALLY OBSTRUCT AND REDUCE THE FLOW, THERE’S STILL SOME FLOW OF BILE. WHETHER DISEASES THAT AFFECT THE.

LIVER CELLS THEMSELVES AND THE SECRETORY PROCESSES THAT CONTRIBUTE TO BILE. AND SO WHAT OFTEN HAPPENS IS PEOPLE SUCH AS THIS PATIENT MAY HAVE PRURITUS FOR YEARS. AND BEFORE DERMATOLOGISTS FOR EXAMPLE KNEW ABOUT PRIMARY BILLIARY CIRRHOSIS, THEY NEVER THOUGHT OF LIVER DISEASE. NOW ANY PATIENT WHO ITCHES A GREAT DEAL PARTICULARLY A PREMENOPAUSAL WOMAN BECAUSE IT’S MORE COMMON IN WOMAN THAN MEN THEY ARE IMMEDIATELY REFERRED TO A GASTRO ENTEROLOGIST OR A LIVER DOCTOR. IT ALSO OCCURS IN PREGNANCY. IN PREGNANCY THERE’S A CURIOUS SYNDROME. LIKE IN THE BEGINNING WOMEN HAVE.

OFTEN VOMITED, AN UPSET STOMACH VOMITING WHEN YOU’RE PREGNANT. IN THE SECOND OR THIRD TRIMESTER OF PREGNANCY, THEY OFTEN BEGIN TO ITCH. NOT JAUNDICE. VERY SMALL PROPORTION OF THEM BECOME JAUNDICE DUE TO OBSTRUCTION OF BILE PROCESS. AND THE AMAZING THING IS THAT WITHIN 48 HOURS AFTER THE BIRTH OF THE BABY, IF NOT SOONER, IT ALL DISAPPEARS. A VERY IMPORTANT CLINICAL OBSERVATION. SO THESE ARE THE ENTITIES. AND IF YOU LOOK AT WHAT’S AT THE TOP, WHAT THAT CARTOON IS, THOSE ARE THE DAYS WAYS TWO LIVER.

CELLS COME TOGETHER. THOSE DARK LINES OR TIGHT JUNCTIONS. THE DOMAIN OF TWO LIVER CELLS COME TOGETHER TO MAKE IT TWO. AND THE TWO IS LIKE A CAPILLARY AND THAT’S THE SMALLEST BRANCH OF THE BILLIARY SYSTEM. THERE WERE MILLIONS OF THEM. AND THEN THEY CONNECT DOWN INTO THE SECONDARY AND TERTIARY BRANCHES AND THEN FINALLY THE BIG DUCT, THAT TAKES IT ALL INTO THE DUCT. THERE ARE DISEASES THAT AFFECT THE CANALICULI INCLUDE MEMBRANE. SO THIS STANDS FOR BENIGN RECURRENT HEPATIC HOMEOSTASIS, AN INCREDIBLE DISEASE WHERE PEOPLE GET EPISODIC SEVERE ITCHING, SOME.

USUALLY JAUNDICE AND THEN FOR REASONS WE REALLY DON’T UNDERSTAND, IT GOES AWAY AND THEN IT RECURS AND THE LIVER REMAINS MORPHOLOGICALLY NORMAL. THIS IS PROGRESSIVE INTRACELLULAR THAT HAPPENS IN CHILDREN WHO HAVE A DEFECT IN ONE OF THE TWO ATP BINDING CASSETTE TRANSPORTERS, ONE THAT PUMPS BIOACIDS OUT OF THE CELL INTO THE CANALICULI HER AND THE OTHER PUMPS ARE RESPONSIBLE FOR PHOSPHOCHOLINE IN THE BILE AND THAT’S THE FORM AND PROTECTS THE BILLIARY SYSTEM. THERE ARE MANY HORMONES. DURING HORMONE PREGNANT SEA, THE SECRETORY CAPACITY OF THE LIVER.

IS REDUCED BY 40. YOU NEVER KNOW IT BECAUSE THERE’S A HUGE FUNCTIONAL RESERVE UNLESS SOMETHING ELSE IS GOING ON. SOME WOMEN WHEN THEY TAKE ESTROGEN OBTAINING ORAL CONTRACEPTIONSIVES IS ALL OF THINKING AND EVEN JAUNDICE. THERE ARE MANY DRUGS THAT HAVE THIS EFFECT, SOME HAVE MORPHOLOGIC FEATURES AND SOME DON’T. IT SOMETIMES OCCURS IN ALCOHOLIC PATIENTS AND IT’S NOT UNCOMMON AND CHRONIC HEPATITIS B AND C TO HAVE THIS ITCHING SYNDROME. NOW THE FIRST IN THAT RED CIRCLE THAT’S WHERE PRIMARY BILLIARY IS, IT’S AN IMMUNE MECHANISM WE THINK TCELL MEDIATED IS POINT.

OUT THAT IT AFFECTS THE SMALLER BRANCHES BUT NOT ALL OF THEM. THE PIPELINE IS REDUCED SUBSTANTIALLY. THAT’S VERY IMPORTANT, I’LL EXPLAIN WHY IN A MOMENT. THEN THERE WAS SOME OTHER DISEASES INCLUDING ONES INVOLVING STARRING SCLEROSIS OF THE BILE REDEDUCT BILLIARY DUCT. FOR THE MOST PAR IT’S INCOMPLETE. THE THING YOU ALWAYS HAVE IN COMMON IN INCOMPLETE BILLIARY OBSTRUCTION. NOW WE’VE GOT TO GO TO A LITTLE BIT OF PHYSIOLOGY. YOU RECOGNIZE THE CARTOON HAS THE CANALICULI THOSE SMALL BOXES OF THE SMALL BILE DUCT AND THE INTESTINES. COMPOUNDS THAT ARE SECRETED BY.

THE LIVER ARE REABSORBED AND RECIRCULATED. THE CLASSIC ONE IS BY I DON’T BIO ACIDS. IT’S THE MAJOR WAY OF GETTING RID OF CHOLESTEROL IN THE BODY. BIOACIDS ARE A DETERGENT THAT FACILITATES FAT ABSORPTION AND THEY DO A LOT OF OTHER THINGS, SIGNALING MOLECULES. THEY’RE GOING TO COME BACK TO THAT. SO 85 OF THE BILE ACIDS THAT ARE SECRETED ARE REABSORBED. WHEN YOU PETE A MEAL EAT A MEAL AND WHEN THE BIO ACIDS GETS DOWN TO THE ILIUM IT’S REABSORBED. THAT CYCLE GOES ON EVERY TIME.

YOU EAT. IF YOU EAT SIX TIMES A DAY, CIRCULATION KEEPS UP WITH IT. IT’S QUITE AN AMAZING PHENOMENA. BIO ACIDS IS NOT THE ONLY THING THAT ENTERS PATTERNS OF ASSOCIATION. DRUGS DO. YEARS AGO WE HAD SOME STUDIES TO SUGGEST THAT SOME DRUGS LIKE WHICH WAS VERY COMMONLY USED IN THOSE DAYS, WE SHOWED HAS A BIG HEPATIC CIRCULATION AND WE TRIED TO ARGUE THAT THE REASON WITH A WHY PEOPLE HAD BECAUSE THE DRUG NEVER WENT AWAY. WHATEVER WENT THROUGH KEPT COMING BACK AND CAUSING PROBLEMS. WE DON’T KNOW.

NOW WHEN THERE IS A DISORDER, COLE STASIS MEANS BILE SECRETORY FAILURE. AND IT COULD BE AT THE LEVEL OF THE CANALICULI, WHERE THE TRANSPORTERS ARE. IT COULD BE AT THE LEVEL OF THE SMALL BILE DUCT AND THE BIGGER ONES. THE NET EFFECT IS IT’S REDUCED BILLIARY SCEATION INTO THE INTESTINE. WHEN THAT HAPPENS IT’S LIKE A PARTIAL OBSTRUCTION IN CERTAIN AREAS OF THE LIVER. AND COMPONENTS OF THE BILE GAIN ACCESS TO THE BLOOD. WE DON’T REALLY KNOW HOW IT HAPPENS. THERE’S SOME EVIDENCE THAT GOES THROUGH THE LIVER AND BECOME.

DEPENDING ON WHAT THE SUBSTANCE IS. IN OTHERS IT GOES BETWEEN THE CELLS WHERE TIGHT JUNCTIONS BECOME LEAKY. ONE THING IS CLEAR THAT THE PLASMA LEVEL OF THESE SUBSTANCES THAT WOULD BE SECRETED GOES UP. NOT THE BILE PIGMENT. NOW WHY AREN’T THESE PEOPLE JAUNDICED THEY ARE JAUNDICED BECAUSE THE BILE PIGMENT IS NOT RECIRCULATED. IT’S A WASTE PRODUCT. YOU PROBABLY KNOW IT COMES FROM THE DEGRADATION OF HEME. SO ONCE IT’S IN THE INTESTINE THE BUGS CONVERTED THE WATER SOLUBLE AND IT’S GONE. SO PEOPLE CAN HAVE BIG TIME AND.

THERE’S A TEN FOLD CAPACITY TO EXCRETE THE BILE PIGMENT THAN IS USED IN THE TEN FOLD EXCESS. IT’S A SAFETY VALVE. SO YOU REALLY HAVE TO HAVE SUBSTANTIAL LIVER DISEASE IN SOMETHING LIKE PBC IN ORDER FOR PEOPLE TO BECOME JAUNDICE. THAT’S A BAD PROGNOSTIC SIGN. BUT ALL THESE OTHER CONDITIONS, PREGNANCY AND WHATNOT. YOU GET THE PICTURE LIKE A GRADATION THAT OCCURS. AND IN ALL OF THOSE CIRCUMSTANCES OF INCOMPLETE BILLIARY OBSTRUCTION, MOST OF THEM ARE NOT JAUNDICED BUT THEY ARE ITCHING. AND THAT IS WHAT I SAID LEADS TO.

SOMETIMES CLINICAL DETOURS BEFORE YOU GET TO SOMEONE WHO RECOGNIZES THIS. LET’S TALK ABOUT THE OF PREGNANCY. THE IT OCCURS IN 1 OF ALL PREGNANT WOMEN. AND THE MAJOR SYMPTOM IS ITCHING AND IT CAN BE VERY SEVERE. IT OCCURS IN THE SECOND TO THIRD TRIMESTER. THERE ARE MILD ELEVATIONS OF THE PLASMA BILE ACID. THEY ARE ELEVATED, THEY CAN GO UP TO FOUR OR FIVE TIMES MUELLER. FOUR OR FIVE TIMES MORE. IT’S NOT A STRUCTURAL THING IF IT CAN TURN ON AND TURN OFF LIKE THAT. WHAT ARE THE CLINICAL CLUES.

ABOUT THE MECHANISM. ONE IS THE RAPID DISAPPEARANCE OF PRURITUS AND AFTER THE DELIVERY OF A BABY. THE OTHER IS SOMETHING THAT WE DID 25 YEARS AGO BUT NOW IT’S BECOME VERY POPULAR, IT’S BECOME REFINED. THAT IS IF YOU PASS IT THROUGH INTO THE STOMACH AND INTO THE DUODENUM AND YOU CAN GET THAT TUBE TO GO INTO THE BILE DUCT AND IT’S COMING OUT OF YOUR NOSE. SO IT’S CALLED NASO BILLIARY DRAINAGE. BASICALLY ANY BILE FROM GETTING INTO THE INTESTINE. AS I’LL SHOW YOU THE PRURITUS AND ALMOST ALWAYS RAPIDLY.

DISAPPEARS. AND HAS BEEN MENTIONED AS PARTIAL RELIEF WITH THESE NONABSORBABLE RESIDENTS I CALL STORY MEAN IS BASICALLY LIKE TRAPPING BIOACIDS AND OTHER THINGS INTO THE INTESTINE THAT PREVENTS THE INTERHEPATIC CIRCULATION OR THE BILE ACID WHICH PROMOTE BILLIARY SECRETION AND IT’S THOUGHT MAYBE THAT MAY ACCELERATE THE RELIEF. AND WITH WE DON’T HAVE A CLUE HOW THAT WORKS. THEN THERE’S PARTIAL RELIEF AND SOMETIMES PRETTY DRAMATIC WITH OPIOID ANTAGONISTS. NOW THOSE ARE THE CLINICAL OBSERVATIONS. NOW THIS CHAP HAS A TUBE COMING OUT OF THE NOSE INTO THE BILE.

DUCT. YOU WON’T VOLUNTEER FOR IT BUT IF YOU’RE ITCHING LIKE CRAZY IT’S A WONDERFUL THING. BECAUSE LOOK WHAT HAPPENS. HERE ITCHING IS MEASURED AS INTENSITY, QUALITATIVELY THE PATIENT’S WORD. BUT IT’S OBVIOUS WHEN YOU SEE IT HAPPENS. SOMEONE WHO IS ITCHING, IT’S LIKE MY GOSH WITHIN 24 HIRES I DON’T FEEL IT. AND THAT’S WHAT HAPPENS AND AS LONG AS THE DRAIN YOU CAN CONTINUES IT’S FINE. YOU TAKE IT OUT AND IT TAKES ACTUALLY A COUPLE WEEKS BEFORE IT GOES BACK TO WHERE IT WAS. I’M GOING TO LEAVE THIS BUT THE.

GENERAL CONCEPT IS THAT SOMETHING IS GETTING INTO THE CIRCULATION THAT IS STIMULATING THE ITCH NEURONS WHICH YOU’RE GOING TO HEAR A GOOD BIT ABOUT IN A MOMENT. SO WE’RE GOING TO LEAVE THAT. NOW, THE WAS VERY MUCH INTERESTED AND TRYING TO PURSUE THIS AND FIND OUT WHAT IT IS IN THE SERUM OF PEOPLE WITH SEVERE ITCHING AND LIVER DISEASE THAT CAN CAUSE PROBLEMS. SO WHAT THEY DID WAS THEY TOOK, BECAUSE I FIGURE ITCHING IS NEURONS. SO THEY TOOK A BUNCH OF NEURONAL CELL LINES AND ADDED SERUM FROM.

PEOPLE WITH ITCHING, WITHOUT ITCHING, SEVERITY AND WHATNOT. AND WHAT ARE THEY GOING TO LOOK FOR WELL THEY LOOK FOR CALCIUM. WHY WAS THE CALCIUM. HE GOES CALCIUM IS A MAJOR SIGNALING EVENT THAT REGULATES ALL KINDS OF PATHWAYS WITHIN A CELL. IT’S A PRETTY GOOD THING TO LOOK FOR. WHAT THEY DISCOVERED WAS QUITE SURPRISING. YOU CAN SEE IT OVER ON YOUR LEFT THERE. THAT’S A DOSE RESPONSE OF ADDING SERUM TO THESE NEUROBLAST THEM AWE CELLS AND YOU’RE MEASURING CALCIUM WITHIN THE CELLS. SO YOU ADD SERUM FROM SOMEBODY.

WHO HAS THE COLE STATIC ITCHING SYNDROME. DEPENDING ON THE AMOUNT YOU ADD, THE CALCIUM GOES UP. THE SIGNALING CALCIUM RELEASE. AND IT INCREASES SERUM CALCIUM THAT’S SHOWN HERE AND IT HAPPENS PRIMARILY WITH SERUM IN PEOPLE WHO HAVE BEEN INTRAPATHIC COLOW STASIS PREGNANCY OR ON THE OTHER SIDE PRIMARY BILLIARY CIRRHOSIS ETCETERA. THIS WAS THE FIRST CLUE. SO THE QUESTION IS WELL CAN WE FIND OUT WHAT IT IS. SO IN A SERIES OF VERY INTERESTING PAPERS, THEY IDENTIFIED WHAT IT IS IN THE SERUM OF THESE INDIVIDUALS THAT CAUSES ITCHING.

IN BRIEF HERE’S WHAT THEY DID. FIRST YOU PUT IT THERE A MOLECULAR SIEVE, YOU TREAT IT WITH A PEP SAID, IT DOESN’T GO AWAY SO IT’S NOT A PEPTIDE. YOU TREAT IT WITH WHY WOULD YOU DO THAT. WELL BECAUSE BLOCKS G PROTEIN MEDIATED COUPLED RECEPTORS. A WHOLE BUNCH OF THEM. PROBABLY ABOUT 40 OR MORE WITHIN THE CELL. AND THIS THING BLOCKED. WELL THAT WAS INTERESTING SO THAT GAVE YOU A CLUE THAT THERE WAS SOMETHING THAT WAS INTERACTING WITH G PROTEIN COUPLED RECEPTORS. AND SO OFF, HE KNEW THE.

LITERATURE AND ONE OF THE THING THAT WAS ACTUALLY DISCOVERED IN HOLLAND IN 2005. NO, MUCH EARLIER. THAT LIE SO PHOSPHO ACID WAS IT. SO THEY STARTED LOOKING FOR A LIPID. AND THEY USED VARIOUS TECHNIQUES TO EVENTUALLY DO IT WHICH I WON’T GO THROUGH. IF YOU’RE INTERESTED I’LL GIVE YOU THE REFERENCE. WHAT THEY FOUND IS THAT THE FACTOR THAT CAUSED THE CALCIUM INCREASE WAS LIE SO PHOSPHOCYTIC ACID. AND THERE’S A FORMULA. SO WHAT’S LIE SO PHOSPHOITIC ACID. IN THE 80’S OR 90’S OF THE LAST CENTURY TO SHOW THAT ACID HAS.

A LOT TO DO WITH THE CYTOSKELETAL ARRANGEMENT OF CELLS WITH ACTIVATING PLATELETS AND ACTUALLY WITH MIGRATION OF CELLS. IT INTERACTS WITH PIP 2 TO HELP WITH THE CENTRALLING PROCESS. AND IT ACTS ON SIX DIFFERENT KNOWN G PROTEIN LINK RECEPTORS. AN IMPORTANT ROLE IN NEUROPATHIC PAIN AND ARE PRESENT IN THE LITERATURE AT THAT TIME. MORE ARE CENTLY THERE WERE DESCRIPTIONS OF REPROGRAMMING GENE EXPRESSION IN NERVE ENDINGS. THAT ALL SOUNDED VERY INTERESTING. SO HOW DOES LIPO PHOSPHOCYTIC A SAID MADE. WHERE DOES IT COME FROM IT COMES FROM CHOLINE WHICH.

IS OVER ON THE FAR SIDE WHICH IS THEN ACTED UPON BY TWO ENZYMES WHICH THEN SLITS THE MOLECULE INTO AND THEN THERE’S AN ENZYME OR TAXING THAT SPLITS OFF CHOLINE. THAT’S HOW YOU GET LIE SO PHOSPHOLYTIC ACID. SO THEY DECIDED THEY WOULD LOOK IN THE SERUM OF PATIENTS WHO HAD PRURITUS. ICP WITH THE INTERPATHIC COLOW STASIS OF PREGNANCY. THESE ARE 13 WOMEN WHO REALLY WERE ITCHING VERY SERIOUSLY. AND THEY MEASURED LIE SO PHOSPHOCYTIC ACID WHICH WAS INCREASED IN THEIR SERUM. BUT THEY PERSISTED. SO WHAT’S R TOXIN.

R TOXIN IS A AND IT WAS FIRST DESCRIBED AS BEING OVER EXPRESSED IN SEVERAL CANCER CELL LINES WHERE IT PROMOTES MOTILITY METASTASIS. IF YOU KNOCK IT OUT, MICE DON’T DEVELOP PROPERLY AS IN AN GENESIS AND NEURONAL DEVELOPMENT. WHERE IS IT. THERE’S SOME DISAGREEMENT ABOUT IT BUT IT SEEMS TO BE EXPRESSED IN HEPATOCYTES. IT CERTAINLY IS IN THE ENDOTHELIAL CELLS. THOSE ARE THE CELLS THAT LINE THE BLOOD SUPPLY WITHIN THE LIVER THAT FEEDS INTO THE HEPATOCYTES. AND IN FAT CELLS. AND THERE ARE A COUPLE REPORTS.

IN THE LITERATURE THAT PEOPLE WITH CHRONIC HEPATITIS HAVE INCREASED AMOUNTS OF R TOXIN ACTUALLY CIRCULATING IN THEIR BLOOD. SO THEY MEASURED R TOXIN BY A BIOCHEMICAL MEANS ESSENTIALLY LOOKING AT THE CLEAVAGE OF CHOLINE. AND THEY USED SERUM FROM PATIENTS WHO ARE CONTROLLED. THAT’S THE ONE ON YOUR FAR LEFT. THOSE ARE, I FORGOT WHAT PC IS. PREGNANT CONTROL, YES. AND WOMEN WHO ARE PREGNANT IN THEIR THIRD TRY SEMESTER WHO AREN’T ITCHING. AND THEN THOSE WITH INTRAPATHIC ITCHING OF PREGNANCY. THERE’S A PIG SIGNIFICANT DIFFER. THERE’S MORE R TALK TOXIN.

CIRCULATING IN THE BLOOD. THEY LOOKED AT OTHER PATIENTS, NONPREGNANT LADIES. HERE ARE A BUNCH OF COLOW STATIC PATIENTS. THIS IS SEVERE ITCHING THESE PEOPLE HAD NOT JUST A LITTLE SCRATCH AS COMPARED TO COLE OWE STATIC PATIENTS WHO DIDN’T ITCH AND HEALTHY CONTROL. AGAIN TOXIN LEVELS WERE SUBSTANTIALLY HIGHER. AND IF THEY LOOK AT ITCHING IN OTHER STATES, IT LOOKS AS IF THE COLE STATIC PATIENTS, THOSE WITH LIVER ITCHING HAVE MUCH HIGHER LEVELS OF R TOXIN THAN DO THE COLOW STATIC PATIENTS THAT AREN’T ITCHING OR PATIENTS WITH CHRONIC RENAL FAILURE.

RENAL FAILURE ALSO GIVES RISE TO THIS ITCHING SYNDROME OR PEOPLE WHO WERE NOT. SO THIS WAS SORT OF GUILT BY ASSOCIATION. THERE ARE A LOT OF DISEASES THAT CAUSE ITCHING. HODGKINS DISEASE, LYMPHOMA IS A VERY COMMON ONE. AND THE ITCHING CAN BE VERY SEVERE. IT CAN BE ALMOST THE INITIAL SYMPTOM. BUT HERE TOXIN LEVELS IN THE BLOOD AND PEOPLE WITH CHRONIC ITCH. THE PEOPLE WITH WOUND HEALING OR YOU CUT YOURSELF EVERYBODY KNOWS YOU ITCH WHERE THE NEW SKIN IS BEING FORMED. THAT DIDN’T MAKE ANY DITCHES. AND ALSO WITH ITCHING, PEOPLE.

WITH ATOPIC DERMATITIS. THEY THOUGHT IT WAS SPECIFIC FOR THIS. NOW WHAT HAPPENS IF YOU PUT THIS TUBE DOWN AND YOU DRAIN THE BILLIARY SYSTEM AND HERE THOSE PATIENTS WOULD ITCH. THEY SYMPTOMATICALLY IMPROVED ASSOCIATED WITH IT. THERE WAS A 50 DECLINE WITH THE SERUM R TOXIN LEVELS. CAN YOU CORRELATE ITCHING WITH THESE BLOOD LEVELS WELL, THEY TRIED. ITCHING IS SUBJECTIVE. THAT’S THE BEST THAT WE HAVE. SO YOU SEE THAT BY ITCHING INTENSITY, IT SEEMS TO CORRELATE WITH THE SERUM R TOXIN LEVELS BUT CERTAINLY NOT WITH THE BIO.

ACID LEVEL WHICH ARE THE ONES ON YOUR RIGHT. NOW OTHER PEOPLE HAVE DESCRIBED VARYING DEGREES OF CORRELATION OF BILE ACID LEVELS AND DIFFERENT BILE ACIDS, A WHOLE BUNCH OF IT WITH ITCHING. SO THIS ISN’T NECESSARILY THE END OF THE LINE FOR IT. SO THEN THEY TRIED TO REPRODUCE THIS IN ANIMALS. SO THEY CAN HAVE SOMETHING TO WORK WITH. THEY DEVELOPED A VERY, I THOUGHT INGENIOUS. THEY PUT A MAGNET UNDER THE SILICONNIZED MAGNET. THE MICE ARE IN A CAGE AND THE CAGE IS SURROUNDED BY A MAGNET. SO EVERY TIME THE MOUSE DOES.

SOMETHING, YOU GET A TRACING. AND THAT HAPPENS MAINLY AT NIGHT. SO MOST INVESTIGATORS DON’T WANT TO SIT THERE IN THE DARK TRYING TO FIGURE OUT IF A MOUSE IS SCRATCHING OR NOT. LET THE MACHINE DO IT. AND IT WORKS. I’LL SHOW YOU A TRACING OF IT. THEY THEN TOOK SOME LIE SO PHOSPHOCYTIC ACID IN VARIOUS AMOUNTS AND INJECTED IT SUBCUTANEOUSLY AND LOOKED UP WHAT HAPPENED A NUMBER OF ACTUAL SCRATCHES THAT TAKE PLACE EVERY 15 MINUTES. THIS IS NOT MOLECULAR SCIENCE. AND AS YOU SEE, THERE’S A DOSE.

RESPONSE CURVE. SO WHY DON’T WE MAKE COLOW STASIS IN A MOUSE. WELL YOU CAN TIE OFF A BILE DUCT. YOU CAN TAKE AMOUNTS THAT’S EFFECTIVE IN ONE OF THE TRANSPORTERS AND YOU CAN ALSO GIVE THEM SOME BILE ACIDS. THAT MAY ACCELERATE IT. OR YOU CAN MAKE THE MOUSE PREGNANT AND GIVE THEM BILE ACID OR NOT. AND YOU MEASURE THE SERUM R TOXIN LEVELS AND YOU MEASURE THEIR SCRATCHING. AND SO IN PREGNANCY IN A MOUSE, NOTHING HAPPENS WITH ANY OF THOSE MODELS. TOXIN LEVELS STAYED THE SAME. THEY DON’T ITCH.

COLOW STATIC MICE DON’T ITCH. YOU CAN MAKE THEM COLE LOW STATIC BUT THEY’RE NOT ITCHING. THIS WAS TRUST TATING BUT THEY ALSO DON’T HAVE VERY HIGH SERUM LIE SO PHOSPHOCYTIC ACID OR R TOXIN. SO HOW AND THIS POTENTIATE ITCH. IT IS INTERESTING THAT AN ITCH RECEPTOR, A FAMILY OF THEM AND SOME OF THE FACTORS THAT ACTIVATE THOSE RECEPTORS EXPERIMENTALLY AND DIRECTLY AS YOU’LL SEE VERY MUCH PARTICIPATE IN THE NEURONAL RESPONSE THAT IS MANIFESTED AS ITCH. NOW, ONE OF THE THINGS IS PROTEIN TGR5. NOW TGR5 IS ESSENTIALLY A BILE.

ACID RECEPTOR. AND IT’S PRESENT IN MACRO PHAGES, ENDOTHELIAL CELLS. IT’S NOT THERE FOR AND WE COULD HAVE A WHOLE SESSION ON IT MUCH HERE’S FROM A RECENT PAPER JCI IN 2013 ON THE POTENTIAL ROLE OF TGR5 AND ITCH. AND SO WHAT YOU SEE THESE ARE NEURONAL CELLS AND THOSE POSITIVE ONES ARE POSITIVE TOWARD TGR5. WHAT THEY’VE DONE IS TO MEASURE SCRATCHING BY A SIMILAR TECHNIQUE I GUESS. I DON’T RECALL. AND THOSE HAVE THE WILD TYPE WHICH IS THE GRAY BARS. THOSE WHERE THEY OVER EXPRESS TGR5.

THAT’S THE BLUE BARS. AND THOSE WHERE THEY KNOCK OUT TGR5. THAT’S THREAD BARS OVER A PERIOD OF TIME. SO YOU SEE ON THE FAR LEFT, WHEN NO BILE ACIDS ARE GIVEN, YOU OVER EXPRESS TGR5. AND THE SCRATCH INDEX IN THE MOUSE GOES UP. IF YOU ADD BILE ACIDS IN ADDITION, THIS IS THE OXY COLLATE SIMILARLY. IN THE OVER EXPRESSED ONES IT GOES UP AND THE OTHERS TAKE PLACE. AT ANY RATE, THEY ARGUE AT THE LOCALIZING TGR45 TO THE NEURON, IT INTERACTS WITH A WHOLE CLUSTER OF PARTS OF THE ITCH.

RECEPTOR SIGNALING MECHANISM. AND THAT’S WHAT THOSE CIRCLES ARE WHICH MARK IS GOING TO TALK ABOUT. SO THERE’S A FEW MORE CLINICAL OBSERVATIONS THAT COME ON. THIS IS A VERY INTERESTING THING BECAUSE YOU KNOW LIKE WITH MUCH OF MEDICINE, INFORMATION COMES FROM BOTH SIDES AND IT’S NOT ONLY FROM ONE. ONE IS NASAL BILLIARY DRAINAGE AND COLOW STATIC PATIENTS RAPIDLY DEVELOP A DECLINE IN THE SERUM PHOSPHOLPA TO MUELLER. THAT ONE’S REPORTED LAST YEAR. THE ORAL REGIMENS HAD A MINIMUM EFFECT. IN PBC PATIENTS THE BILE ACID CAN REDUCE PRURITUS AND THERE’S.

ONE REPORT SUGGESTING THAT THE LEVELS IT’S INTERESTING THAT THE LEVELS IN PREGNANT WOMEN IN COLOW STASIS RAPIDLY DECLINED TO NORMAL AFTER DELIVERY OF THE BABY. WHAT DOES THIS MEAN. WHAT’S BEEN SUGGESTED IS THIS KIND OF MECHANISM. WE HAVE ON ONE SIDE THE SOCALLED COLOW STATIC BILE DUCT, THAT’S THE VERY SMALL BILE DUCT. THAT’S WHERE THE ARE THIS NEEDS TO BE. SOMETHING GOES FROM THERE ULTIMATELY INTO THE CIRCULATION. FACTOR X. WHICH THEY INTERACT PERHAPS IN THE HEPATIC SITE OR CERTAINLY COULD BE IN THE ENDOTHELIAL.

CELLS. TO ACTIVATE R TOXIN TRANSCRIPTION AND EXPRESSION AND SECRETION. AND THE BLOOD LEVEL GOES UP. WHEN THAT HAPPENS, LIE SO PHOSPHOCYTIC ACID IS FORMED. AND LICE OWE PHOSPHOCYTIC ACID DOWN STREAM SIGNALS INTO NERVE RECEPTORS AND STIMULATES THE RESPONSE THAT WE IDENTIFY AS ITCH. BUT THERE’S GOT TO BE MORE BECAUSE THERE ARE SITUATIONS WHERE THE LYSO THERE’S GOT TO BE SOME COFACTOR THAT AUGMENTS THIS PROCESS. NO YOU THAT COFACTOR COULD VERY WELL BE BILE ACID AND IF IN FACT TGR5 ARE PRESENT AND THE BILE ACIDS ARE ELEVATED, THEY DON’T.

HAVE TO BE TOO HIGH OR MAYBE IT’S A SPECIFIC BILE ACID WE JUST DON’T KNOW. THIS IS THE STATE OF THE ART A AT THE MOMENT. SO WHAT DO THEY CONCLUDE. THE HYPOTHESES IS THAT IN COLE OWE STASIS, THE TOXINS LOCALLY, WE’RE NOT SURE WHERE LOCALLY IS GENERAL LYSO PHOSPHOCYTIC AND OTHER FACTORS PERHAPS BILE ACIDS, I THINK THROUGH TGR5 MAY ALSO PLAY A ROLE IN INITIATING OR POTENTIATING THIS TOXIN ANTAGONISTS HAVE NOW REACHED THE STAGE WHERE THEY’RE BEGINNING CLINICAL TRIALS IN CANCER PATIENTS. IT TOOK A LONG TIME TO GET.

THERE. THIS WAS FOUR OR FIVE YEARS AGO. WOULDN’T IT BE AMAZING FAN LPA INHIBITOR OR AN R TOXIN INHIBITOR ACTUALLY THIS PROCESS. WE’LL FIND OUT EVENTUALLY. SO THAT’S THE STORY. I INTRODUCED MARK TO YOU WHO WILL CONTINUE AND APPEARS ALL THE QUESTIONS WHICH YOU HAVE AND I HAVE, RIGHT. gtgt CAN YOU HEAR ME I’M NOT SURE OKAY. SO THIS IS ACTUALLY THE TITLE BUT I REALLY LIKE IT BECAUSE I PROBABLY USE IT TO GO THROUGH THE DIFFERENT PARTS OF THE STORY AND TO INTRODUCE SOME BACKGROUND.

ELEMENTS AS WELL. SO FIRST OF ALL I’M GOING TO TALK ABOUT DISEASES. SO CHRONIC ITCH. THERE’S ACTUALLY A VERY LARGE NUMBER OF PEOPLE, REALLY DIVERSE GROUP OF PEOPLE WITH CHRONIC ITCH. THESE PEOPLE ARE A LOT LIKE MOST INDISCERNIBLE THINK OF ITCH AS SOMETHING REALLY ANNOYING THAT HAPPENS IF YOU SCRATCH FOR HALF AN HOUR AND YOU FORGET ABOUT IT. FOR THESE PEOPLE IT’S LIKE HAVING A MOSQUITO BITE BUT CONTINUOUS ALL THE TIME. I WENT TO A MEETING ON SCRATCH THIS SUMMER AND THE PATIENT GROUPS THERE’S BASICALLY PEOPLE.

WHO ALL THEIR LIVES THEY GO TO BED, WAKE UP IN THE MORNING AND THE BED SHEETS ARE COVERED IN BLOOD BECAUSE THEY SCRATCH ALL NIGHT LONG. SO MECHANICALLY THE GROUP MEETS TOGETHER. THE FIRST GROUP ARE CLEARLY PEOPLE WHO HAVE VARIOUS SKIN CONDITIONS. THERE’S CLEARLY A LARGE NUMBER SKIN CONDITIONS INCLUDING ONES LIKE THIS WHICH ARE GENETICALLY CONTROLLED. AND THEN THERE’S OTHER CONDITIONS WILL HAVE HAD INFECTIONS FROM VARIOUS AGAIN INCREDIBLY ITCHY. THEN THERE’S THE GROUP THAT INCLUDES LIVER DISEASE PATIENTS. BUT ALSO INCLUDES A BUNCH OF OTHER DISEASES THAT SEEM TO BE.

SYSTEMIC. THIS IS IN A PARTICULAR HODGKINS LYMPHOMA. A LARGE NUMBER OF PATIENTS NOW THAT ACTUALLY LIVE THAT BASICALLY HAVE NONFUNCTIONAL KIDNEYS, 85 OF THE PEOPLE WITH KIDNEY FAILURE ON DIALYSIS HAVE DRAWNIC ITCH. AND 15 OF THAT HAVE SEVERE CHRONIC ITCH THAT IS LIFE CHANGING. OTHER DISEASES LIKE UNDERSTAND WHY THESE PEOPLE HAVE CHRONIC ITCH. THERE’S ALSO ANOTHER GROUP GROUPED TOGETHER HERE OF PEOPLE WHICH HAVE A VARIETY OF NEUROLOGICAL DISORDERS THAT ALSO SHOW PRURITUS. I’LL GO TO IN A MOMENT THAT’S PERHAPS MECHANICALLY A LITTLE EASIER TO UNDERSTAND.

AND I WOULD LIKE TO POINT THIS OUT THAT THE CHRONIC ITCH IS SOMEWHAT SIMILAR TO ANOTHER CONDITION THAT MY GROUP IS VERY INTERESTED IN AND THAT’S CHRONIC PAIN. WE ALL HEARD OF PEOPLE WITH CHRONIC PAIN. ALSO MANY PEOPLE HAVE HEARD OF PEOPLE WITH CHRONIC ITCH BUT JUST LIKE WITH CHRONIC PAIN PEOPLE WITH CHRONIC ITCH THERE SEEMS TO BE NO PURPOSE FOR ALL THIS CONDITION. IT JUST SEEMS TO BE SELF DRIVING. THERE’S REALLY NO ADDED POINT FOR MANY OF THESE PATIENTS. SO I’M ESSENTIALLY A BIOLOGIST AND I WORK WITH THE NEURONS.

THIS IS NOW MY TRANSITION INTO THE WORLD OF NERVE CELLS. AND I STARTED OUT BY SHOWING THE END OF ANOTHER CELL. THIS IS THE END OF THE NERVE CELL WHICH IS FOUND IN THE SKIN. AND THE CELLS WHICH ARE IN THE SKIN CLEARLY WITHIN THE SKIN THERE ARE IMMUNE CELLS AS WELL. IT’S AN INTERACTION BETWEEN VARIOUS FACTORS THAT DRIVE FOR INSTANCE THOSE PATIENTS WITH RARE SKIN CONDITIONS. THERE’S AN ABNORMALITY THAT BASICALLY DRIVES ACTIVATION OF THE PERIPHERAL NERVE ENDINGS TO ACTIVATION OF VARIOUS RECEPTORS. SO ON THIS SLIDE I’VE SHOWN A.

TABLE OF RECEPTORS THAT’S BEEN SUGGESTED THAT ARE PRESENT IN THE PERIPHERAL NERVE ENDINGS. AT THE VERY TOP HERE, THE ONE THAT YOU ALL HEARD OF, HISTAMINE RECEPTOR WE ALL KNOW THAT HISTAMINE, IF YOU GO FOR A SKIN TEST, THE CONTROL THEY PUT ON YOUR SKIN IS HISTAMINE PRODUCES A WHEEL AND ALSO INCREDIBLY ITCHY THIS IS RELEASED FROM MASS CELLS FOUND IN THE SKIN THAT ARE ACTIVATED. SO I REMEMBER OTHER RECEPTORS I’VE NOTED THESE TWO HERE, THESE ARE ONES THAT HAVE BEEN IDENTIFIED AND RELATIVELY RECENTLY BY GROUP SO.

COMPOUNDS WHAT’S FOUND ENDOGENOUSLY BUT VERY USEFUL TOOLS FOR NEUROSCIENTISTS INTERESTED IN AN ITCH. AND THEN THERE’S ANOTHER PROCESS OF THESE ARE UP HERE BUT THERE’S ALSO A NUMBER OF OTHER RECEPTORS. IN PARTICULAR THIS ONE INTERLEUKIN 31. I’LL COME BACK WITH THAT A LITTLE LATER. SO I GUESS THIS IS THE PERIPHERY. SO THESE ARE REMARKABLE CELLS, VERY DIFFERENT FROM ANY CELLS IN THE BODY THAT THEY HAVE THE NERVE TERMINALS AT THE SKIN. THEY HAVE THIS ENORMOUSLY LONG AXON THAT STRETCHES ALL THE WAY TO WHERE THE CELL BODIES ARE AND.

THE CELL BODIES ARE FOUND RIGHT BY YOUR SPINAL CORD. IF YOU THINK OF A GIRAFFE THAT’S KIND OF SCRATCHY, IT’S HERE. THIS CAN BE SEVERAL METERS LONG. SO THESE ARE REMARKABLE CELLS. AND THE OTHER END CELL IS FOUND WHERE IT FORMS A CONTACT SIGN UP AND THIS IS FOUND IN THE SPINAL CORD. IT’S AT THIS STAGE THAT THE INFORMATION FROM DEPOLARIZATION AT THIS END OF THE CELL IS TRANSMITTED INTO THE RELEASE OF NEUROTRANSMITTERS WHICH THEN CROSS AND ACTIVATE THE NEXT PARTNER IN THE NERVES. NERVE PATHWAY. SO THAT’S WHAT MY GROUP IS.

INTERESTED IN HOW WE DETECT. THESE NEURONS ARE FOUND IN THE SPINAL CORD WITH THE GANGLION NEURON ARE RESPONSIBLE FOR MORE THAN ITCH CLEARLY. THERE’S A MECHANICAL STIMULATE THROUGH YOUR SKIN, YOU FEEL TEMPERATURE, YOU FEEL PAIN AND YOU FEEL SO ONE OF THE QUESTIONS THAT WE, WHERE WE HAVE IN THE BEGINNING IS HOW DO YOU ACTUALLY DISTINGUISH BETWEEN ALL THESE DIFFERENT TYPES OF STIMULI. IS THAT THERE IS MULTIPLE DIFFERENCE, THERE’S MULTIPLE CELLS IN THERE AND THEY RESPOND A BIT TO ALL THESE DIFFERENT TYPES OF STIMULI AND SOMEHOW.

THEY SEND A CODE ON TO THE NERVOUS SYSTEM. OR IN FACT THIS CASE WHERE ACTUALLY THERE ARE GROUPS OF CELLS THAT ARE MOLECULARLY DEFINED BY A PARTICULAR RECEPTORS. BUT THEN ARE RESPONSIBLE FOR DETECTING CERTAIN TYPES OF RESPONSE. IN A PARTICULAR, WE WERE INTERESTED BECAUSE OF IN THE CLASS OF NEURONS THAT EXPRESS THIS PARTICULAR MOLECULE THE TRIP V1. IT’S AN ION CHANEL FOUND IN THE PLASMA MEMBRANE AND IDENTIFIED AS THE RECEPTOR OF THE CAPSAICIN FOUND IN CHILE PEPPER. IT’S NOT ONLY RESPONSIBLE FOR BOTH HEAT AND ALSO IF THINK.

ABOUT HOT CHILE PEPPER IT’S RESPONSIBLE ALSO FOR PAIN. THIS IS A THROUGH THE GANGLION. YOU CAN SEE THE NEURONS THIS IS IN BLACK THAT EXPRESSES THE RECEPTOR IS HETEROGENEOUS. THE CELLS WHICH ARE PROBABLY SMALL DIALYSIS NOW THERE’S ALSO EVIDENCE THAT IN FACT TRIP V1 AND THE TRIP V1 NEURONS ARE REQUIRED TO ITCH. SO FOR INSTANCE ANTAGONISTS FOR TRIP V1 BLOCK ITCH. AGONISTS CAN CAUSE ITCH. AND NERVE HELP FOR TRIP V1 HAS BASICALLY LOTS OF RESPONSES TO HISTAMINE. WHAT’S INTERESTING IS THIS KNOCKOUT DIDN’T HAVE COMPLETE.

LOSS OF RESPONSES TO OTHER EXOWNLTDZ. OUR QUESTION WAS THOSE NEURONS, THESE NEURONS EXPRESSING TRIP V1 ENCODE FOR ALL ITCH OR DO THEY IN FACT HAVE OTHER RECEPTORS FOR THE OTHER TYPES OF ITCH COMPOUNDS. SO WE TOOK A DIFFERENT APPROACH AND IN THIS APPROACH WE GENERATED ANIMALS. BUT NOW WHERE WE CAN EXPRESS A TRANSGENE. THIS IS A PROMOTER THAT’S DRIVING TWO TRANSGENE GFP WHICH IS TO MARK THE CELLS AND THEN THE R TOXIN RECEPTOR. SO IN MY SENSE YOU HAVE A NATURAL R TOXIN RECEPTOR. IF YOU INJECT NORMAL MICE, THEY.

COULD CARE LESS. THEY COULD DRIVE SPECIFICALLY IN HUMANS RECEPTOR IN SPECIFIC SECTOR NEURONS. YOU CAN ELIMINATE JUST CERTAIN CELLS WITHIN THE WHOLE BODY. THIS IS EXACTLY WHAT WE DID. THIS IS NOW A PANEL OF WE’RE LOOKING AT DISTANT POPULATIONS OF NEURONS. THE ONLY NEURON THAT ARE LOST IN THESE ANIMALS AFTER R TOXIN ABLATION ARE THE ONES THAT EXPRESS THE TRIP V1. SURE ENOUGH THOSE ANIMALS ARE NOW NOT AS EXPECTED RESPONSES TO HISTAMINE OR GREATLY REDUCES RESPONSES TO HIS MEAN THROUGH THERE ARE ALSO LOTS OF RESPONSES.

TO OTHER SETS OF COMPOUNDS THAT WE KNOW CAUSE ITCH IN ANIMALS. SO WE NOW KNOW THE NEURONS. AS I TOLD YOU EARLIER, THE TRIP V1 NEURONS ARE NOT ONLY JUST INVOLVED IN ITCH. WE TESTED THESE ANIMALS. WE KNOW VERY WELL THAT THEY ARE ALSO REQUIRED FOR SOME TYPES OF TEMPERATURE RESPONSE AND SOME TYPES OF PAIN RESPONSES. SO STILL, HOW DO WE DISTINGUISH BETWEEN PAIN INCREASE AND ITCH. WE FAVORED A HYPOTHESES THAT THERE ARE IN FACT SELECT POPULATIONS OF NEURONS WITHIN THE TRIP V1 CELLS THAT ARE I’M.

CODED FOR RESCONSES. WE SET THAT OUT TO TRY TO IDENTIFY MOLECULAR MARKERS ESPECIALLY ONES THAT WOULD ALLOW US TO FUNCTIONAL DEFINE ITCH. AND TO MAKE A VERY LONG STORY SHORT, WE IDENTIFIED THIS MOLECULE, A MOLECULE CALLED NTPB IDENTIFIED 30 YEARS AGO AS A PEPTIDE RELEASE FROM THE EXTRACT. IT’S INVOLVING CONTROLLING AS ITS NAME IMPLIES. WHAT WE FOUND THAT EXPRESSED IN A SMALL SUBSET OF NEURONS AND IMPORTANTLY IN THIS MOUSE THIS MOUSE NOTABLY HAS NO ITCH RESPONSES. SO THIS IS THE CLUE THAT WE HAD.

THIS MAYBE WAS A MOLECULE THAT WAS IMPORTANT. AND FIRST OF ALL WE WANTED TO SHOW IT TO ESTABLISH WHETHER OR NOT IT WAS EXPRESSED IN THE TRIP V1 CELLS. SO THIS IS NOW I’M SHOWING YOU A LABEL OF HYBRIDIZATION. OVER HERE YOU COULD SEE THAT THE CELL IS PRESSION HE ISING NTV1 AND THIS IS PRESSIONED AND THIS IS THE IMAGE. YOU SEE THAT ALL THE V CELLS ALSO EXPRESS TRIP V1. NOT ALL TERRAIN V1 ABOUT A FIFTH OF THE NEURON THAT EXPRESS TRAIN V1 EXPRESS MTB.

THESE ARE A VERY DISTINCT POPULATION. THEY HAVE A CERTAIN SIZE WITH NEURONS THAT EXPRESS TRIP V1. SO, THIS IS THE QUESTION THAT WAS ASKED I DON’T RECALL. I SHOW THAT THE NEURONS ARE SUSPECT OF THE TRIP V1 CELL. IMPORTANTLY WHEN WE NOW PERFORM EXPERIENCE WHERE WE LOOK NOW FOR THE ISSUES I TALKED ABOUT AT THE VERY BEGINNING. THIS IS ONE RECEPTOR THAT’S MUCH RELATED GCBR CLASS AND THIS IS A RELATED ISSUE. IMPORTANTLY THESE RECEPTORS ARE FOUND AND COEXPRESSED WITH NTPB. SO IT LOOKS LIKE THIS WITH.

MOLECULAR MARKER DEFINES THAT THE WHITE CELLS THAT REQUIRE TO ITCH AND IN THE SAME CELLS AS EXPRESSED A FUNCTIONAL RECEPTOR. SO WE GENERATED ENOUGH AND WE SAW THIS CHARACTERIZED KNOCKOUT. THE FIRST THING WE TESTED THE KNOCKOUT FOR ALL THE RESPONSES TO A WHOLE ARRAY OF DIFFERENT TEMPERATURE, TOUCH, PAINFUL TOUCH AND PROPO RECEPTOR SENSORS. THESE ARE COMPLETELY NORMAL THEY HAVE NO DEFECT AT ALL. REMARKABLY THESE ANIMALS HAVE ATTENUATED RESPONSES ALMOST COMPLETE RESPONSES TO ALL THE COMPOUNDS WE COULD THROW AT THEM. SO IT LOOKS LIKE A IS A GREAT.

FUNCTIONAL MARKER OF PEER RECEPTORS. NOW THESE OF WHICH ARE A MEMBER ARE KNOWN TO BE MOLECULES THAT RELEASE SOME CELLS AND CALL ACTIVATION OF CELLS OUTSIDE OF THE CELLS. THE FIRST NEURONS OF A VARIETY OF DIFFERENT NEURO PEPTIDES INCLUDING THIS COMPOUND TGRP AND ANOTHER COMPOUND THAT WE IDENTIFIED. AND THESE MOLECULES ARE KNOWN TO NOT ONLY TO BE REQUIRED BUT THIS END OF THE CELL BUT ALSO ARE RESPONSIBLE FOR A VARIETY OF DIFFERENT RESPONSES ARE FOUND WITHIN THE SKIN. WE ALL KNOW THAT AROUND THE CUT.

THERE’S A RED SWELLING. THIS IS ACTUALLY CALLED BY RELIEF OF CGLP FROM THE END OF THE PERIPHERAL NEURON. THIS IS CALLED AND THE SWELLING THERE. THE FIRST ONE WE DID WAS INJECT NTVB INTO THE SKIN. AND UNLIKE RESPONSES TO THESE NEURO PEPTIDES WE SAW NO RESPONSES AT ALL. NOW WHEN WE INJECTED MTVB INTO THE SPINAL CORD WE CAN NOW ENLIST THE RESPONSES JUST LIKE THE HISTAMINE INJECTED INTO THE SKIN. BY INJECTING DIRECTLY INTO THE SPINAL CORD WE COULD GET RESPONSES. AND THEN UNTIL KNOCK OUTS WE.

COULD ALSO ELICIT SCRATCH RESPONSES. SO THESE KNOCKOUT ANIMALS BECAUSE OF THE DEVELOPMENTAL DEFECTS OR THE DEFECTS IN THE H PATHWAY BECAUSE WE CAN REGENERATE BY INJECTING IT DIRECTLY INTO THIS REGION WHERE THIS ACTS AS A TRANSMITTER. THIS SHOWS THAT NTB IS NOT ONLY REQUIRED BUT ALSO SUFFICIENT FOR A SCRATCH RESPONSE. SO HOW DOES THIS FITS IN WITH WHAT WE’VE KNOWN ALREADY IN THE FIELD. SO A NUMBER OF YEARS AGO GROUP HAD SHOWN ANOTHER NEURO PEPTIDE WAS ALSO REQUIRED IN THIS PATHWAY WHERE IT’S SHOWN THAT PEPTIDE RECEPTOR.

KNOCKOUTS AND ABLATION OF THE RELEASE PEPTIDE RECEPTOR NEURONS BASICALLY A LATE EACH RESPONSE. AGAIN, TO MAKE THIS STORY SHORT, I’LL SHOW YOU THE PATHWAY THAT ALLOWS US TO BRING TOGETHER WHAT WE FOUND TO WHAT WAS ALREADY PUBLISHED. SO THE PEER RECEPTORS AT THE PERIPHERY HAVE THEIR THEIR TERMINALS IN THE SKIN CAN ACTIVATE A NEURON IN THE SPINAL CORD AND A RECEPTOR FOR NTBP. THIS NEURON RELEASES A RELEASING PEPTIDE AND ACTIVATES A TERTIARY PEPTIDE RECEPTOR. THIS MODEL MAKES ALL PREDICTIONS. THE FIRST IS THAT GRP INDUCED.

DOES NOT REQUIRE NPVB. SECOND NPPB RECEPTOR NEURONS DON’T REQUIRE GRP. AND THE THIRD IT REQUIRES THE GRP PATHWAY IN CELLS AND FINALLY THE GRP AND THE NPPB RECEPTOR SHOULD BE IN THE SAME CELL. WE’LL GO THROUGH THOSE PREDICTIONS. THE FIRST IS GRP INDUCED ITCH DOES NOT REQUIRE NPPB. IF WE INJECT INTO THE SPINAL CORD GRP, THIS ALSO CAUSES ITCH. SO DOES IT REQUIRE SO WE HAVE THE KNOCKOUTS WE CAN INJECT GRP INTO THE SPINAL CORD AND WE HAVE THE KNOCKOUT. SECOND, THE NPPB RECEPTOR NEURON WE CAN ABLATE THESE NEURONS.

THIS IS A PANEL WHICH SHOWS THAT WE CAN SPECIFICALLY ELIMINATE THE CELLS THAT EXPRESS THE RECEPTOR. THIS IS UNTREATED ANIMAL FOLLOWING ABLATION. THIS IS A VERY SPECIFIC ABLATION BECAUSE WE DON’T ELIMINATE THE GRP EXPRESSING. WHAT’S ALSO VERY INTERESTING IS THIS IS A VERY EFFECTIVE ABLATION. AS WE EXPECT WE ELIMINATE HISTAMINE AND NPPB BECAUSE WE’RE BASICALLY COOKING THE PATHWAY 59 THIS POINT HERE. BUT WHAT REALLY IS VERY INTERESTING IS THAT WHEN WE ANALYZE AND WE TEST THESE ANIMALS WE FIND THAT THERE’S NO EFFECT ON PAIN ON FURTHER.

SENSATION OR ON SUCH. THIS IS A VERY SPECIFIC ASPECT. AND AS THE PREDICTION STATES THE GRP INDUCED ITCH IS NOT AFFECTED BY ABLATION OF THESE NEURONS BECAUSE GRP IS DOWN STREAM. AND THIRDLY, IF WE NOW THESE ARE BLOCKS OR ABLATE THESE NEURONS WE SHOULD ALSO BLOCK NPPB ITCH. AGAIN WE CAN ABLATE THE GRP RECEPTOR NEURONS. AND AS WAS REPORTED PREVIOUSLY THIS BLOCKS THE INDUCE THE ITCH IT BLOCKS THE GRP INDUCED ITCH AND IT ALSO BLOCKS THE NPPB ITCH. AND THEM FINALLY THE GRP AND NPPB SHOULD BE COEXPRESSED.

FIRST OF ALL, THIS IS NOW A HYBRIDIZATION IN THIS SPINAL CORD WHICH SHOWS THE EXPRESSION OF THE RECEPTOR AND THE GRP EXPRESSION PATHWAY. IT’S VERY SIMILAR INDEED WHEN WE PERFORMED THE ABLATION WITH THE NPPB WE GET A REDUCTION IN THE NUMBER OF NEURON THAT EXPRESS THE GRP. AND INDEED WHEN WE DO THE LABELING, WE CAN SEE COEXPRESSION OF THE RECEPTOR FOR THE NPPB AND THE GRP. THIS IS THE PATHWAY FOR ITCH. AND NUMBERS ARE IMPORTANT PIECES OF INFORMATION. FIRST OF ALL, THIS IS A DEDICATED ITCH PATHWAY.

IT DOESN’T REQUIRE RESPONSES THAT’S VERY USEFUL FOR TREATMENT BECAUSE CLEARLY IF YOU WANTED TO TREAT ITCH, YOU DON’T WANT TO GET RID OF RESPONSES TO PAIN. IT ALSO TELLS US ANOTHER BIT OF USEFUL INFORMATION. AND THAT IS THAT THE TWO NEURO PEPTIDES THAT ARE REQUIRED AT THE ITCH PATHWAY IT’S NOT ONLY NPPB BUT GRP. AND FINALLY, OUR WORK IS SHOWING THAT IN FACT AT THE PERIPHERY SELECTIVE POPULATIONS OF NEURONS IT’S JUST BEEN IN RESPONSES TO ITCH. AGAIN, A HINT TO POSSIBLE WAYS TO TREAT THESE CONDITIONS.

AND SO THIS FINAL THREE SLIDES I WANTED TO GO THROUGH POSSIBLE WAYS AND MECHANISMS FOR TREATMENT OF CHRONIC ITCH. AND FIRST I WANT TO TALK ABOUT THIS GROUP OF TREATMENTS THAT GO VIA THE PERIPHERAL NERVE ENDINGS, THE PERIPHERAL NEURONS. AND THERE ARE A NUMBER OF DIFFERENT TREATMENTS THAT ARE AVAILABLE AND ONES WHICH ARE IN DEVELOPMENT. THE FIRST IS OF COURSE ANTIHISTAMINE WHICH WE ALL USE WHEN WE ARE BITTEN BY A MOSQUITO. IT’S FAIRLY EFFECTIVE. YOU PUT ON ANTIHISTAMINE CREAM IF YOU GET BITTEN BY A MOSQUITO. I GET RELIEF BUT PATIENTS ARE.

COMPLETELY INEFFECTIVE. BECAUSE THIS IS NOT BY WHICH THOSE PEOPLE GET THAT CHRONIC ITCH. THERE ARE OTHER TUMOR DEVELOPMENTS SO I THINK THE PEOPLE THAT HAVE ATOPIC DERMATITIS HAS BEEN FOUND TO HAVE INTERLEUKIN 131 AND THERE’S A NEW HUMANIZED ANTIBODIES IN CLINICAL TRIALS THAT’S BEEN USED TO TREAT THOSE TYPES OF PATIENTS. THERE’S ALSO SOME PAPERS OUT, I READ RECENTLY AN IGE MONOCLONE ANTIBODY THAT’S BEEN USED ALSO WITH PEOPLE WITH CHRONIC ITCH. AGAIN THESE ARE PEOPLE WITH SKIN CONDITIONS AND YOU CAN ACTUALLY START THE MECHANISM BY WHICH.

THESE TYPES OF TREATMENTS MIGHT WORK. BUT CLEARLY, THIS IS A DIFFICULT AREA TO WORK IN BECAUSE FIRST OF ALL YOU HAVE TO IDENTIFY THE MOLECULES OF THE PERIPHERY. AND THEM FIND WAYS TO BLOCK THOSE. ANOTHER APPROACH IS THAT OF AFFECTING AN ITCH CENTRALLY. AND WE HEARD FROM THE INTRODUCTION THE CLINICAL SIDE THAT’S INHIBITING OPIOID RECEPTORS. WHEN YOU TALK ABOUT THESE, THEY ARE FOUND THAT CENTRAL NEURONS WHICH ARE FOUND IN THE SPINAL CORD. AND IN FACT, ONE OF THE CLASSICAL SYMPTOMS OF PREGNANCY. ONE OF THE CLASSICAL SYMPTOMS OF.

EPIDURALS IS INTENSE ITCH. OPIOIDS CAN CAUSE REALLY REALLY STRONG ITCH RESPONSES. AND THEY VERY OFTEN PATIENTS WITH ADMINISTERED BECAUSE IT’S SO BAD. CLEARLY ONE POTENTIAL AREA FOR DEVELOPMENT OF NEW ANTIITCH IS ANTAGONISTS ARE THESE TWO NEURO PEPTIDES, GRP AND ONE THAT WE HAVE NTPB. AND CLEARLY IN ORDER TO BE EFFECTIVE, THEN YOU REALLY NEED TO HAVE SOMETHING THAT’S VERY SPECIFIC. FOR BOTH OF THESE NEUROPEPTIDES ARE FOUND IN DIFFERENT AREAS OF THE BODY. SO THAT COULD EASILY BE OR MIGHT EASILY BE REASONS FOR NOT USING THESE AS TARGETS FOR.

DEVELOPMENTAL ITCH. WHAT IS REALLY REMARKABLE ABOUT THIS ITCH PATHWAY IS THAT THEY BOTH GRP AND NPPB ARE REQUIRED. AND ONE THING THAT MAY IN THE FUTURE BE POSSIBLE TO ACTUALLY USE A MIX ANTAGONIST OF THESE TWO COMPOUNDS AT THE LEVEL OF ANTAGONISM WHERE THEY DON’T HAVE BECAUSE THEY’RE BOTH REQUIRED AN ITCH PATHWAY. THAT CLEARLY IS SOMETHING IN THE FUTURE. AND THE THIRD CLASS OF TREATMENTS TO ITCH REALLY STEMS FROM THE CORRECTION OF HOW DOES PAIN ITCH. WE ALL KNOW FROM MOSQUITO BITES AT LEAST I DO IF THEY ARE.

SO BAD I’LL SCRATCH THEM UNTIL IT BECOMES PAINFUL. AND THEN THE ITCH GOES AWAY. THIS IS WELLKNOWN IF YOU SCRATCH LONG ENOUGH IT BECOMES PAINFUL AND YOU DON’T HAVE ANY ITCH ANYMORE. SO HOW DOES THAT HAPPEN SO IT’S BELIEVED THAT THERE’S AN INHIBITORY PATHWAY THAT STEMS FROM THIS PAIN PATHWAY THAT GOES INTO THE SPINAL CORD. AND BRANCHING OFF OF THE PAIN PATHWAY THERE’S ACTIVATION OF INHIBITORY INTERNEURONS. AND THESE RELEASE SOME FACTORS THAT INHIBITS THIS PATHWAY. AND THIS PATHWAY, THERE’S TWO VERY STRONG PIECES OF EVIDENCE THAT THIS IS INDEED THE PATHWAY.

FIRST OF ALL IN ANIMALS WHERE THERE’S A CONDITIONAL ABLATION OF THE NEUROTRANSMITTER GLUTAMATE, THESE WERE TWO CONDITIONAL KNOCKOUTS. THOSE ANIMALS EXHIBIT SPONTANEOUS UNSUBSTANTIATED ITCH. AFTER ABOUT SIX WEEKS THEY HAVE TO BE EUTHANIZED BECAUSE THEY SCRATCH THEMSELVES WHERE THEY BASICALLY HAVE LARGE LESIONS ALL OVER THEIR BODY. ANOTHER PIECE OF EVIDENCE IN THIS PATHWAY IS BASIC HELIX TRANSMITTER FIVE, B5. AND THESE ANIMALS HAVE LOST THIS CLASS OF INHIBITORY INTERNEURONS. AND THOSE ANIMALS, JUST LIKE THE CONDITIONAL KNOCKOUTS SHOWED SPONTANEOUS AND SUBSTANTIATED ITCH. SO IF YOU GET RID OF THIS.

INHIBITION IN ANIMALS, YOU NOT ONLY DON’T GET, THE CHANCES OF ACTUALLY HAVING THIS IN FACT THIS PATHWAY ACTUALLY ACTS AS A INHIBITORY PATHWAY. IT WORKS ALL THE TIME AND PREVENTS ITCH FROM HAPPENING. THIS IS A TYPE OF ARRANGEMENT THAT’S FOUND IN MANY SENSORY SYSTEMS BETWEEN DIFFERENT SENSORY MODALITIES. AND AGAIN IN THE CASE OF THE PATIENTS TOLD US THAT IN FACT COLD INHIBITS ITCH. AGAIN THERE’S GOOD ACTUAL EVIDENCE THAT THIS OCCURS IN THE SPINAL CORD. IN FACT, WE ALL KNOW THAT COLD ALSO INHIBITS PAIN. AND THAT’S WHY WE PUT A COLD.

COMPRESS ON SOMETHING THAT’S PAINFUL BECAUSE AGAIN THESE PATHWAYS HAVE CROSSED BETWEEN THE DIFFERENT PATHWAY. IT’S DROPS ANOTHER PATHWAY THAT’S COLD AND ANOTHER SET OF INHIBITORY NEURONS THAT WOULD ACT ON THIS MATT WAY HERE FOR MAIN AND AL FOR PAIN AND ALSO ON THE ITCH PATHWAY. WHAT WE STILL DON’T KNOW IS WHAT IS THE TRANSMITTER HERE THAT THIS ACTS TO INHIBIT THIS. AND REALLY A CLUE FROM THAT CAME FAIRLY RECENTLY. AND THIS IS A DIFFERENT THIS IS A KAPPA OPIOID RECEPTOR. IN FACT, THIS COMPOUND IS NOW IN.

THE CLINICAL TRIALS AS THE TREATMENT FOR A TYPE OF ITCH, THE ITCH THAT’S FOUND IN RENAL FAILURE PATIENTS. SO THIS WOULD BE MY THIRD COMPOUND THAT COULD POTENTIALLY BE USED FOR TREATMENT OF CHRONIC ITCH THAT BASICALLY THE ITCH PATHWAY TRYING TO PREVENT IT BY INHIBITING THE AT SOME STAGE HERE IN THE PATHWAY. SO NOW MANY QUESTIONS OF COURSE THAT REMAIN AND I’LL JUST NAME SOME OF THEM HERE. THE FIRST IS THAT A LOT OF THE WORK THAT WE’VE BEEN DOING AND THE NEUROSCIENCE FIELD THAT’S BEEN DOING IT IS BASICALLY THE.

ACUTE ITCH. BECAUSE ALL THE EXPERIMENTS WE PERFORM IS THAT THE CELLS AND MOLECULES ARE THE SAME THAT MIGHT NOT BE A CORRECT ASSUMPTION. SECONDLY, THESE SYSTEMIC CONDITIONS WHERE WE CAN’T UNDERSTAND WHAT’S REALLY HAPPENING, IS THIS THROUGH MODULATION OF INTERMEDIATE PARTS OF THE PATHWAY. ARE THESE AKIN TO NEUROPATHIC PAIN. IS THERE A SIMILAR NEURONEUROPATHIC ITCH THAT CAN ACHE FOR THOSE TYPES. AND ANOTHER OPEN QUESTION, AT LEAST FOR THE PATIENTS THAT HAVE SKIN CONDITIONS, WHAT IS HAPPENING IN THE SKIN THAT’S ACTUALLY CAUSING THE CHRONIC ITCH. AND THERE’S A LOT OF EVIDENCE.

THAT IN FACT THE DYSFUNCTION OF THE INTERACTION WITH THE BETA CELLS AND THIS IS WHAT DRIVES THE CURRENT CONDITIONS. I WOULD LIKE TO SAY I THINK THERE’S DEFINITELY HOPE BY IDENTIFYING THE MOLECULES AND THE CELLS. I THINK THEY ARE NOW IN A UNIQUE POSITION THAT WE’RE ACTUALLY USING ALL THE STAGES OF THE PATHWAY AND HOPEFULLY THIS WILL LEAD TO NEW THERAPIES AND TREATMENTS. FINALLY I WOULD LIKE TO THANK PEOPLE IN MY GROUP THAT ARE INVOLVED THAT DID A MAJORITY OF THE HARD WORK I TALKED ABOUT.

WITH THE NPPB STORY. THANK YOU. APPLAUSE gtgt IF YOU WOULD REPEAT THE QUESTION. gtgt IF I COULD HEAR IT. gtgt INDISCERNIBLE. SO WE WOULD SAY THAT THIS IS WHY NPPB LIKE MOST NEUROPEPTIDES ACT AS A NEURO MODULE LATER. THERE’S VERY GOOD EVIDENCE THAT THESE NEURONS IS ALSO WORKING. SO WE DIDN’T ELIMINATE GLUTAMATE. THERE IS SOME LOW LEVEL TRANSMISSION THAT THIS REQUIRES THE FULL RESPONSE THAT YOU NEED TO HAVE BOTH BOTH TOGETHER. gtgt DO PEOPLE WHO HAVE NEUROLOGIC INHERITABLE DISORDERS CHARACTERIZE BY A FAILURE TO APPRECIATE PAIN.

IS THAT ITCH gtgt SO I DON’T KNOW ABOUT THAT PER SE BUT I KNOW THERE’S A GROUP OF PEOPLE THAT HAVE NO SPONSES TO PAIN. AND THE KNOCKOUTS AS THE SAME GENE THAT’S AFFECTED IN THOSE INDIVIDUALS HAS BEEN MADE RECENTLY AND I KNOW BOTH ANIMALS HAVE NO ITCH RESPONSE. IT’S INDIRECT. IT’S VERY RARE INDIVIDUALS THAT HAVE NO PAIN. THEY ACTUALLY TEND TO DIE EARLY BECAUSE PAIN IS USEFUL. gtgt ARE THESE NEURONS PRESENT IN LATE FETAL LIFE. THESE NEURONS, THE DORSAL, ARE THEY PRESENT IN LATE FETAL LIFE.

THE RECEPTORS gtgt ARE THEY PRESENT IN VITRO YOU’RE ASKING. gtgt YES. THIS IS THE POLITICAL QUESTION. gtgt I DON’T KNOW. gtgt ALONG THE SAME LINES THERE ARE PEOPLE WHO DON’T ITCH. ARE YOU AWARE OF WHETHER WHAT THE EXPRESSION OF AN NPPB ARE IN THOSE INDIDUALS. gtgt ION’T KNOW. I DIDN’T REALIZE THAT THERE ARE ACTUALLY PEOPLE gtgt I MEAN, THIS IS ANECDOTAL. I KNOW THERE ARE PEOPLE WHO NORMAL STIMULI THAT WOULD INDUCE ITCHING, AT LEAST IT’S MUCH MORE DIFFICULT TO INDUCE ITCHING IN THEM. gtgt THAT WOULD BE INTERESTING BUT.

CLEARLY THAT’S A LONG PATHWAY gtgt IT’S INTERESTING THAT THEY ALSO HAVE THE JUICE RESPONSES TO CAPSAICIN AS WELL. gtgt RIGHT. PROBABLY BECAUSE NMPB IS ONE OF THOSE GENES THAT IS NEEDED FOR MORE THAN JUST ITCH. IT IS ACTUALLY REQUIRED. IT’S PRODUCED BY THE ATRIUM IN THE HEART AND DISSTRESSES. I THINK THOSE PEOPLE WOULD HAVE MANY OTHER HEALTH PROBLEMS AS WELL. THEIR BLOOD PRESSURE WOULDN’T BE CONTROLLED AND THEY WOULD HAVE PROBLEMS WITH THEIR HEART. THERE’S PROBABLY AN EXPLANATION BUT CLEAR THREELY IT’S AFFECTED IN THAT PATHWAY. gtgt IS THERE RECIPROCAL TRUTH.

LET’S SAY TREATING WITH HISTAMINE REDUCE PAIN. gtgt SO HISTAMINE IS VERY COMPLICATED BECAUSE IF YOU INJECT HISTAMINE INTO THE DERMAL LAYER, IT CAUSES ITCH. IF YOU ACTUALLY INJECT UNDER SKIN IT’S PAINFUL. THERE ARE RECEPTORS IN THE PAIN PATHWAY AS WELL AS ITCH. SO IT’S NOT CLEAR CUT. HISTAMINE IS NOT THE CLEAN AGENT FOR THE ITCH. SO AGAIN IS FOUND IN BOTH. THIS IS ONE THING THAT ‘VE STARTED TO ACTUALLY THINK WHEN CAREFULLY BECAUSE A LOT OF PEOPLE THINK THAT THE RECEPTORS ARE FOUND IN THE PERIPHERAL.

NEURONS BUT IN FACT THERE ARE IN THE CASE OF INSECTS BITING YOU, IF YOU THINK ABOUT THAT, THE RECEPTOR IS ACTUALLY ON THE BECAUSE WHEN YOU’RE FIRST BITTEN BY MOSQUITOES AS KIDS WE DON’T HAVE A REACTION. AFTER WE GENERATE THE IGE AGAINST THE ANTIGEN AND SALIVA FROM THE MOSQUITO THAT WE ACTUALLY. SO IN THAT CASE THE RECEPTOR’S REALLY ON THE IMMUNE CELLS AND THE IMMUNE CELLS THEN RELEASE THIS AND ACTIVATES THE NEURONS. A LOT OF THESE BIG QUESTIONS ARE SORT OF SOMEWHAT AT LEAST FOR ME.

OPEN. I GOT TO WHERE THE INITIAL RECEPTOR IS BECAUSE IT COULD BE SOME OTHER THAT’S THEN OR IN SOME OF THESE SYSTEMIC CONDITIONS THEY COULD ALSO BE COMPOUNDS THAT ACTIVATE. SO FOR INSTANCE THE TREATMENT FOR COLOSTASIS IS THERE ARE RECEPTORS AT LEAST AT HIGH LELS IN HE PERIPHERAL NEURONS AN FOUND IN THE SPINAL CORD. gtgt YES. SO YOU’VE SHOWN US TODAY THAT ITCH IS ASSOCIATED WITH A SPECIFIC CELLULAR MOLECULAR COMPARTMENT. AND YOU ALSO JUST REMINDED THAT PAIN SERVES AS A FUNCTION. SO WHAT IS THE FUNCTION OF ITCH.

THAT’S A GOOD QUESTION. IT WILL BE ONE OF THE QUESTIONS I WOULD HAVE HAD. I CAN GIVE AN OPINION, I CAN GIVE AN IDEA. THE THING IS THAT CLEARLY WE DON’T KNOW WHAT. ONE EXPLANATION I’VE HEARD AND I THINK IT’S REASONABLE IS THIS IS EVOLUTIONARY. MECHANM TO MOVE PARASITES FROM THE SKIN. SO IF YOU GET, BECAUSE THIS IS A REACTION JUST TO THE VERY SURFACE AREA. SO YOU CAN’T GET ITCH. IF YOU INJECT COMPOUNDS DEEP WITHIN THE SKIN, YOU DON’T GET AN ITCH RESPONSE ACTIVITY DELIVERED WITHIN THAT VERY.

SURFACE AREA OF THE SKIN TO GET HISTAMINE RESPONSE. AND SO THE ARGUMENT IS THAT THIS IS AN EVOLUTION OF MECHANISM TO BASICALLY GET THOSE PARASITES OUT OF YOUR SKIN. QUICKLY. AND THE ARGUMENT IS THAT BASICALLY YOU WANT TO SCRATCH UNTIL IT’S PAINFUL BECAUSE THEN YOU KNOW YOU’VE GOT PASSES THE SKIN WHERE YOU’VE GOT PAIN AND YOU DON’T WANT TO REMOVE ANYMORE BECAUSE YOU’LL GET INFECTIONS AND HAVE PROBLEMS. gtgt WHAT’S THE ROLE CANNABINOIDS. gtgt I DON’T KNOW ALL KINDS OF PLACES IN THE INFLUENCE AND THE.

PERIPHERAL NERVOUS SYSTEM. THERE IS SOME EVIDENCE IN THE PAIN PATHWAY. gtgt MAYBE gtgt SOME OF THESE DISEASES THAT ARE REALLY TRACTABLE THAT’S CRAZY. gtgt THIS IS WHY FOR INSTANCE PATIENTS AT LEAST BEING PUT FORWARD THE REASON WHY PATIENTS BEFORE THEY ARE GOING TO BED SEEM TO FEEL THAT ITCH IS WORTH IT BECAUSE THEY HAVE NOTHING ELSE TO THINK ABOUT. THEY’VE NOW GONE DOWN THEY HAVEN’T GOT ANY OTHER SENSORY INPUT. ITCHING BECAUSE THEY ACTUALLY NOTICE IT. AND SO THERE’S A WHOLE FIELD IN THE CHRONIC PAIN ARENA WHICH IS.

BASICALLY ARE FOR PEOPLE WITH CHRONIC PAIN WITHOUT BASICALLY A DISTRACTION. AND A DISTRACTION IS BASICALLY SEDATION. IF YOU CAN BASICALLY SEDATE THE INDIVIDUAL, THEY WON’T WANT TO SCRATCH OR HAVE ANY PAIN. IT’S GONE DOWN, AND IN FACT PEOPLE WITH PAIN AND I WERE GIVEN DRUGS THAT ARE AGAINST, THESE ARE DRUGS THAT BASICALLY WOULD USE IT REDUCES THE TARGET AND REDUCES THE LEVEL OF SENSORY IMPULSE AND PROCESSING. gtgt ARE YOU INTERESTED IN LOOKING AT THIS TGR5 gtgt I’M NOT FOCUSED TO ACTUALLY RETURNING YOU GO TO THE.

Female Hair Loss or Androgenetic Alopecia

If you’re a woman experiencing hair loss and you’ve been told there’s nothing you can do about it don’t believe it. I was told the same thing, but I refused to accept it. At age 32 my hair began falling out by the handfuls and it didn’t stop until I was practically bald. Within a two month period of time I lost over 90 of my hair. I was experiencing a severe case of telogen effluvium diffuse hair loss along with alopecia areata. I was pretty much the definition of a female hair loss sufferer, also this wasn’t my.

First episode of hair loss but it was definitely the most extensive and the most dramatic. This episode brought me back to the doctors once again, but once again all my lab work came back in the normal range. I was supposed to be thankful which I was that I didn’t have any type of lifethreatening illness. But as far as getting a remedy for my female hair loss I was told there was none. The only advice I was offered was to get a good wig and get on with my life.

Ironically, during this time I happened to be tending a bare patch of lawn in my front yard. Watering and fertilizing the seedlings had me anxiously anticipating the blades of grass that would soon be sprouting. As the bare patch filled in with thick healthy grass, I knew there must be some sort of fertilizer that would help sprout the hair on my bare scalp. I was determined to find out. Through research and with the help of a cosmetologist who specialized in thinning hair, I learned about powerful natural ingredients used to stimulate hair growth. After applying these.

Natural ingredients, my scalp felt energized and invigorated. Within months soft new hair began to appear, eventually becoming thicker, healthier and shinier than it was even before the loss! Needless to say I was amazed, relieved and excited all at the same time. Learning about hair loss became my passion. I immersed myself in every piece of information I could find on the biology of hair growth becoming diligent in my quest to understand why women lose their hair and how to prevent it. My newfound purpose in life was to help other women suffering with female hair loss.

Through education, empowerment and solutions. This offer includes all the information needed for women to understand and take charge of their own hair loss condition and begin growing beautiful, healthy hair. REGROWTH IS POSSIBLE IN ALMOST ALL CASES OF FEMALE HAIR LOSS! The most important thing I learned is that regrowth is possible in most cases of female hair losseven when the cause is hereditary. Many women falsely believe that because androgenetic alopecia is caused by an inherited gene, balding is inevitable. Fortunately this isn’t true. With androgenetic alopecia, the hair doesn’t.

Actually fall out. Instead, the follicle narrows progressively over time, producing thinner, weaker hairs that provide less scalp coverage. This is a slow progressive process. It takes many years for the follicle to atrophy and cease producing hair. As long as the process is not complete, there is potential for improvement. Cicatricial scarring alopecia is the only type of female hair loss that is permanent and irreversible. In this type of hair loss the follicle is destroyed by scar tissue. Fortunately this is a rare form of hair loss, accounting for less than 3 cases.

Regrowth can be achieved in every other type of hair loss as long as the underlying follicles are alive and undamaged. In most cases of female hair loss, the growth cycle becomes disrupted, but the follicles remain alive and fully capable of producing healthy hair once favorable conditions are created. Alopecia areata and telogen effluvium are two forms of hair loss which commonly affect women. These types of hair loss respond well to natural treatments. The potent formulas I use work to reactivate the follicles which have become nonproductive. The sooner treatment is started the better but as long as the follicle is alive, potential.

Remains. Why Learning About Hair Loss Is Important My goal is to make YOU an expert on your own personal hair loss so you can take charge of your own situation and restore your hair to a healthy luxurious state. Once you understand the innerworkings of hair growth you will be surprised how easy it is to improve your hair loss condition! All female hair loss is not alike. It’s important to pinpoint the type and cause of your own personal hair loss. Many cases of female hair loss are temporary and easily.

Corrected once the cause is identified and addressed. Having an intimate understanding of the hair growth cycle allows you to control factors which may trigger your hair loss. The hair growth cycle is sensitive and can be easily disrupted causing hair loss, slow growth and other undesirable changes. Understanding the growth cycle is imperative to optimizing the potential of healthy hair growth. Hair loss is often the first sign of physical or emotional imbalance. Even a slight imbalance can result in hair loss. Identifying and correcting the problem early can prevent further problems.

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