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    Evolutionary and Functional Analysis of Celiac Risk Loci Reveals SH2B3 as a Protective Factor against Bacterial Infection


    Jefferson Adams
    Image Caption: SH2B3 offers protection against bacterial infection.

    Celiac.com 06/15/2010 - A clinical team conducted a functional analysis of celiac risk loci, and found that SH2B3 offers protection against bacterial infection.


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    The team included Alexandra Zhernakova, Clara C. Elbers, Bart Ferwerda, Jihane Romanos,  Gosia Trynka, Patrick C. Dubois, Carolien G.F. de Kovel, Lude Franke, Marije Oosting, Donatella Barisani, Maria Teresa Bardella, the Finnish Celiac Disease Study Group, Leo A.B. Joosten, Paivi Saavalainen, David A. van Heel, Carlo Catassi, Mihai G. Netea, and Cisca Wijmenga.

    Celiac disease has a fairly high morbidity, yet it is prevalent in Western populations at rates of of 1%–2%. So far, scientists don't understand why the celiac disease phenotype is so common despite its obvious negative impact on human health. This is especially true when one considers that doctors only developed a gluten-free diet to treat celiac disease in the 1950's.

    The research team scientists hypothesize that the high prevalence of celiac disease might suggest that the process of natural selection favors genes that trigger celiac disease, and thus, that the gene may convey some evolutionary advantage to those who inherit them.

    The study group included 8,154 controls from four European populations, and 195 individuals from a North African population. By examining haplotype lengths using the integrated haplotype score (iHS) method, the team looked at selection signatures for ten confirmed celiac-associated loci in several genome-wide data sets.

    They found consistent indications of positive selection for celiac-associated derived alleles in three loci: IL12A, IL18RAP, and SH2B3. For the SH2B3 risk allele, they also found a variation in allele frequency distribution (Fst) between HapMapphase II populations.

    Functional investigation of the effect of the SH2B3 genotype in response to lipopolysaccharide and muramyl dipeptide showed that carriers of the SH2B3 rs3184504*A risk allele provided more robust triggering of the NOD2 recognition pathway.

    This suggests that SH2B3 plays a role in protection against bacteria infection, and it provides a possible explanation for the selective sweep on SH2B3, which occurred sometime between 1,200 and 1,700 years ago.

    Source:


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    Wonderful and encouraging article, loved it!

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  • Related Articles

    Jefferson Adams
    Celiac.com 03/04/2009 - Millions of people currently suffer from a potentially deadly condition that can have little or no symptoms, but is easily diagnosed and treated. The condition is called celiac disease, and it is caused by an adverse autoimmune reaction to gliadin (found in wheat gluten), secalin (found in rye gluten), or horedin (found in barley gluten). Because of the broad range of symptoms that celiac disease can present, and the fact that many people will have no symptoms at all, it can often be very difficult for those who do have it to get properly screened for the disease.
    According to Dr. Alessio Fasano, medical director of the Center forCeliac Research, 2.5 million to 3 million people in the USA have celiac disease—it istwice as common as Crohn’s disease, ulceric colitis and cystic fibrosiscombined—yet, to date, no more than 150,000 of them have beendiagnosed. This means that a full 2.35 to 2.85 million people in the USA have not been diagnosed and treated.
    The symptoms of the disease can range from no symptoms at all, to mild weakness, bone pain, aphthousstomatitis (canker sores), chronic diarrhea, abdominal bloating, and progressiveweight loss. If people with celiac disease continue to eat gluten, studies show that their risk of gastrointestinal cancer increases by a factor of 40 to 100 times over the general population. Further, gastrointestinal carcinoma or lymphoma develops in up to 15 percent of patients with untreated or refractory celiac disease. It is thus essential that the disease be quickly diagnosed and treated.
    The last decade has seen an explosion in the understanding and awareness of celiac disease and in higher standards and increased availability of gluten-free foods.
    To help us better appreciate the dramatic changes and developments that have taken place, Celiac.com has put together a list of historical landmarks in the understanding and treatment of celiac disease. A glance at the time line will show that it really has taken centuries just to recognize and diagnose celiac disease, with the greatest strides being made in the last fifty years, and especially in the last decade.

    A Celiac Disease / Gluten-Free Diet Historical Timeline:
    100 A.D.—The first written account of celiac symptoms in western medicine occurs when the Greek Physician, Aretaeus the Cappadocean, known as Galen, describes the characteristic stool, noting that the disease was more common in women than men and that children can also be affected. 1669—The Dutch physician Vincent Ketelaer publishes a book that contains an account of a diarrheal illness in which he notes feces so voluminous that, "several basins or pots scarcely hold these accumulations." 1737—John Bricknell writes of patients who suffer from what he terms the "white flux.” Both Ketelaer and Bricknell were likely describing celiac disease, though that name would not be attached it for another century and a half. 1887—Dr. Samuel Gee ushers in the modern era of celiac disease, when he drew attention to the disorder in a lecture delivered at the Hospital for Sick Children, Great Ormond Street, London. 1888—Dr. Gee publishes his classic paper, "On the Coeliac Affection,” in which he describes aspects of the celiac disease with great accuracy and suggests that, "if the patient can be cured at all, it must be by means of diet.” He experimented with various diets and noted that children who were fed a quart of the best Dutch mussels daily, throve splendidly, but relapsed when the season for mussels ended. 1889—R.A. Gibbons, MD., M.R.C.P. publishes The Celiac Affection in Children in the Edinburgh Medical. Journal.
    1908—British Physician Christian Herter becomes the first to discover that celiac disease can cause stunted growth, especially among children in their middle years. 1921—British Physician John Howland devises the healthy, three-stage diet for celiac patients known as the milk/protein diet. 1932—Danish physician Thorwald Thaysen provides the first clinical explanation of celiac disease in adults, though he lacks detailed knowledge on intestinal pathology for a full understanding of the disease. 1936—Dutch pediatrician Willem Karel Dicke isolates cereal grains as the factor in aggravating the symptoms of celiac disease, especially in children, and begins treating children with the gluten-free diet. Afterwards his Ph.D. thesis was published and he was laughed out of the NYC gastroenterology meeting in 1950 and vowed not to return to the USA.
    1954—Experimenting with surgical biopsy material, Doctor J. W. Paulley makes the first discovery of the intestinal lesions caused by celiac disease in patients. 1955—Margo Shiner invents the tiny biopsy tube that is still used today for confirming the presence of celiac disease in the small intestines. The important celiac disease discoveries of Paulley and Shiner meant that, from the mid 1950s onwards, doctors had a means by which to reliably diagnose the disease. Their discoveries gave rise to an explosion in the understanding of celiac disease that continues to this day. 1965—Dermatologists recognize that people suffering from the itchy skin rash, dermatitis herpetiformis, have an abnormal jejunal biopsy just like those with celiac disease and that the rash usually subsides with the observance of a gluten-free diet. 1970—In the early 1970s, researchers identify genetic markers for celiac disease. Even though the gene or genes that cause celiac disease have not been identified, researchers remain hopeful that they will succeed in doing so, and thereby give rise to a new generation of celiac treatments that do not require a gluten-free diet. 1980s—Fiber optic technology enables doctors to take small bowel biopsies using fiber-optic endoscopes, while the development of reliable screening blood tests greatly increases the number of celiac diagnosis. 1981—The Codex Alimentarius Commission establishes the earliest standards for gluten-free food. Under this original standard, foods labeled “gluten-free” must be made from naturally gluten-free grains, such as corn or rice or from gluten grains (wheat, barley, rye) that had been rendered gluten free through processing. At the time, there was no way to test for the presence of gluten, so tests gauged the levels of gluten by measuring nitrogen levels, an imprecise method. ~1985—It is discovered that gliadin initiate damage to the absorptive epithelium of the small intestine toproduce symptoms of celiac disease in susceptible individuals. 1990s—Early in the decade, doctors thought celiac disease to be rare and affect just 40,000 or so Americans. Over the last decade or so, the number of Americans diagnosed with celiac disease has nearly tripled, to 110,000, but that’s just the start. The National Institutes of Health now estimates that about 1% of the population, or about 3 million people suffer from celiac disease, and that only about 3% of existing cases have been diagnosed. A full 97% of celiac cases remain undiagnosed. That’s about 2.9 million people who remain undiagnosed and in danger. More and more of those who are diagnosed are reporting no symptoms. 1995—In San Francisco, California, Scott Adams launches the Web site that evolves into Celiac.com, the first website on the Internet dedicated solely to celiac disease. The site quickly evolves into one of the most authoritative, informative, and comprehensive sources for celiac disease and gluten-free diet information. The celiac.com forum is one of the most popular places on the web for people with celiac disease to get answers and share information. 1998—Codex Alimentarius revises its standards for foods labeled ‘gluten-free’ to be made from naturally gluten-free ingredients and contain 20 parts gluten per million, or less, while foods processed to be reduce gluten, such as wheat starch, can have no more than 200 parts per million gluten. 1998—The Gluten-Free Mall (www.GlutenFreeMall.com) launches its "Special Diet Superstore!" to provide home delivery of top quality foods and other products that are free of wheat, rye and barley gluten, soy, dairy, eggs, corn, and other common allergens. The Gluten-Free Mall now sells thousands of gluten-free products including breads, cookies, cakes, pizzas, mixes, full meals, frozen foods, cosmetics, gluten-free guides, books, and more. 1997 to 2007, the number of people under-18 diagnosed with food or digestive allergies rises nearly 20%, and nearly 3 million people young people now suffer from food allergies. About 12 million Americans suffer from a food allergy, according to the American Academy of Allergy, Asthma and Immunology, with nearly 90% of all food allergies arising from reactions to just eight foods: Cow’s milk, eggs, peanuts, tree nuts, shellfish, soy and wheat. Since 2004, food retailers have added nearly 2500 new gluten free products to their shelves. 2000—Scientists at the University of Maryland discover Zonulin, which is a protein that participates in tight junctions between cells of the wall of the digestive tract.
    2003—Alessio Fasano, MD, publishes his seminal study in the Archives ofInternal Medicine that indicates that 1 in 133 people in the USA haveceliac disease. 2007—Studies show a high instance of arthritis and osteoporosis in people with celiac disease, and other studies show a high prevalence of celiac disease among people with type-1 diabetes. 2008—A team of researchers works to develop a simple saliva test after concluding that it is possible to accurately measure salivary tTG-Abs; both at initial diagnosis for celiac disease, and also while patients are following a gluten-free diet. 2008—Rates of celiac disease are shown to be 2.5 times higher among elderly people than among the general population. 2009—Canada debuts the home celiac disease test kit as part of its national health care plan. 2009—The company Nexpep is currently preparing for a clinical trial program for a peptide-based therapeutic vaccine, and intends to commence a Phase 1 in the first half of 2009. According to Nexpep, the peptide-based therapeutic vaccine is designed to treat the main problem T-cell epitopes of gluten, and has the potential to treat at about 80% of people with celiac disease and the appropriate genetic background. 2009—Sometime this year the USFDA is expected to adopt long awaited regulations for the use of the term "gluten-free" on USA food labels. The new regulation would require foods with "gluten-free" on their labels to contain less than 20 parts per million of gliadin. Several pharmaceutical companies are currently working on treatments for celiac disease, such as Alvine Pharmaceuticals (enzyme therapy), and Alba Therapeutics is developing a zonulin receptor antagonist called AT-1001, which is currently in phase 2 clinical trials. 2012—All food made in the E.U. with ‘gluten-free’ on its label must contain less than 20 parts per million of gliadin, in accordance with the Codex Alimentarius standards.

    Jefferson Adams
    Celiac.com 09/09/2011 - A team of researchers recently set out to assess the effects of milk-feeding behavior and the HLA-DQ genotype on intestinal colonization of Bacteroides species in infants with a risk of developing celiac disease.
    The research team included E. Sánchez, G. De Palma, A. Capilla, E. Nova, T. Pozo, G. Castillejo, V. Varea, A. Marcos, J. A. Garrote, I. Polanco, A. López, C. Ribes-Koninckx, M. D. García-Novo, C. Calvo, L. Ortigosa, F. Palau, and Y. Sanz.
    They are affiliated with the Ecofisiología Microbiana y Nutrición, Instituto de Agroquímica y Tecnología de Alimentos (CSIC) in Valencia, Spain.
    The team studied 75 full-term newborns with at least one first-degree relative who suffered from celiac disease. They classified the newborns according to milk-feeding practice (breast-fed or formula fed) and HLA-DQ genotype, which indicates high or low genetic risk.
    The team used PCR and denaturing gradient gel electrophoresis (DGGE) to analyze stools at 7 days, 1 month, and 4 months. They found that formula-fed infants showed greater Bacteroides species diversity than did breast-fed infants.  Breast-fed infants showed a higher prevalence of Bacteroides uniformis at 1 and 4 months of age, while formula-fed infants had a higher prevalence of B. intestinalis at all sampling times, of B. caccae at 7 days and 4 months, and of B. plebeius at 4 months.
    Infants with low genetic risk showed greater colonization of B. ovatus, B. plebeius, and B. uniformis, while those with high genetic risk showed a greater colonization of B. vulgatus.
    Among breast-fed infants, those with low genetic risk had greater colonization of B. uniformis than those with high genetic risk, who showed higher rates of B. vulgatus.
    Among formula-fed infants, the prevalence of B. ovatus and B. plebeius was increased in those with low genetic risk, while the presence of B. vulgatus was greater in those with high genetic risk.
    The results indicate that both the type of milk feeding and the HLA-DQ genotype influence the types of Bacteroides that colonize in the intestinal tract, and possibly also influence risk for developing celiac disease.
    Source:

    Appl Environ Microbiol. 2011 Aug;77(15):5316-23. Epub 2011 Jun 3.

    Jefferson Adams
    Celiac.com 01/08/2014 - Push-back mounts against a controversial new report alleging that genetically engineered foods may trigger gluten sensitivity and celiac disease.
    In the first salvo, Celiac Disease Foundation CEO Marilyn Geller derided the report, published last week by the Institute for Responsible Technology (IRT), as merely "speculative."
    Then followed comments by leading plant geneticist, Dr. Wayne Parrott, professor of crop science at the University of Georgia, that the report relied on "a handful of deeply flawed"studies and ignored "more than 1,000 studies that have been published in refereed journals and which show that GM crops are as safe as their counterparts."
    According to Geller, no one has offered scientific evidence "for a GMO/celiac disease link that is supported by the CDF Medical Advisory Board.
    For their part, the authors of the IRT report admit that there is no data to prove that GMO consumption causes gluten sensitivity.
    However, they try to hedge slightly by claiming that more and more research shows that GMO consumption may worsen celiac symptoms or lead to gluten sensitivity. Here again, they offer no good data to support their claims.
    Source:
    FoodNavigator.com

    Jefferson Adams
    Celiac.com 05/12/2014 - Currently, researcher know almost nothing about the natural history and evolution of celiac disease in ancient populations.
    But, a set of recently unearthed bones from ancient Rome show signs of a struggle with celiac disease, and may help researchers to better understand the natural history and evolution of the condition.
    Researchers believe the bones are those of an 18 to 20-year old upper class Roman woman, who likely had celiac disease or gluten intolerance, as her skeleton reveals signs of malnutrition and osteoporosis and her attempts to manage it by changing her diet.
    DNA analysis has confirmed that the woman carried two copies of an immune system gene variant strongly associated with celiac disease. Although celiac disease can be influenced by numerous environmental factors, the gene variant is found in nearly all contemporary celiac populations.
    The combination of genetic risk factors and malnutrition in someone likely to have good access to nutritious food, make celiac disease a reasonable diagnosis, says Gabriele Scorrano, a biological anthropologist at the University of Rome Tor Vergata.
    An article about the study appears in Nature, and the study itself appears in the American Journal of Physical Anthropology.

  • Recent Articles

    Jefferson Adams
    Celiac.com 06/18/2018 - Celiac disease has been mainly associated with Caucasian populations in Northern Europe, and their descendants in other countries, but new scientific evidence is beginning to challenge that view. Still, the exact global prevalence of celiac disease remains unknown.  To get better data on that issue, a team of researchers recently conducted a comprehensive review and meta-analysis to get a reasonably accurate estimate the global prevalence of celiac disease. 
    The research team included P Singh, A Arora, TA Strand, DA Leffler, C Catassi, PH Green, CP Kelly, V Ahuja, and GK Makharia. They are variously affiliated with the Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Boston, Massachusetts; Lady Hardinge Medical College, New Delhi, India; Innlandet Hospital Trust, Lillehammer, Norway; Centre for International Health, University of Bergen, Bergen, Norway; Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Boston, Massachusetts; Gastroenterology Research and Development, Takeda Pharmaceuticals Inc, Cambridge, MA; Department of Pediatrics, Università Politecnica delle Marche, Ancona, Italy; Department of Medicine, Columbia University Medical Center, New York, New York; USA Celiac Disease Center, Columbia University Medical Center, New York, New York; and the Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India.
    For their review, the team searched Medline, PubMed, and EMBASE for the keywords ‘celiac disease,’ ‘celiac,’ ‘tissue transglutaminase antibody,’ ‘anti-endomysium antibody,’ ‘endomysial antibody,’ and ‘prevalence’ for studies published from January 1991 through March 2016. 
    The team cross-referenced each article with the words ‘Asia,’ ‘Europe,’ ‘Africa,’ ‘South America,’ ‘North America,’ and ‘Australia.’ They defined celiac diagnosis based on European Society of Pediatric Gastroenterology, Hepatology, and Nutrition guidelines. The team used 96 articles of 3,843 articles in their final analysis.
    Overall global prevalence of celiac disease was 1.4% in 275,818 individuals, based on positive blood tests for anti-tissue transglutaminase and/or anti-endomysial antibodies. The pooled global prevalence of biopsy-confirmed celiac disease was 0.7% in 138,792 individuals. That means that numerous people with celiac disease potentially remain undiagnosed.
    Rates of celiac disease were 0.4% in South America, 0.5% in Africa and North America, 0.6% in Asia, and 0.8% in Europe and Oceania; the prevalence was 0.6% in female vs 0.4% males. Celiac disease was significantly more common in children than adults.
    This systematic review and meta-analysis showed celiac disease to be reported worldwide. Blood test data shows celiac disease rate of 1.4%, while biopsy data shows 0.7%. The prevalence of celiac disease varies with sex, age, and location. 
    This review demonstrates a need for more comprehensive population-based studies of celiac disease in numerous countries.  The 1.4% rate indicates that there are 91.2 million people worldwide with celiac disease, and 3.9 million are in the U.S.A.
    Source:
    Clin Gastroenterol Hepatol. 2018 Jun;16(6):823-836.e2. doi: 10.1016/j.cgh.2017.06.037.

    Jefferson Adams
    Celiac.com 06/16/2018 - Summer is the time for chips and salsa. This fresh salsa recipe relies on cabbage, yes, cabbage, as a secret ingredient. The cabbage brings a delicious flavor and helps the salsa hold together nicely for scooping with your favorite chips. The result is a fresh, tasty salsa that goes great with guacamole.
    Ingredients:
    3 cups ripe fresh tomatoes, diced 1 cup shredded green cabbage ½ cup diced yellow onion ¼ cup chopped fresh cilantro 1 jalapeno, seeded 1 Serrano pepper, seeded 2 tablespoons lemon juice 2 tablespoons red wine vinegar 2 garlic cloves, minced salt to taste black pepper, to taste Directions:
    Purée all ingredients together in a blender.
    Cover and refrigerate for at least 1 hour. 
    Adjust seasoning with salt and pepper, as desired. 
    Serve is a bowl with tortilla chips and guacamole.

    Dr. Ron Hoggan, Ed.D.
    Celiac.com 06/15/2018 - There seems to be widespread agreement in the published medical research reports that stuttering is driven by abnormalities in the brain. Sometimes these are the result of brain injuries resulting from a stroke. Other types of brain injuries can also result in stuttering. Patients with Parkinson’s disease who were treated with stimulation of the subthalamic nucleus, an area of the brain that regulates some motor functions, experienced a return or worsening of stuttering that improved when the stimulation was turned off (1). Similarly, stroke has also been reported in association with acquired stuttering (2). While there are some reports of psychological mechanisms underlying stuttering, a majority of reports seem to favor altered brain morphology and/or function as the root of stuttering (3). Reports of structural differences between the brain hemispheres that are absent in those who do not stutter are also common (4). About 5% of children stutter, beginning sometime around age 3, during the phase of speech acquisition. However, about 75% of these cases resolve without intervention, before reaching their teens (5). Some cases of aphasia, a loss of speech production or understanding, have been reported in association with damage or changes to one or more of the language centers of the brain (6). Stuttering may sometimes arise from changes or damage to these same language centers (7). Thus, many stutterers have abnormalities in the same regions of the brain similar to those seen in aphasia.
    So how, you may ask, is all this related to gluten? As a starting point, one report from the medical literature identifies a patient who developed aphasia after admission for severe diarrhea. By the time celiac disease was diagnosed, he had completely lost his faculty of speech. However, his speech and normal bowel function gradually returned after beginning a gluten free diet (8). This finding was so controversial at the time of publication (1988) that the authors chose to remain anonymous. Nonetheless, it is a valuable clue that suggests gluten as a factor in compromised speech production. At about the same time (late 1980’s) reports of connections between untreated celiac disease and seizures/epilepsy were emerging in the medical literature (9).
    With the advent of the Internet a whole new field of anecdotal information was emerging, connecting a variety of neurological symptoms to celiac disease. While many medical practitioners and researchers were casting aspersions on these assertions, a select few chose to explore such claims using scientific research designs and methods. While connections between stuttering and gluten consumption seem to have been overlooked by the medical research community, there is a rich literature on the Internet that cries out for more structured investigation of this connection. Conversely, perhaps a publication bias of the peer review process excludes work that explores this connection.
    Whatever the reason that stuttering has not been reported in the medical literature in association with gluten ingestion, a number of personal disclosures and comments suggesting a connection between gluten and stuttering can be found on the Internet. Abid Hussain, in an article about food allergy and stuttering said: “The most common food allergy prevalent in stutterers is that of gluten which has been found to aggravate the stutter” (10). Similarly, Craig Forsythe posted an article that includes five cases of self-reporting individuals who believe that their stuttering is or was connected to gluten, one of whom also experiences stuttering from foods containing yeast (11). The same site contains one report of a stutterer who has had no relief despite following a gluten free diet for 20 years (11). Another stutterer, Jay88, reports the complete disappearance of her/his stammer on a gluten free diet (12). Doubtless there are many more such anecdotes to be found on the Internet* but we have to question them, exercising more skepticism than we might when reading similar claims in a peer reviewed scientific or medical journal.
    There are many reports in such journals connecting brain and neurological ailments with gluten, so it is not much of a stretch, on that basis alone, to suspect that stuttering may be a symptom of the gluten syndrome. Rodney Ford has even characterized celiac disease as an ailment that may begin through gluten-induced neurological damage (13) and Marios Hadjivassiliou and his group of neurologists and neurological investigators have devoted considerable time and effort to research that reveals gluten as an important factor in a majority of neurological diseases of unknown origin (14) which, as I have pointed out previously, includes most neurological ailments.
    My own experience with stuttering is limited. I stuttered as a child when I became nervous, upset, or self-conscious. Although I have been gluten free for many years, I haven’t noticed any impact on my inclination to stutter when upset. I don’t know if they are related, but I have also had challenges with speaking when distressed and I have noticed a substantial improvement in this area since removing gluten from my diet. Nonetheless, I have long wondered if there is a connection between gluten consumption and stuttering. Having done the research for this article, I would now encourage stutterers to try a gluten free diet for six months to see if it will reduce or eliminate their stutter. Meanwhile, I hope that some investigator out there will research this matter, publish her findings, and start the ball rolling toward getting some definitive answers to this question.
    Sources:
    1. Toft M, Dietrichs E. Aggravated stuttering following subthalamic deep brain stimulation in Parkinson’s disease--two cases. BMC Neurol. 2011 Apr 8;11:44.
    2. Tani T, Sakai Y. Stuttering after right cerebellar infarction: a case study. J Fluency Disord. 2010 Jun;35(2):141-5. Epub 2010 Mar 15.
    3. Lundgren K, Helm-Estabrooks N, Klein R. Stuttering Following Acquired Brain Damage: A Review of the Literature. J Neurolinguistics. 2010 Sep 1;23(5):447-454.
    4. Jäncke L, Hänggi J, Steinmetz H. Morphological brain differences between adult stutterers and non-stutterers. BMC Neurol. 2004 Dec 10;4(1):23.
    5. Kell CA, Neumann K, von Kriegstein K, Posenenske C, von Gudenberg AW, Euler H, Giraud AL. How the brain repairs stuttering. Brain. 2009 Oct;132(Pt 10):2747-60. Epub 2009 Aug 26.
    6. Galantucci S, Tartaglia MC, Wilson SM, Henry ML, Filippi M, Agosta F, Dronkers NF, Henry RG, Ogar JM, Miller BL, Gorno-Tempini ML. White matter damage in primary progressive aphasias: a diffusion tensor tractography study. Brain. 2011 Jun 11.
    7. Lundgren K, Helm-Estabrooks N, Klein R. Stuttering Following Acquired Brain Damage: A Review of the Literature. J Neurolinguistics. 2010 Sep 1;23(5):447-454.
    8. [No authors listed] Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 43-1988. A 52-year-old man with persistent watery diarrhea and aphasia. N Engl J Med. 1988 Oct 27;319(17):1139-48
    9. Molteni N, Bardella MT, Baldassarri AR, Bianchi PA. Celiac disease associated with epilepsy and intracranial calcifications: report of two patients. Am J Gastroenterol. 1988 Sep;83(9):992-4.
    10. http://ezinearticles.com/?Food-Allergy-and-Stuttering-Link&id=1235725 
    11. http://www.craig.copperleife.com/health/stuttering_allergies.htm 
    12. https://www.celiac.com/forums/topic/73362-any-help-is-appreciated/
    13. Ford RP. The gluten syndrome: a neurological disease. Med Hypotheses. 2009 Sep;73(3):438-40. Epub 2009 Apr 29.
    14. Hadjivassiliou M, Gibson A, Davies-Jones GA, Lobo AJ, Stephenson TJ, Milford-Ward A. Does cryptic gluten sensitivity play a part in neurological illness? Lancet. 1996 Feb 10;347(8998):369-71.

    Jefferson Adams
    Celiac.com 06/14/2018 - Refractory celiac disease type II (RCDII) is a rare complication of celiac disease that has high death rates. To diagnose RCDII, doctors identify a clonal population of phenotypically aberrant intraepithelial lymphocytes (IELs). 
    However, researchers really don’t have much data regarding the frequency and significance of clonal T cell receptor (TCR) gene rearrangements (TCR-GRs) in small bowel (SB) biopsies of patients without RCDII. Such data could provide useful comparison information for patients with RCDII, among other things.
    To that end, a research team recently set out to try to get some information about the frequency and importance of clonal T cell receptor (TCR) gene rearrangements (TCR-GRs) in small bowel (SB) biopsies of patients without RCDII. The research team included Shafinaz Hussein, Tatyana Gindin, Stephen M Lagana, Carolina Arguelles-Grande, Suneeta Krishnareddy, Bachir Alobeid, Suzanne K Lewis, Mahesh M Mansukhani, Peter H R Green, and Govind Bhagat.
    They are variously affiliated with the Department of Pathology and Cell Biology, and the Department of Medicine at the Celiac Disease Center, New York Presbyterian Hospital/Columbia University Medical Center, New York, USA. Their team analyzed results of TCR-GR analyses performed on SB biopsies at our institution over a 3-year period, which were obtained from eight active celiac disease, 172 celiac disease on gluten-free diet, 33 RCDI, and three RCDII patients and 14 patients without celiac disease. 
    Clonal TCR-GRs are not infrequent in cases lacking features of RCDII, while PCPs are frequent in all disease phases. TCR-GR results should be assessed in conjunction with immunophenotypic, histological and clinical findings for appropriate diagnosis and classification of RCD.
    The team divided the TCR-GR patterns into clonal, polyclonal and prominent clonal peaks (PCPs), and correlated these patterns with clinical and pathological features. In all, they detected clonal TCR-GR products in biopsies from 67% of patients with RCDII, 17% of patients with RCDI and 6% of patients with gluten-free diet. They found PCPs in all disease phases, but saw no significant difference in the TCR-GR patterns between the non-RCDII disease categories (p=0.39). 
    They also noted a higher frequency of surface CD3(−) IELs in cases with clonal TCR-GR, but the PCP pattern showed no associations with any clinical or pathological feature. 
    Repeat biopsy showed that the clonal or PCP pattern persisted for up to 2 years with no evidence of RCDII. The study indicates that better understanding of clonal T cell receptor gene rearrangements may help researchers improve refractory celiac diagnosis. 
    Source:
    Journal of Clinical Pathologyhttp://dx.doi.org/10.1136/jclinpath-2018-205023

    Jefferson Adams
    Celiac.com 06/13/2018 - There have been numerous reports that olmesartan, aka Benicar, seems to trigger sprue‐like enteropathy in many patients, but so far, studies have produced mixed results, and there really hasn’t been a rigorous study of the issue. A team of researchers recently set out to assess whether olmesartan is associated with a higher rate of enteropathy compared with other angiotensin II receptor blockers (ARBs).
    The research team included Y.‐H. Dong; Y. Jin; TN Tsacogianis; M He; PH Hsieh; and JJ Gagne. They are variously affiliated with the Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School in Boston, MA, USA; the Faculty of Pharmacy, School of Pharmaceutical Science at National Yang‐Ming University in Taipei, Taiwan; and the Department of Hepato‐Gastroenterology, Chi Mei Medical Center in Tainan, Taiwan.
    To get solid data on the issue, the team conducted a cohort study among ARB initiators in 5 US claims databases covering numerous health insurers. They used Cox regression models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for enteropathy‐related outcomes, including celiac disease, malabsorption, concomitant diagnoses of diarrhea and weight loss, and non‐infectious enteropathy. In all, they found nearly two million eligible patients. 
    They then assessed those patients and compared the results for olmesartan initiators to initiators of other ARBs after propensity score (PS) matching. They found unadjusted incidence rates of 0.82, 1.41, 1.66 and 29.20 per 1,000 person‐years for celiac disease, malabsorption, concomitant diagnoses of diarrhea and weight loss, and non‐infectious enteropathy respectively. 
    After PS matching comparing olmesartan to other ARBs, hazard ratios were 1.21 (95% CI, 1.05‐1.40), 1.00 (95% CI, 0.88‐1.13), 1.22 (95% CI, 1.10‐1.36) and 1.04 (95% CI, 1.01‐1.07) for each outcome. Patients aged 65 years and older showed greater hazard ratios for celiac disease, as did patients receiving treatment for more than 1 year, and patients receiving higher cumulative olmesartan doses.
    This is the first comprehensive multi‐database study to document a higher rate of enteropathy in olmesartan initiators as compared to initiators of other ARBs, though absolute rates were low for both groups.
    Source:
    Alimentary Pharmacology & Therapeutics