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    Live Fluorescence Imaging of Exogenous Enzyme Action in the Gastrointestinal Tract


    Jefferson Adams
    Image Caption: Photo: CC-timbrauhn

    Photo: CC-timbrauhnCeliac.com 09/12/2011 - Exogenous enzymes are enzymes that are created outside of the body. Doctors use exogenous enzymes, usually orally, to treat several diseases, such as pancreatic insufficiency and lactose intolerance.


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    Because these enzymes are protein-based, they can be inactivated and/or digested in the gastrointestinal (GI) tract.

    A research team recently established a convenient fluorescence-based test to measure the activity of therapeutic enzymes live and in real time in the GI tract.

    The research team included Gregor Fuhrmann and Jean-Christophe Leroux. They are affiliated with the Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences in Zurich, Switzerland.

    To establish proof of their principle, the team applied their assay to proline-specific endopeptidases (PEPs), a group of enzymes recently proposed as adjuvant therapy for celiac disease, which is a very common immunogenetic enteropathy.

    To do so, they took a short PEP-specific peptide sequence from larger immunotoxic sequences of gluten. They then labeled each sequence with a fluorescent dye and a corresponding quencher.

    Once the enzyme sequence split, they dequenched the fluorescence emission and then used an live imaging system to detect the result.

    The team then evaluated PEPs originating from Flavobacterium meningosepticum (FM) and Myxococcus xanthus (MX) after oral administration in rats.

    While MX PEP could not split the peptide in the stomach, FM PEP showed significant gastric activity reaching 40–60% of the maximal live signal intensity. However, both enzymes produced similar fluorescence signals in the small intestine.

    Using an antacid significantly enhanced MX PEP’s gastric activity due to increased pH and/or inhibition of stomach proteases. By using this simple method, the team was able to observe differences in the live performance of PEPs, which could not be identified under laboratory conditions.

    This imaging method could be used for live study other oral enzymes and may prove useful in improving current treatments.


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  • Related Articles

    Scott Adams
    Journal of Clinical Gastroenterology 2003; 36(3):219-221
    Celiac.com 03/28/2003 - A study by Antonio Tursi, M.D, et al, was recently conducted to evaluate the correlation between the degree of histologic intestinal damage in celiac patients and their level of positivity (serum value) to anti-tissue transglutaminase antibodies (anti-tTG). The study looked at 119 adult celiac patients who were diagnosed consecutively (47 men and 72 women; mean age, 28 years; range, 22-51 years), and were stratified for histologic damage according to Marsh classification. The final step was to compare their Marsh histologic intestinal damage classification with their anti-tTG serum values. Here are their results:


    Marsh I lesions were present in 13 patients (10.92%), Marsh II in 24 anti-tTG (20.16%), Marsh IIIa in 27 anti-tTG (22.68%), Marsh IIIb in 31 anti-tTG (26.05%) and Marsh IIIc in 24 anti-tTG (20.16%). Anti-tTG positivity was ranging from 1 of 13 anti-tTG (7.69%) in Marsh I lesions to 23 of 24 anti-tTG (95.83%) in Marsh IIIc lesions respectively (P
    The researchers conclude that the mean serum value in celiacs with severe enteropathy (Marsh IIIb-c lesions) was higher than in those with only slight enteropathy (Marsh I-IIIa). Further, serologic test results in the absence of histologic evaluation (biopsy) may "underestimate the real prevalence of celiac disease," thus delaying a proper diagnosis and putting patients at risk for a large variety of serious health problems.

    Jefferson Adams
    Celiac.com 03/22/2010 - The main cause for gluten intolerance continues to puzzle scientists, but pathogenesis theories include both genetic susceptibility and environmental triggers, like a virus or infection.
    For the first time, scientists working with the Academy of Finland’s Research Program on Nutrition, Food, and Health have found genes in the body that are associated both with the immune system and with the body's ability to properly digest gluten in the intestinal tract.
    Gluten intolerance arises from an autoimmune reaction in the small intestine to the gluten protein found in wheat, barley and rye. Academy Research Fellow Paivi Saavalainen, a veteran researcher in hereditary risk factors for gluten intolerance, says that "some of the genes we have identified are linked with human immune defense against viruses. This may indicate that virus infections may be connected in some way with the onset of gluten intolerance.”
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    Since the early 1980s, the percentage of Finns with gluten intolerance has risen from about 1 percent of adults to about 2 percent, according to Professor Markku Mäki, head of a research project in the Academy of Finland's Research Program on Nutrition, Food and Health.
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    Source:
    Academy of Finland
     

    Tina Turbin
    Celiac.com 06/28/2010 - Studies on the genetic links to celiac disease are leading to more research which may lead to new and more effective ways to treat the disease, an exciting  prospect for celiacs who may want to enjoy some gluten now and then.  Celiac disease is an autoimmune disease, the source of this being gluten, a protein found in wheat, rye, and barley, affecting about 1% of the population and 300 million Americans. The disease attacks the villi,the finger-like structure which line the small intestine, leading to stomach troubles and malabsorption of nutrients. Left untreated, it can cause severe health conditions and complications such as anemia, osteoporosis, miscarriage, and even cancer.
    David van Heel, a gastrointestinal genetics professor at Barts and The London School of Medicine and Dentistry, headed a group of researchers from around the world who studied the genetic maps of more than 9,400 celiacs.
    British researchers have found what they term “substantial” evidence that the genes which are connected with celiac disease are also linked to other autoimmune disease such as rheumatoid arthritis. As a result, scientists are able to understand how the genetic risk factors for the disease operate—by changing the number of immune system genes that cells make. Furthermore, it is now understood that there are “hundreds” of genetic risk factors, which means that scientists should be able to “have a good guess at nearly half of the genetic risk at present," van Heel wrote in the Nature Genetics journal in his published study.
    Why is that only 3% of celiac Americans have been properly diagnosed? It’s likely that they or their doctors haven’t even heard of the disease. Research on celiac disease in the U.S. depends completely on the generosity of benefactors for its funding. Without charitable donations, there would be no way to continue this research and the efforts to raise awareness. Out of the estimated fifty autoimmune diseases that have been discovered by doctors, it is the only one for which research isn’t supported by the U.S. government.
    I spent years running in circles with doctors who had no clue as to the cause of my painful symptoms, which finally drove me to research my symptoms on my own. I’m grateful lto have been properly diagnosed, but managing the gluten-free diet can be a challenge. The prospect of a pill to offset genetic factors will appeal to many celiacs like myself. Although the treatment for celiac disease is simple, it calls for a lot of work and can be disheartening at times, requiring a total lifestyle change and a lot of home cooking.
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    Source: Reuters

    Jefferson Adams
    Celiac.com 06/03/2015 - Although dietary gluten is the trigger for celiac disease, risk is strongly influenced by genetic variation in the major histocompatibility complex (MHC) region.
    A team of researchers recently set out to fine map the MHC association signal to identify additional celiac disease risk factors independent of the HLA-DQA1 and HLA-DQB1 alleles. The researchers included J. Gutierrez-Achury, A. Zhernakova, S.L. Pulit, G. Trynka, K.A. Hunt, J. Romanos, S. Raychaudhuri, D.A. van Heel, C. Wijmenga, and P.I. de Bakker.
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    Research team members are variously affiliated with the Department of Genetics, University Medical Center, University of Groningen, Groningen, the Netherlands, the Department of Medical Genetics at the Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands, the Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK, the Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA, the Division of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA, the Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA, the Arthritis Research UK Epidemiology Unit, Centre for Musculoskeletal Research, Institute of Inflammation and Repair, University of Manchester, Manchester, UK, the Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands, and with the Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.
    Source:
    Nat Genet. 2015 Apr 20. doi: 10.1038/ng.3268.

  • Recent Articles

    Jefferson Adams
    Celiac.com 06/19/2018 - Could baking soda help reduce the inflammation and damage caused by autoimmune diseases like rheumatoid arthritis, and celiac disease? Scientists at the Medical College of Georgia at Augusta University say that a daily dose of baking soda may in fact help reduce inflammation and damage caused by autoimmune diseases like rheumatoid arthritis, and celiac disease.
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    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. 
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    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.
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    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