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1.  Latest In vitro and in vivo models of celiac disease 
Expert opinion on drug discovery  2013;8(4):445-457.
Introduction
Currently, the only treatment for celiac disease is a gluten free diet, and there is an increased desire for alternative therapies. In vitro and in vivo models of celiac disease have been generated in order to better understand the pathogenesis of celiac disease, and this review will discuss these models as well as the testing of alternative therapies using these models.
Areas Covered
The research discussed describes the different in vitro and in vivo models of celiac disease that currently exist and how they have contributed to our understanding of how gluten can stimulate both innate and adaptive immune responses in celiac patients. We also provide a summary on the alternative therapies that have been tested with these models and discuss whether subsequent clinical trials were done based on these tests done with these models of celiac disease.
Expert Opinion
Only a few of the alternative therapies that have been tested with animal models have gone on to clinical trials; however, those that did go on to clinical trial have provided promising results from a safety standpoint. Further trials are required to determine if some of these therapies may serve as an effective adjunct to a gluten free diet to alleviate the adverse affects associated with accidental gluten exposure. A “magic-bullet” approach may not be the answer to celiac disease, but possibly a future cocktail of these different therapeutics may allow celiac patients to consume an unrestricted diet.
doi:10.1517/17460441.2013.761203
PMCID: PMC3605231  PMID: 23293929
celiac; gliadin; gluten; in vitro; in vivo; model; monkey; mouse; nondietary; rat; T cell; therapy; treatment
2.  LIVER INVOLVEMENT IN CELIAC DISEASE 
Minerva medica  2008;99(6):595-604.
Celiac disease is a chronic immune-mediated multisystem disorder that may affect several organs. Liver abnormalities are common extraintestinal manifestations of celiac disease. Isolated hypertransaminasemia, with mild or nonspecific histologic changes in the liver biopsy, also known as “celiac hepatitis”, is the most frequent presentation of liver injury in celiac disease. Both, histologic changes and liver enzymes reverse to normal after treatment with a gluten-free diet in most patients. Celiac disease may also be associated with severe forms of liver disease and/or coexist with other chronic liver disorders (i.e., autoimmune liver diseases). The mechanisms underlying liver injury in celiac disease are poorly understood. Predisposition to autoimmunity by shared genetic factors (i.e., HLA genes) as well as the systemic effects of abnormal intestinal permeability, cytokines, autoantibodies, and/or other yet undefined biologic mediators induced by gluten exposure in susceptible persons may play a pathogenic role. The aims of this article are 1) to review the spectrum of liver injury related to celiac disease and 2) to understand the clinical implications of celiac disease in patients with chronic liver disorders.
PMCID: PMC3941070  PMID: 19034257
autoimmune; hepatitis; cirrhosis; serology; liver
3.  Review Article: Celiac Disease, New Approaches to Therapy 
STRUCTURED SUMMARY
Background
Celiac disease is managed by life-long gluten withdrawal from the diet. However strict adherence to a gluten-free diet is difficult and is not always effective. Novel therapeutic approaches are needed to supplement or even replace the dietary treatment.
Aims
To review recent advances in new therapeutic options for celiac disease.
Methods
A literature search was performed on MEDLINE, EMBASE, Web of Science, Scopus, DDW.org and ClinicalTrial.gov for English articles and abstracts. The search terms used include but not limited to “Celiac disease”, “new”, “novel”, Advances”, “alternatives” and “Drug therapy”. The cited articles were selected based on the relevancy to the review objective.
Results
Several new therapeutic approaches for celiac disease are currently under development by targeting its underlying pathogenesis. Alternative therapies range from reproduction of harmless wheat strains to immunomodulatory approaches. Some of these therapies such as enzymatic cleavage of gluten and permeability inhibitors have shown promise in clinical studies.
Conclusion
Gluten-free diet is still the only practical treatment for patients with celiac disease. Novel strategies provide promise of alternative adjunctive approaches to diet restriction alone for patients with this disorder.
doi:10.1111/j.1365-2036.2012.05013.x
PMCID: PMC3912561  PMID: 22324389
gluten; zonulin; inflammation; malabsorption
4.  Autoimmune Enteropathy: A Review and Update of Clinical Management 
Current gastroenterology reports  2012;14(5):380-385.
Autoimmune Enteropathy (AIE) is a rare condition characterized by intractable diarrhea, histologic changes on small intestinal biopsy, failed response to dietary manipulation that also may present with extra-intestinal manifestations. In many patients, immunosuppressive therapies are necessary. Although AIE is more common in infants, adult involvement has also been documented. Much of what is known about AIE has been gathered from case reports and small case series; therefore more research in this evolving field is needed. IPEX (Immunodysregulation Polyendocrinopathy Enteropathy X-linked Syndrome) or APECED (Autoimmune Phenomena, Polyendocrinopathy, Candidiasis, and Ectodermal Dystrophy) are systemic forms of AIE.
doi:10.1007/s11894-012-0276-2
PMCID: PMC3912565  PMID: 22810979
Autoimmune Enteropathy (AIE); Immunodysregulation Polyendocrinopathy Enteropathy X-linked Syndrome (IPEX); Autoimmune Phenomena Polyendocrinopathy Candidiasis and Ectodermal Dystrophy (APECED); intractable diarrhea
5.  Mucosal Healing and Mortality in Celiac Disease 
BACKGROUND AND OBJECTIVES
Celiac disease (CD), characterized by the presence of villous atrophy (VA) in the small intestine, is associated with increased mortality, but it is unknown if this excess mortality is influenced by mucosal recovery. We examined overall mortality according to mucosal recovery in CD.
METHODS
Through biopsy reports from all pathology departments (n=28) in Sweden we identified 7,648 individuals with CD (defined as VA) who had undergone a follow-up biopsy within 5 years following diagnosis. We then used Cox regression to examine overall mortality according mucosal recovery in the follow-up biopsy (persistence of VA vs. recovery).
RESULTS
The mean age of CD diagnosis was 28.4, 63% were female, and the median follow-up after diagnosis was 11.5 years. Of the 7,648 patients, persistent VA was present in 3,317 (43%). There were 606 (8%) deaths. Patients with persistent VA were not at increased risk of death compared to those with mucosal healing (Hazard Ratio 1.01; 95% Confidence Interval 0.86-1.19). Mortality was not increased in children with persistent VA (HR 1.09 95% CI 0.37-3.16) or adults (HR 1.00 95% CI 0.85-1.18), including adults older than age 50 years (HR 0.96 95% CI 0.80-1.14).
CONCLUSION
Persistent VA was not associated with increased mortality in CD in this population followed for a median of 11.5 years. While a follow-up biopsy will determine if there is improvement in histology and allow detection of refractory disease in symptomatic patients, our study suggests that early routine follow up biopsies performed within 5 years does not predict long-term mortality risk.
doi:10.1111/apt.12164
PMCID: PMC3566869  PMID: 23190299
coeliac; death; inflammation; serial biopsy (British spelling of coeliac)
6.  Does haemochromatosis predispose to coeliac disease? A study of 29,096 coeliac disease patients 
Background and aim
Case reports suggest an association between hereditary haemochromatosis (HH) and coeliac disease (CD), but estimates of association are lacking. We estimated the association between HH and CD in a population-based study.
Materials and methods
Case-control study. We identified 29,096 individuals with biopsy-verified CD (equal to villous atrophy, Marsh stage III) through biopsy reports from all 28 pathology departments in Sweden. We then investigated the risk of a clinical diagnosis of HH in CD and in 144,522 controls matched for age, sex, county and calendar year. Conditional logistic regression was used to calculate odds ratios (ORs) for CD in patients with HH.
Results
HH was seen in 30 patients with CD and in 60 matched controls. HH was hence associated with an increased risk of CD (OR=2.30; 95%CI=1.53–3.25). Restricting HH to individuals with at least 2 records of HH, the OR for CD was 2.54 (95%CI=1.57–4.11), with a similar risk estimate when we only looked at HH diagnosed before CD (and matched date in controls) (OR=2.64; 95%CI=1.24–5.60).
Conclusion
HH seems to be associated with an increased risk of CD.
doi:10.3109/00365521.2012.749511
PMCID: PMC3576703  PMID: 23256862
autoimmunity; celiac; coeliac; hemochromatosis; haemochromatosis; inflammation
7.  Antibody repertoire profiling using bacterial display identifies reactivity signatures of celiac disease 
Analytical chemistry  2012;85(2):1215-1222.
A general strategy to identify serum antibody specificities associated with a given disease state, and peptide reagents for their detection was developed using bacterial display peptide libraries and multiparameter flow cytometry (MPFC). Using sera from patients with celiac disease (CD) (n = 45) or healthy subjects (n = 40), bacterial display libraries were screened for peptides that react specifically with antibodies from CD patients and not those from healthy patients. The libraries were screened for peptides that simultaneously cross-react with CD patient antibodies present in two separate patient groups labeled with spectrally distinct fluorophores, but do not react with unlabeled non-CD antibodies, thus affording a quantitative separation. A panel of six unique peptide sequences yielded 85% sensitivity and 91% specificity (AUC = 0.91) on a set of 60 samples not used for discovery, using leave-one-out cross-validation (LOOCV). Individual peptides were dissimilar with known CD specific antigens tissue transglutaminase (tTG) and deamidated gliadin, and classifier accuracy was independent of anti-tTG antibody titer. These results demonstrate that bacterial display/MPFC provides a highly effective tool for the unbiased discovery of disease-associated antibody specificities and peptide reagents for their detection that may have broad utility for diagnostic development.
doi:10.1021/ac303201d
PMCID: PMC3903178  PMID: 23234559
serum antibody; diagnostic; peptide
9.  Celiac disease: Diagnosis of celiac disease in pediatric patients 
Children and adolescents with untreated celiac disease display disease-related, histological alterations in the duodenal bulb, according to a new study. In 16 of the 665 patients enrolled in the study, lesions were confined to the duodenal bulb.
doi:10.1038/nrgastro.2009.58
PMCID: PMC3896877  PMID: 19404264
10.  The Oslo definitions for coeliac disease and related terms 
Gut  2012;62(1):43-52.
Background
The literature suggests a lack of consensus on the use of terms related to coeliac disease (CD) and gluten.
Methods
A multi-disciplinary task force of 16 physicians from 7 countries used the electronic database PubMed to review the literature with regards to CD-related terms up to January 2011. Teams of physicians then suggested a definition for each term, followed by feedback of these definitions through a web survey on definitions, discussions during a meeting in Oslo, and phone conferences. We evaluated the following terms (in alphabetical order): Coeliac disease and the following descriptors of CD: asymptomatic, atypical, classical, latent, non-classical, overt, paediatric classical, potential, refractory, silent, subclinical, symptomatic, typical, CD serology, CD autoimmunity, genetically at risk of CD, dermatitis herpetiformis, gluten, gluten ataxia, gluten intolerance, gluten sensitivity, and gliadin-specific antibodies.
Results
CD was defined as “a chronic small intestinal immune-mediated enteropathy precipitated by exposure to dietary gluten in genetically predisposed individuals”. Classical CD was defined as “CD presenting with signs and symptoms of malabsorption. Diarrhoea, steatorrhoea, weight loss or growth failure is required.” We suggest that “gluten-related disorders” is the umbrella term for all diseases triggered by gluten and that the term gluten intolerance is not to be used. Other definitions are presented in the paper.
Conclusion
This paper presents the Oslo definitions for CD-related terms.
doi:10.1136/gutjnl-2011-301346
PMCID: PMC3440559  PMID: 22345659
adult; autoimmunity; child; coeliac; gluten; sensitivity; intolerance
11.  Season of Birth in a Nationwide Cohort of Coeliac Disease Patients 
Background and objective
Genetic factors alone cannot explain the risk of developing coeliac disease (CD). Children born in summer months are likely to be weaned and introduced to gluten during winter when viral infections are more frequent. Earlier studies on birth season and CD are limited in sample size and results are contradictory.
Method
Case-control study. We used biopsy reports from all 28 Swedish pathology departments to identify individuals with CD, defined as small intestinal villous atrophy (n=29,096). The government agency Statistics Sweden then identified 144,522 controls matched for gender, age, calendar year and county. Through conditional logistic regression we examined the association between summer birth (March-August) and later CD diagnosis (outcome measure).
Results
Some 54.10% of individuals with CD vs. 52.75% of controls were born in the summer months. Summer birth was hence associated with a small increased risk of later CD (Odds ratio: 1.06; 95%CI=1.03–1.08; p<0.0001). Stratifying CD patients according to age at diagnosis, we found the highest OR in those diagnosed before age 2 years (OR=1.17; 95%CI=1.10–1.26), while summer birth was not associated with a CD diagnosis in later childhood (age 2–18 years: OR=1.02; 95%CI=0.97–1.08), but had a marginal effect on the risk of CD in adulthood (age ≥18years: OR=1.04; 95%CI=1.01–1.07).
Conclusions
In this study, summer birth was associated with an increased risk of later CD, but the excess risk was small, and general infectious disease exposure early in life is unlikely to be a major cause of CD.
doi:10.1136/archdischild-2012-302360
PMCID: PMC3560933  PMID: 23172784
celiac; coeliac; epidemiology; risk factors; seasons; viral infection
12.  Low Incidence of Spontaneous Type 1 Diabetes in Non-Obese Diabetic Mice Raised on Gluten-Free Diets Is Associated with Changes in the Intestinal Microbiome 
PLoS ONE  2013;8(11):e78687.
Human and animal studies strongly suggest that dietary gluten could play a causal role in the etiopathogenesis of type 1 diabetes (T1D). However, the mechanisms have not been elucidated. Recent reports indicate that the intestinal microbiome has a major influence on the incidence of T1D. Since diet is known to shape the composition of the intestinal microbiome, we investigated using non-obese diabetic (NOD) mice whether changes in the intestinal microbiome could be attributed to the pro- and anti-diabetogenic effects of gluten-containing and gluten-free diets, respectively. NOD mice were raised on gluten-containing chows (GCC) or gluten-free chows (GFC). The incidence of diabetes was determined by monitoring blood glucose levels biweekly using a glucometer. Intestinal microbiome composition was analyzed by sequencing 16S rRNA amplicons derived from fecal samples. First of all, GCC-fed NOD mice had the expected high incidence of hyperglycemia whereas NOD mice fed with a GFC had significantly reduced incidence of hyperglycemia. Secondly, when the fecal microbiomes were compared, Bifidobacterium, Tannerella, and Barnesiella species were increased (p = 0.03, 0.02, and 0.02, respectively) in the microbiome of GCC mice, where as Akkermansia species was increased (p = 0.02) in the intestinal microbiomes of NOD mice fed GFC. Thirdly, both of the gluten-free chows that were evaluated, either egg white based (EW-GFC) or casein based (C-GFC), significantly reduced the incidence of hyperglycemia. Interestingly, the gut microbiome from EW-GFC mice was similar to C-GFC mice. Finally, adding back gluten to the gluten-free diet reversed its anti-diabetogenic effect, reduced Akkermansia species and increased Bifidobacterium, Tannerella, and Barnesiella suggesting that the presence of gluten is directly responsible for the pro-diabetogenic effects of diets and it determines the gut microflora. Our novel study thus suggests that dietary gluten could modulate the incidence of T1D by changing the gut microbiome.
doi:10.1371/journal.pone.0078687
PMCID: PMC3827256  PMID: 24236037
13.  Happiness and Depression in Adolescence after Maternal Smoking during Pregnancy: Birth Cohort Study 
PLoS ONE  2013;8(11):e80370.
Background
Prenatal cigarette smoke exposure may have adverse psychological effects on offspring. The objective was to assess the association between parental smoking during pregnancy and offspring happiness at age 18, as well as depression.
Methodology
Participants were part of a birth cohort study in Pelotas, Brazil (5,249 participants). Happiness was measured by the Subjective Happiness Scale, a Likert-like scale with four questions generating a score from 1 to 7, with ≥ 6 indicating "happiness". Depression was measured using the Mini International Psychiatric Interview.
​Results
About one third of mothers reported having smoked during pregnancy and 4.6% reported smoking 20 or more cigarettes a day. The prevalence of happiness was 32.2% (95% CI 30.8; 33.7), depression 6.8% (95% CI 6.1; 7.6), and simultaneous happiness and depression less than 1%. The prevalence of offspring happiness decreased as smoking in pregnancy increased, even after control for confounding variables, showing an OR = 0.79 [95% CI 0.55; 1.13]. The opposite happened to depression; the prevalence of offspring depression increased as smoking in pregnancy increased (<20 cigarettes/day OR = 1.38 [95% CI 1.03; 1.84] and ≥20 cigarettes/day OR = 2.11[95% CI 1.31; 3.40]. Smoking by the partner was associated with decreased offspring happiness after adjustment for confounders, but did no show association with offspring depression.
Conclusions
Offspring were less likely to be happy and more likely to be depressed if their mother smoked during pregnancy, and less likely to be happy if their father smoked during mother’s pregnancy. Although we can not affirm that this is a “causal pathway”, public policies to reduce smoking in pregnancy could improve the health of the offspring in the short and long term.
doi:10.1371/journal.pone.0080370
PMCID: PMC3827230  PMID: 24265817
14.  Bugs & us: The role of the gut in autoimmunity 
Rheumatoid arthritis (RA) is a multifactorial disease and requires interaction between genetic and environmental factors for predisposition. The presence of bacterial DNA of the gut residing commensals in synovium as well as dysbiosis of certain commensal bacteria in faecal samples of RA patients as compared to controls suggest a significant role of the gut flora in pathogenesis of RA. The gut commensals are involved in host immune development and function suggesting they might be critical epigenetic factors modifying autoimmune diseases like RA. This raises the question if gut-derived commensal can be exploited to generate a biomarker profile along with genetic factors to define individuals at risk. Genomic wide association studies have confirmed the HLA (human leukocyte antigen) class II genes as the strongest risk factor for predisposition to RA. HLA-DQ8 and DRB1*0401 molecules predispose to develop arthritis while DRB1*0402 provides protection. Interaction between host genetic factors like major histocompatibility complex (MHC) and gut microbiota and its impact on the development of RA is difficult to study in humans due to high variability in the genetic factors and diet. Animal models provide a means to study the molecular basis of pathogenesis thereby providing a basis for developing therapeutic strategies. Using transgenic mice expressing RA-associated and resistant HLA genes, we have developed a collagen-induced arthritis (CIA) model that shares similarities with human disease in sex-bias, autoantibody profile and phenotype. Studies in transgenic mice suggest that arthritis-susceptibility may be associated with dysbiosis in the gut microbiome. Studies in animal models underscore the impact of the gut flora in extra-intestinal diseases. Exploring the role of gut microbes will significantly advance our understanding of RA pathogenesis and may further help develop strategies for mucosal modulation of RA.
PMCID: PMC3928703  PMID: 24434325
Autoimmunity; CIA model; gut; microbiome; microbiota; rheumatoid arthritis; type 1 diabetes
15.  Celiac Disease – Advances in Treatment via Gluten Modification 
Celiac Disease (CD) is an autoimmune enteropathy which occurs in genetically susceptible individuals carrying the prerequisite genetic markers HLA DQ2 or DQ8. These genetic markers are present in approximately 30% of the population, and the worldwide prevalence of CD is estimated to be approximately 1-2%. Currently a gluten-free diet is the only treatment for CD, but novel therapies aimed at gluten modification are underway. This review will discuss gluten based therapies including wheat alternatives and wheat selection, enzymatic alteration of wheat, oral enzyme supplements, and polymeric binders as exciting new therapies for treatment of Celiac Disease.
doi:10.1016/j.cgh.2012.06.005
PMCID: PMC3788609  PMID: 22728383
16.  Patients with Celiac Disease Have an Increased Risk for Pancreatitis 
BACKGROUND & AIMS
Patients with celiac disease have been reported to be at increased risk for pancreatitis and pancreatic insufficiency, but the risk might have been overestimated because of patient selection and limited numbers of patients for analysis. Furthermore, no distinction has been made between patients with gallstone-related and non gallstone-related pancreatitis. We performed a nationwide study to determine the risk for any pancreatitis or subtype of pancreatitis among patients with biopsy-verified celiac disease.
METHODS
We analyzed data from patients in Sweden with celiac disease (n=28,908), identified based on small intestinal biopsy records from 28 pathology departments (those with villous atrophy, Marsh 3). Biopsies were performed from 1969 to 2008 and biopsy report data were collected from 2006 to 2008. Patients with pancreatitis were identified based on diagnostic codes in the Swedish Patient Register and records of pancreatic enzyme use in the Swedish Prescribed Drug Register. Data were matched with those from 143,746 individuals in the general population; Cox regression was used to estimate hazard ratios (HRs) for pancreatitis.
RESULTS
We identified 406 individuals with celiac disease who were later diagnosed with pancreatitis (and 143 with expected pancreatitis) (HR=2.85; 95% confidence interval [CI], 2.53–3.21). The absolute risk of any pancreatitis among patients with celiac disease was 126/100,000 person-years with an excess risk of 81/100,000 person-years. The HR for gallstone-related acute pancreatitis was 1.59 (95% CI, 1.06–2.40), for non-gallstone-related acute pancreatitis was 1.86 (1.52–2.26), for chronic pancreatitis was 3.33 (95% CI, 2.33–4.76), and for supplementation with pancreatic enzymes was 5.34 (95% CI, 2.99–9.53). The risk of any pancreatitis within 5 years of diagnosis was 2.76 (95% CI, 2.36–3.22).
CONCLUSIONS
Based on an analysis of medical records in Sweden, patients with celiac disease were at an almost 3-fold increase in risk of developing pancreatitis.
doi:10.1016/j.cgh.2012.06.023
PMCID: PMC3494459  PMID: 22801059
Coeliac Disease; Celiac Disease; Cohort study; Inflammation; Pancreatitis; Epidemiology; retrospective analysis; gluten intolerance; complication
17.  Diarrhoea due to small bowel diseases 
Small intestinal diseases are a common, though often overlooked cause of diarrhoeal illness. Fully 1% of the Caucasian population are affected by coeliac disease and a substantial portion of children living in poverty in the developing world are affected by environmental enteropathy. These are but two examples of the many diseases that cause mucosal injury to the primary digestive and absorptive organ in our body. While diarrhoea may be a common, though not universally seen symptom of small bowel mucosal disease, the consequent malabsorption can lead to substantial malnutrition and nutrient deficiencies. The small intestine, unlike the colon, has been relatively inaccessible, and systematic evaluation is often necessary to identify and treat small intestinal mucosal diseases that lead to diarrhoea. Immunodeficiency states, including HIV enteropathy, adult autoimmune enteropathy, drug-associated enteropathy, and tropical sprue continue to occur and require specific therapy. All patients with severe diarrhoea or diarrhoea associated with features suggestive of malabsorption may have a disease of the small intestinal mucosa that requires careful evaluation and targeted management.
doi:10.1016/j.bpg.2012.11.013
PMCID: PMC3621726  PMID: 23384804
Autoimmune enteropathy; Coeliac disease; HIV enteropathy; Malabsorption; Tropical sprue steatorrhoea
18.  The role of HLA-DQ8 β57 polymorphism in the anti-gluten T-cell response in coeliac disease 
Nature  2008;456(7221):534-538.
Major histocompatibility complex (MHC) class II alleles HLA-DQ8 and the mouse homologue I-Ag7 lacking a canonical aspartic acid residue at position β57 are associated with coeliac disease1,2 and type I diabetes3,4. However, the role of this single polymorphism in disease initiation and progression remains poorly understood. The lack of Asp 57 creates a positively charged P9 pocket, which confers a preference for negatively charged peptides. Gluten lacks such peptides, but tissue transglutaminase (TG2) introduces negatively charged residues at defined positions into gluten T-cell epitopes by deamidating specific glutamine residues5,6 on the basis of their spacing to proline residues7. The commonly accepted model, proposing that HLA-DQ8 simply favours binding of negatively charged peptides, does not take into account the fact that TG2 requires inflammation for activation8 and that T-cell responses against native gluten peptides are found9,10, particularly in children11. Here we show that β57 polymorphism promotes the recruitment of T-cell receptors bearing a negative signature charge in the complementary determining region 3β (CDR3β) during the response against native gluten peptides presented by HLA-DQ8 in coeliac disease. These T cells showed a crossreactive and heteroclitic (stronger) response to deamidated gluten peptides. Furthermore, gluten peptide deamidation extended the T-cell-receptor repertoire by relieving the requirement for a charged residue in CDR3β. Thus, the lack of a negative charge at position β57 in MHC class II was met by negatively charged residues in the T-cell receptor or in the peptide, the combination of which might explain the role of HLA-DQ8 in amplifying the T-cell response against dietary gluten.
doi:10.1038/nature07524
PMCID: PMC3784325  PMID: 19037317
19.  Crime and violence in Brazil: Systematic review of time trends, prevalence rates and risk factors☆ 
Aggression and Violent Behavior  2013;18(5):471-483.
Between 1980 and 2010 there were 1 million homicides in Brazil. Dramatic increases in homicide rates followed rises in inequality, more young men in the population, greater availability of firearms, and increased drug use. Nevertheless, disarmament legislation may have helped reduce homicide rates in recent years. Despite its very high rate of lethal violence, Brazil appears to have similar levels of general criminal victimization as several other Latin American and North American countries. Brazil has lower rates of drug use compared to other countries such as the United States, but the prevalence of youth drug use in Brazil has increased substantially in recent years. Since 1990, the growth of the Brazilian prison population has been enormous, resulting in the fourth largest prison population in the world. Through a systematic review of the literature, we identified 10 studies assessing the prevalence of self-reported offending in Brazil and 9 studies examining risk factors. Levels of self-reported offending seem quite high among school students in Brazil. Individual and family-level risk factors identified in Brazil are very similar to those found in high-income countries.
Highlights
•Between 1980–2010 the Brazilian homicide rate rose to one of the highest worldwide.•Levels of non-lethal victimization in Brazil seem similar to other American nations.•Rates of self-reported offending are quite high among school children in Brazil.•Individual and family risk factors are similar to those in high-income countries.•More systematic official and self-report crime data collection is needed in Brazil.
doi:10.1016/j.avb.2013.07.003
PMCID: PMC3763365  PMID: 24027422
Crime; Violence; Systematic review; Prevalence; Risk factors; Middle-income country
20.  The Need for International Terminology and Definitions for Texture-Modified Foods and Thickened Liquids Used in Dysphagia Management: Foundations of a Global Initiative 
Conservative estimates suggest that dysphagia (difficulty swallowing) affects approximately 8 % of the world’s population. Dysphagia is associated with malnutrition, dehydration, chest infection and potentially death. While promising treatments are being developed to improve function, the modification of food texture and liquid thickness has become a cornerstone of dysphagia management. Foods are chopped, mashed or puréed to compensate for chewing difficulties or fatigue, improve swallowing safety and avoid asphyxiation. Liquids are typically thickened to slow their speed of transit through the oral and pharyngeal phases of swallowing, to avoid aspiration of material into the airway and improve transit to the esophagus. Food texture and liquid modification for dysphagia management occurs throughout the world. However, the names, the number of levels of modification and characteristics vary within and across countries. Multiple labels increase the risk to patient safety. National standardization of terminology and definitions has been promoted as a means to improve patient safety and inter-professional communication. This article documents the need for international standardized terminology and definitions for texture-modified foods and liquids for individuals with dysphagia. Furthermore, it documents the research plan and foundations of a global initiative dedicated to this purpose.
doi:10.1007/s40141-013-0024-z
PMCID: PMC3873065  PMID: 24392282
Dysphagia; Deglutition; Deglutition disorders; Thickened liquids; Texture-modified food; Diet
21.  Patients with Celiac Disease Are Not Followed Adequately 
Background & Aims
Adherence to a gluten-free diet is the only effective treatment for celiac disease. It has been recommended that patients be followed, make regular visits to the clinic, and undergo serologic analysis for markers of celiac disease, although a follow-up procedure has not been standardized. We determined how many patients with celiac disease are actually followed.
Methods
We collected data on 122 patients with biopsy-proven celiac disease, diagnosed between 1996 and 2006 in Olmsted County, Minnesota (70% women, median age of 42 years) for whom complete medical records and verification of residency were available. We determined the frequency at which patients received follow-up examinations, from 6 months to 5 years after diagnosis. The Kaplan-Meier method was used to estimate event rates at 1 and 5 year(s). Patients were classified according to categories of follow-up procedures recommended by the American Gastroenterology Association (AGA).
Results
We estimated that by 1 and 5 year(s) after diagnosis with celiac disease, 41.0% and 88.7% of the patients had follow-up visits, 33.6% and 79.8% were assessed for compliance with a gluten-free diet, 3.3% and 15.8% met with a registered dietitian, 2.5% and 18.1% had an additional intestinal biopsy, and 22.1% and 65.6% received serologic testing for markers of celiac disease. Among 113 patients (93%) who were followed for more than 4 years, only 35% received follow-up analyses that were consistent with AGA recommendations.
Conclusions
Patients with celiac disease are not followed consistently. Follow-up examinations are often inadequate and do not follow AGA recommendations. Improving follow-up strategies for patients with celiac disease could improve management of this disease.
doi:10.1016/j.cgh.2012.05.007
PMCID: PMC3402703  PMID: 22610009
food allergy; therapy; long-term; assessment
22.  The Incidence and Risk of Celiac Disease in a Healthy US Adult Population 
OBJECTIVES
Celiac disease (CD) is an increasingly common disease that may affect as many as 1% of the North American population. Recent population-based data suggest a substantial increase in the prevalence of CD over the last several decades. Several factors are hypothesized as possible disease triggers including intercurrent illnesses, such as gastroenteritis, surgeries, and trauma. We used the active duty US military, a unique healthy worker population with essentially complete medical diagnostic coding, as an opportunity to describe trends in CD and deployment-related risk factors.
METHODS
Using electronic medical encounter data (1999–2008) on active duty US military (over 13.7 million person-years), a matched, nested case–control study describing the epidemiology and risk determinants of CD (based on ≥2 ICD-9 medical encounters) was conducted. Incidence and duration of CD-related medical care were estimated, and conditional logistic regression was utilized to evaluate CD risk following infectious gastroenteritis (IGE) occurring within 3 years before CD diagnosis while controlling for other risk factors.
RESULTS
A total of 455 incident cases of CD were identified and age, gender, and time matched to 1,820 controls. The incidence of CD increased five-fold from 1.3 per 100,000 in 1999 to 6.5 per 100,000 in 2008, with the highest rates of increase among those over 34 years of age (average annual increase of 0.8 cases per 100,000). A total of 172 IGE episodes, predominately of “viral etiology” (60.5%), were documented. In multivariate models, a significant association between IGE and CD was found (Odds ratio (OR): 2.06, 95% confidence interval (CI) 1.43, 2.97). Risk generally increased with temporal proximity to, and non-viral etiology of, exposure. Other notable risk factors for CD in multivariate models were Caucasian race (OR: 3.1, P < 0.001), non-Army service (OR: 1.5, P = 0.001), and greater than a high-school education (OR: 1.3, P = 0.05).
CONCLUSIONS
Incidence of CD diagnosis in the US military is increasing, particularly among those in the fourth and fifth decades of life and appears higher than other population-based estimates. An association between antecedent IGE and risk of CD was noted, but the potential for exposure misclassification cannot be ruled out and further study is needed to link pathogen-specific exposure to incident CD anti-gluten antibody development or symptom onset.
doi:10.1038/ajg.2012.130
PMCID: PMC3493152  PMID: 22584218
23.  Animal Models to Study Gluten Sensitivity1 
Seminars in immunopathology  2012;34(4):497-511.
The initial development and maintenance of tolerance to dietary antigens is a complex process that, when prevented or interrupted, can lead to human disease. Understanding the mechanisms by which tolerance to specific dietary antigens is attained and maintained is crucial to our understanding of the pathogenesis of diseases related to intolerance of specific dietary antigens. Two diseases that are the result of intolerance to a dietary antigen are celiac disease (CD) and dermatitis herpetiformis (DH). Both of these diseases are dependent upon the ingestion of gluten (the protein fraction of wheat, rye, and barley) and manifest in the gastrointestinal tract and skin, respectively. These gluten-sensitive diseases are two examples of how devastating abnormal immune responses to a ubiquitous food can be. The well-recognized risk genotype for both is conferred by either of the HLA class II molecules DQ2 or DQ8. However, only a minority of individuals who carry these molecules will develop either disease. Also of interest is that the age at diagnosis can range from infancy to 70–80 years of age. This would indicate that intolerance to gluten may potentially be the result of two different phenomena. The first would be that, for various reasons, tolerance to gluten never developed in certain individuals, but that for other individuals, prior tolerance to gluten was lost at some point after childhood. Of recent interest is the concept of non-celiac gluten sensitivity, which manifests as chronic digestive or neurologic symptoms due to gluten, but through mechanisms that remain to be elucidated. This review will address how animal models of gluten-sensitive disorders have substantially contributed to a better understanding of how gluten intolerance can arise and cause disease.
doi:10.1007/s00281-012-0315-y
PMCID: PMC3410984  PMID: 22572887
24.  In reply 
Mayo Clinic Proceedings  2012;87(12):1232.
doi:10.1016/j.mayocp.2012.10.006
PMCID: PMC3547580
25.  A large nationwide population-based case–control study of the association between intussusception and later celiac disease 
BMC Gastroenterology  2013;13:89.
Background
Case reports and case series studies suggest a positive association between intussusception and celiac disease (CD).
Methods
We contacted Sweden’s 28 pathology departments and obtained data on 29,096 patients with biopsy-verified CD (equal to Marsh stage 3) through biopsy reports. Patients with CD were matched for age, sex, calendar period and county of residence with up to five reference individuals from the general population (n = 144,522). Cases of intussusception were identified from nationwide inpatient, hospital-based outpatient and day-surgery data from the Swedish Patient Register.
Odds ratios (ORs) for future CD in patients with intussusception were estimated using conditional logistic regression.
Results
34 (0.12%) individuals with CD had a diagnosis of intussusception vs. 143 (0.10%) reference individuals, suggesting that intussusception was not a risk factor for later CD (OR = 1.17; 95% confidence interval (CI) = 0.82–1.67). The OR for CD in patients with at least two records of intussusception was 0.40 (95% CI = 0.06–2.99).
In contrast, a post-hoc analysis showed that CD was associated with a statistically significantly increased risk of intussusception after CD diagnosis (hazard ratio = 1.95; 95% CI = 1.01–3.77); however, this analysis was based on only 12 cases with both CD and intussusception.
Conclusion
We found no association between intussusception and future CD; and a mostly modest increased risk of intussusception after a diagnosis of CD.
doi:10.1186/1471-230X-13-89
PMCID: PMC3661363  PMID: 23679928
Celiac; Coeliac, Gluten; Inflammation; Intussusception; Population-based

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