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1.  Perinatal and sociodemographic factors at birth predicting conduct problems and violence to age 18 years: comparison of Brazilian and British birth cohorts 
Background
Many low- and middle-income countries have high levels of violence. Research in high-income countries shows that risk factors in the perinatal period are significant precursors of conduct problems which can develop into violence. It is not known whether the same early influences are important in lower income settings with higher rates of violence. This study compared perinatal and sociodemographic risk factors between Brazil and Britain, and their role in explaining higher rates of conduct problems and violence in Brazil.
Methods
Prospective population-based birth cohort studies were conducted in Pelotas, Brazil (N = 3,618) and Avon, Britain (N = 4,103). Eleven perinatal and sociodemographic risk factors were measured in questionnaires completed by mothers during the perinatal period. Conduct problems were measured in questionnaires completed by mothers at age 11, and violence in self-report questionnaires completed by adolescents at age 18.
Results
Conduct problems were predicted by similar risk factors in Brazil and Britain. Female violence was predicted by several of the same risk factors in both countries. However, male violence in Brazil was associated with only one risk factor, and several risk factor associations were weaker in Brazil than in Britain for both females and males. Almost 20% of the higher risk for conduct problems in Brazil compared to Britain was explained by differential exposure to risk factors. The percentage of the cross-national difference in violence explained by early risk factors was 15% for females and 8% for males.
Conclusions
A nontrivial proportion of cross-national differences in antisocial behaviour are related to perinatal and sociodemographic conditions at the start of life. However, risk factor associations are weaker in Brazil than in Britain, and influences in other developmental periods are probably of particular importance for understanding male youth violence in Brazil.
doi:10.1111/jcpp.12369
PMCID: PMC4508966  PMID: 25471542
Conduct problems; violence; risk factors; cohort study; middle-income country; ALSPAC
2.  Clinical Reasoning: A 55-year-old man with weight loss, ataxia, and foot drop 
Neurology  2014;82(24):e214-e219.
A 55-year-old man with prior alcohol abuse and an 80 pack-year smoking history was referred for evaluation of a 3-month history of subacute-onset, progressively worsening imbalance without back pain. He began using a cane to ambulate after multiple falls. He also described recent right foot weakness, numbness in his feet and fingertips, and unintentional 25-pound weight loss over the past year. His medical history was significant for hypertension, gastroesophageal reflux disease, diverticulitis, and pelvic abscesses. A paternal grandfather had lung cancer. He reported a remote history of IV drug use. General examination revealed cachexia. Neurologic examination findings were complex. Gait examination revealed severe ataxia, a high steppage gait on the right, and a positive Romberg sign. The total ataxia score using the Scale for Assessment and Rating of Ataxia (higher scores indicate increased severity)1 was 14/40, including gait, 5/8; stance, 4/6; sitting, 1/4; speech disturbance, 0/4; finger chase, 0/4; nose-finger test, 0/4; fast alternating hand movements, 2/4; and heel-shin slide, 2/4. Nystagmus was not present. Strength testing revealed hip and knee flexion weakness bilaterally (grade 4/5) and severe (grade 2/5) weakness of right ankle dorsiflexion and eversion but preserved inversion strength. Reflexes were brisk in the upper extremities and normal in the lower extremities and plantar responses were flexor. Sensory testing revealed absent lower extremity vibration, absent joint position at the toes, and reduced pinprick in the feet without a sensory level. Initial laboratory testing revealed a hemoglobin of 9.3 g/dL (normal range 13.5–17.5).
doi:10.1212/WNL.0000000000000525
PMCID: PMC4113461  PMID: 24960835
3.  Non-celiac gluten hypersensitivity: What is all the fuss about? 
F1000Prime Reports  2015;7:54.
Non-celiac gluten sensitivity (NCGS) has been introduced recently as a potentially common disease on the basis of studies of patients with claimed reactivity to gluten but without the characteristics of celiac disease (CD). CD is characterized by antibody reactivity toward the autoantigen transglutaminase 2, characteristic histological abnormalities of the small intestine, and an almost obligatory genetic haplotype (HLA-DQ2 or DQ8). The diagnosis of NCGS is based largely on the clinical suspicion of hyper-reactivity to gluten and the absence of the characteristics of CD. Few published studies have used double-blind placebo-controlled food challenges (DBPCFCs) for the diagnosis of NCGS, and none in children. Innate immune reactivity to amylase trypsin inhibitors has been suggested as the pathogenic principle in NCGS, but confirmatory evidence is lacking. Also, further clinical studies including DBPCFCs are needed.
doi:10.12703/P7-54
PMCID: PMC4447038  PMID: 26097727
4.  Novel role of the serine protease inhibitor elafin in gluten-related disorders 
Objectives
Elafin, an endogenous serine protease inhibitor, modulates colonic inflammation. We investigated the role of elafin in celiac disease (CD) using human small intestinal tissues and in vitro assays of gliadin deamidation. We also investigated potential beneficial effects of elafin in a mouse model of gluten sensitivity.
Methods
Epithelial elafin expression in the small intestine of patients with active CD, treated CD and controls without CD was determined by immunofluorescence. Interaction of elafin with human tissue transglutaminase-2 (TG-2) was investigated in vitro. The 33-mer peptide, a highly immunogenic gliadin peptide, was incubated with TG-2 and elafin at different concentrations. The degree of deamidation of the 33-mer peptide was analyzed by liquid chromatography-mass spectrometry. Elafin was delivered to the intestine of gluten-sensitive mice using a recombinant Lactococcus lactis vector. Small intestinal barrier function, inflammation, proteolytic activity, and zonula occludens-1 (ZO-1) expression were assessed.
Results
Elafin expression in the small intestinal epithelium was lower in patients with active CD compared to control patients. In vitro, elafin significantly slowed the kinetics of the deamidation of the 33-mer peptide to its more immunogenic form. Treatment of gluten-sensitive mice with elafin delivered by the L. lactis vector normalized inflammation, improved permeability and maintained ZO-1 expression.
Conclusions
The decreased elafin expression in small intestine of patients with active CD, the reduction of 33-mer peptide deamidation by elafin, coupled to the barrier enhancing and anti-inflammatory effects observed in gluten sensitive mice, suggest this molecule may have pathophysiological and therapeutic importance in gluten-related disorders.
doi:10.1038/ajg.2014.48
PMCID: PMC4219532  PMID: 24710505
Gluten-sensitivity; elafin; celiac disease; proteolytic therapy
5.  Development of drugs for celiac disease: review of endpoints for Phase 2 and 3 trials 
Gastroenterology Report  2015;3(2):91-102.
Celiac disease is a lifelong disorder for which there is currently only one known, effective treatment: a gluten-free diet. New treatment approaches have recently emerged; several drugs are in Phase 2 trials and results appear promising; however, discussion around regulatory endpoints is in its infancy. We will briefly discuss the drugs that are under development and then shift our attention to potential trial endpoints, such as patient-reported outcomes, histology, serology, gene expression analysis and other tests. We will outline the differing requirements for proof-of-concept Phase 2 trials and Phase 3 registration trials, with a particular emphasis on current thinking in regulatory agencies. We conclude our paper with recommendations and a glossary of regulatory terms, to enable readers who are less familiar with regulatory language to take maximum advantage of this review.
doi:10.1093/gastro/gov006
PMCID: PMC4423465  PMID: 25725041
celiac disease; clinical trials; endpoints
6.  Screening for celiac disease in the general population and in high-risk groups 
Background
Celiac disease (CD) occurs in approximately 1% of the Western population. It is a lifelong disorder that is associated with impaired quality of life (QOL) and an excessive risk of comorbidity and death.
Objectives
To review the literature on screening for CD in relation to the current World Health Organization (WHO) criteria for mass screening.
Methods
We performed a PubMed search to identify indexed papers on CD screening with a publication date from 1900 until 1 June 2014. When we deemed an abstract relevant, we read the corresponding paper in detail.
Results
CD fulfills several WHO criteria for mass screening (high prevalence, available treatment and difficult clinical detection), but it has not yet been established that treatment of asymptomatic CD may reduce the excessive risk of severe complications, leading to higher QOL nor that it is cost-effective.
Conclusions
Current evidence is not sufficient to support mass screening for CD, but active case-finding may be appropriate, as we recognize that most patients with CD will still be missed by this strategy. Although proof of benefit is still lacking, screening for CD may be appropriate in high-risk groups.
doi:10.1177/2050640614561668
PMCID: PMC4406899  PMID: 25922671
Celiac disease; gluten; gluten-free diet; review; screening; prevention; risk; quality of life; World Health Organization
7.  Trajectories of maternal depression and offspring psychopathology at 6 years: 2004 Pelotas cohort study 
Journal of Affective Disorders  2015;174:424-431.
Background
Few studies have addressed the course and severity of maternal depression and its effects on child psychiatric disorders from a longitudinal perspective. This study aimed to identify longitudinal patterns of maternal depression and to evaluate whether distinct depression trajectories predict particular psychiatric disorders in offspring.
Methods
Cohort of 4231 births followed-up in the city of Pelotas, Brazil. Maternal depressive symptoms were assessed with the Edinburgh Postnatal Depression Scale (EPDS) at 3, 12, 24 and 48 months and 6 years after delivery. Psychiatric disorders in 6-year-old children were evaluated through the development and well-being assessment (DAWBA) instrument. Trajectories of maternal depression were calculated using a group-based modelling approach.
Results
We identified five trajectories of maternal depressive symptoms: a “low” trajectory (34.8%), a “moderate low” (40.9%), a “increasing” (9.0%), a “decreasing” (9.9%), and a “high-chronic” trajectory (5.4%). The probability of children having any psychiatric disorder, as well as both internalizing and externalizing problems, increased as we moved from the “low” to the “high-chronic” trajectory. These differences were not explained by maternal and child characteristics examined in multivariate analyses.
Limitations
Data on maternal depression at 3-months was available on only a sub-sample. In addition, we had to rely on maternal report of child’s behavior alone.
Conclusions
The study revealed an additive effect on child outcome of maternal depression over time. We identified a group of mothers with chronic and severe symptoms of depression throughout the first six years of the child life and for this group child psychiatric outcome was particularly compromised.
Highlights
•Maternal postnatal depressive symptomatology was modeled using group-based approach.•5 maternal trajectories were identified from 3 months through 6 years postpartum.•Offspring psychiatric disorders were assessed at age 6 years.•Psychiatric disorders increased from the “low” to the “high-chronic” trajectory.•We revealed an additive effect on child outcome of maternal depression over time.
doi:10.1016/j.jad.2014.12.012
PMCID: PMC4351190  PMID: 25553403
DAWBA, development and well-being assessment; EPDS, Edinburgh Post-natal Depression Scale; LMP, last menstrual period; C-section, caesarean section; OR, odds ratio, 95% CI, 95% confidence interval.; Maternal postnatal depression; Group-based modelling; Development and well-being assessment; Mental health; Children; Cohort study
8.  Predictors of persistent villous atrophy in coeliac cisease; a population-based study 
Background
Villous atrophy (VA) with intraepithelial lymphocytosis is the histologic hallmark of coeliac disease (CD) but reported rates of mucosal recovery are variable.
Aim
To determine the impact of age and other demographic variables on the probability of persistent VA on follow-up biopsy.
Methods
We identified patients with VA on duodenal histology at all 28 Swedish pathology departments during the years spanning 1969–2008. We examined age, gender, calendar period, duration of disease, and educational attainment, to determine predictors of persistent VA.
Results
Of 7,648 patients with CD who underwent follow-up biopsy, persistent VA was present in 3,317 (43%; 95% CI 42%–44%). The effect of age on persistent VA varied according to time period; among those biopsied in the years spanning 2000–2008, the prevalence of persistent VA was 31%, and increasing age was associated with increasing rates of persistent VA (17% among those younger than 2 years compared to 56% among those ≥70 years). In contrast, persistent VA did not vary widely by age in earlier years. On multivariate analysis (restricted to the calendar period 2000–2008, 2–5 years after CD diagnosis), persistent VA was more common among males (OR 1.43; 95%CI 1.07–1.90) and less common among patients with higher educational attainment (OR for college degree versus <2 years of high school 0.52, 95%CI 0.35–0.78).
Conclusions
The prevalence of persistent VA has changed over time, with greater rates of healing in recent years. Social differences in persistent VA suggests that access and/or education regarding the gluten-free diet impacts mucosal healing.
doi:10.1111/apt.12621
PMCID: PMC4012428  PMID: 24428688
coeliac disease; epidemiology; histology
9.  Synthetic lethal screening reveals FGFR as one of the combinatorial targets to overcome resistance to Met-targeted therapy 
Oncogene  2014;34(9):1083-1093.
Met is a receptor tyrosine kinase that promotes cancer progression. In addition, Met has been implicated in resistance of tumors to various targeted therapies such as EGFR inhibitors in lung cancers, and has been prioritized as a key molecular target for cancer therapy. However, the underlying mechanism of resistance to Met targeting drugs is poorly understood. Here, we describe screening of 1310 genes to search for key regulators related to drug resistance to an anti-Met therapeutic antibody (SAIT301) by employing a siRNA-based synthetic lethal screening method. We found that knockdown of 69 genes in Met-amplified MKN45 cells sensitized the anti-tumor activity of SAIT301. Pathway analysis of these 69 genes implicated FGFR as a key regulator for anti-proliferative effects of Met targeting drugs. Inhibition of FGFR3 increased target cell apoptosis through the suppression of Bcl-xL expression, followed by reduced cancer cell growth in the presence of Met targeting drugs. Treatment of cells with the FGFR inhibitors substantially restored the efficacy of SAIT301 in SAIT301-resistant cells and enhanced the efficacy in SAIT301-sensitive cells. In addition to FGFR3, integrin β3 is another potential target for combination treatment with SAIT301. Suppression of integrin β3 decreased AKT phosphorylation in SAIT301-resistant cells and restores SAIT301 responsiveness in HCC1954 cells, which are resistant to SAIT301. Gene expression analysis using CCLE database shows cancer cells with high levels of FGFR and integrin β3 are resistant to crizotinib treatment, suggesting FGFR and integrin β3 could be used as predictive markers for Met targeted therapy and provide a potential therapeutic option to overcome acquired and innate resistance for the Met targeting drugs.
doi:10.1038/onc.2014.51
PMCID: PMC4300291  PMID: 24662823
Met; FGFR; integrin; SAIT301; resistance
10.  Increased use of hypnotics in individuals with celiac disease: a nationwide case-control study 
BMC Gastroenterology  2015;15:10.
Background
Although poor sleep is common in numerous gastrointestinal diseases, data are scarce on the risk of poor sleep in celiac disease. The objective of this study was to estimate the risk of repeated use of hypnotics among individuals with celiac disease as a proxy measure for poor sleep.
Methods
This is a nationwide case–control study including 2933 individuals with celiac disease and 14,571 matched controls from the general Swedish population. Poor sleep was defined as ≥2 prescriptions of hypnotics using prospective data from the National Prescribed Drug Register (data capture: July 2005-January 2008). We estimated odds ratios and hazard ratios for poor sleep before and after celiac disease diagnosis respectively.
Results
In this study, poor sleep was seen in 129/2933 individuals (4.4%) with celiac disease, as compared with 487/14,571 controls (3.3%) (odds ratio = 1.33; 95% CI = 1.08-1.62). Data restricted to sleep complaints starting ≥1 year before celiac disease diagnosis revealed largely unchanged risk estimates (odds ratio = 1.23; 95% CI = 0.88-1.71) as compared with the overall risk (odds ratio 1.33). The risk of poor sleep in celiac disease was essentially not influenced by adjustment for concomitant psychiatric comorbidity (n = 1744, adjusted odds ratio =1.26; 95% CI = 1.02-1.54) or restless legs syndrome (n = 108, adjusted odds ratio = 1.33; 95% CI = 1.08-1.63). Poor sleep was also more common after celiac disease diagnosis as compared with matched controls (hazard ratio = 1.36; 95% CI = 1.30-1.41).
Conclusions
In conclusion, individuals with celiac disease suffer an increased risk of poor sleep, both before and after diagnosis. Although we cannot rule out that surveillance bias has contributed to our findings, our results are consistent with previous data suggesting that sleep complaints may be a manifestation of celiac disease.
Electronic supplementary material
The online version of this article (doi:10.1186/s12876-015-0236-z) contains supplementary material, which is available to authorized users.
doi:10.1186/s12876-015-0236-z
PMCID: PMC4322544  PMID: 25649738
Coeliac; Immune-mediated; Insomnia; Sleep disorders; Small intestine
11.  A Case of Severe Sprue-Like Enteropathy Associated With Valsartan 
ACG Case Reports Journal  2015;2(2):92-94.
Olmesartan sprue-like enteropathy is an adverse drug reaction that mimics the appearance of celiac disease and is related to the use of olmesartan. We present the case of a 71-year-old female with severe enteropathy attributed to celiac disease for 5 years that improved only after valsartan cessation. This is the first case associating valsartan with sprue-like enteropathy.
doi:10.14309/crj.2015.15
PMCID: PMC4435362  PMID: 26157924
12.  An old Twist in HLA-A: CDR3α Hook up at an R65-joint 
T-cell ontogeny optimizes the α/β T-cell receptor (TCR) repertoire for recognition of major histocompatibility complex (MHC) class-I/II genetic polymorphism, and co-evolution of TCR germline V-gene segments and the MHC must entail somatic diversity generated in the third complimentary determining regions (CDR3α/β); however, it is still not clear how. Herein, a conspicuous structural link between the V-Jα used by several different TCR [all in complex with the same MHC molecule (HLA-A2)], and a conserved MHC motif (a.a., R65-X-X-K-A-X-S-Q72) is described. We model this R65-joint in detail, and show that the same TCR’s CDR3α loop maintains its CDR2α loop at a distance of ~4 Å from polymorphic amino acid (a.a.) positions of the α-2 helix in all but one of the analyzed crystal structures. Indeed, the pitch of docked TCRs varies as their twist/tilt/sway maintains the R65-joint and peptide contacts. Thus, the R65-joint appears to have poised the HLA-A lineage toward alloreactivity.
doi:10.3389/fimmu.2015.00268
PMCID: PMC4445401  PMID: 26074926
immunogenetics; TCR; MHC; HLA; alloreactivity; placentation; primate; evolution
13.  Risk of lymphoproliferative malignancy in celiac patients with a family history of lymphoproliferative malignancy 
Journal of gastroenterology  2013;48(12):10.1007/s00535-013-0757-6.
Background and aims
Individuals with celiac disease (CD) are at increased risk of lymphoproliferative malignancy (LPM). We examined if a family history of LPM or any cancer influenced the risk of LPM in individuals with CD.
Methods
We identified 28,996 individuals with biopsy-verified CD (equal to villous atrophy, Marsh histopathology stage 3), of whom 616 had family history of LPM. Cox regression then estimated hazard ratios (HRs) for LPM in these 616 compared with two control groups. We also examined the risk of LPM in CD individuals with a family history of any cancer (n=8,439).
Results
During follow-up, 2/616 CD individuals with a family history of LPM, and 235/28,380 CD individuals without a family history of LPM developed LPM themselves. CD individuals with a family history of LPM were not at increased risk of LPM compared to general population controls (HR=1.18; 95%CI=0.27–5.10), or compared to CD individuals without a family history of LPM (adjusted HR=0.31; 95%CI=0.08–1.23). We found no increased risk of LPM in CD individuals with a family history of any cancer.
Conclusion
This study found no evidence that a family history of LPM or any cancer increases the risk of future LPM in individuals with CD. Despite the large number of study participants, this study is however limited by few positive events due to a low absolute risk of LPM even in individuals with CD.
doi:10.1007/s00535-013-0757-6
PMCID: PMC3664649  PMID: 23440554
cancer; celiac; coeliac; lymphoma; lymphoproliferative; malignancy
14.  Use of computerized algorithm to identify individuals in need of testing for celiac disease 
Background and aim
Celiac disease (CD) is a lifelong immune-mediated disease with excess mortality. Early diagnosis is important to minimize disease symptoms, complications, and consumption of healthcare resources. Most patients remain undiagnosed. We developed two electronic medical record (EMR)-based algorithms to identify patients at high risk of CD and in need of CD screening.
Methods
(I) Using natural language processing (NLP), we searched EMRs for 16 free text (and related) terms in 216 CD patients and 280 controls. (II) EMRs were also searched for ICD9 (International Classification of Disease) codes suggesting an increased risk of CD in 202 patients with CD and 524 controls. For each approach, we determined the optimal number of hits to be assigned as CD cases. To assess performance of these algorithms, sensitivity and specificity were calculated.
Results
Using two hits as the cut-off, the NLP algorithm identified 72.9% of all celiac patients (sensitivity), and ruled out CD in 89.9% of the controls (specificity). In a representative US population of individuals without a prior celiac diagnosis (assuming that 0.6% had undiagnosed CD), this NLP algorithm could identify a group of individuals where 4.2% would have CD (positive predictive value). ICD9 code search using three hits as the cut-off had a sensitivity of 17.1% and a specificity of 88.5% (positive predictive value was 0.9%).
Discussion and conclusions
This study shows that computerized EMR-based algorithms can help identify patients at high risk of CD. NLP-based techniques demonstrate higher sensitivity and positive predictive values than algorithms based on ICD9 code searches.
doi:10.1136/amiajnl-2013-001924
PMCID: PMC3861918  PMID: 23956016
algorithm; artificial intelligence; celiac; decision support system, clinical; inflammation
15.  BL-7010 Demonstrates Specific Binding to Gliadin and Reduces Gluten-Associated Pathology in a Chronic Mouse Model of Gliadin Sensitivity 
PLoS ONE  2014;9(11):e109972.
Celiac disease (CD) is an autoimmune disorder in individuals that carry DQ2 or DQ8 MHC class II haplotypes, triggered by the ingestion of gluten. There is no current treatment other than a gluten-free diet (GFD). We have previously shown that the BL-7010 copolymer poly(hydroxyethyl methacrylate-co-styrene sulfonate) (P(HEMA-co-SS)) binds with higher efficiency to gliadin than to other proteins present in the small intestine, ameliorating gliadin-induced pathology in the HLA-HCD4/DQ8 model of gluten sensitivity. The aim of this study was to investigate the efficiency of two batches of BL-7010 to interact with gliadin, essential vitamins and digestive enzymes not previously tested, and to assess the ability of the copolymer to reduce gluten-associated pathology using the NOD-DQ8 mouse model, which exhibits more significant small intestinal damage when challenged with gluten than HCD4/DQ8 mice. In addition, the safety and systemic exposure of BL-7010 was evaluated in vivo (in rats) and in vitro (genetic toxicity studies). In vitro binding data showed that BL-7010 interacted with high affinity with gliadin and that BL-7010 had no interaction with the tested vitamins and digestive enzymes. BL-7010 was effective at preventing gluten-induced decreases in villus-to-crypt ratios, intraepithelial lymphocytosis and alterations in paracellular permeability and putative anion transporter-1 mRNA expression in the small intestine. In rats, BL-7010 was well-tolerated and safe following 14 days of daily repeated administration of 3000 mg/kg. BL-7010 did not exhibit any mutagenic effect in the genetic toxicity studies. Using complementary animal models and chronic gluten exposure the results demonstrate that administration of BL-7010 is effective and safe and that it is able to decrease pathology associated with gliadin sensitization warranting the progression to Phase I trials in humans.
doi:10.1371/journal.pone.0109972
PMCID: PMC4217726  PMID: 25365555
16.  A nationwide study of small intestinal histopathology and risk of autistic spectrum disorders 
JAMA psychiatry  2013;70(11):10.1001/jamapsychiatry.2013.2048.
Context and objective
Most case reports suggest an association between autistic spectrum disorders (ASD) and celiac disease (CD) or positive CD serology, but larger studies are contradictory. We examined the association between ASD and CD according to small intestinal histopathology.
Setting
Sweden.
Design
Nationwide case-control study.
Participants and outcome measure
Through 28 Swedish biopsy registers, we collected data on 26,995 individuals with CD (equal to villous atrophy, Marsh histopathology stage 3), 12,304 individuals with inflammation (Marsh 1–2), and 3,719 individuals with normal mucosa (Marsh 0) but positive CD serology (IgA/IgG gliadin, endomysium, tissue transglutaminase) and compared them with 213,208 age-and sex-matched controls. Conditional logistic regression estimated odds ratios (ORs) for having a prior diagnosis of ASD according to the Swedish Patient Register. In a second analysis we used Cox regression to estimate hazard ratios (HRs) for future ASD in individuals undergoing small intestinal biopsy.
Results
Prior ASD was not associated with CD (OR=0.93; 95% CI=0.51–1.68) or inflammation (OR=1.03; 95% CI=0.40–2.64) but was associated with a markedly increased risk of having a normal mucosa but positive CD serology (OR=4.57; 95% CI=1.58–13.22).
Restricting our data to individuals without a diagnosis of ASD at the time of biopsy, CD (HR=1.39; 95% CI=1.13–1.71) and inflammation (HR=2.01; 95% CI=1.29–3.13) were both associated with moderate excess risks of later ASD, whereas the HR for later ASD in individuals with normal mucosa but positive CD serology was 3.09 (95% CI=1.99–4.80).
Conclusion
Although this study found no association between CD or inflammation and earlier ASD, there was a markedly increased risk of ASD in individuals with a normal mucosa but positive CD serology.
doi:10.1001/jamapsychiatry.2013.2048
PMCID: PMC3884520  PMID: 24068245
autism; autistic spectrum disorder; autoimmunity; celiac; coeliac; inflammation
17.  HLA Genetics and Clinical Features of Self-Treated Patients on a Gluten-Free Diet 
Background and Aims
Increasingly, persons start a gluten-free diet (GFD) without a clear celiac disease (CD) diagnosis. Human leukocyte antigen (HLA) genotyping is useful in ruling out CD in patients with equivocal results of serologic testing or small-bowel biopsy (SBB), but its utility and the clinical features of patients on self-treated GFD (ST-GFD) are largely unknown.
Methods
Retrospective study of single tertiary care center cohort compared 137 patients on ST-GFD and 443 patients with well-defined CD. We compared HLA genotype, symptoms, serologic and SBB results, and response to GFD between the 2 groups. Analysis used univariate logistic regression modeling, adjusted for age and sex.
Results
Patients with ST-GFD presented more often with diarrhea (P<.001), abdominal distention (P<.001), flatulence (P=.002), cramping (P=.02), itchy skin (P=.02), oral inflammation (P=.04), and constipation (P=.01) and less often with anemia (P<.001) or malaise (P=.02) than CD patients. In addition, 41% did not carry DQ2.5 and DQ8 vs 6% of CD patients (P<.001). Only 2% of ST-GFD patients had SBB clearly consistent with CD. Family history of CD showed no difference between groups (P=.77). Although CD patients had a statistically higher rate of GFD benefit, both groups had a high responsiveness rate (98% vs 94%; P=.03).
Conclusions
HLA genotyping is useful in evaluating patients on a ST-GFD. Although confirmed CD is rare in self-treated patients, most still report benefit from GFD regardless of DQ2 and DQ8 status. Nonceliac gluten sensitivity may play a role.
doi:10.1097/MCG.0b013e31828f531c
PMCID: PMC3735773  PMID: 23632357
celiac disease; diet; food intolerance; gluten-sensitive enteropathy
18.  Childhood behaviour problems predict crime and violence in late adolescence: Brazilian and British birth cohort studies 
Purpose
Most children live in low- and middle-income countries (LMICs), many of which have high levels of violence. Research in high-income countries (HICs) shows that childhood behaviour problems are important precursors of crime and violence. Evidence is lacking on whether this is also true in LMICs. This study examines prevalence rates and associations between conduct problems and hyperactivity and crime and violence in Brazil and Britain.
Methods
A comparison was made of birth cohorts in Brazil and Britain, including measures of behaviour problems based on parental report at age 11, and self-reports of crime at age 18 (N = 3,618 Brazil; N = 4,103 Britain). Confounders were measured in the perinatal period and at age 11 in questionnaires completed by the mother and, in Brazil, searches of police records regarding parental crime.
Results
Conduct problems, hyperactivity and violent crime were more prevalent in Brazil than in Britain, but nonviolent crime was more prevalent in Britain. Sex differences in prevalence rates were larger where behaviours were less common: larger for conduct problems, hyperactivity, and violent crime in Britain, and larger for nonviolent crime in Brazil. Conduct problems and hyperactivity predicted nonviolent and violent crime similarly in both countries; the effects were partly explained by perinatal health factors and childhood family environments.
Conclusions
Conduct problems and hyperactivity are similar precursors of crime and violence across different social settings. Early crime and violence prevention programmes could target these behavioural difficulties and associated risks in LMICs as well as in HICs.
Electronic supplementary material
The online version of this article (doi:10.1007/s00127-014-0976-z) contains supplementary material, which is available to authorized users.
doi:10.1007/s00127-014-0976-z
PMCID: PMC4361758  PMID: 25319112
Conduct problems; Hyperactivity; Crime; Cohort study; Middle-income country; ALSPAC
19.  Does urticaria risk increase in patients with celiac disease? A large population-based cohort study 
Background
Case reports and smaller case-control studies suggest an association between celiac disease (CD) and urticaria, but risk estimates have varied considerably across studies and as yet there are no studies on CD and the risk of future urticaria.
Objective
To examine the association between CD and urticaria.
Methods
We identified 28,900 patients with biopsy-verified CD (equal to Marsh stage 3) and compared them with 143,397 age- and sex-matched controls with regards to the risk of urticaria and chronic urticaria (duration ≥6 weeks). Hazard ratios (HRs) were estimated using a Cox regression model.
Results
During follow-up, 453 patients with CD and no previous diagnosis of urticaria developed urticaria (expected n=300) and 79 of these 453 had chronic urticaria (expected n=41). The corresponding HRs were 1.51 for any urticaria (95%CI=1.36–1.68) and 1.92 for chronic urticaria (95%CI=1.48–2.48). The absolute risk for urticaria in CD was 140/100,000 person-years (excess risk=47/100,000 person-years). Corresponding figures for chronic urticaria were 24/100,00 person-years and 12/100,000 person-years. Patients with CD were also at increased risk of having both urticaria (odds ratio, OR=1.31; 95%CI=1.12–1.52) and chronic urticaria (OR=1.54; 95%CI=1.08–2.18) prior to the CD diagnosis.
Conclusion
This study suggests that CD is associated with urticaria, especially chronic urticaria.
doi:10.1684/ejd.2013.2158
PMCID: PMC3896876  PMID: 24135663
autoimmunity; celiac; coeliac; gluten; inflammation; population-based; skin; urticaria
20.  Mucosal Healing and Risk of Lymphoproliferative Malignancy in Celiac Disease 
Annals of internal medicine  2013;159(3):169-175.
Background
Celiac disease (CD) is associated with an increased risk of lymphoproliferative malignancy (LPM). It is unknown whether this risk is affected by the results of the follow-up intestinal biopsy, performed to document mucosal healing.
Objective
To examine the association between mucosal healing in CD and later LPM.
Design
Population-based cohort study
Setting
We identified patients with CD from all of Sweden’s 28 pathology departments.
Patients
Individuals with CD who had a follow-up biopsy after initial diagnosis.
Measurements
We compared the risk of LPM to that of the general population using expected rates; and through Cox regression we compared the rate of LPM in those with persistent villous atrophy to those with mucosal healing.
Results
Among 7,625 patients with CD and a follow-up biopsy, persistent villous atrophy was present in 3,308 (43%). The overall risk of LPM was increased compared to the general population (Standardized incidence ratio, SIR 2.81; 95%CI 2.10–3.67), but this increase was greater among those with persistent villous atrophy (SIR 3.78; 95%CI 2.71–5.12) as compared to those with mucosal healing (SIR 1.50; 95%CI 0.77–2.62). Persistent villous atrophy compared to mucosal healing was associated with an increased risk of LPM (Hazard ratio, HR 2.26; 95%CI 1.18–4.34). We found an increased risk of T cell lymphoma (HR 3.51; 95%CI 0.75–16.34), but no excess risk of B cell lymphoma (HR 0.97; 95%CI 0.21–4.49).
Limitation
We had no data on dietary compliance.
Conclusions
The increased LPM risk in CD is associated with the results of the follow-up biopsy, with a higher risk among those with persistent villous atrophy. Follow-up biopsy may be a means to effectively stratify CD patients regarding subsequent LPM risk.
Primary funding source
the National Center for Advancing Translational Sciences, National Institutes of Health, The American Scandinavian Foundation, the Celiac Sprue Association, Örebro University Hospital, Karolinska Institutet, the Swedish Society of Medicine, the Swedish Research Council, and the Swedish Celiac Society.
doi:10.7326/0003-4819-159-3-201308060-00006
PMCID: PMC3788608  PMID: 23922062
21.  Risk of Thyroid Cancer in a Nationwide Cohort of Patients with Biopsy-Verified Celiac Disease 
Thyroid  2013;23(8):971-976.
Background
In earlier studies based on selected populations, the relative risk for thyroid cancer in celiac disease has varied between 0.6 and 22.5. We aimed to test this relationship in a population-based setting.
Methods
We collected small intestinal biopsy report data performed in 1969–2008 from all 28 Swedish pathology departments. 29,074 individuals with celiac disease (villous atrophy; Marsh histopathology stage III) were matched for sex, age, calendar year, and county to 144,440 reference individuals from the Swedish general population. Through Cox regression, we then estimated hazard ratios (HRs) and confidence intervals (CIs) for any thyroid cancer and papillary thyroid cancer (defined according to relevant pathology codes in the Swedish Cancer Register) in patients with celiac disease.
Results
During follow-up, any thyroid cancer developed in seven patients with celiac disease (expected=12) and papillary thyroid cancer developed in five patients (expected=7). Celiac disease was not associated with an increased risk of any thyroid cancer (HR 0.6 [CI 0.3–1.3]) or of papillary thyroid cancer (HR 0.7 [CI 0.3–1.8]). All cases of thyroid cancer in celiac disease occurred in female patients. Risk estimates were similar before and after the year 2000 and independent of age at celiac diagnosis (≤24 years vs. ≥25 years).
Conclusions
We conclude that, in the Swedish population, there is no increased risk of thyroid cancer in patients with celiac disease. This differs from what has been reported in smaller studies in Italy and the United States.
doi:10.1089/thy.2012.0306
PMCID: PMC3752514  PMID: 23281890
22.  Genome-Wide Association Study of Celiac Disease in North America Confirms FRMD4B as New Celiac Locus 
PLoS ONE  2014;9(7):e101428.
We performed a genome-wide association study (GWAS) of 1550 North American celiac disease cases and 3084 controls. Twelve SNPs, distributed across four regions (3p21.31, 4q27, 6q15, 6q25), were significantly associated with disease (p-value <1.0×10−7), and a further seven SNPs, across four additional regions (1q24.3, 10p15.1, 6q22.31, 17q21.32) had suggestive evidence (1.0×10−7 < p-value < 1.0×10−6). This study replicated a previous suggestive association within FRMD4B (3p14.1), confirming it as a celiac disease locus. All four regions with significant associations and two regions with suggestive results (1q24.3, 10p15.1) were known disease loci. The 6q22.31 and 10p11.23 regions were not replicated. A total of 410 SNPs distributed across the eight significant and suggestive regions were tested for association with dermatitis herpetiformis and microscopic colitis. Preliminary, suggestive statistical evidence for association with the two traits was found at chromosomes 3p21.31, 6q15, 6q25, 1q24.3 and 10p11.23, with future studies being required to validate the reported associations.
doi:10.1371/journal.pone.0101428
PMCID: PMC4084811  PMID: 24999842
23.  Coeliac disease, eosinophilic oesophagitis and gastro-oesophageal reflux disease, an adult population-based study 
Objective
Coeliac disease (CD) has been linked to gastro-oesophageal reflux disease (GORD) and eosinophilic oesophagitis (EoE), but population-based studies of the prevalence of CD in these conditions are lacking, that is, the aim of this study.
Materials and methods
An endoscopic study of 1000 randomly selected adults from the general population. CD was defined on the basis of positive serology in parallel with mucosal abnormalities of the small intestine. Any eosinophil infiltration of the oesophageal epithelium was defined as oesophageal eosinophilia and EoE was defined as having at least 15 eosinophils/high power field in biopsies from the distal oesophagus. We used Fisher’s exact test to compare the prevalence of GORD, oesophageal eosinophilia and EoE in subjects with CD vs. controls.
Results
400 subjects (40%) had gastro-oesophageal reflux symptoms (GORS), 155 (15.5%) had erosive oesophagitis, 16 (1.6%) had Barrett’s oesophagus, 48 (4.8%) had oesophageal eosinophilia and 11 (1.1%) had EoE. CD was diagnosed in 8/400 (2.0%) individuals with GORS (vs. controls: 10/600 (1.7%), p=0.81), in 3/155 (1.9%) with erosive oesophagitis (vs. 15/845 controls (1.8%), p=0.75) and in 2/48 (4.2%) individuals with oesophageal eosinophilia (controls: 16/952 (1.7%) p=0.21), but in none of those 16 with Barrett’s oesophagus (vs. 18/984 controls (1.8%), p=1.0) or of the 11 individuals with EoE (controls: 18/989 (1.8%), p=1.0).
Conclusions
This population-based study found no increased risk of CD among individuals with GORD, oesophageal eosinophilia or EoE. CD screening of individuals with GORD or EoE of individuals with CD cannot be recommended.
doi:10.3109/00365521.2013.792389
PMCID: PMC3778444  PMID: 23672638
Barrett’s oesophagus; coeliac disease; eosinophilic oesophagitis; erosive oesophagitis; gastro-oesophageal reflux disease
24.  Association Between Celiac Disease and Iron Deficiency in Caucasians, but not Non-Caucasians 
Background & Aims
Celiac disease is an increasingly recognized disorder in Caucasian populations of European origin. Little is known about its prevalence in non-Caucasians. Although it is thought to be a cause of iron deficiency anemia, little is known about the extent to which celiac disease contributes to iron deficiency in Caucasians, and especially non-Caucasians. We analyzed samples collected from participants in the Hemochromatosis and Iron Overload Screening (HEIRS) study to identify individuals with iron deficiency and assess the frequency of celiac disease.
METHODS
We analyzed serum samples from white men (25 y old or older) and women (50 y old or older) who participated the HEIRS study; cases were defined as individuals with iron deficiency (serum level of ferritin ≤12 mg/L) and controls were those without (serum level of ferritin >100 mg/L in men and >50 mg/L in women). All samples were also analyzed for human recombinant tissue transglutaminase immunoglobulin A; positive results were confirmed by an assay for endomysial antibodies. Patients with positive results from both celiac disease tests were presumed to have untreated celiac disease, and those with a positive result from only 1 test were excluded from analysis. We analyzed HLA genotypes and frequencies of celiac disease between Caucasians and non-Caucasians with iron deficiency.
RESULTS
Celiac disease occurred in 14 of 567 of cases (2.5%) and in only 1 of 1136 controls (0.1%; Fisher’s exact test, P=1.92 × 10−6). Celiac disease was more common in Caucasian cases (14/363, 4%) than non-Caucasian cases (0/204; P=.003). Only 1 Caucasian control and no non-Caucasian controls had celiac disease. The odds of celiac disease in individuals with iron deficiency was 28-fold (95% confidence interval, 3.7–212.8) that of controls; 13/14 cases with celiac disease carried the DQ2.5 variant of the HLA genotype.
CONCLUSIONS
Celiac disease is associated with iron deficiency of Caucasians. Celiac disease is rare among non-Caucasians—even among individuals with features of celiac disease, such as iron deficiency. Celiac disease is also rare among individuals without iron deficiency. Men and post-menopausal women with iron deficiency should be tested for celiac disease.
doi:10.1016/j.cgh.2013.02.009
PMCID: PMC3843318  PMID: 23416278
SNP; risk factor; gluten allergy; intestine; absorption
25.  Does celiac disease influence survival in lymphoproliferative malignancy? 
European journal of epidemiology  2013;28(6):10.1007/s10654-013-9789-8.
Celiac disease (CD) is associated with both lymphoproliferative malignancy (LPM) and increased death from LPM. Research suggests that co-existing autoimmune disease may influence survival in LPM. Through Cox regression we examined overall and cause-specific mortality in 316 individuals with CD+LPM vs. 689 individuals with LPM only. CD was defined as having villous atrophy according to biopsy reports at any of Sweden’s 28 pathology departments, and LPM as having a relevant disease code in the Swedish Cancer Register. During follow-up, there were 551 deaths (CD: n=200; non-CD: n=351). Individuals with CD+LPM were at an increased risk of death compared with LPM-only individuals (adjusted hazard ratio (aHR)=1.23; 95% confidence interval (CI)=1.02–1.48). However, this excess risk was only seen in the first year after LPM diagnosis (aHR=1.76), with HRs decreasing to 1.09 in years 2–5 after LPM diagnosis and to 0.90 thereafter. Individuals with CD and non-Hodgkin lymphoma (NHL) were at a higher risk of any death as compared with NHL-only individuals (aHR=1.23; 95%CI=0.97–1.56). This excess risk was due to a higher proportion of T-cell lymphoma in CD patients. Stratifying for T- and B-cell status, the HR for death in individuals with CD+NHL was 0.77 (95%CI=0.46–1.31
In conclusion, we found no evidence that co-existing CD influences survival in individuals with LPM. The increased mortality in the first year after LPM diagnosis is related to the predominance of T-NHL in CD individuals. Individuals with CD+LPM should be informed that their prognosis is similar to that of individuals with LPM only. However, this study had low statistical power to rule our excess mortality in patients with CD and certain LPM subtypes.
doi:10.1007/s10654-013-9789-8
PMCID: PMC3886816  PMID: 23463575
cancer; celiac; coeliac; death; lymphoproliferative; malignancy mortality

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