An age-stratified serosurvey against purified Salmonella enterica serovar Typhi antigens in the Lao People´s Democratic Republic

The epidemiology of typhoid fever in Lao People`s Democratic Republic is poorly defined. Estimating the burden of typhoid fever in endemic countries is complex due to the cost and limitations of population-based surveillance; serological approaches may be a more cost-effective alternative. ELISAs were performed on 937 serum samples (317 children and 620 adults) from across Lao PDR to measure IgG antibody titers against Vi polysaccharide and the experimental protein antigens, CdtB and HlyE. We measured the significance of the differences between antibody titers in adults and children and fitted models to assess the relationship between age and antibody titers. The median IgG titres of both anti-HylE and CdtB were significantly higher in children compared to adults (anti-HylE; 351.7 ELISA Units (EU) vs 198.1 EU, respectively; p<0.0001 and anti-CdtB; 52.6 vs 12.9 EU; p<0.0001). Conversely, the median anti-Vi IgG titer was significantly higher in adults than children (11.3 vs 3.0 U/ml; p<0.0001). A non-linear trend line fitted to the anti-CdtB and anti-HlyE IgG data identified a peak in antibody concentration in children <5 years of age. We identified elevated titers of anti-HlyE and anti-CdtB IgG in the serum of children residing in Lao PDR in comparison to adults. These antigens are associated with seroconversion after typhoid fever and may be a superior measure of disease burden than anti-Vi IgG. This approach is scalable and may be developed to assess the burden of typhoid fever in countries where the disease may be endemic, and evidence is required for the introduction of typhoid vaccines.     

Association Study of Serotonin Transporter SLC6A4 Gene with Chinese Han Irritable Bowel Syndrome

Objective

Irritable bowel syndrome (IBS) is a common clinical gastrointestinal dysfunction disorders. 5-sertonon (5-hydroxytryptamine, 5-HT) is a very important neurotransmitter, which is involved in gastrointestinal motion and sensation. Solute carrier family 6 member 4 (SLC6A4) gene encode serotonin transporter (SERT) which function is to rapidly reuptake the most of 5-HT. Therefore, it is needed to explore the association between SLC6A4 gene polymorphisms and IBS.

Methods

119 patients and 238 healthy controls were administrated to detect the SLC6A4 gene polymorphisms including 5-HT-transporter-gene-linked polymorphic region (5-HTTLPR), variable number of tandem repeats (VNTRs) and three selected tag Single Nucleotide Polymorphisms (SNPs) rs1042173, rs3794808, rs2020936 by using polymerase chain reaction (PCR) and TaqMan® SNP Genotyping.

Results

There were significant difference for 5-HTTLPR between IBS and control groups (X2 = 106.168, P<0.0001). In control group, genotypes were mainly L/L (58.4%), however, the genotypes in IBS were S/S (37.8%). The significant difference was shown in D-IBS subjects when compared to the controls (X² = 50.850, P<0.0001) for 5-HTTLPR. For STin2 VNTR, rs1042173, rs3794808, and rs2020936 polymorphisms, there were no any significant differences between IBS and control groups. There were no statistical significantly haplotypes for 5-HTTLPR, VNTRs and the three SNPs between IBS and controls.

Conclusion

The S allele in 5-HTTLPR was a susceptible allele with Chinese Han IBS, but other associations of VNTRs, three selected Tag SNPs and positive haplotype with IBS were not found. It is indicated that much research are needed to study the relationship between other polymorphisms in SLC6A4 gene and IBS.     

Differentiating Coeliac Disease from Irritable Bowel Syndrome by Urinary Volatile Organic Compound Analysis – A Pilot Study

Coeliac disease (CD), a T-cell-mediated gluten sensitive enteropathy, affects ∼1% of the UK population and can present with wide ranging clinical features, often being mistaken for Irritable Bowel Syndrome (IBS). Heightened clinical awareness and serological screening identifies those with potential coeliac disease; the diagnosis is confirmed with duodenal biopsies, and symptom improvement with a gluten-free diet. Limitations to diagnosis are false negative serology and reluctance to undergo biopsy. The gut microbiome is altered in several gastrointestinal disorders, causing altered gut fermentation patterns recognisable by volatile organic compounds (VOC) analysis in urine, breath and faeces. We aimed to determine if CD alters the urinary VOC pattern, distinguishing it from IBS. 47 patients were recruited, 27 with established CD, on gluten free diets, and 20 with diarrhoea-predominant IBS (D-IBS). Collected urine was stored frozen in 10 ml aliquots. For assay, the specimens were heated to 40±0.1°C and the headspace analysed by Field Asymmetric Ion Mobility Spectrometry (FAIMS). Machine learning algorithms were used for statistical evaluation. Samples were also analysed using Gas chromatography and mass spectroscopy (GC-MS). Sparse logistic regression showed that FAIMS distinguishes VOCs in CD vs D-IBS with ROC curve AUC of 0.91 (0.83–0.99), sensitivity and specificity of 85% respectively. GCMS showed a unique peak at 4′67 found only in CD, not D-IBS, which correlated with the compound 1,3,5,7 cyclooctatetraene. This study suggests that FAIMS offers a novel, non-invasive approach to identify those with possible CD, and distinguishes from D-IBS. It offers the potential for monitoring compliance with a gluten-free diet at home. The presence of cyclooctatetraene in CD specimens will need further validation.     

Serological Investigation of Food Specific Immunoglobulin G Antibodies in Patients with Inflammatory Bowel Diseases

Objective

Dietary factors have been indicated to influence the pathogenesis and nature course of inflammatory bowel diseases (IBD) with their wide variances. The aim of the study was to assess the prevalence and clinical significance of 14 serum food specific immunoglobulin G (sIgG) antibodies in patients with IBD.

Methods

This retrospective study comprised a total of 112 patients with IBD, including 79 with Crohn''s disease (CD) and 33 with ulcerative colitis (UC). Medical records, clinical data and laboratory results were collected for analysis. Serum IgG antibodies against 14 unique food allergens were detected by semi-quantitative enzyme linked immunosorbent assay (ELISA).

Results

Food sIgG antibodies were detected in 75.9% (60/79) of CD patients, 63.6% (21/33) of UC patients and 33.1% (88/266) of healthy controls (HC). IBD patients showed the significantly higher antibodies prevalence than healthy controls (CD vs. HC, P = 0.000; UC vs. HC, P = 0.001). However no marked difference was observed between CD and UC groups (P = 0.184). More subjects were found with sensitivity to multiple antigens (≥3) in IBD than in HC group (33.9% vs.0.8%, P = 0.000). Egg was the most prevalent food allergen. There was a remarkable difference in the levels of general serum IgM (P = 0.045) and IgG (P = 0.041) between patients with positive and negative sIgG antibodies. Patients with multiple positive allergens (≥3) were especially found with significant higher total IgG levels compared with sIgG-negative patients (P = 0.003). Age was suggested as a protective factor against the occurrence of sIgG antibodies (P = 0.002).

Conclusions

The study demonstrates a high prevalence of serum IgG antibodies to specific food allergens in patients with IBD. sIgG antibodies may potentially indicate disease status in clinical and be utilized to guide diets for patients.     

Molecular analysis of the luminal- and mucosal-associated intestinal microbiota in diarrhea-predominant irritable bowel syndrome

Alterations in the intestinal microbiota have been suggested as an etiological factor in the pathogenesis of irritable bowel syndrome (IBS). This study used a molecular fingerprinting technique to compare the composition and biodiversity of the microbiota within fecal and mucosal niches between patients with diarrhea-predominant IBS (D-IBS) and healthy controls. Terminal-restriction fragment (T-RF) length polymorphism (T-RFLP) fingerprinting of the bacterial 16S rRNA gene was used to perform microbial community composition analyses on fecal and mucosal samples from patients with D-IBS (n = 16) and healthy controls (n = 21). Molecular fingerprinting of the microbiota from fecal and colonic mucosal samples revealed differences in the contribution of T-RFs to the microbiota between D-IBS patients and healthy controls. Further analysis revealed a significantly lower (1.2-fold) biodiversity of microbes within fecal samples from D-IBS patients than healthy controls (P = 0.008). No difference in biodiversity in mucosal samples was detected between D-IBS patients and healthy controls. Multivariate analysis of T-RFLP profiles demonstrated distinct microbial communities between luminal and mucosal niches in all samples. Our findings of compositional differences in the luminal- and mucosal-associated microbiota between D-IBS patients and healthy controls and diminished microbial biodiversity in D-IBS fecal samples further support the hypothesis that alterations in the intestinal microbiota may have an etiological role in the pathogenesis of D-IBS and suggest that luminal and mucosal niches need to be investigated.     

Risk of Ischaemic Heart Disease in Patients with Inflammatory Bowel Disease: Cohort Study Using the General Practice Research Database

ObjectivePatients with inflammatory bowel disease (IBD) demonstrate an inflammatory response which bears some similarities to that seen in ischaemic heart disease (IHD). The nature of the association of IBD with IHD is uncertain. We aimed to define the extent and direction of that association.DesignThis retrospective cohort study examined records from patients aged ≥ 15 years with IBD from 1987–2009 (n = 19163) who were age and gender matched with patients without IBD (n = 75735) using the General Practice Research Database. The primary outcome was the hazard ratio for IHD.ResultsA higher proportion of IBD patients had a recorded diagnosis of IHD ever, 2220 (11.6%) compared with 6504 (8.6%) of controls. However, the majority (4494, 51.5%) developed IHD prior to IBD diagnosis (1404 (63.2%) of IBD cases and 3090 (47.5%) of controls). There was increased IHD incidence in the first year after IBD diagnosis. Mean age at IHD diagnosis was statistically similar across all IBD groups apart from for those with Ulcerative Colitis (UC) who were slightly younger at diagnosis of angina compared to controls (64.5y vs. 67.0y, p = 0.008) and coronary heart disease (65.7y vs.67.9y, p = 0.015). Of those developing IHD following IBD diagnosis, UC patients were at higher risk of IHD (unadjusted HR 1.3 (95% CI 1.1–1.5), p<0.001) or MI (unadjusted HR 1.4 (95% CI 1.1–1.6), p = 0.004).ConclusionAlthough IHD prevalence was higher in IBD patients, most IHD diagnoses predated the diagnosis of IBD. This implies a more complex relationship than previously proposed between the inflammatory responses associated with IHD and IBD, and alternative models should be considered.     

The Vitamin D Status in Inflammatory Bowel Disease

Context

There is no consensus on the vitamin D status of children and adolescents with inflammatory bowel disease (IBD).

Aim

To determine the vitamin D status of patients with IBD by comparing their serum 25(OH)D concentration to that of healthy controls.

Hypothesis

Serum 25(OH)D concentration will be lower in patients with IBD compared to controls.

Subjects and Methods

A case-controlled retrospective study of subjects with IBD (n = 58) of 2–20 years (male n = 31, age 16.38±2.21 years; female n = 27, age16.56±2.08 years) and healthy controls (n = 116; male n = 49, age 13.90±4.59 years; female n = 67, age 15.04±4.12years). Study subject inclusion criteria: diagnosis of Crohn’s disease (CD) or ulcerative colitis (UC). Vitamin D deficiency was defined as 25(OH)D of (<20 ng/mL) (<50 nmol/L), overweight as BMI of ≥85^th but <95^th percentile, and obesity as BMI ≥95^th percentile. Data were expressed as mean ± SD.

Results

Patients with CD, UC, and their controls had mean serum 25(OH)D concentrations of 61.69±24.43 nmol/L, 53.26±25.51, and 65.32±27.97 respectively (ANOVA, p = 0.196). The overweight/obese controls had significantly lower 25(OH)D concentration compared to the normal-weight controls (p = 0.031); whereas 25(OH)D concentration was similar between the normal-weight and overweight/obese IBD patients (p = 0.883). There was no difference in 25(OH)D between patients with UC and CD, or between subjects with active IBD and controls. However, IBD subjects with elevated ESR had significantly lower 25(OH)D than IBD subjects with normal ESR (p = 0.025), as well as controls (65.3±28.0 nmol/L vs. 49.5±25.23, p = 0.045).

Conclusion

There is no difference in mean serum 25(OH)D concentration between children and adolescents with IBD and controls. However, IBD subjects with elevated ESR have significantly lower 25(OH)D than controls. Therefore, IBD subjects with elevated ESR should be monitored for vitamin D deficiency.     

Irritable Bowel Syndrome Is Associated with an Increased Risk of Dementia: A Nationwide Population-Based Study

Purpose

Abnormal interaction in the brain–gut axis has emerged as one of the relevant pathophysiological mechanisms for the development of irritable bowel syndrome (IBS). Moreover, the brain–gut axis has recently been demonstrated to be crucial for the maintenance of cognitive performance. Therefore, we assessed the risk of dementia following diagnosis of IBS.

Methods

Using the Taiwan National Health Insurance Research Database (NHIRD) to obtain medical claims data from 2000 to 2011, we employed a random sampling method to enroll32 298 adult patients with IBS and frequency-matched them according to sex, age, and baseline year with 129 192 patients without IBS.

Results

The patients with IBS exhibited an increased risk of dementia [adjusted hazard ratio (aHR) = 1.26, 95% confidence interval (CI) = 1.17–1.35]after adjustment for age, sex, diabetes, hypertension, stroke, coronary artery disease (CAD), head injury, depression, and epilepsy, and the overall incidence of dementia for the cohorts with and without IBS was 4.86 and 3.41 per 1000 person-years, respectively. IBS was associated with an increased risk of dementia in patients older than 50 years in both male and female, and in those with comorbidity or without comorbidity. After adjustment for age, sex, and comorbidity, patients with IBS were also more likely to develop either non- Alzheimer’s disease (AD) dementia (aHR = 1.24, 95% CI = 1.15–1.33) or AD (aHR = 1.76, 95% CI = 1.28–2.43).

Conclusions

IBS is associated with an increased risk of dementia, and this effect is obvious only in patients who are ≥50 years old.     

Gender distribution in irritable bowel syndrome is proportional to the severity of constipation relative to diarrhea

Background: A significant gender disparity has been observed in individuals with irritable bowel syndrome (IBS), with females outnumbering males, especially in constipation-predominant IBS (C-IBS). However, this observation is based on Rome criteria categorization and does not take into account the severity of constipation or diarrhea.Objective: In a large prospective data set, gender differences across the severity of constipation and diarrhea were examined in patients with IBS.Methods: Consecutive adult patients with Rome I positive IBS who were referred to a tertiary care medical center (Cedars-Sinai Medical Center, Los Angeles, California) in 1999–2003 were given a questionnaire. The questionnaire asked subjects to rate their constipation and diarrhea according to perceived severity using a scale from 0 (none) to 5 (very severe). C-IBS was determined to be present if the severity of constipation was greater than the severity of diarrhea (sevC > sevD). If sevD > sevC, subjects were considered to have diarrhea-predominant IBS (D-IBS). To further categorize their symptoms, subjects were then grouped by the difference between the severity of constipation and diarrhea, creating a range of values from ?5 to +5. For each of these 11 constipation/diarrhea severity values, the female:male ratio was determined. The severity of constipation to diarrhea was compared by Spearman rank correlation.Results: A total of 429 subjects with IBS (325 women: mean [SD] age, 42.5 [0.8] years; 104 men: mean age, 42.2 [1.7] years) completed the questionnaire. Constipation occurred more frequently in women (79.7%) compared with men (61.5%) (odds ratio [OR] = 2.49; 95% CI, 1.55–4.02). The prevalence of diarrhea was similar between the sexes. Whereas C-IBS was more common in women (31.8%) than in men (26.0%) (OR = 2.03; 95% CI, 1.24–3.30), D-IBS was more prevalent in men (62.5%) than in women (36.3%) (OR = 2.39; 95% CI, 1.53–3.75). When the female:male ratio was evaluated across the 11 severity score categories of constipation and diarrhea, the greater the sevC — sevD score, the higher the proportion of women (R = 0.80; P = 0.003).Conclusion: In this study of patients with IBS, the observation of the association of constipation and gender in IBS is extended to indicate that the female:male ratio significantly increases according to the severity of constipation relative to the severity of diarrhea.     

Gluten-free diet in the management of patients with irritable bowel syndrome,fibromyalgia and lymphocytic enteritis

An evaluation of the effect of 1 year of a gluten-free diet was performed in patients with irritable bowel syndrome and fibromyalgia syndrome displaying lymphocytic enteritis. Gluten withdrawal produced a slight but significant improvement of the functional symptoms, suggesting that gluten might be partly responsible for this clinical picture. This hypothesis should be confirmed by a double-blind placebo-controlled trial since it cannot be ruled out that the studied patients displayed a subjective sensation of improvement due to the placebo effect of gluten withdrawal. Further investigations are needed before recommending gluten withdrawal in patients with fibromyalgia and lymphocytic enteritis.In their paper published in a recent issue of Arthritis Research and Therapy, Rodrigo and colleagues evaluated the effect of 1 year of a gluten-free diet on the clinical evolution of irritable bowel syndrome (IBS) plus fibromyalgia syndrome (FMS) in patients with lymphocytic enteritis (LE) [1]. The study sample included 97 adult females with IBS and FMS, of whom 58 had LE and the remaining 39 had a normal intraepithelial lymphocytic (IEL) count. All subjects fulfilled the Rome III criteria for IBS and the American College of Rheumatology 1990 criteria for FMS and none of them satisfied the diagnostic criteria for celiac disease diagnosis (absence of villous atrophy and negativity for tissue transglutaminase antibodies).IBS and FMS are two chronic functional disorders that are found in a high number of people in the general population and are frequently detected in the same subject [2]. A subset of patients complaining of IBS and FMS displays LE, a morphological finding that by itself is not specific for celiac disease, also being found in many other pathological conditions such as food allergy, autoimmune disorders, Helicobacter pylori infection, nonsteroidal anti-inflammatory drug treatment and common variable immunodeficiency [3].The spectrum of gluten-related disorders has recently acquired a new syndrome, defined as nonceliac gluten sensitivity according to the criteria established in the two Consensus Conferences held in London and Munich [4]. This new clinical entity is characterized by IBS-like symptoms and several extraintestinal manifestations occurring after gluten ingestion in patients without celiac disease and wheat allergy. In a recent prospective multicenter survey of 486 patients with nonceliac gluten sensitivity, IBS and FMS were respectively detected in 47% and 31% of cases and about one-third of these patients had LE [5].Along with IBS-related and FMS-related symptoms, the patients studied by Rodrigo and colleagues also showed other manifestations resembling the clinical picture of nonceliac gluten sensitivity such as skin rash, cognitive dysfunction, headache, numbness, anxiety and depression [1].In Rodrigo and colleagues’ paper, the gluten-free diet produced a slight but significant improvement of both IBS-related (chronic abdominal pain, changes in intestinal habit, bloating) and FMS-related symptoms (chronic widespread pain, generalized tender points, fatigue and restless sleep) in the LE subgroup versus the non-LE subgroup. These results stress the potential role of gluten as a trigger of the clinical manifestations of IBS and FMS and indicate that LE might be useful to identify those patients who potentially benefit from gluten withdrawal. One relevant limitation of this study is the lack of a double-blind placebo-controlled challenge, which is the only procedure to confirm the role of gluten proteins in the development of these clinical manifestations. Indeed, it cannot be ruled out that some patients displayed a subjective sensation of improvement due to the placebo effect of a gluten-free diet [6]. The search for antigliadin antibodies could be of help to elucidate whether gluten can be partly responsible for the clinical picture observed in Rodrigo and colleagues’ patients. Indeed, antigliadin antibodies (particularly those belonging to the IgG class) are the only marker observed in patients with symptoms elicited by gluten ingestion, being positive in more than 50% of cases [7]. These antibodies are not specific for gluten-related symptoms, but their finding in patients with symptoms potentially evoked by gluten ingestion should be regarded as an indication for a gluten-free diet trial in patients with LE [8]. Antigliadin antibodies of the IgG class are closely related to the gluten-induced symptoms and tend to disappear very quickly (within a few weeks) together with the remission of symptoms after a gluten-free diet [9].An interesting finding emerging from the Spanish study is that about 20% of IBS/FMS patients with LE had relatives with celiac disease, whereas no familial case of celiac disease was observed among patients without LE [1]. In the same guise, familial cases of FMS were found, although to a lesser extent, only in the group with LE (7%). These data suggest that first-degree relatives of IBS/FMS patients with LE should be carefully investigated for the possible presence of undetected cases of celiac disease and FMS. For LE, the mean IEL number reported in Rodrigo and colleagues’ paper was 35/100. This result confirms that LE found in gluten-sensitive patients is mild, with a lower mean IEL number than that usually observed in celiac disease patients (usually >40/100) [10].The caution in the conclusions of Rodrigo and colleagues’ study is appreciable and shareable. A gluten-free diet is not appropriate in patients with IBS/FMS with normal intestinal mucosa (normal IEL count). Moreover, although the reported results suggest a significant improvement of symptomatology after a gluten-free diet in the LE subgroup, further studies including double-blind placebo-controlled trials are needed before proposing gluten withdrawal in IBS/FMS patients with LE.     

Association of Proteinuria Threshold in Pre-Eclampsia with Maternal and Perinatal Outcomes: A Nested Case Control Cohort of High Risk Women

Objectives

To evaluate occurrence of adverse maternal and perinatal outcomes with different thresholds of proteinuria (300-499mg and ≥500mg/24 hours) in pre-eclamptic women, comparing outcomes against women with chronic and gestational hypertension.

Design

Secondary analysis of the Vitamins in Pre-Eclampsia Trial.

Setting

25 UK hospitals in ten geographical areas.

Population

946 women with pre-existing risk factors for pre-eclampsia.

Methods

Women with pre-eclampsia and proteinuria 300-499mg/24h (PE300, referent group, n=60) or proteinuria ≥500 mg/24h (PE500, n=161) were compared with two groups of non-proteinuric women with chronic hypertension (CHT, n=615) or gestational hypertension (GH, n=110).

Main Outcome Measures

Maternal: progression to severe hypertension. Perinatal: small for gestational age (SGA) <5^th centile, gestation at delivery.

Results

Severe hypertension occurred more frequently in PE500 (35%) and PE300 (27%) than CHT (5.9%; P≤0.01) and GH (10%; p≤0.001). Gestation at delivery was earlier in PE500 (33.2w) than PE300 (37.3w; P≤0.001), and later in CHT (38.3w; P≤0.05) and GH (39.1w; P≤0.001). SGA infants were more frequent in PE300 (32%) than in CHT (13.3%; P≤0.001) and GH (16.5%; P≤0.05). Women in PE500 were more likely to have a caesarean section than PE300 (78% vs. 48%; P≤0.001), and to receive magnesium sulphate (17% vs. 1.7%, P≤0.05).

Conclusion

Women with PE300 have complication rates above those of women managed as out-patients (GH and CHT), meriting closer surveillance and confirming 300 mg/d as an appropriate threshold for determining in-patient management. Adverse perinatal outcomes are higher still in women with PE500.     

Mucosa-Associated Faecalibacterium prausnitzii Phylotype Richness Is Reduced in Patients with Inflammatory Bowel Disease

Faecalibacterium prausnitzii depletion in intestinal diseases has been extensively reported, but little is known about intraspecies variability. This work aims to determine if subjects with gastrointestinal disease host mucosa-associated F. prausnitzii populations different from those hosted by healthy individuals. A new species-specific PCR-denaturing gradient gel electrophoresis (PCR-DGGE) method targeting the 16S rRNA gene was developed to fingerprint F. prausnitzii populations in biopsy specimens from 31 healthy control (H) subjects and 36 Crohn''s disease (CD), 23 ulcerative colitis (UC), 6 irritable bowel syndrome (IBS), and 22 colorectal cancer (CRC) patients. The richness of F. prausnitzii subtypes was lower in inflammatory bowel disease (IBD) patients than in H subjects. The most prevalent operational taxonomic units (OTUs) consisted of four phylotypes (OTUs with a 99% 16S rRNA gene sequence similarity [OTU99]), which were shared by all groups of patients. Their distribution and the presence of some disease-specific F. prausnitzii phylotypes allowed us to differentiate the populations in IBD and CRC patients from that in H subjects. At the level of a minimum similarity of 97% (OTU97), two phylogroups accounted for 98% of the sequences. Phylogroup I was found in 87% of H subjects but in under 50% of IBD patients (P = 0.003). In contrast, phylogroup II was detected in >75% of IBD patients and in only 52% of H subjects (P = 0.005). This study reveals that even though the main members of the F. prausnitzii population are present in both H subjects and individuals with gut diseases, richness is reduced in the latter and an altered phylotype distribution exists between diseases. This approach may serve as a basis for addressing the suitability of F. prausnitzii phylotypes to be quantified as a putative biomarker of disease and depicting the importance of the loss of these subtypes in disease pathogenesis.     

Combination of High Ankle–Brachial Index and Hard Coronary Heart Disease Framingham Risk Score in Predicting the Risk of Ischemic Stroke in General Population

Our previous study showed that the patients with more metabolic risk factors had higher risk of high ankle–brachial index (ABI), but the relationship between high ABI and the risk of severe cardiovascular and cerebrovascular diseases is still under debate. This study aims to evaluate this association in the general population. 1486 subjects of South China were recruited in the study. 61 subjects were defined as high ABI group (ABI≥1.3) and 65 subjects were randomly selected as normal ABI group (0.9<ABI<1.3). Biochemical parameters, clinical characteristics and 10-year hard coronary heart disease (HCHD) Framingham Risk Score (FRS) were compared between two groups. The results showed that the 10-year HCHD FRS of high ABI group was significantly higher than normal ABI group (7.87±6.11 vs. 3.98±2.90%, P<0.001). There was a positive correlation between ABI value and HCHD FRS in overweight participants (R = 0.576, P<0.01). The prevalence of ischemic stroke was higher in high ABI group than normal ABI group (21.3% vs. 6.2%, P<0.05), and it was higher in participants with HCHD FRS≥6% than those with HCHD FRS<6% (19.1% vs. 6.9%, P<0.05). Moreover, the prevalence of ischemic stroke was higher in participants with high ABI and HCHD FRS≥6% than those with normal ABI and HCHD FRS<6% (26.7% vs. 4.1%, P<0.05). BMI, hypertension, hsCRP and smoking were proved to be the independent factors and effective predictors for high ABI (P<0.05). In conclusion, high ABI combined with high HCHD FRS should be a potential predictor of ischemic stroke in the general population of South China.     

Use of Thiopurines and Risk of Colorectal Neoplasia in Patients with Inflammatory Bowel Diseases: A Meta-Analysis

Objective

Inflammatory bowel disease (IBD) is commonly treated with thiopurines such as azathioprine and mercaptopurine for the maintenance of remission. Studies examining chemopreventive of these medications on colorectal neoplasm in IBD patients have yielded conflicting results. We performed a meta-analysis to assess the role of thiopurines for this indication.

Methods

We performed a systematic search of PubMed, Web of Science, EMBASE and Cochrane to identify studies reporting colorectal neoplasm from IBD patients treated with thiopurines and conducted a meta-analysis of pooled relative risk (RR) using the random effects model.

Results

Nine case-control and ten cohort studies fulfilled the inclusion criteria. The use of thiopurines was associated with a statistically significant decreased incidence of colorectal neoplasm (summary RR=0.71, 95% CI=0.54–0.94, p=0.017), even after adjustment for duration and extent of the disease, but there was high heterogeneity among studies (I ²=68.0%, p<0.001). The RR of advanced neoplasm (high-grade dysplasia and cancer) was 0.72 (95%CI=0.50–1.03, p=0.070) and that of cancer was 0.70 (95% CI=0.46–1.09, p=0.111) for thiopurine-treated patients. Heterogeneity of the studies was affected by the sample size (</≥100 cases) and whether the patients had longstanding colitis (≥7 years).

Conclusion

The current meta-analysis revealed that thiopurines had a chemopreventive effect of colorectal neoplasms and a tendency of reducing advanced colorectal neoplasms in IBD. Due to the heterogeneity of included studies, these results should be interpreted with caution.     

The Incidence of Other Gastroenterological Disease following Diagnosis of Irritable Bowel Syndrome in the UK: A Cohort Study

Background

Guidelines recommend Irritable Bowel Syndrome (IBS) diagnosis and management in primary care with minimal investigations; however little evidence exists regarding risk of organic gastrointestinal conditions following diagnosis of IBS and how such risks vary over the long term. This study assesses excess incidence of coeliac disease, inflammatory bowel disease (IBD) and colorectal cancer (CRC) and variation with age and time after IBS diagnosis.

Methods

IBS patients and controls were identified within the UK Clinical Practice Research Dataset. Incidence rates were calculated and stratified by age and time since IBS diagnosis with incident rate ratios generated.

Results

Fifteen years after IBS diagnosis there is a significant cumulative excess incidence of coeliac disease, IBD and CRC in IBS of 3.7% compared to 1.7% in controls. For every 10000 patient years, IBS patients experienced an additional 4 diagnoses of coeliac disease, 13 of IBD and 4 CRCs. In each condition peak excess incidence was in the 6 months following diagnosis. After one year, increased incidence of coeliac disease remained consistent without variation by age. IBD incidence fell slowly, with higher rates in those under 30. CRC incidence was increased only in patients aged 30 to 74 during the first 5 years.

Conclusion

Some IBS patients later receive organic gastrointestinal diagnoses, with the early excess incidence likely detected during diagnostic investigation at the time of IBS diagnosis. More than 5 years after IBS diagnosis there is no increased risk of CRC compared to the general population, but a small excess risk of coeliac disease and IBD persists. Overall, though our findings provide reassurance that non-specialists, especially those in primary care, are unlikely to be missing an organic condition in the majority of their patients. This suggests that current guidelines suggesting avoidance of universal referral for these patients are appropriate.     

Factors Associated with Higher Sitting Time in General,Chronic Disease,and Psychologically-Distressed,Adult Populations: Findings from the 45 & Up Study

This study examined factors associated with higher sitting time in general, chronic disease, and psychologically-distressed, adult populations (aged ≥45 years). A series of logistic regression models examined potential socio-demographic and health factors associated with higher sitting (≥6hrs/day) in adults from the 45 and Up Study (n = 227,187), including four separate subsamples for analysis comprising those who had ever had heart disease (n = 26,599), cancer (n = 36,381), diabetes (n = 19,550) or psychological distress (n = 48,334). Odds of higher sitting were significantly (p<.01) associated with a number of factors across these groups, with an effect size of ORs≥1.5 observed for the high-income ≥$70,000AUD, employed full-time and severe physical limitations demographics. Identification of key factors associated with higher sitting time in this population-based sample will assist development of broad-based, public health and targeted strategies to reduce sitting-time. In particular, those categorized as being high-income earners, full-time workers, as well as those with severe physical limitations need to be of priority, as higher sitting appears to be substantial across these groups.     

Identification of Non-HLA Genes Associated with Celiac Disease and Country-Specific Differences in a Large,International Pediatric Cohort

Objectives

There are significant geographical differences in the prevalence and incidence of celiac disease that cannot be explained by HLA alone. More than 40 loci outside of the HLA region have been associated with celiac disease. We investigated the roles of these non-HLA genes in the development of tissue transglutaminase autoantibodies (tTGA) and celiac disease in a large international prospective cohort study.

Methods

A total of 424,788 newborns from the US and European general populations and first-degree relatives with type 1 diabetes were screened for specific HLA genotypes. Of these, 21,589 carried 1 of the 9 HLA genotypes associated with increased risk for type 1 diabetes and celiac disease; we followed 8676 of the children in a 15 y prospective follow-up study. Genotype analyses were performed on 6010 children using the Illumina ImmunoChip. Levels of tTGA were measured in serum samples using radio-ligand binding assays; diagnoses of celiac disease were made based on persistent detection of tTGA and biopsy analysis. Data were analyzed using Cox proportional hazards analyses.

Results

We found 54 single-nucleotide polymorphisms (SNPs) in 5 genes associated with celiac disease (TAGAP, IL18R1, RGS21, PLEK, and CCR9) in time to celiac disease analyses (10⁻⁴>P>5.8x10⁻⁶). The hazard ratios (HR) for the SNPs with the smallest P values in each region were 1.59, 1.45, 2.23, 2.64, and 1.40, respectively. Outside of regions previously associated with celiac disease, we identified 10 SNPs in 8 regions that could also be associated with the disease (P<10⁻⁴). A SNP near PKIA (rs117128341, P = 6.5x10⁻⁸, HR = 2.8) and a SNP near PFKFB3 (rs117139146, P<2.8x10⁻⁷, HR = 4.9) reached the genome-wide association threshold in subjects from Sweden. Analyses of time to detection of tTGA identified 29 SNPs in 2 regions previously associated with celiac disease (CTLA4, P = 1.3x10⁻⁶, HR = 0.76 and LPP, P = 2.8x10⁻⁵, HR = .80) and 6 SNPs in 5 regions not previously associated with celiac disease (P<10⁻⁴); non-HLA genes are therefore involved in development of tTGA.

Conclusions

In conclusion, using a genetic analysis of a large international cohort of children, we associated celiac disease development with 5 non-HLA regions previously associated with the disease and 8 regions not previously associated with celiac disease. We identified 5 regions associated with development of tTGA. Two loci associated with celiac disease progression reached a genome-wide association threshold in subjects from Sweden.