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Childhood gut dysfunction (enteropathy) is common in resource-poor environments. Stunting is its presumed major consequence. Identification of biomarkers of gut dysfunction could identify the presence of, and, ideally, assess interventions for, enteropathy. Classically, enteropathy has been identified histopathologically. However, less invasive assays may be more sensitive for detecting earlier perturbations reflecting specific functional derangements. The most commonly used test has been the urinary lactulose to mannitol ratio (L:M), which primarily assesses gut leakiness, and which also measures absorption. We systematically reviewed the L:M literature published from 2000 to 2010 pertinent to children in developing country settings, and identified 25 relevant publications representing heterogeneous studies. We conclude that the L:M test has many attributes, including reflecting 2 physiologic processes (absorption and permeability) and likely correlation with growth failure consequent to child gut dysfunction. However, improved test technical performance, data reporting, and correlation with host phenotypes are needed to maximize the utility of this test.

A central hypothesis of The Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) study is that enteropathogens contribute to growth faltering. To examine this question, the MAL-ED network of investigators set out to achieve 3 goals: (1) develop harmonized protocols to test for a diverse range of enteropathogens, (2) provide quality-assured and comparable results from 8 global sites, and (3) achieve maximum laboratory throughput and minimum cost. This paper describes the rationale for the microbiologic assays chosen and methodologies used to accomplish the 3 goals.

Intestinal parasitic infections are a major public health problem in inter-tropical areas. The aim of our study was to describe the situation in Mahajanga, Madagascar with a particular focus on two protozoa, Dientamoeba fragilis and Blastocystis sp. This was a prospective study from February to June 2015. Stool samples from symptomatic hospitalized patients and asymptomatic volunteers were submitted to microscopy and molecular assays in order to detect parasites. A wide panel of intestinal parasites were identified among the 265 included subjects, protozoa being the most prevalent with 72.8% whereas the prevalence of helminths and microsporidia was of 7.9% and 4.5%, respectively. Blastocystis sp. was the most prevalent protozoa (64.5% of the entire cohort) followed by various amoebas (35.5%) and flagellates (27,5%). We only detected subtypes 1, 2 and 3 of Blastocystis sp. Among the patients positive for D. fragilis (9.4%), 23 carried genotype 1 and 1 genotype 2. For the first time, we detected in 4 human stools the DNA of a recently described protozoon, Simplicimonas similis. Interestingly, subjects living in urban areas harbored significantly more different parasitic species than subjects living in rural areas with a correlation between sanitary level of neighborhood and protozoan infection. However, there was no difference in prevalence of digestive symptoms between parasite-free and parasite-infected subjects, except for Giardia intestinalis which had more symptomatic carriers. Our study reveals a high overall parasite prevalence, similar to what had been found in 2003 in the same city and to other prevalence studies conducted in Africa. The poor access of the population to sanitary infrastructures may explain this result. Data from our study provide valuable key for sanitation programs and prevention of fecal-related infectious diseases.

Context.—An increased intraepithelial lymphocyte density in an architecturally normal proximal small intestinal mucosal biopsy is a common finding facing surgical pathologists dealing with gastrointestinal biopsy specimens. Approximately 1% to 2% of all proximal small intestinal biopsies will show this change. It is increasingly recognized by surgical pathologists that gluten-sensitive enteropathy is an important cause of this pattern; however, gluten-sensitive enteropathy accounts for the minority of all cases. A wide variety of immunologic stimuli can raise intraepithelial lymphocyte numbers. Among the other common associations are enteric infection, autoimmune disease, drugs, and gastric Helicobacter infection. Objective.—To outline the causes of intraepithelial lymphocytosis, to highlight the importance and the difficulties faced in establishing gluten-sensitive enteropathy as the cause, and to aid the surgical pathologist in the routine sign out of these cases. Data Sources.—A review of the literature detailing the causes or associations of proximal small intestinal intraepithelial lymphocytosis is presented. Conclusions.—Increased lymphocyte numbers in the epithelium of architecturally preserved proximal small intestinal biopsies is a morphologic feature associated with a broad differential diagnosis.

Small bowel pathology can be diagnosed using enteroscopy (which has limitations) and by x-ray (which is not sensitive for flat lesions). For the first time ever, we used a new technique, wireless-capsule video endoscopy, to diagnose small bowel pathology. Our aim was to prove the effectiveness and safety of this technology. We used the Given (M2A) system in 35 patients, aged 18–80 yr, who suffered from unexplained GI bleeding or in whom there was a clinical suspicion of small bowel disease. All patients had a small bowel x-ray. Patients with suspected narrowing of the bowel or a clinical suspicion of intestinal obstruction, or with a history of major abdominal surgery, were excluded from the study. No pregnant women or patients with diabetes mellitus were included. Abnormal findings were found in 29 of 35 (82.9%) patients. Twenty-two of 29 (75.9%) patients had significant pathological findings explaining their clinical situation. Diagnostic yield was therefore 62.9% (22 of 35 patients). Among the various findings, the capsule detected ulcers, erosions, angiodysplasia, and submucosal lesions. The source of bleeding was found in 15 of 20 patients with iron deficiency anemia. There were no immediate significant side effects and none reported up to 1 month after ingestion of the capsule. The capsule was evacuated by all patients. The wireless-capsule video endoscope, in our study of feasibility, was proven to be a safe, painless, ambulatory, and effective procedure, with a high diagnostic yield. Its major importance is in diagnosing small bowel pathology where all other imaging techniques have failed.

To systematically review the prophylactic and therapeutic interventions for reducing the incidence or severity of intestinal symptoms among cancer patients receiving radiotherapy. A literature search was conducted in the PubMed database using various search terms, including ‘radiation enteritis’, ‘radiation enteropathy’, ‘radiation-induced intestinal disease’, ‘radiation-induced intestinal damage’ and ‘radiation mucositis’. The search was limited to studies, clinical trials and meta-analyses published in English with no limitation on publication date. Other relevant literature was identified based on the reference lists of selected studies. The pathogenesis of acute and chronic radiation-induced intestinal damage as well as the prevention and treatment approaches were reviewed. There is inadequate evidence to strongly support the use of a particular strategy to reduce radiation-induced intestinal damage. More high-quality randomized controlled trials are required for interventions with limited evidence suggestive of potential benefits.

Urinary excretion of two orally-administered non-metabolizable sugars, lactulose and mannitol, is a valuable marker for evaluating intestinal permeability. Usually this test involves a time consuming procedure of about 5 hour's urine collection, which makes the test incompatible to some extent. As the results are expressed as the ratio of lactulose and mannitol recovered in urine within certain time, it may be possible to get similar result despite the reduced urine collection time of 2 hours. Moreover, different laboratories do the test by different methods, which make the results incomparable between laboratories. Here, we are also trying to find the correlation between results from most commonly used methods: HPAE-PAD and LC-MSMS. The lactulose: mannitol (LM) test was performed in a cohort of Bangladeshi infants considered at-risk for environmental enteropathy. 208 urine specimens from 104 (52 male and 52 female) infants were collected at 2 and 5 hours after LM solution administration and were tested for lactulose and mannitol by two different methods, one HPAE-PAD platform and another LC-MSMS platform. Median age of the children was 15.0 months (range 6.9 to 25.8 months) and their mean weight-for-age z-score was -0.92. A higher percentage of lactulose and mannitol recovery was found in 5 hours urine collection than in the corresponding 2 hours by both HPAE-PAD and LC-MSMS method, but when results were expressed as lactulose to mannitol ratio (LMR) there was no significant difference between 2 and 5 hours urine collection in both HPAE-PAD (P = 0.138) and LC-MSMS (P = 0.099) method. LMR based on 2 hours urine collection correlated well with LMR based on traditional 5 hours urine collection (Spearman's correlation coefficient 0.578 and 0.604 respectively for HPAE-PAD and LC-MSMS). In future, LM test to assess intestinal permeability in children can be simplified by shortening the urine collection time from 5 hours to 2 hours.

Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) Syndrome is a rare recessive disorder caused by mutations in the gene. In addition, there has been an increasing number of patients with wild-type gene and, in some cases, mutations in other immune regulatory genes. To molecularly asses a cohort of 173 patients with the IPEX phenotype and to delineate the relationship between the clinical/immunologic phenotypes and the genotypes. We reviewed the clinical presentation and laboratory characteristics of each patient and compared clinical and laboratory data of mutation-positive (IPEX patients) with those from mutation-negative patients (IPEX-like). A total of 173 affected patients underwent direct sequence analysis of the gene while 85 IPEX-like patients with normal FOXP3 were investigated by a multiplex panel of \"Primary Immune Deficiency (PID-related) genes.\" Forty-four distinct variants were identified in 88 IPEX patients, 9 of which were not previously reported. Among the 85 IPEX-like patients, 19 different disease-associated variants affecting 9 distinct genes were identified. We provide a comprehensive analysis of the clinical features and molecular bases of IPEX and IPEX-like patients. Although we were not able to identify major distinctive clinical features to differentiate IPEX from IPEX-like syndromes, we propose a simple flow-chart to effectively evaluate such patients and to focus on the most likely molecular diagnosis. Given the large number of potential candidate genes and overlapping phenotypes, selecting a panel of PID-related genes will facilitate a molecular diagnosis.

The bleeding source of hematochezia is unknown without performing colonoscopy. We sought to identify whether colonoscopy is a risk-stratifying tool to identify etiology and predict outcomes and whether presenting symptoms can differentiate the etiologies in patients with hematochezia. This multicenter retrospective cohort study conducted at 49 hospitals across Japan analyzed 10,342 patients admitted for outpatient-onset acute hematochezia. Patients were mostly elderly population, and 29.5% had hemodynamic instability. Computed tomography was performed in 69.1% and colonoscopy in 87.7%. Diagnostic yield of colonoscopy reached 94.9%, most frequently diverticular bleeding. Thirty-day rebleeding rates were significantly higher with diverticulosis and small bowel bleeding than with other etiologies. In-hospital mortality was significantly higher with angioectasia, malignancy, rectal ulcer, and upper gastrointestinal bleeding. Colonoscopic treatment rates were significantly higher with diverticulosis, radiation colitis, angioectasia, rectal ulcer, and postendoscopy bleeding. More interventional radiology procedures were needed for diverticulosis and small bowel bleeding. Etiologies with favorable outcomes and low procedure rates were ischemic colitis and infectious colitis. Higher rates of painless hematochezia at presentation were significantly associated with multiple diseases, such as rectal ulcer, hemorrhoids, angioectasia, radiation colitis, and diverticulosis. The same was true in cases of hematochezia with diarrhea, fever, and hemodynamic instability. This nationwide data set of acute hematochezia highlights the importance of colonoscopy in accurately detecting bleeding etiologies that stratify patients at high or low risk of adverse outcomes and those who will likely require more procedures. Predicting different bleeding etiologies based on initial presentation would be challenging.

Crohn's disease is often purely inflammatory at presentation, but most patients develop strictures and fistulae over time (complicated disease). Many studies have suggested that nucleotide-binding oligomerization domain 2 (NOD2) mutations are associated with a varying but increased risk of complicated disease. An accurate and sufficiently powerful predictor of complicated disease could justify the early use of biological therapy in high-risk individuals. We performed a systematic review and meta-analysis to obtain accurate estimates of the predictive power of the identified mutations (such as p.R702W, P.G908R, and p.Leu1007fsX1008) in NOD2 for the risk of complicated disease. An electronic search of MEDLINE, Embase, and Web of Science identified 917 relevant papers. Inclusion required specification of genetic mutations at the individual level and disease phenotypes by Vienna classification (inflammatory (B1), stricturing (B2), and fistulizing (B3)). A total of 49 studies met these criteria, which included 8,893 subjects, 2,897 of whom had NOD2 mutations. Studies were weighted by median disease duration. Studies not providing duration data were weighted at the level of the study with the shortest disease duration (3.9 years). The relative risk (RR) of the presence of any NOD2 mutant allele for complicated disease (B2 or B3) was 1.17 (95% confidence interval (95% CI) 1.10-1.24; P<0.001). P.G908R was associated with an RR of complicated disease of 1.33 (95% CI 1.11-1.60; P=0.002). NOD2 did not predict perianal disease (P=0.4). The RR of surgery was 1.58 (95% CI 1.38-1.80; P<0.001). There was substantial heterogeneity across all studies (I(2)=66.7%). On the basis of logistic regression of these data, the sensitivity of any mutation in predicting complicated disease was 36% and specificity was 73%, with the area under the receiver operating characteristic curve 0.56. The presence of a single NOD2 mutation predicted an 8% increase in the risk for complicated disease (B2 or B3), and a 41% increase with 2 mutations. Surgery risk is increased by 58% with any NOD2 mutation, whereas perianal disease was unchanged. The predictive power associated with a single NOD2 mutation is weak. The RR of any NOD2 mutations for complicated disease was only 17% across 36 studies. However, the presence of two NOD2 mutations had 98% specificity for complicated disease. These data provide insufficient evidence to support top-down therapy based solely on single NOD2 mutations, but suggest that targeted early-intensive therapy for high-risk patients with two NOD2 mutations might be beneficial, if prospective trials can demonstrate changes in the natural history in this subset of patients.