Juan Cristóbal Gana

NADPH oxidase complex and IBD candidate gene studies: identification of a rare variant in NCF2 that results in reduced binding to RAC2

Objective The NOX2 NADPH oxidase complex produces reactive oxygen species and plays a critical role in the killing of microbes by phagocytes. Genetic mutations in genes encoding components of the complex result in both X-linked and autosomal recessive forms of chronic granulomatous disease (CGD). Patients with CGD often develop intestinal inflammation that is histologically similar to Crohns colitis, suggesting a common aetiology for both diseases. The aim of this study is to determine if polymorphisms in NOX2 NADPH oxidase complex genes that do not cause CGD are associated with the development of inflammatory bowel disease (IBD). Methods Direct sequencing and candidate gene approaches were used to identify susceptibility loci in NADPH oxidase complex genes. Functional studies were carried out on identified variants. Novel findings were replicated in independent cohorts. Results Sequence analysis identified a novel missense variant in the neutrophil cytosolic factor 2 (NCF2) gene that is associated with very early onset IBD (VEO-IBD) and subsequently found in 4% of patients with VEO-IBD compared with 0.2% of controls (p=1.3×10−5, OR 23.8 (95% CI 3.9 to 142.5); Fisher exact test). This variant reduced binding of the NCF2 gene product p67phox to RAC2. This study found a novel genetic association of RAC2 with Crohns disease (CD) and replicated the previously reported association of NCF4 with ileal CD. Conclusion These studies suggest that the rare novel p67phox variant results in partial inhibition of oxidase function and are associated with CD in a subgroup of patients with VEO-IBD; and suggest that components of the NADPH oxidase complex are associated with CD.

A Clinical Prediction Rule and Platelet Count Predict Esophageal Varices in Children

BACKGROUND & AIMS The validation of noninvasive tests to diagnose esophageal varices is a priority in children because repeated endoscopic evaluations are too invasive. We measured the ability of a previously developed noninvasive clinical prediction rule (CPR) to predict the presence of esophageal varices in children. METHODS We analyzed data from 108 children, younger than age 18, who received endoscopies at 8 centers, to assess portal hypertension from chronic liver disease or portal vein obstruction. Blood test and abdominal ultrasound scan results were obtained within 4 months of endoscopy. Grading of varices identified by endoscopy was confirmed by independent blinded review. Spleen size, based on data from the ultrasound scan, was expressed as a standard deviation score relative to normal values for age. RESULTS Of the children studied, 74 had esophageal varices (69%), including 35 with large varices (32%). The best noninvasive predictors of esophageal varices of any size were as follows: platelet:spleen size z-score ratio (area under the receiver operating characteristic curve [AUROC], 0.84; 95% confidence interval [CI] 0.75-0.93), CPR (AUROC, 0.80; 95% CI, 0.70-0.91), and platelet count (AUROC, 0.79; 95% CI, 0.69-0.90). The positive predictive values for the CPR and platelet count were 0.87 and 0.86, the negative predictive values were 0.64 and 0.63, the positive likelihood ratios were 3.06 and 2.76, and the negative likelihood ratios were 0.64 and 0.63, respectively. Based on positive and negative predictive values, the most accurate noninvasive tests were the CPR and platelet counts. CONCLUSIONS Noninvasive tests such as CPR and platelet count can assist in triaging children for endoscopy to identify esophageal varices.

Congenital portosystemic shunt: characterization of a multisystem disease.

Objectives: Congenital portosystemic shunts (CPSSs) are rare but increasingly recognized as a cause of important multisystem morbidity. We present new cases and a systematic literature review and propose an algorithm for the identification and care of affected patients. Methods: We reviewed the charts of consecutive patients seen in our pediatric liver clinic between 2003 and 2010 and systematically reviewed the literature of cases with CPSS. Results: We identified 316 published cases and 12 patients in our own clinic. Of the published cases (177 male), 185 had an extrahepatic and 131 an intrahepatic portosystemic shunt. Diagnosis was made at any age, from prenatal to late adulthood. Cardiac anomalies were found in 22% of patients. The main complications were hyperammonemia/neurological abnormalities (35%), liver tumors (26%), and pulmonary hypertension or hepatopulmonary syndrome (18%). The spectrum of neurological involvement ranged from changes in brain imaging, subtle abnormalities on neuropsychological testing, through learning disabilities to overt encephalopathy. Spontaneous shunt closure occurred mainly in infants with intrahepatic shunts. Therapeutic interventions included shunt closure by surgery or interventional radiology techniques (35%) and liver transplantation (10%) leading to an improvement of symptoms in the majority. These findings mirror the observations in our own patients. Conclusions: In this largest review of the reported clinical experience, we identify that children with CPSS may present with otherwise unexplained developmental delay, encephalopathy, pulmonary hypertension, hypoxemia, or liver tumors. When CPSS is diagnosed, children should be screened for all of these complications. Spontaneous closure of intrahepatic shunts may occur in infancy. Closure of the shunt is indicated in symptomatic patients and is associated with a favorable outcome.

Derivation of a Clinical Prediction Rule for the Noninvasive Diagnosis of Varices in Children

Background and Objectives: Identification of children who are at high risk for having varices using noninvasive tests would enable the selection of children for future studies of primary prophylaxis of variceal hemorrhage, but this has been inadequately studied. The objective of the study was to derive a noninvasive clinical prediction rule that is able to identify children with esophageal varices. Methods: Fifty-one consecutive children with liver disease or portal hypertension who underwent endoscopy were included in the present retrospective study. At endoscopy, variceal size was graded on a 4-point Likert scale. Results of physical examination, blood tests, and abdominal ultrasound scan (USS) were recorded. Spleen length on USS was expressed as a standard deviation score (z score). A descriptive univariate analysis was performed on variables that were potentially associated with esophageal varices and multivariate logistic regression was then modeled to derive a clinical prediction rule. Results: Esophageal varices were found in 17 of the 51 children (33%). Variables found to differ significantly between children with and without varices included platelet/spleen-length z score ratio (P < 0.001), platelet count (P < 0.001), international normalized ratio (P = 0.001), aspartate aminotransferase/alanine aminotransferase ratio (P = 0.002), and albumin (P = 0.003). Using multivariate logistic regression, a model with platelet count, spleen length z score, and albumin as the independent variables had the best fit. Area under the receiver operating characteristic curve for this clinical prediction rule was 0.93 (95% confidence interval 0.85–0.99), sensitivity 94%, specificity 81%, positive predictive value 0.83, negative predictive value 0.94, positive likelihood ratio 5, and negative likelihood ratio 0.06. Conclusions: This clinical prediction rule is a simple noninvasive measure that may identify children at high risk for esophageal varices. A prospective validation study is in progress.

Variation in Care for Children With Esophageal Varices: A Study of Physicians', Patients', and Families' Approaches and Attitudes

Background and Aims:Inadequate evidence to guide the management of children with esophageal varices may lead to variation in care and the provision of poor-quality care to some children. The aims of the study were to describe approaches taken by pediatric gastroenterologists for the management of esophageal varices in children, and to determine the attitudes of children, parents, and physicians toward screening endoscopy for identification of varices. Methods:Canadian pediatric gastroenterologists and hepatologists were questioned about their approaches to screening for esophageal varices and therapy to prevent or treat variceal hemorrhage. Consecutive children with portal hypertension and their parents were surveyed about attitudes to screening endoscopy. Results:Forty-seven of 72 (65%) physicians responded. Seventy percent of respondents screen for esophageal varices in selected children, most using endoscopy (77%). Fifty-eight percent of respondents who screen for varices would provide primary prophylactic treatment. Most would treat an acute variceal bleed with antibiotics, acid suppression, octreotide, and endoscopy within 24 hours (76%) and then secondary prophylaxis with endoscopic variceal ligation (96%) or β-blockers (28%). Among 29 families surveyed, 63% of parents and 50% of patients would agree to screening endoscopy to understand their risk of variceal bleeding and 67% if prophylactic therapy were available. Families were more concerned about the risk of endoscopic adverse events than were gastroenterologists. Conclusions:Pediatric gastroenterologists vary in the care they provide for children at risk for esophageal varices and their attitudes toward the role of screening endoscopy differ from that of their patients. Further evidence is required to support practice guidelines that may reduce variation in care and thus improve its quality.

Early endoscopic, laboratory and clinical predictors of poor disease course in paediatric ulcerative colitis

Objective Data to support treatment algorithms in ambulatory paediatric UC are scarce. We aimed to explore the 1 year outcome in an inception cohort of paediatric UC patients and to identify early predictors of good outcome that might serve as short term treatment targets. Design A chart review of 115 children with new onset UC was performed (age 11±4.1 years; 58 (50%) males; 86 (75%) extensive colitis; 70 (61%) moderate–severe disease; 63 (55%) received steroids at baseline). We assessed the Paediatric Ulcerative Colitis Activity Index (PUCAI) and laboratory variables at the time of diagnosis and at 3 months, and endoscopy at diagnosis. Results The 3 month PUCAI was the strongest predictor of 1 year sustained steroid free remission (SSFR) (area under the receiver operating characteristic curve (AUROC)=0.7 (95% CI 0.6 to 0.8) and colectomy by 2 years (AUROC=0.75 (0.6 to 0.89)). SSFR was achieved in 9/54 (17%) children who had active disease (PUCAI ≥10) at 3 months (negative predictive value (NPV)=83%) and by 4/46 (8.6%) of those with a PUCAI score >10; (NPV=91%, positive predictive value=52%; p<0.001), implying that PUCAI >10 at 3 months has a probability of 9% for achieving SSFR versus 48% with a PUCAI value of ≤10. None of the variables at baseline was predictive of SSFR or colectomy (endoscopic severity, disease extent, age, PUCAI or C reactive protein/erythrocyte sedimentation rate/albumin/haemoglobin; all AUROC<0.6, p>0.05) but baseline PUCAI predicted subsequent acute severe colitis and the need for salvage medical therapy. Conclusions Completeness of the early response appears more important than baseline UC severity for predicting outcome in children, and supports using PUCAI<10 as a feasible treatment goal. Our data suggest that treatment escalation should be considered with a PUCAI value of ≥10 at 3 months.

Management of Helicobacter pylori infection in Latin America: a Delphi technique-based consensus.

AIM To optimize diagnosis and treatment guidelines for this geographic region, a panel of gastroenterologists, epidemiologists, and basic scientists carried out a structured evaluation of available literature. METHODS Relevant questions were distributed among the experts, who generated draft statements for consideration by the entire panel. A modified three-round Delphi technique method was used to reach consensus. Critical input was also obtained from representatives of the concerned medical community. The quality of the evidence and level of recommendation supporting each statement was graded according to United States Preventive Services Task Force criteria. RESULTS A group of ten experts was established. The survey included 15 open-ended questions that were distributed among the experts, who assessed the articles associated with each question. The levels of agreement achieved by the panel were 50% in the first round, 73.3% in the second round and 100% in the third round. Main consensus recommendations included: (1) when available, urea breath and stool antigen test (HpSA) should be used for non-invasive diagnosis; (2) detect and eradicate Helicobacter pylori (H. pylori) in all gastroscopy patients to decrease risk of peptic ulcer disease, prevent o retard progression in patients with preneoplastic lesions, and to prevent recurrence in patients treated for gastric cancer; (3) further investigate implementation issues and health outcomes of H. pylori eradication for primary prevention of gastric cancer in high-risk populations; (4) prescribe standard 14-d triple therapy or sequential therapy for first-line treatment; (5) routinely assess eradication success post-treatment in clinical settings; and (6) select second- and third-line therapies according to antibiotic susceptibility testing. CONCLUSION These achievable steps toward better region-specific management can be expected to improve clinical health outcomes.

Infliximab as Salvage Therapy in Paediatric Intestinal Transplant With Steroid- and Thymoglobulin-resistant Late Acute Rejection

Received August 12, 201 From the Division of Hospital for Sick Chi enterology, Hepatolog zTransplant centre, t Children, Toronto, Ca and Liver Disease, t Children’s Medical #Department of Pedi Santiago, Chile. Address correspondence Division of Gastroent Sick Children, 555 U (e-mail: yaron.avitzur The authors report no co Copyright # 2012 by E Hepatology, and Nut Gastroenterology, He DOI: 10.1097/MPG.0b01

Angiogenesis and portal-systemic collaterals in portal hypertension.

In patients with advanced liver disease with portal hypertension, portal-systemic collaterals contribute to circulatory disturbance, gastrointestinal hemorrhage, hepatic encephalopathy, ascites, hepatopulmonary syndrome and portopulmonary hypertension. Angiogenesis has a pivotal role in the formation of portal-systemic shunts. Recent research has defined many of the mediators and mechanisms involved in this angiogenic process, linking the central roles of hepatic stellate cells and endothelial cells. Studies of animal models have demonstrated the potential therapeutic impact of drugs to inhibit angiogenesis in cirrhosis. For example, inhibition of VEGF reduces portal pressure, hyperdynamic splanchnic circulation, portosystemic collateralization and liver fibrosis. An improved understanding of the role of other angiogenic factors provides hope for a novel targeted therapy for portal hypertension with a tolerable adverse effect profile.In patients with advanced liver disease with portal hypertension, portal-systemic collaterals contribute to circulatory disturbance, gastrointestinal hemorrhage, hepatic encephalopathy, ascites, hepatopulmonary syndrome and portopulmonary hypertension. Angiogenesis has a pivotal role in the formation of portal-systemic shunts. Recent research has defined many of the mediators and mechanisms involved in this angiogenic process, linking the central roles of hepatic stellate cells and endothelial cells. Studies of animal models have demonstrated the potential therapeutic impact of drugs to inhibit angiogenesis in cirrhosis. For example, inhibition of VEGF reduces portal pressure, hyperdynamic splanchnic circulation, portosystemic collateralization and liver fibrosis. An improved understanding of the role of other angiogenic factors provides hope for a novel targeted therapy for portal hypertension with a tolerable adverse effect profile.

Long-term effects of adenotonsillectomy in children with obstructive sleep apnoea: protocol for a systematic review

Introduction Adenotonsillar hypertrophy is the most important anatomical factor associated with obstructive sleep apnoea syndrome in children. The American Academy of Pediatrics recommends adenotonsillectomy as the first line of treatment. AT can reduce the apnoea hypopnoea index; however, its effect on long-term outcomes remains unclear. Methods and analysis We will conduct an electronic search for randomised controlled trials in MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL) and EMBASE. We will also identify literature by reviewing the references included in the selected studies and relevant reviews, screening through important scientific conferences, and searching for ongoing trials in the WHO International Clinical Trials Registry Platform. Two researchers will independently undertake selection of studies, data extraction and assessment of the risk of bias of included studies. We will estimate pooled risk ratios for dichotomous data, and mean difference or standardised mean difference for continuous outcomes. A random-effects model will be used for meta-analyses. Data synthesis and other analyses will be conducted using RevMan V.5.3 software. Ethics and dissemination No ethics approval is considered necessary. The results of this study will be disseminated via peer-reviewed publications and social networks. Trial registration number CRD42015022102.