Colonic Diverticula Are Not Associated With an Increased Risk of Colorectal Adenomas.

OBJECTIVES: Patients with missed colorectal cancer have been reported to be more likely to have colonic diverticulosis. Such an association could be due to either higher risk of neoplasia or difficulty examining the colon in patients with diverticulosis. The aim of this study was to determine whether colonic diverticula are associated with an increased risk for colonic neoplasia. METHODS: We analyzed data from a prospective study of patients undergoing screening colonoscopy that included detailed assessment of all colonic diverticula and colorectal polyps. We used logistic regression to estimate odds ratios and 95% confidence intervals while adjusting for confounding variables. RESULTS: Our analyses included 624 participants. Of these, 216 (35%) had one or more colorectal adenomas. Diverticula on colonoscopy were not associated with an increased risk of adenomas (odds ratio (OR) 1.0, 95% confidence interval (CI) 0.7-1.4) or advanced adenomas (OR 0.8, 95% CI 0.4-1.5). Those with the greatest burden of diverticula (10 or more) did not have an increased risk of adenomas (OR 1.1, 95% CI 0.7-1.8) compared with no diverticula. Colonic diverticula were not associated with an increased risk of proximal (OR 1.0, 95% CI 0.6-1.6) or distal adenomas (OR 1.0, 95% CI 0.6-1.7). CONCLUSIONS: Patients with colonic diverticula do not have an increased risk of colorectal adenomas or advanced adenomas.

A Clinical Prediction Tool Identifies Cases of Eosinophilic Esophagitis Without Endoscopic Biopsy: A Prospective Study.

OBJECTIVES: Eosinophilic esophagitis (EoE) is difficult to distinguish from gastroesophageal reflux (GERD) and other causes of dysphagia. We assessed the utility of a set of clinical and endoscopic features for predicting EoE without obtaining esophageal biopsies. METHODS: We prospectively enrolled consecutive adults undergoing outpatient upper endoscopy at the University of North Carolina from July 2011 through December 2013. Incident cases of EoE were diagnosed per consensus guidelines. Non-EoE controls had either GERD- or dysphagia-predominant symptoms. A predictive model containing clinical and endoscopic, but no histological, data was assessed. Receiver operator characteristic curves were constructed and the area under the curve (AUC) was calculated. RESULTS: A total of 81 EoE cases (mean age 38 years; 60% male; 93% white; 141 eosinophils per high-power field (eos/hpf)) and 144 controls (mean age 52, 38% male; 82% white; 3 eos/hpf) were enrolled. A combination of clinical (age, sex, dysphagia, food allergy) and endoscopic (rings, furrows, plaques, hiatal hernia) features was highly predictive of EoE. The AUC was 0.944, with sensitivity, specificity, and accuracy of 84, 97, and 92%. Similar values were seen after limiting controls to those with only reflux or dysphagia or to those with esophageal eosinophilia not due to EoE. CONCLUSIONS: We validated a set of clinical and endoscopic features to predict EoE with a high degree of accuracy and allow identification of those at very low risk of disease. Use of these predictors at the point-of-care will avoid the effort and expense of low-yield histological examinations for EoE.

Clinical and endoscopic characteristics do not reliably differentiate PPI-responsive esophageal eosinophilia and eosinophilic esophagitis in patients undergoing upper endoscopy: a prospective cohort study.

OBJECTIVES: Proton-pump inhibitor-responsive esophageal eosinophilia (PPI-REE) is a newly recognized entity that must be differentiated from eosinophilic esophagitis (EoE). Little is known about this condition. We aimed to determine the prevalence of PPI-REE and EoE in patients undergoing upper endoscopy and determine features that distinguish the two groups. METHODS: This prospective study conducted at the University of North Carolina from 2009 to 2011 enrolled consecutive adult patients undergoing outpatient upper endoscopy. Subjects had esophageal biopsies to quantify the maximum eosinophil count per high-power field (eos/hpf; hpf=0.24 mm(2)). If biopsies revealed ≥15 eos/hpf, subjects were treated with twice daily PPI for 8 weeks and endoscopy was repeated. If ≥15 eos/hpf persisted despite PPI therapy, EoE was diagnosed. If there were <15 eos/hpf, PPI-REE was diagnosed. The proportion of patients in each group was calculated, and patients with EoE and PPI-REE were compared. RESULTS: Of the 223 subjects enrolled, 173 had dysphagia and 50 did not. Of those with dysphagia, 66 (38%) had ≥15 eos/hpf. After the PPI trial, 40 (23%) were confirmed to have EoE, and 24 (14%) had PPI-REE. Of those without dysphagia, 2 (4%) had ≥15 eos/hpf, and after the PPI trial, 1 (2%) had EoE. Compared with EoE, PPI-REE patients were more likely to be older and male and less likely to have typical endoscopic findings of EoE. However, none of the individual factors was independently predictive of PPI-REE status on multivariable analysis. Similarly, although some endoscopic findings were differentially distributed between PPI-REE and EoE, none were significantly associated with disease status on multivariable analysis. CONCLUSIONS: Esophageal eosinophilia is common among patients undergoing esophagogastroduodenoscopy for dysphagia. Although EoE was seen in nearly a quarter of patients with dysphagia, PPI-REE was almost as common, and accounted for over one-third of those with ≥15 eos/hpf. No clinical or endoscopic features independently distinguished PPI-REE from EoE before the PPI trial.

Improved methods for 1H-3H heteronuclear shift correlation.

A better understanding of the structure of complex 3H-labeled molecules can be obtained by complete assignment of their 1H and 3H solution-state NMR spectra. The assignment process is aided by the detection of heteronuclear chemical shift correlations between 1H and 3H nuclei. Heteronuclear correlation (HETCOR) experiments previously applied to this task exhibit several drawbacks caused by the nature of both the pulse sequences and 1H-3H spin systems. The range of J-couplings involved in 1H-3H coupling networks make it challenging to perform correlation experiments using methods that rely on coherences created during free precession periods and interrupted by transfer pulses. Two alternative HETCOR experiments are demonstrated for 1H-3H systems in the present work and are shown to have advantages over earlier methods. The first experiment is known as hetero-TOCSY and correlates heteronuclear chemical shifts using J-cross polarization. This experiment achieves both homonuclear and heteronuclear mixing and connects the chemical shifts of all 1H and 3H nuclei in a coupling network. A second HETCOR experiment uses the heteronuclear Overhauser effect to obtain through-space correlations between nearby nuclei. The 1H-3H HETCOR experiments are phase sensitive and typically contain more correlations than other methods, which is beneficial for assignment purposes, while being sensitive enough to be applicable to routine analytical samples. The experiments were used to analyze 3H incorporation in sub-milligram quantities of 3H-labeled pharmaceutical derivatives with complex labeling schemes.

Tyrosine agonists reverse the molecular defects associated with dominant-negative mutations in human peroxisome proliferator-activated receptor gamma.

Loss-of-function mutations in the ligand-binding domain of human peroxisome proliferator-activated receptor gamma (PPARgamma) are associated with a novel syndrome characterized by partial lipodystrophy and severe insulin resistance. Here we have further characterized the properties of natural dominant-negative PPARgamma mutants (P467L, V290M) and evaluated the efficacy of putative natural ligands and synthetic thiazolidinedione (TZD) or tyrosine-based (TA) receptor agonists in rescuing mutant receptor function. A range of natural ligands failed to activate the PPARgamma mutants and their transcriptional responses to TZDs (e.g. pioglitazone, rosiglitazone) were markedly attenuated, whereas TAs (e.g. farglitazar) corrected defects in ligand binding and coactivator recruitment by the PPARgamma mutants, restoring transcriptional function comparable with wild-type receptor. Transcriptional silencing via recruitment of corepressor contributes to dominant-negative inhibition of wild type by the P467L and V290M mutants and the introduction of an artificial mutation (L318A) disrupting corepressor interaction abrogated their dominant-negative activity. More complete ligand-dependent corepressor release and reversal of dominant-negative inhibition was achieved with TA than TZD agonists. Modeling suggests a structural basis for these observations: both mutations destabilize helix 12 to favor receptor-corepressor interaction; conversely, farglitazar makes more extensive contacts than rosiglitazone within the ligand-binding pocket, to stabilize helix 12, facilitating corepressor release and transcriptional activation. Farglitazar was a more potent inducer of PPARgamma target gene (aP2) expression in peripheral blood mononuclear cells with the P467L mutation. Having shown that rosiglitazone is of variable and limited efficacy in these subjects, we suggest that TAs may represent a more rational therapeutic approach.