Love, Professional Responsibility, the Rule of Law, and Clinical Legal Education

The primary purpose of this article is to explore the tensions which arise in persons who come to law school because they view the practice of law as an expression of their love and concern for people. In examining the underlying causes of these tensions, six related factors will be looked at: (1) the relationship between the values of traditional legal education and the support or lack of support which these values afford to the affective characteristics of students; (2) the role of one\u27s job as a means of expressing love; (3) the role of job satisfaction in one\u27s life; (4)the tensions between expressing love and the requirements of the rule of law; (5) the tensions between expressing love and the requirements of the Code of Professional Responsibility; and (6) the opportunity which clinical legal education affords students to learn how to integrate objective and affective values

Gene Expression Changes Associated with Resistance to Intravenous Corticosteroid Therapy in Children with Severe Ulcerative Colitis

Microarray analysis of RNA expression allows gross examination of pathways operative in inflammation. We aimed to determine whether genes expressed in whole blood early following initiation of intravenous corticosteroid treatment can be associated with response.From a prospectively accrued cohort of 128 pediatric patients hospitalized for intravenous corticosteroid treatment of severe UC, we selected for analysis 20 corticosteroid responsive (hospital discharge or PUCAI ≤45 by day 5) and 20 corticosteroid resistant patients (need for second line medical therapy or colectomy, or PUCAI >45 by day 5). Total RNA was extracted from blood samples collected on day 3 of intravenous corticosteroid therapy. The eluted transcriptomes were quantified on Affymetrix Human Gene 1.0 ST arrays. The data was analysed by the local-pooled error method for discovery of differential gene expression and false discovery rate correction was applied to adjust for multiple comparisons.A total of 41 genes differentially expressed between responders and non-responders were detected with statistical significance. Two of these genes, CEACAM1 and MMP8, possibly inhibited by methylprednisolone through IL8, were both found to be over-expressed in non-responsive patients. ABCC4 (MRP4) as a member of the multi-drug resistance superfamily was a novel candidate gene for corticosteroid resistance. The expression pattern of a cluster of 10 genes selected from the 41 significant hits were able to classify the patients with 80% sensitivity and 80% specificity.Elevated expression of several genes involved in inflammatory pathways was associated with resistance to intravenous corticosteroid therapy early in the course of treatment. Gene expression profiles may be useful to classify resistance to intravenous corticosteroids in children with severe UC and assist with clinical management decisions

Dysfunction of the Intestinal Microbiome in Inflammatory Bowel Disease and Treatment

Background: The inflammatory bowel diseases (IBD) Crohn's disease and ulcerative colitis result from alterations in intestinal microbes and the immune system. However, the precise dysfunctions of microbial metabolism in the gastrointestinal microbiome during IBD remain unclear. We analyzed the microbiota of intestinal biopsies and stool samples from 231 IBD and healthy subjects by 16S gene pyrosequencing and followed up a subset using shotgun metagenomics. Gene and pathway composition were assessed, based on 16S data from phylogenetically-related reference genomes, and associated using sparse multivariate linear modeling with medications, environmental factors, and IBD status. Results: Firmicutes and Enterobacteriaceae abundances were associated with disease status as expected, but also with treatment and subject characteristics. Microbial function, though, was more consistently perturbed than composition, with 12% of analyzed pathways changed compared with 2% of genera. We identified major shifts in oxidative stress pathways, as well as decreased carbohydrate metabolism and amino acid biosynthesis in favor of nutrient transport and uptake. The microbiome of ileal Crohn's disease was notable for increases in virulence and secretion pathways. Conclusions: This inferred functional metagenomic information provides the first insights into community-wide microbial processes and pathways that underpin IBD pathogenesis

Compositional and Temporal Changes in the Gut Microbiome of Pediatric Ulcerative Colitis Patients Are Linked to Disease Course

Evaluating progression risk and determining optimal therapy for ulcerative colitis (UC) is challenging as many patients exhibit incomplete responses to treatment. As part of the PROTECT (Predicting Response to Standardized Colitis Therapy) Study, we evaluated the role of the gut microbiome in disease course for 405 pediatric, new-onset, treatment-naive UC patients. Patients were monitored for 1 year upon treatment initiation, and microbial taxonomic composition was analyzed from fecal samples and rectal biopsies. Depletion of core gut microbes and expansion of bacteria typical of the oral cavity were associated with baseline disease severity. Remission and refractory disease were linked to species-specific temporal changes that may be implicative of therapy efficacy, and a pronounced increase in microbiome variability was observed prior to colectomy. Finally, microbial associations with disease-associated serological markers suggest host-microbial interactions in UC. These insights will help improve existing treatments and develop therapeutic approaches guiding optimal medical car

Natural History of Very Early Onset Inflammatory Bowel Disease in North America: A Retrospective Cohort Study

Background: The incidence of very early onset inflammatory bowel disease (VEOIBD) is increasing, yet the phenotype and natural history of VEOIBD are not well described. Methods: We performed a retrospective cohort study of patients diagnosed with VEOIBD (6 years of age and younger) between 2008 and 2013 at 25 North American centers. Eligible patients at each center were randomly selected for chart review. We abstracted data at diagnosis and at 1, 3, and 5 years after diagnosis. We compared the clinical features and outcomes with VEOIBD diagnosed younger than 3 years of age with children diagnosed with VEOIBD at age 3 to 6 years. Results: The study population included 269 children (105 [39%] Crohn\u27s disease, 106 [39%] ulcerative colitis, and 58 [22%] IBD unclassified). The median age of diagnosis was 4.2 years (interquartile range 2.9-5.2). Most (94%) Crohn\u27s disease patients had inflammatory disease behavior (B1). Isolated colitis (L2) was the most common disease location (70% of children diagnosed younger than 3 years vs 43% of children diagnosed 3 years and older; P = 0.10). By the end of follow-up, stricturing/penetrating occurred in 7 (6.6%) children. The risk of any bowel surgery in Crohn\u27s disease was 3% by 1 year, 12% by 3 years, and 15% by 5 years and did not differ by age at diagnosis. Most ulcerative colitis patients had pancolitis (57% of children diagnosed younger than 3 years vs 45% of children diagnosed 3 years and older; P = 0.18). The risk of colectomy in ulcerative colitis/IBD unclassified was 0% by 1 year, 3% by 3 years, and 14% by 5 years and did not differ by age of diagnosis. Conclusions: Very early onset inflammatory bowel disease has a distinct phenotype with predominantly colonic involvement and infrequent stricturing/penetrating disease. The cumulative risk of bowel surgery in children with VEOIBD was approximately 14%-15% by 5 years. These data can be used to provide anticipatory guidance in this emerging patient population

Budesonide Oral Suspension Improves Symptomatic, Endoscopic, and Histologic Parameters Compared With Placebo in Patients With Eosinophilic Esophagitis

BACKGROUND & AIMS: Pharmacologic treatment of eosinophilic esophagitis (EoE) is limited to off-label use of corticosteroids not optimized for esophageal delivery. We performed a randomized, controlled phase 2 trial to assess the ability of budesonide oral suspension (BOS), a novel muco-adherent topical steroid formulation, to reduce symptoms and esophageal eosinophilia in adolescents and adults with EoE. METHODS: In this multicenter, randomized, double-blind, placebo-controlled, parallel-group trial, 93 EoE patients between the ages of 11 and 40 years with dysphagia and active esophageal eosinophilia were randomized to receive either BOS 2 mg or placebo twice daily for 12 weeks. Co-primary outcomes were change in Dysphagia Symptom Questionnaire (DSQ) score from baseline, and proportion of patients with a histologic response (≤6 eosinophils/high-power field) after treatment. Endoscopic severity scores and safety parameters were assessed. RESULTS: At baseline, mean DSQ scores were 29.3 and 29.0, and mean peak eosinophil counts were 156 and 130 per hpf in the BOS and placebo groups, respectively. After treatment, DSQ scores were 15.0 and 21.5, and mean peak eosinophil counts were 39 and 113 per high-power field, respectively (P < .05 for all). For BOS vs placebo, change in DSQ score was -14.3 vs -7.5 (P = .0096), histologic response rates were 39% vs 3% (P < .0001), and change in endoscopic severity score was -3.8 vs 0.4 (P < .0001). Adverse events were similar between groups. CONCLUSIONS: Treatment with BOS was well tolerated in adolescent and young adult patients with EoE and resulted in improvement in symptomatic, endoscopic, and histologic parameters using validated outcome instruments. ClinicalTrials.gov ID NCT01642212

Achieving synergy: Linking an internet-based inflammatory bowel disease cohort to a community-based inception cohort and multicentered cohort in inflammatory bowel disease

Background: Traditional cohort studies are important contributors to our understanding of inflammatory bowel diseases, but they are labor intensive and often do not focus on patient-reported outcomes. Internet-based studies provide new opportunities to study patient-reported outcomes and can be efficiently implemented and scaled. If a traditional cohort study was linked to an Internet-based study, both studies could benefit from added synergy. Existing cohort studies provide an opportunity to develop and test processes for cohort linkage. The Crohn's and Colitis Foundation of America's (CCFA) Partners study is an Internet-based cohort of more than 14,000 participants. The Ocean State Crohn's and Colitis Area Registry (OSCCAR) is an inception cohort. The Sinai-Helmsley Alliance for Research Excellence (SHARE) is a multicentered cohort of inflammatory bowel disease patients. Both the later cohorts include medical record abstraction, patient surveys, and biospecimen collection. Objective: Given the complementary nature of these existing cohorts, we sought to corecruit and link data. Methods: Eligible OSCCAR and SHARE participants were invited to join the CCFA Partners study and provide consent for data sharing between the 2 cohorts. After informed consent, participants were directed to the CCFA Partners website to complete enrollment and a baseline Web-based survey. Participants were linked across the 2 cohorts by the matching of an email address. We compared demographic and clinical characteristics between OSCCAR and SHARE participants who did and did not enroll in CCFA Partners and the data linkage. Results: Of 408 participants in the OSCCAR cohort, 320 were eligible for participation in the CCFA Partners cohort. Of these participants, 243 consented to participation; however, only 44 enrolled in CCFA Partners and completed the linkage. OSCCAR participants who enrolled in CCFA Partners were better educated (17% with doctoral degrees) than those who did not (3% with doctoral degrees, P=.01). In the SHARE cohort, 436 participants enrolled and linked to the Partners cohort. More women (60% vs 50%) linked and those who linked were predominantly white (96%; P<.01). Crohn's disease patients who linked had lower mean scores on the Harvey-Bradshaw Index (3.6 vs 4.4, P<.01). Ulcerative colitis patients who linked had less extensive disease than those who did not link (45% vs 60%, P<.01). Conclusions: Linkage of CCFA Partners with cohorts such as OSCCAR and SHARE may be a cost-effective way to expand the infrastructure for clinical outcomes and translational research. Although linkage is feasible from a technical, legal, and regulatory perspective, participant willingness appears to be a limiting factor. Overcoming this barrier will be needed to generate meaningful sample sizes to conduct studies of biomarkers, natural history, and clinical effectiveness using linked data

Acute reduction of serum 8-iso-PGF2-alpha and advanced oxidation protein products in vivo by a polyphenol-rich beverage; a pilot clinical study with phytochemical and in vitro antioxidant characterization

<p>Abstract</p> <p>Background</p> <p>Measuring the effects of the acute intake of natural products on human biomarker concentrations, such as those related to oxidation and inflammation, can be an advantageous strategy for early clinical research on an ingredient or product.</p> <p>Methods</p> <p>31 total healthy subjects were randomized in a double-blinded, placebo-controlled, acute pilot study with post-hoc subgroup analysis on 20 of the subjects. The study examined the effects of a single dose of a polyphenol-rich beverage (PRB), commercially marketed as "SoZo^®", on serum anti-inflammatory and antioxidant markers. In addition, phytochemical analyses of PRB, and <it>in vitro </it>antioxidant capacity were also performed.</p> <p>Results</p> <p>At 1 hour post-intake, serum values for 8-iso-PGF2-alpha and advanced oxidation protein products decreased significantly by 40% and 39%, respectively. Additionally, there was a trend toward decreased C-reactive protein, and increased nitric oxide levels. Both placebo and PRB treatment resulted in statistically significant increases in hydroxyl radical antioxidant capacity (HORAC) compared to baseline; PRB showed a higher percent change (55-75% versus 23-74% in placebo group), but the two groups did not differ significantly from each other.</p> <p>Conclusions</p> <p>PRB produced statistically significant changes in several blood biomarkers related to antioxidant/anti-inflammatory effects. Future studies are justified to verify results and test for cumulative effects of repeated intakes of PRB. The study demonstrates the potential utility of acute biomarker measurements for evaluating antioxidant/anti-inflammatory effects of natural products.</p

Gut Flora Metabolism of Phosphatidylcholine Promotes Cardiovascular Disease

Metabolomics studies hold promise for the discovery of pathways linked to disease processes. Cardiovascular disease (CVD) represents the leading cause of death and morbidity worldwide. Here we used a metabolomics approach to generate unbiased small-molecule metabolic profiles in plasma that predict risk for CVD. Three metabolites of the dietary lipid phosphatidylcholine—choline, trimethylamine N-oxide (TMAO) and betaine—were identified and then shown to predict risk for CVD in an independent large clinical cohort. Dietary supplementation of mice with choline, TMAO or betaine promoted upregulation of multiple macrophage scavenger receptors linked to atherosclerosis, and supplementation with choline or TMAO promoted atherosclerosis. Studies using germ-free mice confirmed a critical role for dietary choline and gut flora in TMAO production, augmented macrophage cholesterol accumulation and foam cell formation. Suppression of intestinal microflora in atherosclerosis-prone mice inhibited dietary-choline-enhanced atherosclerosis. Genetic variations controlling expression of flavin monooxygenases, an enzymatic source of TMAO, segregated with atherosclerosis in hyperlipidaemic mice. Discovery of a relationship between gut-flora-dependent metabolism of dietary phosphatidylcholine and CVD pathogenesis provides opportunities for the development of new diagnostic tests and therapeutic approaches for atherosclerotic heart disease