Citations

OBJECTIVES: ImproveCareNow (ICN) is the largest pediatric learning health system in the nation and started as a quality improvement collaborative. To test the feasibility and validity of using ICN data for clinical research, we evaluated the effectiveness of anti-tumor necrosis factor-α (anti-TNFα) agents in the management of pediatric Crohn disease (CD). METHODS: Data were collected in 35 pediatric gastroenterology practices (April 2007 to March 2012) and analyzed as a sequence of nonrandomized trials. Patients who had moderate to severe CD were classified as initiators or non-initiators of anti-TNFα therapy. Among 4130 patients who had pediatric CD, 603 were new users and 1211 were receiving anti-TNFα therapy on entry into ICN. RESULTS: During a 26-week follow-up period, rate ratios obtained from Cox proportional hazards models, adjusting for patient and disease characteristics and concurrent medications, were 1.53 (95% confidence interval [CI], 1.20–1.96) for clinical remission and 1.74 (95% CI, 1.33–2.29) for corticosteroid-free remission. The rate ratio for corticosteroid-free remission was comparable to the estimate produced by the adult SONIC study, which was a randomized controlled trial on the efficacy of anti-TNFα therapy. The number needed to treat was 5.2 (95% CI, 3.4–11.1) for clinical remission and 5.0 (95% CI, 3.4–10.0) for corticosteroid-free remission. CONCLUSIONS: In routine pediatric gastroenterology practice settings, anti-TNFα therapy was effective at achieving clinical and corticosteroid-free remission for patients who had Crohn disease. Using data from the ICN learning health system for the purpose of observational research is feasible and produces valuable new knowledge.

Abstract LIGHT is a recently identified member of the TNF superfamily and its receptors, herpesvirus entry mediator and lymphotoxin β receptor, are found in T cells and stromal cells. In this study, we demonstrate that LIGHT is selectively expressed on immature dendritic cells (DCs) generated from human PBMCs. In contrast, LIGHT is not detectable in DCs either freshly isolated from PBMCs or rendered mature in vitro by LPS treatment. Blockade of LIGHT by its soluble receptors, lymphotoxin β receptor-Ig or HVEM-Ig, inhibits the induction of DC-mediated primary allogeneic T cell response. Furthermore, engagement of LIGHT costimulates human T cell proliferation, amplifies the NF-κB signaling pathway, and preferentially induces the production of IFN-γ, but not IL-4, in the presence of an antigenic signal. Our results suggest that LIGHT is a costimulatory molecule involved in DC-mediated cellular immune responses.

Abstract Decoy receptor 3 (DcR3), a soluble receptor belonging to the TNFR superfamily, is a receptor for both Fas ligand (FasL) and LIGHT. It has been demonstrated that DcR3 is up-regulated in lung and colon cancers, thus promoting tumor growth by neutralizing the cytotoxic effects of FasL and LIGHT. In this study, we found that DcR3.Fc profoundly modulated dendritic cell differentiation and maturation from CD14+ monocytes, including the up-regulation of CD86/B7.2, and the down-regulation of CD40, CD54/ICAM-1, CD80/B7.1, CD1a, and HLA-DR. Moreover, DcR3-treated dendritic cells suppressed CD4+ T cell proliferation in an allogeneic MLR and up-regulated IL-4 secretion of CD4+CD45RA+ T cells. This suggests that DcR3.Fc may act not only as a decoy receptor to FasL and LIGHT, but also as an effector molecule to skew T cell response to the Th2 phenotype.

Abstract Background: The existence, etiology, diagnosis, and treatment of median arcuate ligament syndrome (MALS) have long been subjects of debate. To our knowledge, there have not been any studies assessing the effectiveness of surgical treatment in improving physical and psychological quality of life in pediatric patients. Subjects and Methods: This is an Institutional Review Board–approved prospective study including all patients undergoing surgical treatment of MALS between 2009 and 2012 at our institution. Demographic information, presenting symptoms, radiological imaging, procedure duration, hospital length of stay, and perioperative complications were gathered for analysis. Patients and their parents were asked to complete the Child Health Questionnaire, a physical and psychological health survey, both within 1 week prior to and at least 3 months following their surgery. Results: Six patients underwent laparoscopic release for MALS. The majority of patients were female ( n =5 [83.3%]), with an average age of 15.7±1.5 years. Presenting symptoms lasted on average 16.5±12.7 months prior to treatment. Average pre- and postsurgical ultrasound celiac artery peak velocities with inspiration were 332.0±34.1 cm/second and 224.3±31.2 cm/second, respectively, with a statistically significant decrease of 107.67 cm/second ( P =.03). The average follow-up period from time of surgery to time of quality of life survey completion was 13±11.3 months, with a range of 3–29 months. A significant improvement from pre- to postsurgical scores was observed in the physical functioning ( P =.03), mental health ( P =.03), and self-esteem categories ( P =.03) of the child assessment. Similarly, there was a significant postsurgical improvement in all categories pertaining to the parent's quality of life ( P =.03). Improvement was also seen in the parents' perception of their child's physical functioning ( P =.03), bodily pain/discomfort ( P =.03), mental health ( P =.03), and general health perceptions ( P =.03). No intraoperative or postoperative complications occurred. Conclusions: Our preliminary results demonstrate that laparoscopic median arcuate ligament release for MALS in the pediatric population is safe and effective and improves overall quality of life for the patients and their parents. In carefully selected patients, laparoscopic release for MALS without additional celiac artery reconstruction normalizes blood flow in the celiac artery and improves physical and psychosocial quality of life for the child and his or her parents.

ABSTRACTThe objective of this study was to evaluate the correlations between deformation and displacement of median nerve and flexor tendons during finger motion in the carpal tunnel for both carpal tunnel syndrome (CTS) patients and healthy controls. Sixty‐two wrists of 31 asymptomatic volunteers and fifty‐one wrists of 28 idiopathic CTS patients were evaluated by ultrasound. The displacement of the median nerve and the middle finger flexor digitorum superficialis (FDS) tendon, as well as area, perimeter, aspect ratio of a minimum enclosing rectangle, and circularity of the median nerve were measured in finger extension and flexion positions. Deformation indices were defined as the ratios of indices in finger extension and flexion positions. The correlations between displacement and deformation indices were evaluated. There were significant correlations between nerve palmar–dorsal displacement and deformation indices (p < 0.05). The aspect ratio deformation index showed the strongest correlation to palmar–dorsal displacement of the nerve (−0.572, p < 0.01). This study showed that there is a relationship between median nerve deformation indices and nerve palmar–dorsal displacement in the carpal tunnel. Since the highest correlations were between palmar–dorsal nerve displacement direction and aspect ratio deformation index, these parameters may be helpful to understand the pathophysiology of CTS. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31:1876–1880, 2013

ABSTRACTObjective:Microscopic colitis (MC) is prevalent in adults investigated for chronic watery diarrhea, yet characterization of pediatric MC is limited.Methods:Our pathology database was searched from 1995 to 2011 for pediatric cases of lymphocytic colitis (LC) or collagenous colitis (CC). Those with diarrhea persisting for >2 weeks and visually normal colonoscopy were accepted as cases. Demographics, laboratory results, medication use within 3 months of presentation, medical and family history of autoimmune disease, and response to treatment were abstracted.Results:A total of 27 cases were histologically consistent with MC on biopsy; 5 with concomitant enteric infection or isolated abdominal pain were excluded. Twenty‐two cases of MC (female patients, 59%; median age at diagnosis, 15.3 years) were included (19 LC and 3 CC). Two had type 1 diabetes mellitus, 2 were anti‐nuclear antibody positive, and 2 had common variable immunodeficiency. Of 20 patients who underwent an esophagogastroduodenoscopy, 1 had collagenous sprue and 4 had celiac disease. One presented after the clearance of recurrent Clostridium difficile infection. Previous drug exposures included nonsteroidal anti‐inflammatory drugs (n = 7), proton pump inhibitors (n = 6), and selective serotonin reuptake inhibitors (n = 3). Common symptoms in addition to diarrhea included abdominal pain (77.3%) and weight loss (27.3%). Of 17 patients with follow‐up, all of the 8 treated with steroids had some response: 57.1% (4/7) responded to mesalamine and 42.9% (3/7) responded to bismuth subsalicylate.Conclusions:In this cohort of pediatric patients, LC was much more common than CC. As described in adults, we observed associations with celiac disease, type 1 diabetes mellitus, and medications; we additionally saw an association with immunodeficiency. Our patients showed greater response to steroids than mesalamine or bismuth.

Many primary care providers feel uncomfortable discussing end-of-life care. The aim of this intervention was to assess internal medicine residents’ advance care planning (ACP) practices and improve residents’ ACP confidence. Residents participated in a facilitated ACP quality improvement workshop, which included an interactive presentation and chart audit of their own patients. Pre- and postintervention surveys assessed resident ACP-related confidence. Only 24% of the audited patients had an advance directive (AD), and 28% of the ACP-documentation was of no clinical utility. Terminally ill patients (odds ratio 2.8, P < .001) were more likely to have an AD. Patients requiring an interpreter were less likely to have participated in ACP. Residents reported significantly improved confidence with ACP and identified important training gaps. Future studies examining the impact on ACP quality are needed.

Effects of ER-001533 (ER), a newly synthesized vasorelaxant, on the membrane currents were examined in single ventricular cells of guinea pigs. The patch-clamp technique was used in the "whole-cell" and "inside-out" patch configurations. In the whole-cell clamp condition, ER induced a time-independent K(+)-dominant current, which was inhibited by glibenclamide (1-3 microM), suggesting that ER activated the cardiac ATP-sensitive K+ channel (KATP). To elucidate the mechanism of ER-mediated KATP channel activation, the drug was applied to the inside-out patches before and after channel "run-down." Since nucleotide diphosphates could induce the channel openings after complete run-down, effects of the drug on the nucleotide diphosphate-induced channel openings were also examined. Before run-down, ER activated the KATP channel only in the presence of ATP. ER shifted the relation between [ATP]i and the channel activity to the right in a concentration-dependent fashion without a significant alteration of the slope. After channel run-down, ER did not affect the channel openings either in the absence or in the presence of UDP. However, ER could relieve the ATP-gamma-S inhibition of the UDP-induced channel openings. Thus, we conclude that ER antagonizes the inhibitory effect of ATP on the KATP channel in a competitive manner, thereby enhancing the channel openings.

Vasorelaxant agents such as pinacidil, lemakalim, and nicorandil, known as K+ channel openers, can activate the ATP-sensitive K+ channel (KATP channel) in cardiac myocytes. The aim of this study was to elucidate the molecular mechanisms underlying the K+ channel opener-mediated cardiac KATP channel activation by using the inside-out patch-clamp technique in guinea pig ventricular myocytes. Effects of pinacidil, lemakalim, and nicorandil on the KATP channel were examined both before and after channel "run-down". Since nucleotide diphosphates (NDPs) could activate the channel after complete run-down, effects of the drugs on the NDP-induced channel openings were also examined. We made the following observations: 1) Pinacidil (10-100 microM) and lemakalim (300 microM) activated the KATP channel before run-down and after run-down when NDPs were present. 2) Nicorandil (30 microM-1 mM) activated the KATP channel only in the presence of NDPs regardless of the condition of the channel with respect to run-down. 3) None of these K+ channel openers activated the channel after run-down in the absence of NDPs. These observations suggest that NDP binding is essential for nicorandil-mediated activation of the KATP channel and indicate that the molecular mechanisms underlying nicorandil activation are distinct from those of pinacidil and lemakalim activation of the KATP channel. We discuss the possible interactions between the drugs and the KATP channel based on a functional channel model.