Radar plots: A novel modality for displaying disparate data on the efficacy of eluxadoline for the treatment of irritable bowel syndrome with diarrhea.

BACKGROUND: Patients with irritable bowel syndrome with diarrhea (IBS-D) experience a range of abdominal and bowel symptoms; successful management requires alleviation of this constellation of symptoms. Eluxadoline, a locally active mixed µ- and κ-opioid receptor agonist and δ-opioid receptor antagonist, is approved for the treatment of IBS-D in adults based on the results of 2 Phase 3 studies. Radar plots can facilitate comprehensive, visual evaluation of diverse but interrelated efficacy endpoints. METHODS: Two double-blind, placebo-controlled, Phase 3 trials (IBS-3001 and IBS-3002) randomized patients meeting Rome III criteria for IBS-D to twice-daily eluxadoline 75 or 100 mg or placebo. Radar plots were prepared showing pooled Weeks 1-26 response rates for the primary efficacy composite endpoint (simultaneous improvement in abdominal pain and stool consistency), stool consistency, abdominal pain, urgency-free days, and adequate relief, and change from baseline to Week 26 in IBS-D global symptom score, abdominal discomfort, abdominal pain, abdominal bloating, and daily number of bowel movements. KEY RESULTS: The studies enrolled 2428 patients. Eluxadoline increased Weeks 1-26 responder proportions vs placebo for the composite endpoint, stool consistency, abdominal pain, urgency-free days, and adequate relief. Changes from baseline to Week 26 in IBS-D global symptom score, abdominal discomfort, abdominal pain, abdominal bloating, and number of bowel movements were greater with eluxadoline vs placebo. CONCLUSIONS AND INFERENCES: Data presentation in radar plot format facilitates interpretation across multiple domains, demonstrating that eluxadoline treatment led to improvements vs placebo across 13 endpoints representing the range of symptoms experienced by patients with IBS-D.

Abnormal esophageal acid exposure on high-dose proton pump inhibitor therapy is common in systemic sclerosis patients.

BACKGROUND: Esophageal dysfunction and gastro-esophageal reflux disease (GERD) are common among patients with systemic sclerosis (SSc). Although high-dose proton pump inhibitors (PPIs) typically normalize esophageal acid exposure, the effectiveness of PPI therapy has not been systematically studied in SSc patients. The aim of this study was to characterize reflux in SSc patients on high-dose PPI using esophageal pH-impedance testing. METHODS: In this case-controlled retrospective analysis, 38 patients fulfilling 2013 American College of Rheumatology SSc criteria who underwent esophageal pH-impedance testing on twice-daily PPI between January 2014 and March 2017 at a tertiary referral center were compared with a control-cohort of 38 non-SSc patients matched for PPI formulation and dose, hiatal hernia size, age, and gender. Patient clinical characteristics, including endoscopy and high-resolution manometry findings, were assessed via chart review. KEY RESULTS: On pH-impedance, SSc patients had higher acid exposure times (AETs) than controls. Sixty-one percent of the SSc patients and 18% of the control patients had a total AET ≥4.5% (P < .001). Systemic sclerosis patients also had significantly longer AETs, longer median bolus clearance, and lower nocturnal impedance values. CONCLUSIONS & INFERENCES: Abnormal esophageal acid exposure despite high-dose PPI therapy was common among patients with SSc. The lack of increased reflux episodes in the SSc patients, and longer bolus clearance times and lower nocturnal impedance, supports ineffective clearance as the potential mechanism. Systemic sclerosis patients may require adjunctive therapies to PPIs to control acid reflux.

Gender differences in irritable bowel syndrome: the interpersonal connection.

BACKGROUND: While irritable bowel syndrome (IBS) affects women more than men, the reasons are unclear. Research on the female preponderance of IBS has focused on gender differences in sex-linked biological processes; much less attention has been paid to the role of psychosocial factors. Interpersonal difficulties may be one source of stress that may significantly impact on women with IBS. Because of the importance that women attach to relationships, we suspected they would be more reactive to interpersonal stress. METHODS: A total of 283 (M age = 41 years, F = 80%), Rome III-diagnosed IBS patients completed a test battery that included the IBS Symptom Severity Scale, McGill Pain Questionnaire, Inventory of Interpersonal Problems (IIP), interpersonal support evaluation list (social support), Negative Interactions Scale, Brief Symptom Inventory (distress), Beck Depression Inventory, Anxiety Sensitivity Inventory, and IBS-Quality of Life as part of baseline assessment of an NIH trial. KEY RESULTS: Males scored higher on two IIP scales reflecting a hostile-dominant interpersonal pattern, and reported less social support. The quality of relationship problems (more interpersonal difficulties, lower support) correlated with IBS symptom severity as measured mainly by gastroenterologists. CONCLUSIONS & INFERENCES: Male, not female, IBS patients reported more interpersonal difficulties. Male patients-a population for whom little is known-are characterized by hostile-dominant interpersonal problems. This finding has clinical importance, given that relationship problems may influence MDs' estimation of IBS symptom severity and undermine the physician-patient relationship.

Haloperidol blocks increased locomotor activity elicited by carbachol infusion into the ventral hippocampal formation.

Previous studies have demonstrated that stimulation of the ventral hippocampal (VH) formation (including the ventral CA1 and subicular areas) elicits increased locomotor activity in rats. The locomotor-activating effects of VH stimulation have been hypothesized to be mediated via hippocampal output to cortical and subcortical dopamine (DA) systems. This study examined whether increased locomotor activity produced by VH stimulation was blocked by pretreatment with a DA receptor antagonist, and whether DA metabolism in subdivisions of the nucleus accumbens, caudate-putamen, and prefrontal cortex was elevated by VH stimulation. Stimulation of the VH (defined as the ventral CA1 and its borders, ventral subiculum, and entorhinal cortex) with the cholinergic agonist carbachol was found to elevate locomotor activity, while pretreatment with the D2 receptor antagonist haloperidol blocked this effect. Stimulation of the VH did not alter DA metabolism (i.e., ratio of the DA metabolites DOPAC or HVA/DA) in any of the brain regions studied. These results indicate that the increased locomotor activity elicited by VH stimulation is not associated with dramatic increases in DA metabolism, but that it does require tonic activation of D2 receptors.

Fine-structural correlates of growth in hyphae of Ascodesmis sphaerospora.

Mycelial mats of Ascodesmis sphaerospora were fixed and embedded for electron microscopy, and thin sections of 1-mm blocks, taken from the 1st to the 7th mm behind the hyphal tips, were cut parallel to the long axis of the hyphae. The hyphal tip region is characterized by an outer zone of electron-transparent vesicles, 500 to 1,000 A in diameter, and is apparently associated with wall elaboration. Immediately behind this region, dense granules become evident along convoluted membrane systems and along the plasma membrane; in the same region are numerous small lomasomes in the lateral wall. As the hypha grows, septa are laid down at 3- to 7-min intervals at a distance of 200 to 250 mu behind the hyphal tip. A cylinder of endoplasmic reticulum is intimately involved in cross-wall deposition from its earliest stages; as the wall grows in, it becomes increasingly constricted in the pore region, finally assuming a torus-like configuration. Woronin bodies are shown to have a crystalline substructure and to originate in pouch-like membrane systems. Cross-walls from a 7- to 13-hr-old mycelium frequently show highly ordered structures in the vicinity of the pore. These structures may appear either as laminar stacks of discs to one side of the pore or as series of stubby concentric rings within the pore area itself. In the latter case, a mass of granular material is frequently seen plugging the pore. Other unusual organelles and inclusions in 7- to 13-hr hyphae are vesicles containing swirls of beaded or dilated membrane, membrane-enclosed rods, and stacks of unit membranes associated with spherical, electron-transparent vesicles.