Therapeutic potential of Takeda‐G‐protein‐receptor‐5 (TGR5) agonists. Hope or hype?

The gastrointestinal tract regulates glucose and energy metabolism, and there is increasing recognition that bile acids function as key signalling molecules in these processes. For example, bile acid changes that occur after bariatric surgery have been implicated in the effects on satiety, lipid and cholesterol regulation, glucose and energy metabolism, and the gut microbiome. In recent years, Takeda‐G‐protein‐receptor‐5 (TGR5), a bile acid receptor found in widely dispersed tissues, has been the target of significant drug discovery efforts in the hope of identifying effective treatments for metabolic diseases including type 2 diabetes, obesity, atherosclerosis, fatty liver disease and cancer. Although the benefits of targeting the TGR5 receptor are potentially great, drug development work to date has identified risks that include histopathological changes, tumorigenesis, gender differences, and questions about the translation of animal data to humans. The present article reviews the noteworthy challenges that must be addressed along the path of development of a safe and effective TGR5 agonist therapy.     

Is Non‐suicidal Self‐injury Related to Impulsivity in Anorexia Nervosa? Results from Self‐report and Performance‐based Tasks

The present study investigates the association between non‐suicidal self‐injury (NSSI) and impulsivity in anorexia nervosa (AN) patients by means of self‐report and behavioural tasks. In total, 60 female AN patients were included in the study, filled out the Barratt Impulsiveness Scale‐11 (BIS‐11) and performed three performance‐based tasks to assess different facets of impulsivity. Overall, 30% of the AN patients engaged in at least one form of NSSI during their lifetime. AN patients with and without NSSI did not significantly differ on the BIS‐11 impulsiveness scale. On the performance‐based measures, few differences emerged between AN patients with and without NSSI. Patients with NSSI showed more perseverations and perseveration errors (p < .05). The associations between self‐report and performance‐based measures were rather low, except for the association between the BIS‐11 and Wisconsin Card Sorting Task perseveration responses and errors (correlations |r| range between .32 and .42). The implications for theory and treatment of AN patients with and without NSSI will be discussed. Copyright © 2014 John Wiley & Sons, Ltd and Eating Disorders Association.     

Can Methylphenidate Reduce Fall Risk in Community‐Living Older Adults? A Double‐Blind,Single‐Dose Cross‐Over Study

OBJECTIVES: To test the hypothesis that methylphenidate modifies markers of fall risk in older adults.
DESIGN: Randomized, double-blind, placebo-controlled, single-dose cross-over study.
SETTING: Outpatient movement disorders clinic.
PARTICIPANTS: Twenty-six community-living older adults without dementia (mean age 73.8) with subjective complaints of "memory problems."
INTERVENTIONS: The study examined the effects of a single dose of 20 mg of methylphenidate (MPH) on cognitive function and gait. Participants were evaluated before and 2 hours after taking MPH or a placebo in sessions 1 to 2 weeks apart.
MEASUREMENTS: The Timed Up and Go and gait variability quantified mobility and fall risk. A computerized neuropsychology battery quantified memory and executive function (EF).
RESULTS: Timed Up and Go times, stride time variability, and measures of EF significantly improved in response to MPH but not in response to the placebo. In contrast, MPH did not significantly affect memory or finger tapping abilities.
CONCLUSION: In older adults, MPH appears to improve certain aspects of EF, mobility, and gait stability. Although additional studies are required to assess clinical utility and efficacy, the present findings suggest that methylphenidate and other drugs that are designed to enhance attention may have a role as a therapeutic option for reducing fall risk in older adults.     

Is Wolff‐Parkinson‐White Syndrome a Genetic Disease?

Family studies, and more recent molecular genetic investigations, indicate that the Wolff-Parkinson-White (WPW) syndrome and associated preexcitation disorders can have a substantial genetic component. Because preexcitation disorders are sometimes inherited as single gene disorders, key mechanistic insights can be gained that are expected to be relevant also to the more common multifactorial forms of these traits. Potentially, such insights will inform the future management of these conditions. Where WPW is inherited as a familial trait, with or without associated cardiac defects or a systemic syndrome, there are clinical genetic ramifications that are already of practical importance.     

One‐per‐Occasion or Less: Are Moderate‐Drinking Postmenopausal Women Really Healthier Than Their Nondrinking and Heavier‐Drinking Peers?

Background: While some reported benefits of moderate drinking are thought to be the direct results of physiological mechanisms associated with consumption, other effects may be attributable to mediating factors. Both explanations suggest that moderate drinkers may be healthier than nondrinking and heavier‐drinking peers. The purpose of this study was to determine whether moderate‐drinking postmenopausal women report healthier dietary and exercise patterns, and whether they demonstrate better physiological functioning compared with peers. This study also aimed to describe patterns of relationships between alcohol and measures of general health functioning in postmenopausal women. Methods: One‐hundred and fifteen women aged 50 to 65 participated. Participants completed alcohol interviews, diet and exercise questionnaires, and bone density examination. Blood pressure, height, and weight were assessed, and blood was collected to conduct basic chemistry and complete blood count tests. Results: Postmenopausal moderate drinkers failed to demonstrate healthier dietary or exercise habits, and did not exhibit significantly better health‐functioning compared with peers. They did evidence positive associations between drinking and healthy behavior, and between drinking and cardiovascular health. Relationships between alcohol and blood analytes differed between drinking groups, some of which suggested possible negative health consequences for higher‐end drinkers in both drinking groups. Conclusions: These data suggested that moderate‐drinking postmenopausal women are not significantly healthier than their non‐ or heavier‐drinking peers, but may drink as part of a larger effort to take care of their health. Despite this, even 1‐drink‐per‐drinking‐day moderate drinkers may have tendencies toward unhealthy conditions. Limitations include small sample size, inability to assess specific cardiac risk and socioeconomic status, small number of correlations, and clinical relevance of analyte values.     

Why have meta‐analyses of randomized controlled trials of the association between non‐white‐blood‐cell‐reduced allogeneic blood transfusion and postoperative infection produced discordant results?

Intention-to-treat analyses of randomized controlled trials (RCTs) of the association between non-white-blood-cell (WBC)-reduced allogeneic blood transfusion (ABT) and postoperative infection were reported as the reason why meta-analyses of RCTs of this association have produced discordant results. We examined three possible reasons for disagreements between meta-analyses: (i) sources of medical heterogeneity and integration of RCTs despite extreme heterogeneity; (ii) reliance on as-treated (vs. intention-to-treat) comparisons; and (iii) inclusion (or not) of the three most recent RCTs. When nine RCTs reported up to 2002 were combined despite extreme heterogeneity, both intention-to-treat and as-treated comparisons found an association between non-WBC-reduced ABT and postoperative infection [summary odds ratio (OR) = 1.38, 95% confidence interval (CI) 1.03-1.85, P < 0.05; and summary OR = 1.56, 95% CI 1.06-2.31, P < 0.05, respectively]. When 12 RCTs reported up to 2005 were integrated despite extreme heterogeneity, both intention-to-treat and as-treated comparisons found no association of non-WBC-reduced ABT with postoperative infection (summary OR = 1.24, 95% CI 0.98-1.56, P > 0.05; and summary OR = 1.31, 95% CI 0.98-1.75, P > 0.05, respectively). In both analyses, the separate integration of four RCTs transfusing red blood cells (RBCs) or whole blood filtered after storage showed an association between non-WBC-reduced ABT and postoperative infection, whereas the separate integration of six (or nine) RCTs, reported through 2002 or 2005, and transfusing prestorage-filtered RBCs showed no association, whether intention-to-treat or as-treated comparisons were used. Thus, the published meta-analyses have produced discordant results because they did (or did not) investigate medical sources of heterogeneity and did (or did not) include the most recent RCTs. Intention-to-treat and as-treated comparisons produced concordant results.