Voluntary Exercise Ameliorates Chronic Ethanol Withdrawal-Induced Adaptations of Opioid Receptor Expression in the Nucleus Accumbens, Dopamine Release, and Ethanol Consumption.

Exercise has increasingly been recognized as an adjunctive therapy for alcohol-use disorder (AUD), yet our understanding of its underlying neurological mechanisms remains limited. This knowledge gap impedes the development of evidence-based exercise guidelines for AUD treatment. Chronic ethanol (EtOH) exposure has been shown to upregulate and sensitize kappa opioid receptors (KORs) in the nucleus accumbens (NAc), which is innervated by dopamine (DA) neurons in the midbrain ventral tegmental area (VTA), which may contribute to AUD-related behaviors.

Association Between a Medical School Applicant's Community College Attendance and the Likelihood of Application Acceptance: An Investigation of Select Medical School Characteristics.

Purpose: One-third of medical school applicants attend a community college (CC), and they represent a diverse group of applicants. However, they have a lower likelihood of being accepted to medical school. Using application-level data, this study examines how an applicant's CC attendance impacts the likelihood of application acceptance and how 3 medical school characteristics moderate this association.

Description and development of a nurse-led cardiac assessment team.

A problem was identified where patient care was affected because of delays in receiving specialist cardiology input. This report describes the experience of developing a specialist cardiac assessment where senior cardiac nurses were trained to provide a 24-hour presence in the emergency department (ED). We describe the service and our evaluation of the service.

Acute Negative Allosteric Modulation of M Muscarinic Acetylcholine Receptors Inhibits Oxycodone Self-Administration and Cue-Induced Reactivity with No Effect on Antinociception.

Opioid use disorder (OUD) is a debilitating neuropsychiatric condition characterized by compulsive opioid use, dependence, and repeated relapse after periods of abstinence. Given the high risk of developing OUD following prescription opioid use, the continued need for opioid-induced analgesia, and the limitations of current OUD treatments, it is necessary to develop novel, non-opioid-based treatments for OUD and decrease abuse potential of prescription opioids. Recent evidence suggests that negative allosteric modulation (NAM) of the M muscarinic acetylcholine receptor (M mAChR) may provide an alternative therapeutic approach for the treatment of OUD.

A Risk Index and Data Display for Process Performance in the Pharmaceutical Industry.

We propose a new index and graphical display for quantifying and visualizing process performance in the pharmaceutical industry. These tools can provide management a comprehensive, high level overview of the process performance of a global manufacturing network suitable for risk ranking, by which is meant: identifying those processes at greatest risk of failing to meet specifications, and prioritizing resources to drive continuous process improvement. Our index, like others currently in use, compares the observed variation of CQAs-critical quality attributes-to their specifications.

Selective inhibition of M muscarinic acetylcholine receptors attenuates cocaine self-administration in rats.

Cocaine use disorder (CUD) remains a debilitating health problem in the United States for which there are no Food and Drug Administration-approved treatment options. Accumulating anatomical and electrophysiological evidence indicates that the muscarinic acetylcholine receptor (mAChR) subtype 5 (M ) plays a critical role in the regulation of the mesolimbic dopaminergic reward circuitry, a major site of action for cocaine and other psychostimulants. In addition, M knockout mice exhibit reduced cocaine self-administration behaviors with no differences in sugar pellet-maintained responding relative to wild-type mice.

Cognitive enhancement and antipsychotic-like activity following repeated dosing with the selective M PAM VU0467154.

Although selective activation of the M muscarinic acetylcholine receptor (mAChR) subtype has been shown to improve cognitive function in animal models of neuropsychiatric disorders, recent evidence suggests that enhancing M mAChR function can also improve memory performance. Positive allosteric modulators (PAMs) targeting the M mAChR subtype have shown therapeutic potential for the treatment of multiple symptoms observed in schizophrenia, including positive and cognitive symptoms when assessed in acute preclinical dosing paradigms. Since the cholinergic system has been implicated in multiple stages of learning and memory, we evaluated the effects of repeated dosing with the highly selective M PAM VU0467154 on either acquisition and/or consolidation of learning and memory when dosed alone or after pharmacologic challenge with the N-methyl-d-aspartate subtype of glutamate receptors (NMDAR) antagonist MK-801.

Non-steroidal anti-inflammatory drug-induced cardiovascular adverse events: a meta-analysis.

What Is Known And Objective: Although non-steroidal anti-inflammatory drugs (NSAIDs) have been studied in randomized, controlled trials and meta-analyses in an effort to determine their cardiovascular (CV) risks, no consensus has been reached. These studies continue to raise questions, including whether cyclooxygenase-2 (COX-2) selectivity plays a role in conferring CV risk. We performed a meta-analysis of current literature to determine whether COX-2 selectivity leads to an increased CV risk.

Neural Correlates of the False Consensus Effect: Evidence for Motivated Projection and Regulatory Restraint.

The false consensus effect (FCE), the tendency to project our attitudes and opinions on to others, is a pervasive bias in social reasoning with a range of ramifications for individuals and society. Research in social psychology has suggested that numerous factors (anchoring and adjustment, accessibility, motivated projection, etc.) may contribute to the FCE.

Benzodiazepine and neuroactive steroid combinations in rats: anxiolytic-like and discriminative stimulus effects.

Rationale: Benzodiazepines are effective anxiolytics, hypnotics, and anticonvulsants but unwanted side effects, including abuse potential, limit their use. A possible strategy to increase the therapeutic index of this drug class is to combine benzodiazepines with neuroactive steroids.

Objectives: The present study evaluated the extent to which combinations of benzodiazepines (triazolam, clonazepam) and neuroactive steroids (pregnanolone, ganaxolone) induced additive, supra-additive, or infra-additive effects in an elevated zero maze and a drug discrimination procedure in rats.

The mere green effect: An fMRI study of pro-environmental advertisements.

Self-report evidence suggests that consumers prefer green products (i.e., pro-environmental) to standard products, but this is not reflected in purchase behaviors.

Attenuation of social interaction-associated ultrasonic vocalizations and spatial working memory performance in rats exposed to chronic unpredictable stress.

Exposure to unpredictable chronic mild stress (CUS) is a commonly used protocol in rats that is reported to evoke antidepressant-reversible behaviors such as loss of preference for a sweetened water solution which is taken as an analog of the anhedonia seen in major depression. However, the induction of anhedonic-like behavior by chronic mild stress, gauged by an animal's preference for sucrose solution, is not fully reproducible and consistent across laboratories. In this study, we compared a widely used behavioral marker of anhedonia - the sucrose preference test, with another phenotypic marker of emotional valence, social interaction-associated ultrasonic vocalizations as well as a marker of an anxiety-like phenotype, novelty-suppressed feeding, and cognitive performance in the eight arm radial maze task in adult male Sprague-Dawley rats.

Differential interactions engendered by benzodiazepine and neuroactive steroid combinations on schedule-controlled responding in rats.

Benzodiazepines are positive allosteric modulators of the GABAA receptor and are prescribed as anxiolytics, hypnotics, and anticonvulsants. While these drugs clearly have clinical value, their use is associated with unwanted side effects such as sedation and motor impairment. Neuroactive steroids are endogenous modulators of GABAA receptors and recent evidence has shown that combinations of the triazolo-benzodiazepine triazolam and the endogenous neuroactive steroid pregnanolone can produce both supra-additive anxiolytic effects and infra-additive reinforcing effects.

UK policy on social networking sites and online health: From informed patient to informed consumer?

Background: Social networking sites offer new opportunities for communication between and amongst health care professionals, patients and members of the public. In doing so, they have the potential to facilitate public access to health care information, peer-support networks, health policy fora and online consultations. Government policies and guidance from professional organisations have begun to address the potential of these technologies in the domain of health care and the responsibilities they entail for their users.

Expectations in the field of the internet and health: an analysis of claims about social networking sites in clinical literature.

This article adopts a critical sociological perspective to examine the expectations surrounding the uses of social networking sites (SNSs) articulated in the domain of clinical literature. This emerging body of articles and commentaries responds to the recent significant growth in SNS use, and constitutes a venue in which the meanings of SNSs and their relation to health are negotiated. Our analysis indicates how clinical writing configures the role of SNSs in health care through a range of metaphorical constructions that frame SNSs as a tool, a conduit for information and a traversable space.

Utilizing design of experiments to characterize assay robustness.

Background: Design of experiments (DOE) is a systematic approach to assess the effects of many factors on a response of an assay. This paper provides a case study whereby DOE was successfully utilized to evaluate robustness parameters for a ligand-binding assay (LBA).

Methodology: A 24-run Plackett-Burman design was developed to investigate factors that may have caused a lack of robustness in this particular LBA.

Acyloxy nitroso compounds inhibit LIF signaling in endothelial cells and cardiac myocytes: evidence that STAT3 signaling is redox-sensitive.

We previously showed that oxidative stress inhibits leukemia inhibitory factor (LIF) signaling by targeting JAK1, and the catalytic domains of JAK 1 and 2 have a cysteine-based redox switch. Thus, we postulated that the NO sibling and thiophylic compound, nitroxyl (HNO), would inhibit LIF-induced JAK-STAT3 activation. Pretreatment of human microvascular endothelial cells (HMEC-1) or neonatal rat cardiomyocytes with the HNO donors Angeli's salt or nitrosocyclohexyl acetate (NCA) inhibited LIF-induced STAT3 activation.

The effect of different linkers on target cell catabolism and pharmacokinetics/pharmacodynamics of trastuzumab maytansinoid conjugates.

Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate consisting of the anti-HER2 antibody trastuzumab linked via a nonreducible thioether linker to the maytansinoid antitubulin agent DM1. T-DM1 has shown favorable safety and efficacy in patients with HER2-positive metastatic breast cancer. In previous animal studies, T-DM1 exhibited better pharmacokinetics (PK) and slightly more efficacy than several disulfide-linked versions.

Obesity in the news: directions for future research.

Obesity attracts large volumes of news coverage. This in turn has spawned academic studies investigating how news framing may affect views about causes of and solutions to obesity. We use key studies to demonstrate that although existing research has made valuable discoveries about how obesity is defined in various media outlets, some methodological and theoretical questions remain unaddressed.

Identification of a redox-sensitive switch within the JAK2 catalytic domain.

Four cysteine residues (Cys866, Cys917, Cys1094, and Cys1105) have direct roles in cooperatively regulating Janus kinase 2 (JAK2) catalytic activity. Additional site-directed mutagenesis experiments now provide evidence that two of these residues (Cys866 and Cys917) act together as a redox-sensitive switch, allowing JAK2's catalytic activity to be directly regulated by the redox state of the cell. We created several variants of the truncated JAK2 (GST/(NΔ661)rJAK2), which incorporated cysteine-to-serine or cysteine-to-alanine mutations.

An fMRI study of the brain responses of traumatized mothers to viewing their toddlers during separation and play.

This study tested whether mothers with interpersonal violence-related posttraumatic stress disorder (IPV-PTSD) vs healthy controls (HC) would show greater limbic and less frontocortical activity when viewing young children during separation compared to quiet play. Mothers of 20 children (12-42 months) participated: 11 IPV-PTSD mothers and 9 HC with no PTSD. During fMRI, mothers watched epochs of play and separation from their own and unfamiliar children.

Effects of anti-VEGF treatment duration on tumor growth, tumor regrowth, and treatment efficacy.

Purpose: Inhibition of the vascular endothelial growth factor (VEGF) axis is the basis of all currently approved antiangiogenic therapies. In preclinical models, anti-VEGF blocking antibodies have shown broad efficacy that is dependent on both tumor context and treatment duration. We aimed to characterize this activity and to evaluate the effects of discontinuation of treatment on the dynamics of tumor regrowth.

An FMRI study of frontostriatal circuits during the inhibition of eye blinking in persons with Tourette syndrome.

Objective: The authors sought to study activity in neural circuits that subserve the inhibition of a semi-involuntary motor behavior, eye blinking, in children and adults with Tourette syndrome and in healthy comparison subjects.

Method: Functional magnetic resonance imaging was used to scan 120 participants (51 with Tourette syndrome and 69 comparison subjects) as they either blinked normally or successfully inhibited eye blinking. The authors compared the blood-oxygen-level dependent signal during these two conditions across the Tourette and comparison groups.

Suppression of HER2/HER3-mediated growth of breast cancer cells with combinations of GDC-0941 PI3K inhibitor, trastuzumab, and pertuzumab.

Purpose: Oncogenic activation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway is prevalent in breast cancer and has been associated with resistance to HER2 inhibitors in the clinic. We therefore investigated the combinatorial activity of GDC-0941, a novel class I PI3K inhibitor, with standard-of-care therapies for HER2-amplified breast cancer.

Experimental Design: Three-dimensional laminin-rich extracellular matrix cultures of human breast cancer cells were utilized to provide a physiologically relevant approach to analyze the efficacy and molecular mechanism of combination therapies ex vivo.