The future of translational research on alcohol use disorder.

In March 2019, a scientific meeting was held at the University of California, Los Angeles (UCLA) Luskin Center to discuss approaches to expedite the translation of neurobiological insights to advances in the treatment of alcohol use disorder (AUD). A guiding theme that emerged was that while translational research in AUD is clearly a challenge, it is also a field ripe with opportunities. Herein, we seek to summarize and disseminate the recommendations for the future of translational AUD research using four sections.

Steep Discounting of Future Rewards as an Impulsivity Phenotype: A Concise Review.

This chapter provides an overview over the behavioral economic index of impulsivity known as delay discounting. Specifically, delay discounting refers to an individual's preference for smaller immediate rewards over a larger delayed rewards. The more precipitously an individual discounts future rewards, the more impulsive they are considered to be.

Tumor Necrosis Factor Inhibitor Dose Reduction for Axial Spondyloarthritis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Objective: The present study was undertaken to investigate the effectiveness and safety of dose reduction of tumor necrosis factor inhibitor (TNFi) therapy in the treatment of axial spondyloarthritis (SpA) compared to usual care.

Methods: We searched the Cochrane Central Register of Controlled Trials, Embase, Medline, and trial registries. We screened, extracted data, and assessed risk of bias in duplicate.

Protein misfolding in endoplasmic reticulum stress with applications to renal diseases.

Protein misfolding may be the result of a variety of different processes that disrupt the ability of a protein to form a thermodynamically stable tertiary structure that allows it to perform its proper function. In this chapter, we explore the nature of a protein's form that allows it to have a stable tertiary structure, and examine specific mutation that are known to occur in the coding regions of DNA that disrupt a protein's ability to be folded into a thermodynamically stable tertiary structure. We examine the consequences of these protein misfoldings in terms of the endoplasmic reticulum stress response and resulting unfolded protein response.

Association Between Side Effects and Blood microRNA Expression Levels and Their Targeted Pathways in Patients With Major Depressive Disorder Treated by a Selective Serotonin Reuptake Inhibitor, Escitalopram: A CAN-BIND-1 Report.

Introduction: Antidepressant drugs are effective therapies for major depressive disorder; however, they are frequently associated with side effects. Although there is some evidence for a relationship between genetic variation and side effects, little is known regarding the role of dynamic molecular factors as moderators of side effects. The aim of this study was to assess microRNA (miRNA) changes associated with side effects during escitalopram treatment and their downstream effects on target gene expression.

Differential biomarker signatures in unipolar and bipolar depression: A machine learning approach.

Objective: This study used machine learning techniques combined with peripheral biomarker measurements to build signatures to help differentiating (1) patients with bipolar depression from patients with unipolar depression, and (2) patients with bipolar depression or unipolar depression from healthy controls.

Methods: We assessed serum levels of interleukin-2, interleukin-4, interleukin-6, interleukin-10, tumor necrosis factor-α, interferon-γ, interleukin-17A, brain-derived neurotrophic factor, lipid peroxidation and oxidative protein damage in 54 outpatients with bipolar depression, 54 outpatients with unipolar depression and 54 healthy controls, matched by sex and age. Depressive symptoms were assessed using the Hamilton Depression Rating Scale.

Behavioral economic tobacco demand in relation to cigarette consumption and nicotine dependence: a meta-analysis of cross-sectional relationships.

Background And Aims: A cigarette purchase task (CPT) aims to characterize individual variation in the reinforcing value of tobacco. This meta-analysis estimated the associations between cigarette demand, tobacco consumption and nicotine dependence using this task.

Design: A meta-analysis of cross-sectional studies identified by PubMed and PsycINFO databases was conducted.

Correction to: Availability of legalized cannabis reduces demand for illegal cannabis among Canadian cannabis users: evidence from a behavioural economic substitution paradigm.

The published version of Fig. 1 contained a mistake in the colour scale for the vertical lines and corresponding labels for the P values.

Endoplasmic reticulum stress inhibition blunts the development of essential hypertension in the spontaneously hypertensive rat.

Essential hypertension is the leading cause of premature death worldwide. However, hypertension's cause remains uncertain. endoplasmic reticulum (ER) stress has recently been associated with hypertension, but it is unclear whether ER stress causes hypertension.

Availability of legalized cannabis reduces demand for illegal cannabis among Canadian cannabis users: evidence from a behavioural economic substitution paradigm.

In the context of cannabis legalization, an important question among clinicians, policymakers, and the public is whether availability of legal cannabis will significantly reduce consumption (demand) of illegal cannabis. Using paradigms from behavioural economics, we tested the prediction that legal cannabis would be an asymmetrical substitute for illegal cannabis, with legal cannabis operating as a superior commodity based on its regulated status. In a sample of 289 adult cannabis users in Ontario, we found evidence of substitutability for both legal and illegal cannabis, but significantly lower substitutability of illegal for legal cannabis, a pattern that was also present for price elasticity (α) and P.

Price elasticity of illegal versus legal cannabis: a behavioral economic substitutability analysis.

Background And Aims: The evolving legal status of cannabis world-wide necessitates evidence-based regulatory policies to minimize risks associated with cannabis misuse. A prominent concern is the impact legalization may have on the illegal cannabis market, including whether illegal cannabis will serve as a substitute for legal cannabis. Empirical data on this issue are virtually non-existent.

Systematic review of the effects of acute stress in binge eating disorder.

Binge eating disorder (BED) is characterized by recurrent episodes of eating an excessive amount of food over a discrete time period, while feeling a loss of control over one's eating. Although stress is one of the most commonly reported triggers of binge eating in individuals with BED, there has been little work examining the stress response specifically in individuals with the disorder. In this review, we examine what is known about how individuals with BED respond to acute stressors.

2018 Canadian Cardiovascular Society/Canadian Association of Interventional Cardiology Focused Update of the Guidelines for the Use of Antiplatelet Therapy.

Antiplatelet therapy (APT) has become an important tool in the treatment and prevention of atherosclerotic events, particularly those associated with coronary artery disease. A large evidence base has evolved regarding the relationship between APT prescription in various clinical contexts and risk/benefit relationships. The Guidelines Committee of the Canadian Cardiovascular Society and Canadian Association of Interventional Cardiology publishes regular updates of its recommendations, taking into consideration the most recent clinical evidence.

Occurrence of Serious Infection in Patients with Rheumatoid Arthritis Treated with Biologics and Denosumab Observed in a Clinical Setting.

Objective: Previous studies combining biologic disease-modifying antirheumatic drugs (bDMARD) to treat rheumatoid arthritis (RA) have shown an increased risk of infection. However, the risk of infection with concurrent use of denosumab, a biologic agent for the treatment of osteoporosis, and a bDMARD remains unclear. Here, we evaluated the incidence of serious and opportunistic infections in patients treated concurrently with denosumab and a bDMARD and patients treated with a bDMARD alone.

Autoantibodies against the cell surface-associated chaperone GRP78 stimulate tumor growth via tissue factor.

Tumor cells display on their surface several molecular chaperones that normally reside in the endoplasmic reticulum. Because this display is unique to cancer cells, these chaperones are attractive targets for drug development. Previous epitope-mapping of autoantibodies (AutoAbs) from prostate cancer patients identified the 78-kDa glucose-regulated protein (GRP78) as one such target.

MicroRNAs 146a/b-5 and 425-3p and 24-3p are markers of antidepressant response and regulate MAPK/Wnt-system genes.

Antidepressants (ADs) are the most common treatment for major depressive disorder (MDD). However, only ∼30% of patients experience adequate response after a single AD trial, and this variability remains poorly understood. Here, we investigated microRNAs (miRNAs) as biomarkers of AD response using small RNA-sequencing in paired samples from MDD patients enrolled in a large, randomized placebo-controlled trial of duloxetine collected before and 8 weeks after treatment.

Sputum cell counts to manage prednisone-dependent asthma: effects on FEV and eosinophilic exacerbations.

Background: Prednisone dependence in asthma is usually described based on clinical and spirometric characteristics. It is generally believed that these patients have frequent exacerbations and lose lung function rapidly because of uncontrolled airway eosinophilia.

Objectives: The objectives of this study are to report the effect on asthma exacerbations and the change in lung function over time in prednisone-dependent asthma when severe asthma is managed using a protocol that aims to maintain normal sputum cell counts.

Endoplasmic reticulum stress inhibition attenuates hypertensive chronic kidney disease through reduction in proteinuria.

Endoplasmic reticulum (ER) stress is implicated in chronic kidney disease (CKD) development in patients and in animal models. Here we show that ER stress inhibition through 4-phenylbutyric acid (4-PBA) administration decreases blood pressure, albuminuria, and tubular casts in an angiotensin II/deoxycorticosterone acetate/salt murine model of CKD. Lower albuminuria in 4-PBA-treated mice was associated with higher levels of cubilin protein in renal tissue membrane fractions.

Endoplasmic reticulum stress inhibition limits the progression of chronic kidney disease in the Dahl salt-sensitive rat.

Proteinuria is one of the primary risk factors for the progression of chronic kidney disease (CKD) and has been implicated in the induction of endoplasmic reticulum (ER) stress. We hypothesized that the suppression of ER stress with a low molecular weight chemical chaperone, 4-phenylbutyric acid (4-PBA), would reduce the severity of CKD and proteinuria in the Dahl salt-sensitive (SS) hypertensive rat. To induce hypertension and CKD, 12-wk-old male rats were placed on a high-salt (HS) diet for 4 wk with or without 4-PBA treatment.