Valsartan Improves Adipose Tissue Function in Humans with Impaired Glucose Metabolism: A Randomized Placebo-Controlled Double-Blind Trial

<div><h3>Background</h3><p>Blockade of the renin-angiotensin system (RAS) reduces the incidence of type 2 diabetes mellitus. In rodents, it has been demonstrated that RAS blockade improved adipose tissue (AT) function and glucose homeostasis. However, the effects of long-term RAS blockade on AT function have not been investigated in humans. Therefore, we examined whether 26-wks treatment with the angiotensin II type 1 receptor blocker valsartan affects AT function in humans with impaired glucose metabolism (IGM).</p> <h3>Methodology/Principal Findings</h3><p>We performed a randomized, double-blind, placebo-controlled parallel-group study, in which 38 subjects with IGM were treated with valsartan (VAL, 320 mg/d) or placebo (PLB) for 26 weeks. Before and after treatment, an abdominal subcutaneous AT biopsy was collected for measurement of adipocyte size and AT gene/protein expression of angiogenesis/capillarization, adipogenesis, lipolytic and inflammatory cell markers. Furthermore, we evaluated fasting and postprandial AT blood flow (ATBF) (¹³³Xe wash-out), systemic inflammation and insulin sensitivity (hyperinsulinemic-euglycemic clamp). VAL treatment markedly reduced adipocyte size (<em>P</em><0.001), with a shift toward a higher proportion of small adipocytes. In addition, fasting (<em>P</em> = 0.043) and postprandial ATBF (<em>P</em> = 0.049) were increased, whereas gene expression of angiogenesis/capillarization, adipogenesis and macrophage infiltration markers in AT was significantly decreased after VAL compared with PLB treatment. Interestingly, the change in adipocyte size was associated with alterations in insulin sensitivity and reduced AT gene expression of macrophage infiltration markers. VAL did not alter plasma monocyte-chemoattractant protein (MCP)-1, TNF-α, adiponectin and leptin concentrations.</p> <h3>Conclusions/Significance</h3><p>26-wks VAL treatment markedly reduced abdominal subcutaneous adipocyte size and AT macrophage infiltration markers, and increased ATBF in IGM subjects. The VAL-induced decrease in adipocyte size was associated with reduced expression of macrophage infiltration markers in AT. Our findings suggest that interventions targeting the RAS may improve AT function, thereby contributing to a reduced risk of developing cardiovascular disease and type 2 diabetes.</p> <h3>Trial Registration</h3><p>Trialregister.nl NTR721 (ISRCTN Registry: ISRCTN<a href="http://www.controlled-trials.com/isrctn/pf/42786336">42786336</a>)</p> </div

C. elegans rrf-1 Mutations Maintain RNAi Efficiency in the Soma in Addition to the Germline

Gene inactivation through RNA interference (RNAi) has proven to be a valuable tool for studying gene function in C. elegans. When combined with tissue-specific gene inactivation methods, RNAi has the potential to shed light on the function of a gene in distinct tissues. In this study we characterized C. elegans rrf-1 mutants to determine their ability to process RNAi in various tissues. These mutants have been widely used in RNAi studies to assess the function of genes specifically in the C. elegans germline. Upon closer analysis, we found that two rrf-1 mutants carrying different loss-of-function alleles were capable of processing RNAi targeting several somatically expressed genes. Specifically, we observed that the intestine was able to process RNAi triggers efficiently, whereas cells in the hypodermis showed partial susceptibility to RNAi in rrf-1 mutants. Other somatic tissues in rrf-1 mutants, such as the muscles and the somatic gonad, appeared resistant to RNAi. In addition to these observations, we found that the rrf-1(pk1417) mutation induced the expression of several transgenic arrays, including the FOXO transcription factor DAF-16. Unexpectedly, rrf-1(pk1417) mutants showed increased endogenous expression of the DAF-16 target gene sod-3; however, the lifespan and thermo-tolerance of rrf-1(pk1417) mutants were similar to those of wild-type animals. In sum, these data show that rrf-1 mutants display several phenotypes not previously appreciated, including broader tissue-specific RNAi-processing capabilities, and our results underscore the need for careful characterization of tissue-specific RNAi tools

Moral injury in the context of substance use disorders: a narrative review.

The rate of annual drug overdose deaths in the USA recently topped 100,000 (CDC/National Center for Health Statistics 2021), an illustration of the critical need to prevent and treat substance use disorders (SUDs). As a complex, chronic medical condition, substance use treatment requires psychological, emotional, and spiritual interventions along with medical care. The recently developed concept of moral injury has been increasingly studied and applied to military service members who experience conflict between the expectations or survival needs of combat and their moral values. This review explores whether moral injury, along with the related emotional, psychological, and spiritual symptoms, can also develop in the context of SUDs. This review identified 5 manuscripts related to moral injury arising in a substance use context. These studies were small in sample size and qualitative in nature but did indicate the presence of moral injury within the context of substance use. Further studies are needed to better understand and treat moral injury related to SUDs. A conceptualization of how moral injury may arise in the context of substance use is presented here. It is suggested that the activation of the primitive dopaminergic reward system causes a potential conflict between the experienced need for the addictive substance and a person's moral code or values. The moral injury resulting from this collision may impact treatment and recovery

The Use of Opioids in the Management of Chronic Pain: Synopsis of the 2022 Updated U.S. Department of Veterans Affairs and U.S. Department of Defense Clinical Practice Guideline

DESCRIPTION: In May 2022, leadership within the U.S. Department of Veterans Affairs (VA) and U.S. Department of Defense (DoD) approved a joint clinical practice guideline for the use of opioids when managing chronic pain. This synopsis summarizes the recommendations that the authors believe are the most important to highlight. METHODS: In December 2020, the VA/DoD Evidence-Based Practice Work Group assembled a team to update the 2017 VA/DoD Clinical Practice Guideline for Opioid Therapy for Chronic Pain. The guideline development team included clinical stakeholders and conformed to the National Academy of Medicine\u27s tenets for trustworthy clinical practice guidelines. The guideline team developed key questions to guide a systematic evidence review that was done by an independent third party and distilled 20 recommendations for care using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. The guideline team also created 3 one-page algorithms to help guide clinical decision making. This synopsis presents the recommendations and highlights selected recommendations on the basis of clinical relevance. RECOMMENDATIONS: This guideline is intended for clinicians who may be considering opioid therapy to manage patients with chronic pain. This synopsis reviews updated recommendations for the initiation and continuation of opioid therapy; dose, duration, and taper of opioids; screening, assessment, and evaluation; and risk mitigation. New additions are highlighted, including recommendations about the use of buprenorphine instead of full agonist opioids; assessing for behavioral health conditions and factors associated with higher risk for harm, such as pain catastrophizing; and the use of pain and opioid education to reduce the risk for prolonged opioid use for postsurgical pain