MRP8/14 Is a Molecular Signature Triggered by Dopamine in HIV Latent Myeloid Targets That Increases HIV Transcription and Distinguishes HIV+ Methamphetamine Users with Detectable CSF Viral Load and Brain Pathology.

There is a significant overlap between HIV infection and substance-use disorders. Dopamine (DA) is the most abundantly upregulated neurotransmitter in methamphetamine abuse, with receptors (DRD1-5) that are expressed by neurons as well as by a large diversity of cell types, including innate immune cells that are the targets of HIV infection, making them responsive to the hyperdopaminergic environment that is characteristic of stimulant drugs. Therefore, the presence of high levels of dopamine may affect the pathogenesis of HIV, particularly in the brain. The stimulation of HIV latently infected U1 promonocytes with DA significantly increased viral p24 levels in the supernatant at 24 h, suggesting effects on activation and replication. Using selective agonists to different DRDs, we found that DRD1 played a major role in activating viral transcription, followed by DRD4, which increased p24 with a slower kinetic rate compared to DRD1. Transcriptome and systems biology analyses led to the identification of a cluster of genes responsive to DA, where S100A8 and S100A9 were most significantly correlated with the early increase in p24 levels following DA stimulation. Conversely, DA increased the expression of these genes' transcripts at the protein level, MRP8 and MRP14, respectively, which form a complex also known as calprotectin. Interestingly, MRP8/14 was able to stimulate HIV transcription in latent U1 cells, and this occurred via binding of the complex to the receptor for an advanced glycosylation end-product (RAGE). Using selective agonists, both DRD1 and DRD4 increased MRP8/14 on the surface, in the cytoplasm, as well as secreted in the supernatants. On the other hand, while DRD1/5 did not affect the expression of RAGE, DRD4 stimulation caused its downregulation, offering a mechanism for the delayed effect via DRD4 on the p24 increase. To cross-validate MRP8/14 as a DA signature with a biomarker value, we tested its expression in HIV+ Meth users' postmortem brain specimens and peripheral cells. MRP8/14+ cells were more frequently identified in mesolimbic areas such as the basal ganglia of HIV+ Meth+ cases compared to HIV+ non-Meth users or to controls. Likewise, MRP8/14+ CD11b+ monocytes were more frequent in HIV+ Meth users, particularly in specimens from participants with a detectable viral load in the CSF. Overall, our results suggest that the MRP8 and MRP14 complex may serve as a signature to distinguish subjects using addictive substances in the context of HIV, and that this may play a role in aggravating HIV pathology by promoting viral replication in people with HIV who use Meth.

Quantitative Assessment of Tendon Backscatter Anisotropy in B-Mode Ultrasound.

To test the anisotropy of human tendons in conventional B-mode ultrasound, we prospectively performed ultrasound scans of 40 normal patella tendons and 24 patella tendons with chronic tendinopathy in adults. We scanned all tendons in longitudinal orientation (parallel to tendon fibers) using a linear array transducer (8.5 MHz) with beam steering at 0°, 5°, 10°, 15° and 20°. We used ImageJ histogram analysis to process B-mode images offline for assessing backscatter as a function of angle, known as backscatter anisotropy, between normal tendons and the subcutaneous tissues and between normal tendons and tendons with tendinopathy. We compared the results using the slopes of linear regression lines drawn through the angle-dependent data, and we concluded that the tissue anisotropy was significantly different if the 95% confidence intervals of the line slopes for different tissues did not overlap. We observed significant differences between normal tendons and both the adjacent subcutaneous tissues and tendons with tendinopathy. However, the difference in the regression slopes between tendons with tendinopathy and the adjacent subcutaneous soft tissues was not significant. It appears that changes in anisotropic backscatter could be used to detect tendon abnormalities and in assessing the significance of disease and the effectiveness of therapy.

Feasibility of time-restricted eating and impacts on cardiometabolic health in 24-h shift workers: The Healthy Heroes randomized control trial.

Over a quarter of the workforce in industrialized countries does shift work, which increases the risk for cardiometabolic disease. Yet shift workers are often excluded from lifestyle intervention studies to reduce this risk. In a randomized control trial with 137 firefighters who work 24-h shifts (23-59 years old, 9% female), 12 weeks of 10-h time-restricted eating (TRE) was feasible, with TRE participants decreasing their eating window (baseline, mean 14.13 h, 95% CI 13.78-14.47 h; intervention, 11.13 h, 95% CI 10.73-11.54 h, p = 3.29E-17) with no adverse effects, and improved quality of life assessed via SF-36 (ClinicalTrials.gov: NCT03533023). Compared to the standard of care (SOC) arm, TRE significantly decreased VLDL particle size. In participants with elevated cardiometabolic risks at baseline, there were significant reductions in TRE compared to SOC in glycated hemoglobin A1C and diastolic blood pressure. For individuals working a 24-h shift schedule, TRE is feasible and can improve cardiometabolic health, especially for individuals with increased risk. VIDEO ABSTRACT.

Heart-Healthy Diets and the Cardiometabolic Jackpot.

This review highlights the key components of a heart-healthy diet and presents an evidence-based overview of recent research. Diets that increase plant-based food sources and healthy unsaturated fats consumption and limit foods that are processed and/or high in sodium, refined sugar, and saturated fat are recommended. Dietary modification can be supplemented with lifestyle-based therapies (eg, exercise, time-restricted eating) to maximize clinical benefit and achieve the "cardiometabolic jackpot." Physicians should take into account cultural preferences, affordability and accessibility of foods, and their patients' cultural values or expectations when recommending dietary interventions.

Protocol for a randomised controlled trial on the feasibility and effects of 10-hour time-restricted eating on cardiometabolic disease risk among career firefighters doing 24-hour shift work: the Healthy Heroes Study.

INTRODUCTION: Career firefighters experience chronic circadian rhythm disruption, increasing their risk of cardiometabolic disease. The recent discovery that eating patterns regulate circadian rhythmicity in metabolic organs has raised the hypothesis that maintaining a consistent daily cycle of eating and fasting can support circadian rhythms and reduce disease risks. Preclinical animal studies and preliminary clinical trials have shown promising effects of time-restricted eating (TRE) to reduce disease risk without compromising physical performance. However, there is a lack of research on TRE in shift workers including firefighters. This study aims to investigate the feasibility and efficacy of 10-hour TRE on health parameters that contribute to cardiometabolic disease risks among career firefighters who work on a 24-hour shift schedule. METHODS AND ANALYSES: The Healthy Heroes Study is a randomised controlled parallel open-label clinical trial with 150 firefighters over 1 year. Firefighters are randomised with a 1:1 ratio to either the control or intervention group. The control group receives Mediterranean diet nutritional counselling (standard of care, 'SOC'). The intervention group receives the same SOC and a self-selected 10-hour TRE window. After the 2-week baseline, participants enter a 3-month monitored intervention, followed by a 9-month self-guided period with follow-up assessments. The impact of TRE on blood glucose, body weight, body composition, biomarkers (neuroendocrine, inflammatory and metabolic), sleep and mood is evaluated. These assessments occur at baseline, at the end of intervention and at 6, 9 and 12-month follow-ups. Temporal calorie intake is monitored with the smartphone application myCircadianClock throughout the study. Continuous glucose monitors, wrist-worn actigraphy device and questionnaires are used to monitor glucose levels, activity, sleep and light exposure. ETHICS AND DISSEMINATION: The study was approved by the Institutional Review Boards of the University of California San Diego and the Salk Institute for Biological Studies. Results will be disseminated through peer-reviewed manuscripts, reports and presentations. TRIAL REGISTRATION NUMBER: NCT03533023; Pre result.

Sex differences and Tat expression affect dopaminergic receptor expression and response to antioxidant treatment in methamphetamine-sensitized HIV Tat transgenic mice.

Methamphetamine (Meth) abuse is a common HIV comorbidity. Males and females differ in their patterns of Meth use, associated behaviors, and responses, but the underlying mechanisms and impact of HIV infection are unclear. Transgenic mice with inducible HIV-1 Tat protein in the brain (iTat) replicate many neurological aspects of HIV infection in humans. We previously showed that Tat induction enhances the Meth sensitization response associated with perturbation of the dopaminergic system, in male iTat mice. Here, we used the iTat mouse model to investigate sex differences in individual and interactive effects of Tat and Meth challenge on locomotor sensitization, brain expression of dopamine receptors (DRDs) and regulatory adenosine receptors (ADORAs). Because Meth administration increases the production of reactive oxygen species (ROS), we also determined whether the effects of Meth could be rescued by concomitant treatment with the ROS scavenger N-acetyl cysteine (NAC). After Meth sensitization and a 7-day abstinence period, groups of Tat+ and Tat-male and female mice were challenged with Meth in combination with NAC. We confirmed that Tat expression and Meth challenge suppressed DRD mRNA and protein in males and females' brains, and showed that females were particularly susceptible to the effects of Meth on D1-like and D2-like DRD subtypes and ADORAs. The expression of these markers differed strikingly between males and females, and between females in different phases of the estrous cycle, in a Tat -dependent manner. NAC attenuated Meth-induced locomotor sensitization and preserved DRD expression in all groups except for Tat + females. These data identify complex interactions between sex, Meth use, and HIV infection on addiction responses, with potential implications for the treatment of male and female Meth users in the context of HIV, especially those with cognitive disorders.

Cardiac Rehab for Functional Improvement.

PURPOSE OF REVIEW: Cardiac Rehabilitation (CR) was originally designed to return patients to their prior level of functioning after myocardial infarction (MI). Research has since revealed the mortality benefit of CR, and CR has been given a class 1A recommendation by the American Heart Association/American College of Cardiology (AHA/ACC). In this review, we shift our focus back to function and highlight the most recent research on the functional benefits of CR in a broad range of cardiac diseases and conditions. RECENT FINDINGS: Currently, CR is indicated for patients with coronary artery disease (CAD), heart failure with reduced ejection fraction (HFrEF), peripheral arterial disease (PAD), transcatheter aortic valve replacement (TAVR), left ventricular assist devices (LVADs), and cardiac transplant. Among patients with those conditions, CR has been shown to improve exercise capacity, cognition, mental health, and overall quality of life. As survival of cardiac diseases increases, CR emerges as an increasingly important tool to lend quality to patients' lives and therefore give meaning to survival.