Gut microbial trimethylamine is elevated in alcohol-associated hepatitis and contributes to ethanol-induced liver injury in mice.

There is mounting evidence that microbes residing in the human intestine contribute to diverse alcohol-associated liver diseases (ALD) including the most deadly form known as alcohol-associated hepatitis (AH). However, mechanisms by which gut microbes synergize with excessive alcohol intake to promote liver injury are poorly understood. Furthermore, whether drugs that selectively target gut microbial metabolism can improve ALD has never been tested. We used liquid chromatography tandem mass spectrometry to quantify the levels of microbe and host choline co-metabolites in healthy controls and AH patients, finding elevated levels of the microbial metabolite trimethylamine (TMA) in AH. In subsequent studies, we treated mice with non-lethal bacterial choline TMA lyase (CutC/D) inhibitors to blunt gut microbe-dependent production of TMA in the context of chronic ethanol administration. Indices of liver injury were quantified by complementary RNA sequencing, biochemical, and histological approaches. In addition, we examined the impact of ethanol consumption and TMA lyase inhibition on gut microbiome structure via 16S rRNA sequencing. We show the gut microbial choline metabolite TMA is elevated in AH patients and correlates with reduced hepatic expression of the TMA oxygenase flavin-containing monooxygenase 3 (FMO3). Provocatively, we find that small molecule inhibition of gut microbial CutC/D activity protects mice from ethanol-induced liver injury. CutC/D inhibitor-driven improvement in ethanol-induced liver injury is associated with distinct reorganization of the gut microbiome and host liver transcriptome. The microbial metabolite TMA is elevated in patients with AH, and inhibition of TMA production from gut microbes can protect mice from ethanol-induced liver injury.

Fatigue After Traumatic Brain Injury: A Systematic Review.

OBJECTIVE: To provide a systematic review of published interventions for posttraumatic brain injury fatigue (PTBIF). METHODS: PubMed and OneSearch were systematically searched for PTBIF interventions published between January 1, 1989, and March 31, 2019. Search results were evaluated for inclusion based on an abstract and full-text review. Inclusion criteria were (1) an investigation of an intervention, (2) participant sample including individuals with traumatic brain injury (TBI), (3) report of fatigue outcome data among individuals with TBI, and (4) articles available in English, Spanish, French, German, Afrikaans, or Dutch. A risk of bias assessment was conducted on all included publications. RESULTS: The search resulted in 2343 publications, with 37 meeting inclusion criteria for this review. Categories of PTBIF interventions were pharmacological ( n = 13), psychological ( n = 9), exercise-based ( n = 4), complementary alternative medicine ( n = 5), electrotherapeutic ( n = 3), and multimodal ( n = 3). Only methylphenidate, modafinil, and cognitive behavioral therapy interventions included multiple cohorts. Pharmacological and psychological interventions represented the groups with the lowest risk of bias. CONCLUSIONS: This review includes 37 studies, with 21 studies published after 2014. Methylphenidate and melatonin were the only pharmacological agents found to reduce fatigue in randomized controlled trials. Creatine given to children prospectively at onset of injury reduced fatigue at follow-up. Walking and water aerobics were effective exercise interventions in isolated randomized controlled studies. One multimodal study of children after concussion was more effective at reducing fatigue and postconcussion symptoms than community standard of care. Other interventions had equivocal results. Overall, more work remains to understand and develop treatments for PTBIF.

Lipids activate skeletal muscle mitochondrial fission and quality control networks to induce insulin resistance in humans.

BACKGROUND AND AIMS: A diminution in skeletal muscle mitochondrial function due to ectopic lipid accumulation and excess nutrient intake is thought to contribute to insulin resistance and the development of type 2 diabetes. However, the functional integrity of mitochondria in insulin-resistant skeletal muscle remains highly controversial. METHODS: 19 healthy adults (age:28.4 ±â€¯1.7 years; BMI:22.7 ±â€¯0.3 kg/m2) received an overnight intravenous infusion of lipid (20% Intralipid) or saline followed by a hyperinsulinemic-euglycemic clamp to assess insulin sensitivity using a randomized crossover design. Skeletal muscle biopsies were obtained after the overnight lipid infusion to evaluate activation of mitochondrial dynamics proteins, ex-vivo mitochondrial membrane potential, ex-vivo oxidative phosphorylation and electron transfer capacity, and mitochondrial ultrastructure. RESULTS: Overnight lipid infusion increased dynamin related protein 1 (DRP1) phosphorylation at serine 616 and PTEN-induced kinase 1 (PINK1) expression (P = 0.003 and P = 0.008, respectively) in skeletal muscle while reducing mitochondrial membrane potential (P = 0.042). The lipid infusion also increased mitochondrial-associated lipid droplet formation (P = 0.011), the number of dilated cristae, and the presence of autophagic vesicles without altering mitochondrial number or respiratory capacity. Additionally, lipid infusion suppressed peripheral glucose disposal (P = 0.004) and hepatic insulin sensitivity (P = 0.014). CONCLUSIONS: These findings indicate that activation of mitochondrial fission and quality control occur early in the onset of insulin resistance in human skeletal muscle. Targeting mitochondrial dynamics and quality control represents a promising new pharmacological approach for treating insulin resistance and type 2 diabetes. CLINICAL TRIAL REGISTRATION: NCT02697201, ClinicalTrials.gov.

Prevalence of Substance Use in an HIV Primary Care Safety Net Clinic: A Call for Screening.

Substance use complicates HIV care and prevention. Primary care clinics are an ideal setting to screen for and offer interventions for unhealthy alcohol and drug use; however, few HIV clinics routinely screen for substance use. We enrolled 208 clinic patients at an urban underserved HIV primary care clinic. We screened the patients for substance use with the Alcohol, Smoking, and Substance Involvement Score Test and measured urine toxicology. Of the 168 participants who completed screening, the majority reported tobacco or nonprescribed substance use in the previous 3 months. More African American participants reported low or no risk amphetamine use compared to Hispanic, White, or Other race participants (p < .001). Implementing standard clinic practice for screening and assessing substance use in HIV primary care clinics is needed.

Prevalence, self-care behaviors, and self-care activities for peripheral neuropathy symptoms of HIV/AIDS.

As part of a larger randomized controlled trial examining the efficacy of an HIV/AIDS symptom management manual (n = 775), this study examined the prevalence of peripheral neuropathy in HIV-infected individuals at 12 sites in the USA, Puerto Rico, and Africa. Neuropathy was reported by 44% of the sample; however, only 29.4% reported initiating self-care behaviors to address the neuropathy symptoms. Antiretroviral therapy was found to increase the frequency of neuropathy symptoms, with an increased mean intensity of 28%. A principal axis factor analysis with Promax rotation was used to assess the relationships in the frequency of use of the 18 self-care activities for neuropathy, revealing three distinct factors: (i) an interactive self-care factor; (ii) a complementary medicine factor; and (iii) a third factor consisting of the negative health items of smoking, alcohol, and street drugs. The study's results suggest that peripheral neuropathy is a common symptom and the presence of neuropathy is associated with self-care behaviors to ameliorate HIV symptoms. The implications for nursing practice include the assessment and evaluation of nursing interventions related to management strategies for neuropathy.

Quantifiable effects of osteopathic manipulative techniques on patients with chronic asthma.

In this pilot study, the authors evaluated the immediate effects of osteopathic manipulative procedures compared with sham procedures on 10 subjects who were diagnosed with chronic asthma. The research followed a pretest-posttest crossover design wherein each subject served as her own control. Blinded examiners recorded respiratory excursion, peak expiratory flow rates, and subjective measures of asthma symptoms. Measurements of both upper thoracic and lower thoracic forced respiratory excursion statistically increased after osteopathic manipulative procedures compared with sham procedures. Changes in peak expiratory flow rates and asthma symptoms were not statistically significant.