GIMAP5 deficiency reveals a mammalian ceramide-driven longevity assurance pathway.

Preserving cells in a functional, non-senescent state is a major goal for extending human healthspans. Model organisms reveal that longevity and senescence are genetically controlled, but how genes control longevity in different mammalian tissues is unknown. Here, we report a new human genetic disease that causes cell senescence, liver and immune dysfunction, and early mortality that results from deficiency of GIMAP5, an evolutionarily conserved GTPase selectively expressed in lymphocytes and endothelial cells. We show that GIMAP5 restricts the pathological accumulation of long-chain ceramides (CERs), thereby regulating longevity. GIMAP5 controls CER abundance by interacting with protein kinase CK2 (CK2), attenuating its ability to activate CER synthases. Inhibition of CK2 and CER synthase rescues GIMAP5-deficient T cells by preventing CER overaccumulation and cell deterioration. Thus, GIMAP5 controls longevity assurance pathways crucial for immune function and healthspan in mammals.

Targeting Molecular Mechanisms of Obesity- and Type 2 Diabetes Mellitus-Induced Skeletal Muscle Atrophy with Nerve Growth Factor.

Skeletal muscle plays a critical role in metabolic diseases, such as obesity and type 2 diabetes mellitus (T2DM). Muscle atrophy, characterized by a decrease in muscle mass and function, occurs due to an imbalance between the rates of muscle protein synthesis and degradation. This study aimed to investigate the molecular mechanisms that lead to muscle atrophy in obese and T2DM mouse models. Additionally, the effect of nerve growth factor (NGF) on the protein synthesis and degradation pathways was examined. Male mice were divided into three groups: a control group that was fed a standard chow diet, and two experimental groups that were fed a Western diet. After 8 weeks, the diabetic group was injected with streptozotocin to induce T2DM. Each group was then further divided into NGF-treated or non-treated control group. In the gastrocnemius muscles of the Western diet group, increased expressions of myostatin, autophagy markers, and ubiquitin ligases were observed. Skeletal muscle tissue morphology indicated signs of muscle atrophy in both obese and diabetic mice. The NGF-treated group showed a prominent decrease in the protein levels of myostatin and autophagy markers. Furthermore, the NGF-treated group showed an increased Cyclin D1 level. Western diet-induced obesity and T2DM may be linked to muscle atrophy through upregulation of myostatin and subsequent increase in the ubiquitin and autophagy systems. Moreover, NGF treatment may improve muscle protein synthesis and cell cycling.

Placental pathology is necessary to understand common pregnancy complications and achieve an improved taxonomy of obstetrical disease.

The importance of a fully functioning placenta for a good pregnancy outcome is unquestioned. Loss of function can lead to pregnancy complications and is often detected by a thorough placental pathologic examination. Placental pathology has advanced the science and practice of obstetrics and neonatal-perinatal medicine by classifying diseases according to underlying biology and specific patterns of injury. Many past obstacles have limited the incorporation of placental findings into both clinical studies and day-to-day practice. Limitations have included variability in the nomenclature used to describe placental lesions, a shortage of perinatal pathologists fully competent to analyze placental specimens, and a troubling lack of understanding of placental diagnoses by clinicians. However, the potential use of placental pathology for phenotypic classification, improved understanding of the biology of adverse pregnancy outcomes, the development of treatment and prevention, and patient counseling has never been greater. This review, written partly in response to a recent critique published in a major obstetrics-gynecology journal, reexamines the role of placental pathology by reviewing current concepts of biology; explaining the most recent terminology; emphasizing the usefulness of specific diagnoses for obstetrician-gynecologists, neonatologists, and patients; previewing upcoming changes in recommendations for placental submission; and suggesting future improvements. These improvements should include further consideration of overall healthcare costs, cost-effectiveness, the clinical value added of placental assessment, improvements in placental pathology education and practice, and leveraging of placental pathology to identify new biomarkers of disease and evaluate novel therapies tailored to specific clinicopathologic phenotypes of both women and infants.

Oleocanthal Ameliorates Metabolic and Behavioral Phenotypes in a Mouse Model of Alzheimer's Disease.

Aging is a major risk factor for Alzheimer's disease (AD). AD mouse models are frequently used to assess pathology, behavior, and memory in AD research. While the pathological characteristics of AD are well established, our understanding of the changes in the metabolic phenotypes with age and pathology is limited. In this work, we used the Promethion cage systems® to monitor changes in physiological metabolic and behavioral parameters with age and pathology in wild-type and 5xFAD mouse models. Then, we assessed whether these parameters could be altered by treatment with oleocanthal, a phenolic compound with neuroprotective properties. Findings demonstrated metabolic parameters such as body weight, food and water intake, energy expenditure, dehydration, and respiratory exchange rate, and the behavioral parameters of sleep patterns and anxiety-like behavior are altered by age and pathology. However, the effect of pathology on these parameters was significantly greater than normal aging, which could be linked to amyloid-ß deposition and blood-brain barrier (BBB) disruption. In addition, and for the first time, our findings suggest an inverse correlation between sleep hours and BBB breakdown. Treatment with oleocanthal improved the assessed parameters and reduced anxiety-like behavior symptoms and sleep disturbances. In conclusion, aging and AD are associated with metabolism and behavior changes, with the changes being greater with the latter, which were rectified by oleocanthal. In addition, our findings suggest that monitoring changes in metabolic and behavioral phenotypes could provide a valuable tool to assess disease severity and treatment efficacy in AD mouse models.

Plasma and fecal zonulin are not altered by a high green leafy vegetable dietary intervention: secondary analysis of a randomized control crossover trial.

BACKGROUND: Zonulin is observed in animal models to regulate intestinal permeability and influenced by dietary intake, gut microbiota, and inflammation. We conducted a secondary analysis of a randomized controlled crossover trial (NCT03582306) in individuals with a BMI greater than 30 kg/m2 and high habitual red meat intake and low habitual green leafy vegetable (GLV) intake. METHODS: Participants were provided with frozen GLV during the first or last four weeks (immediate or delayed intervention) of the twelve-week trial. Biological and anthropometric measures were taken at the beginning and at each four-week interval. A subset of 20 participants was selected for this secondary analysis of the intestinal permeability and inflammation-related biomarkers: serum and fecal zonulin; serum lipopolysaccharide binding protein (LBP), Alpha-1-acid glycoprotein 1 (ORM-1), tumor necrosis factor α (TNFα), interleukin-6 (IL-6), and C-reactive protein; 8-hydroxy-2'-deoxyguanosine (8OHdG) and plasma Vitamin K1 as a marker of protocol adherence. Nutrient and food group intake from two-24-h dietary recalls collected at each time point were assessed. Fecal microbiota was measured by 16 s rRNA PCR sequencing. Changes in biological markers, dietary factors, and microbial taxa were assessed with Wilcoxon Sign Ranks Tests. Exploratory analyses of the relationship between changes in outcome variables were conducted with Spearman correlations. RESULTS: No changes in serum and fecal zonulin and serum LBP were observed. Plasma Vitamin K (p = 0.005) increased, while plasma 8OHdG (p = 0.023) decreased during the intervention compared to the control. The only dietary factors that changed significantly were increases during intervention in Vitamin K and Dark GLV (p < 0.001 for both) compared to control. Fecal microbiota did not change significantly across all times points; however, change in serum zonulin was associated with change in Proteobacteria (ρ = - 0.867, p = 0.001) in females and Bifidobacterium (ρ = - 0.838, p = 0.009) and Bacteroidaceae (ρ = 0.871, p = 0.005) in men. CONCLUSIONS: A high GLV dietary intervention increased serum zonulin levels and had no effect on fecal zonulin. Lack of concordance between several inflammation-associated biomarkers and zonulin corroborate recent reports of limited utility of zonulin in obese adults free of lower gastrointestinal disease. Trial Registration information: https://clinicaltrials.gov/ct2/show/NCT03582306 (NCT03582306) registered on 07/11/2018.

Psychobiotics as treatment for anxiety, depression, and related symptoms: a systematic review.

Objective: Altering the gut microflora may produce health benefits in individuals suffering from mood disorders. The purpose of this review was to evaluate the efficacy of probiotics, prebiotics, or synbiotics as a potential treatment for symptoms of depression, anxiety, and stress (as psychobiotics).Methods: Google Scholar, PubMed, PsychINFO, and Web of Science were utilized to identify and evaluate studies through October 31, 2019. Studies were included if subjects were evaluated for altered mood or stress levels at start of the study and consumed probiotics, prebiotics, and/or synbiotics for intervention.Results: Search results yielded 142 articles, while only 12 studies met all inclusion criteria. Nine of the 12 studies identified evaluated the efficacy of various probiotic strains, while only two evaluated synbiotics and one evaluated prebiotics. Six out of 12 studies found probiotics to reduce depression, while two studies found probiotics to reduce anxiety.Discussion: Translational research in this field is limited and further investigation of the efficacy of psychobiotics in mood disorders is warranted.

Sustainable and replicable clinical and financial outcomes in an interprofessional education and collaborative practice nexus.

Our Interprofessional Education and Collaborative Practice (IPECP) Nexus previously reported significant reductions in Emergency Department (ED) visits, hospitalizations, hemoglobin A1c levels, and patient charges. This study examines sustainability of these results over two additional years and replication in two subsequent independent patient cohorts. Participants in the sustainability cohort (N = 276) met ≥1 of the following criteria: (a) ≥3 ED visits in first or second half of the year, (b) hemoglobin A1c level ≥ 9, or (c) Length of Stay, Acuity, Comorbidities, and ER (Emergency Room) Visits (LACE) score ≥ 10. Participants in two replicability cohorts (N = 255) and (N = 160) met the same criteria, but the LACE criterion was changed to ≥3 hospitalizations in baseline years. The Nexus, housed in a family medicine (FM) residency clinic, included professionals and students from multiple disciplines. IPECP skills and interventions included communication, team building, and conflict engagement skills training, daily huddles and pre-visit planning, immediate consultations, small teamlet IPECP interactions, and weekly IPECP case conferences for complex patients. Original health improvements and charge reductions were sustained for two additional years for ED visits, hospitalizations, A1c, and patient charges, and replicated in two additional patient cohorts. The IPECP Nexus interventions were associated with Quadruple Aim outcomes while training the next generation of health care professionals.

Improving Staff Experience With Vaccine Data Entry With 2D Barcode Scanning.

BACKGROUND: Small fonts on vaccine labels make manually recording vaccine data in patient records time-consuming and challenging. Vaccine 2-dimensional (2D) barcode scanning is a promising alternative to manually recording these data. PROBLEM: While vaccine 2D barcode scanning assists in data entry, adoption of scanning technology is still low. APPROACH: Pilot sites (n = 27) within a health system scanned 2D barcodes to record vaccine data for 6 months. The time to record through scanning and nonscanning methods was measured for 13 vaccinators at 9 sites. A survey was administered to participants across all sites about their experience. OUTCOMES: On average, 22 seconds were saved per vaccine scanned versus entered manually (7 vs 29 seconds, respectively). Participants reported preference for scanning over other vaccine entry options and identified benefits of scanning. CONCLUSION: Expanded use of 2D barcode scanning can meaningfully improve clinical practices by improving efficiency and staff satisfaction during vaccine data entry.

Western diet-induced obesity disrupts the diurnal rhythmicity of hippocampal core clock gene expression in a mouse model.

Western diet (WD) feeding disrupts core clock gene expression in peripheral tissues and contributes to WD-induced metabolic disease. The hippocampus, the mammalian center for memory, is also sensitive to WD feeding, but whether the WD disrupts its core clock is unknown. To this end, male mice were maintained on a WD for 16 weeks and diurnal metabolism, gene expression and memory were assessed. WD-induced obesity disrupted the diurnal rhythms of whole-body metabolism, markers of inflammation and hepatic gene expression, but did not disrupt diurnal expression of hypothalamic Bmal1, Npas2 and Per2. However, all measured core clock genes were disrupted in the hippocampus after WD feeding and the expression pattern of genes implicated in Alzheimer's disease and synaptic function were altered. Finally, WD feeding disrupted hippocampal memory in a task- and time-dependent fashion. Our results implicate WD-induced alterations in the rhythmicity of hippocampal gene expression in the etiology of diet-induced memory deficits.

The effects of popular diets on type 2 diabetes management.

Type 2 diabetes can be managed with the use of diabetes self-management skills. Diet and exercise are essential segments of the lifestyle changes necessary for diabetes management. However, diet recommendations can be complicated in a world full of different diets. This review aims to evaluate the evidence on the effects of three popular diets geared towards diabetes management: low-carbohydrate and ketogenic diet, vegan diet, and the Mediterranean diet. While all three diets have been shown to assist in improving glycaemic control and weight loss, patient adherence, acceptability, and long-term manageability play essential roles in the efficacy of each diet.

Development and Characterization of a Novel Congenic Rat Strain for Obesity and Cancer Research.

The association between a Western Diet and colon cancer suggests that dietary factors and/or obesity may contribute to cancer progression. Our objective was to develop a new animal model of obesity and the associated pathophysiology to investigate human cancer independent of dietary components that induce obesity. A novel congenic rat strain was established by introducing the fa allele from the Zucker rat into the Rowett Nude rat to generate a "fatty nude rat". The obese phenotype was first characterized in the new model. To then examine the utility of this model, lean and obese rats were implanted with HT-29 human colon cancer xenografts and tumor growth monitored. Fatty nude rats were visibly obese and did not develop fasting hyperglycemia. Compared to lean rats, fatty nude rats developed fasting hyperinsulinemia, glucose intolerance, and insulin resistance. Colon cancer tumor growth rate and final weight were increased (P < 0.05) in fatty nude compared to lean rats. Final tumor weight was associated with p38 kinase phosphorylation (P < 0.01) in fatty nude rats. We have established a novel model of obesity and pre-type 2 diabetes that can be used to investigate human cancer and therapeutics in the context of obesity and its associated pathophysiology.

A Content Analysis of Hospitals' Community Health Needs Assessments in the Most Violent U.S. Cities.

The emergence of evidence-supported interventions allows hospitals the opportunity to reduce future reinjury among patients who are violently injured. However, hospital knowledge of these interventions and their perceived role in violence prevention is unknown. The Patient Protection and Affordable Care Act created new legal requirements for non-profit hospitals to conduct community health needs assessments (CHNA) every three years to maintain not-for-profit status. In turn, this allows an empiric evaluation of hospital recognition and response to community violence. To do so, this study performed a content analysis of hospital CHNAs from the 20 U.S. cities with the highest violent crime rates. A total of 77 CHNAs were examined for specific violence-related keywords as well as whether violence prevention was listed as a priority community need. Overall, 74% of CHNAs mentioned violence-related terms and only 32% designated violence prevention as a priority need. When discussed, 88% of CHNAs referenced community violence, 42% intimate partner or sexual violence, and 22% child abuse. This study suggests that hospitals may lack awareness of violence as an actionable, preventable public health issue. Further, evidence-based program models are available to hospitals that can reduce the recurrence of assaultive injuries.

Experience and Compliance With Scanning Vaccines' Two-Dimensional Barcodes to Record Data.

Automated population of data into health information system fields offers the potential to increase efficiencies and save time. Increasingly, as two-dimensional barcoded vaccine products and barcode scanning technology become more widely available, manual recording of vaccine data can be reduced. This evaluation explores how often two-dimensional barcodes on vaccine vials and syringes were scanned and the perceived benefits and challenges reported by vaccine providers. Eighty-two facilities that administer vaccines completed the evaluation. Twenty-seven of those facilities provided records from vaccines administered between July 2014 and January 2015. Among the 63 179 two-dimensional barcoded vaccine administrations recorded, 12 408 (19%) were scanned. We received 116 user surveys from 63 facilities; using content analysis, we identified perceived benefits of scanning, workflow challenges, scanning challenges, and other challenges. The findings of this evaluation can guide health information system developers, vaccine manufacturers, and vaccine providers on how to remove potential barriers to using two-dimensional barcode scanning.