Social Determinants of Health and Cumulative Incidence of Mortality Among US Adults Without Major Chronic Diseases.

Background: Social determinants of health (SDOH) are associated with poor health outcomes among individuals with prevalent diseases.

Objective: To quantify the association between adverse SDOH and mortality among adults without major chronic diseases in the United States (US).

Design: Prospective observational study.

End Organ Affection in Sickle Cell Disease.

Sickle cell disease is an orphan disease affecting ethnic minorities and characterized by profound systemic manifestations. Although around 100,000 individuals with SCD are living in the US, the exact number of individuals is unknown, and it is considered an orphan disease. This single-gene disorder leads to red blood cell sickling and the deoxygenation of hemoglobin, resulting in hemolysis.

Impact of microbiota and host immunologic response on the efficacy of anticholinergic treatment for urgency urinary incontinence.

Introduction And Hypothesis: Studies within the past decade have suggested associations among composition of the urinary microbiota, local immune responses, and urinary incontinence symptoms. To investigate these relationships, we evaluated the structure of the urinary microbiome, local inflammatory markers, and patient responses prior to and at 6-weeks after treatment with anticholinergic medication for urgency urinary incontinence (UUI).

Methods: Using a prospective pilot study, we enrolled women who presented with UUI symptoms and were prescribed treatment with anticholinergics.

Patients' Perspectives on Race and the Use of Race-Based Algorithms in Clinical Decision-Making: a Qualitative Study.

Background: Clinical algorithms that incorporate race as a modifying factor to guide clinical decision-making have recently been criticized for propagating racial bias in medicine. Equations used to calculate lung or kidney function are examples of clinical algorithms that have different diagnostic parameters depending on an individual's race. While these clinical measures have multiple implications for clinical care, patients' awareness of and their perspectives on the application of such algorithms are unknown.

Intractable hyponatremia complicated by a reset osmostat: a case report.

Background: Hyponatremia associated with a low serum osmolality is a common and confounding electrolyte disorder. Correcting hyponatremia is also complicated, especially in the setting of chronic hyponatremia. Here, we provide a rational approach to accurately detecting and safely treating acute on chronic euvolemic hyponatremia in the setting of acute polydipsia with a chronic reset osmostat.

Aldosterone in chronic kidney disease and renal outcomes.

Aims: Randomized controlled trials have demonstrated the efficacy of mineralocorticoid receptor (MR) antagonism in delaying chronic kidney disease (CKD) progression in diabetes; however, they have not investigated the role of aldosterone or whether these beneficial effects could be achieved in individuals without diabetes.

Methods And Results: The association between serum aldosterone concentrations and kidney disease progression was investigated among 3680 participants in the Chronic Renal Insufficiency Cohort. The primary outcome was CKD progression [defined as the composite of 50% decline in estimated glomerular filtration rate (eGFR) or end-stage kidney disease, whichever occurred first].

Correlation of Fibromyalgia Survey Questionnaire and Quantitative Sensory Testing Among Patients With Active Rheumatoid Arthritis.

Objective: Patients with rheumatoid arthritis (RA) commonly demonstrate disordered pain processing associated with high pain sensitization. Pain sensitization is often assessed using quantitative sensory testing (QST), which is burdensome to patients. The self-administered Fibromyalgia Survey Questionnaire (FSQ) has been proposed as a low-burden, surrogate measure of central pain sensitization.

Deletion of ABCB10 in beta-cells protects from high-fat diet induced insulin resistance.

Objective: The contribution of beta-cell dysfunction to type 2 diabetes (T2D) is not restricted to insulinopenia in the late stages of the disease. Elevated fasting insulinemia in normoglycemic humans is a major factor predicting the onset of insulin resistance and T2D, demonstrating an early alteration of beta-cell function in T2D. Moreover, an early and chronic increase in fasting insulinemia contributes to insulin resistance in high-fat diet (HFD)-fed mice.

Mechanisms of nucleophosmin (NPM)-mediated regulated cell death elucidated by Hsp70 during renal ischemia.

Nucleophosmin (NPM), a nucleolar-based protein chaperone, promotes Bax-mediated mitochondrial injury and regulates cell death during acute kidney injury. However, the steps that transform NPM from an essential to a toxic protein during stress are unknown. To localize NPM-mediated events causing regulated cell death during ischemia, wild type (WT) and Hsp70 mutant proteins with characterized intracellular trafficking defects that restrict movement to either the nucleolar region (M45) or cytosol (985A) were expressed in primary murine proximal tubule epithelial cells (PTEC) harvested from Hsp70 null mice.

ABCB10 exports mitochondrial biliverdin, driving metabolic maladaptation in obesity.

Although the role of hydrophilic antioxidants in the development of hepatic insulin resistance and nonalcoholic fatty liver disease has been well studied, the role of lipophilic antioxidants remains poorly characterized. A known lipophilic hydrogen peroxide scavenger is bilirubin, which can be oxidized to biliverdin and then reduced back to bilirubin by cytosolic biliverdin reductase. Oxidation of bilirubin to biliverdin inside mitochondria must be followed by the export of biliverdin to the cytosol, where biliverdin is reduced back to bilirubin.

Effective Medical Lecturing: Practice Becomes Theory: A Narrative Review.

Effective lecturing stimulates learning, creates a verbal history for our profession, and is a central basis for evaluating academic promotion. Unfortunately, few resources exist in the medical literature to guide the academician toward success as an effective lecturer. Using evidence-based principles, this review fosters adult learning in academic venues by incorporating the latest innovations in educational theory for both online and traditional teaching.

Cristae undergo continuous cycles of membrane remodelling in a MICOS-dependent manner.

The mitochondrial inner membrane can reshape under different physiological conditions. How, at which frequency this occurs in living cells, and the molecular players involved are unknown. Here, we show using state-of-the-art live-cell stimulated emission depletion (STED) super-resolution nanoscopy that neighbouring crista junctions (CJs) dynamically appose and separate from each other in a reversible and balanced manner in human cells.

Nanoparticle-mediated lysosomal reacidification restores mitochondrial turnover and function in β cells under lipotoxicity.

Chronic exposure of pancreatic β cells to high concentrations of free fatty acids leads to lipotoxicity (LT)-mediated suppression of glucose-stimulated insulin secretion. This effect is in part caused by a decline in mitochondrial function as well as by a reduction in lysosomal acidification. Because both mitochondria and lysosomes can alter one another's function, it remains unclear which initiating dysfunction sets off the detrimental cascade of LT, ultimately leading to β-cell failure.

Elamipretide Promotes Mitophagosome Formation and Prevents Its Reduction Induced by Nutrient Excess in INS1 β-cells.

Elamipretide is a tetrapeptide that restores defects in mitochondrial function, binds to cardiolipin, and is being tested in clinical trials for mitochondria-related diseases. However, whether elamipretide modulates mitochondrial quality control and dynamics, processes essential to preserve mitochondrial function, is unclear. Thus, we tested the effects of elamipretide on mitochondrial morphology, mitophagosome formation, and their early disruption induced by excess nutrients in INS1 β-cells.

BET proteins in abnormal metabolism, inflammation, and the breast cancer microenvironment.

Obesity and its associated pathology Type 2 diabetes are two chronic metabolic and inflammatory diseases that promote breast cancer progression, metastasis, and poor outcomes. Emerging critical opinion considers unresolved inflammation and abnormal metabolism separately from obesity; settings where they do not co-occur can inform disease mechanism. In breast cancer, the tumor microenvironment is often infiltrated with T effector and T regulatory cells programmed by metabolic signaling.

Distinct roles for dietary lipids and Porphyromonas gingivalis infection on atherosclerosis progression and the gut microbiota.

Mounting evidence in humans supports an etiological role for the microbiota in inflammatory atherosclerosis. Atherosclerosis is a progressive disease characterized by accumulation of inflammatory cells and lipids in vascular tissue. While retention of lipoprotein into the sub-endothelial vascular layer is believed to be the initiating stimulus leading to the development of atherosclerosis, activation of multiple pathways related to vascular inflammation and endothelial dysfunction sustain the process by stimulating recruitment of leukocytes and immune cells into the sub-endothelial layer.

Modulation of mTOR signaling as a strategy for the treatment of Pompe disease.

Mechanistic target of rapamycin (mTOR) coordinates biosynthetic and catabolic processes in response to multiple extracellular and intracellular signals including growth factors and nutrients. This serine/threonine kinase has long been known as a critical regulator of muscle mass. The recent finding that the decision regarding its activation/inactivation takes place at the lysosome undeniably brings mTOR into the field of lysosomal storage diseases.

Lysosome acidification by photoactivated nanoparticles restores autophagy under lipotoxicity.

In pancreatic β-cells, liver hepatocytes, and cardiomyocytes, chronic exposure to high levels of fatty acids (lipotoxicity) inhibits autophagic flux and concomitantly decreases lysosomal acidity. Whether impaired lysosomal acidification is causally inhibiting autophagic flux and cellular functions could not, up to the present, be determined because of the lack of an approach to modify lysosomal acidity. To address this question, lysosome-localizing nanoparticles are described that, upon UV photoactivation, enable controlled acidification of impaired lysosomes.

Nanoparticle tumor localization, disruption of autophagosomal trafficking, and prolonged drug delivery improve survival in peritoneal mesothelioma.

The treatment outcomes for malignant peritoneal mesothelioma are poor and associated with high co-morbidities due to suboptimal drug delivery. Thus, there is an unmet need for new approaches that concentrate drug at the tumor for a prolonged period of time yielding enhanced antitumor efficacy and improved metrics of treatment success. A paclitaxel-loaded pH-responsive expansile nanoparticle (PTX-eNP) system is described that addresses two unique challenges to improve the outcomes for peritoneal mesothelioma.

The Role of BCL-2 Family Members in Acute Kidney Injury.

B-cell lymphoma 2 (BCL-2) family proteins gather at the biologic cross-roads of renal cell survival: the outer mitochondrial membrane. Despite shared sequence and structural features, members of this conserved protein family constantly antagonize each other in a life-and-death battle. BCL-2 members innocently reside within renal cells until activated or de-activated by physiologic stresses caused by common nephrotoxins, transient ischemia, or acute glomerulonephritis.

What Can We Learn from Interventions That Change Fat Distribution?

Epidemiological studies have illustrated convincingly that fat distribution is associated with cardiometabolic risk. Fat deposition preferentially in the lower body, commonly seen in premenopausal women, is associated with lower risk, while central obesity in men and postmenopausal women is associated with higher risk. Studies of the physiology and the tissue and cellular characteristics of different adipose tissue depots, visceral and abdominal, gluteal, and femoral subcutaneous, corroborate this idea.

BET Bromodomain Proteins Brd2, Brd3 and Brd4 Selectively Regulate Metabolic Pathways in the Pancreatic β-Cell.

Displacement of Bromodomain and Extra-Terminal (BET) proteins from chromatin has promise for cancer and inflammatory disease treatments, but roles of BET proteins in metabolic disease remain unexplored. Small molecule BET inhibitors, such as JQ1, block BET protein binding to acetylated lysines, but lack selectivity within the BET family (Brd2, Brd3, Brd4, Brdt), making it difficult to disentangle contributions of each family member to transcriptional and cellular outcomes. Here, we demonstrate multiple improvements in pancreatic β-cells upon BET inhibition with JQ1 or BET-specific siRNAs.

Murine Mesenchymal Stem Cell Commitment to Differentiation Is Regulated by Mitochondrial Dynamics.

Mouse skin mesenchymal stem cells (msMSCs) are dermis CD105(+) CD90(+) CD73(+) CD29(+) CD34(-) mesodermal precursors which, after in vitro induction, undergo chondro, adipo, and osteogenesis. Extensive metabolic reconfiguration has been found to occur during differentiation, and the bioenergetic status of a cell is known to be dependent on the quality and abundance of the mitochondrial population, which may be regulated by fusion and fission. However, little is known regarding the impact of mitochondrial dynamics on the differentiation process.