Amelioration of Acute Kidney Injury in Lipopolysaccharide-Induced Systemic Inflammatory Response Syndrome by an Aldose Reductase Inhibitor, Fidarestat

Systemic inflammatory response syndrome is a fatal disease because of multiple organ failure. Acute kidney injury is a serious complication of systemic inflammatory response syndrome and its genesis is still unclear posing a difficulty for an effective treatment. Aldose reductase (AR) inhibitor is recently found to suppress lipopolysaccharide (LPS)-induced cardiac failure and its lethality. We studied the effects of AR inhibitor on LPS-induced acute kidney injury and its mechanism.Mice were injected with LPS and the effects of AR inhibitor (Fidarestat 32 mg/kg) before or after LPS injection were examined for the mortality, severity of renal failure and kidney pathology. Serum concentrations of cytokines (interleukin-1β, interleukin-6, monocyte chemotactic protein-1 and tumor necrosis factor-α) and their mRNA expressions in the lung, liver, spleen and kidney were measured. We also evaluated polyol metabolites in the kidney.Mortality rate within 72 hours was significantly less in LPS-injected mice treated with AR inhibitor both before (29%) and after LPS injection (40%) than untreated mice (90%). LPS-injected mice showed marked increases in blood urea nitrogen, creatinine and cytokines, and AR inhibitor treatment suppressed the changes. LPS-induced acute kidney injury was associated with vacuolar degeneration and apoptosis of renal tubular cells as well as infiltration of neutrophils and macrophages. With improvement of such pathological findings, AR inhibitor treatment suppressed the elevation of cytokine mRNA levels in multiple organs and renal sorbitol accumulation.AR inhibitor treatment ameliorated LPS-induced acute kidney injury, resulting in the lowered mortality

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

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Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease. </p

BRIEF REPORT: Multiprogram Evaluation of Reading Habits of Primary Care Internal Medicine Residents on Ambulatory Rotations

OBJECTIVE: To assess the reading habits and educational resources of primary care internal medicine residents for their ambulatory medicine education. DESIGN: Cross-sectional, multiprogram survey of primary care internal medicine residents. PARTICIPANTS/SETTING: Second- and third-year residents on ambulatory care rotations at 9 primary care medicine programs (124 eligible residents; 71% response rate). MEASUREMENTS AND MAIN RESULTS: Participants were asked open-ended and 5-point Likert-scaled questions about reading habits: time spent reading, preferred resources, and motivating and inhibiting factors. Participants reported reading medical topics for a mean of 4.3 ± 3.0 SD hours weekly. Online-only sources were the most frequently utilized medical resource (mean Likert response 4.16 ± 0.87). Respondents most commonly cited specific patients' cases (4.38 ± 0.65) and preparation for talks (4.08 ± 0.89) as motivating factors, and family responsibilities (3.99 ± 0.65) and lack of motivation (3.93 ± 0.81) as inhibiting factors. CONCLUSIONS: To stimulate residents' reading, residency programs should encourage patient- and case-based learning; require teaching assignments; and provide easy access to online curricula