Circulating markers of endothelial and alveolar epithelial dysfunction are associated with mortality in pediatric acute respiratory distress syndrome

Purpose

Angiopoietin 2 (Ang2) and soluble receptor for advanced glycation end products (sRAGE) are markers of endothelial and pulmonary epithelial damage with prognostic implications in adult acute respiratory distress syndrome (ARDS), but unclear significance in pediatric ARDS (PARDS).

Methods

This was a prospective, observational study in children with PARDS (2012 Berlin and 2015 PALICC definitions) at the Children’s Hospital of Philadelphia. Plasma was collected within 48 h of PARDS onset and biomarkers quantified by enzyme-linked immunosorbent assay.

Results

In 82 children with PARDS (12 deaths, 15 %), Ang2 and sRAGE were higher in non-survivors than survivors (p < 0.01 for both). Mortality was highest in patients with Ang2 and sRAGE levels both above median values. Ang2 and sRAGE correlated with the number of non-pulmonary organ failures (both p < 0.001). Ang2 was higher in indirect lung injury and in immunocompromised children. In stratified analysis, both Ang2 and sRAGE were associated with mortality only in direct lung injury and in immunocompetent children, with no association evident in indirect lung injury or in immunocompromised children.

Conclusions

Ang2 and sRAGE in early PARDS were higher in non-survivors than survivors and strongly correlated with number of non-pulmonary organ failures. When stratified by type of lung injury, Ang2 and sRAGE were associated with mortality only in direct lung injury. Similarly, when stratified by immunocompromised status, Ang2 and sRAGE were associated with mortality only in immunocompetent children. The utility of these biomarkers for prognostication and risk stratification requires investigation.

     

Self-perceived natural history of pelvic organ prolapse described by women presenting for treatment

Introduction and hypothesis  This study aimed to describe the self-perceived natural history of pelvic organ prolapse (POP) in women seeking care. Methods  Women presenting to a university-based urogynecology clinic for POP (n = 107) completed a questionnaire including questions about how and when their prolapse was discovered. A urogynecologic examination including the pelvic organ prolapse quantification (POP-Q) was also performed. Results  Forty-eight percent of these women sought medical attention “immediately” after discovering a bulge. The median time to seek care was 4 months (range from 1 month to 45 years). Twenty-six percent associated their prolapse with a specific event (e.g., moving furniture or pushing a car). POP was self-discovered by 76% (81/107) of women. Self-discovered prolapses were larger than those diagnosed by physicians (Ba +1.3 vs 0.1 cm, P = .03, respectively). Conclusions  Women seek medical advice within months of discovering their prolapse. Self-discovery is associated with higher stage prolapse than prolapse diagnosed by health care providers.     

Impaired contractile reserve in severe mitral valve regurgitation with a preserved ejection fraction

BACKGROUND: Impaired contractile reserve in chronic MR results from load-independent, myocyte contractile abnormalities. AIMS: Investigate the mechanisms of contractile dysfunction in chronic mitral valve regurgitation (MR). METHODS: Mild MR was produced in eight dogs followed by pacing induced left ventricular (LV) dilatation over eight months. In-vivo LV dP/dt was measured at several pacing rates. Contractile function was measured in isolated LV trabeculae and myocytes at several stimulation rates and during changes in extracellular [Ca2+]. Identical studies were performed with six control dogs. RESULTS: Chronic MR resulted in a preserved ejection fraction with decreased dP/dt (p<0.01). LV trabeculae demonstrated significantly lower developed force and a negative force-frequency relation with chronic MR (p<0.05). Myocytes exhibited a negative shortening-frequency relationship in both groups with a greater decline with chronic MR (p<0.001) paralleled by decreases in peak [Ca2+](i) transients. Increases in extracellular [Ca2+] abrogated the defects in force generation in trabeculae from animals with chronic MR. CONCLUSION: Even with a preserved EF, chronic severe MR results in a significant reduction in intrinsic contractile function and reserve. Functional impairment was load-independent reflecting a predominant defect in calcium cycling rather than impaired peak force generating capacity due to myofibrillar attenuation.     

Age Effects on Internal Anal Sphincter Thickness and Diameter in Nulliparous Females

Purpose Age can affect the delicate physiologic balance of the internal anal sphincter diameters and pressure governed by Laplace’s law. This study compares the effect of aging on the internal anal sphincter thickness and diameter in younger and older nulliparous females without symptoms of fecal incontinence undisturbed by an endoanal probe. Methods Magnetic resonance images were selected from a large database of nulliparous females to form two groups: “younger” females, aged 30 years and younger (n = 32), and “older” females, aged 50 years and older (n = 32). All patients were scanned without endoanal coils to allow undistorted measurement of the internal anal sphincter diameters. Inner and outer diameters were measured from axial magnetic resonance images and used to calculate sphincter thickness and mean radius by two independent investigators blinded to patient age. Results The mean age in the younger group was 26 ± 2.8 years, whereas that of the older group was 61.8 ± 7.6 years. Older females had a 33 percent thicker internal anal sphincter (younger vs. older: 4.5 ± 0.7 vs. 5.9 ± 1 mm; P < 0.001), a 20 percent larger inner diameter (7.1 ± 1.3 vs. 8.5 ± 1.8 mm; P = 0.001), and a 27 percent larger outer diameter (16 ± 2.1 vs. 20.3 ± 3.3 mm; P < 0.001) than younger females. Neither sphincter thickness nor inner or outer diameter correlated with body mass index. Conclusions There is an increase in internal anal sphincter thickness, inner diameter, and outer diameter, which correlates with age in asymptomatic nulliparous females. Supported by the National Institutes of Health, ORWH & NICHD Sex & Gender Factors Affecting Women’s Health SCOR: P50, and NICHD R01 HD 044406: NICHD R01 DK 051405, R01 HD 038665; German Research Foundation (DFG, HU1502/1–1). Presented as a poster at the annual meeting of the American Urogynecologic Society, October 19 to 21, 2006, Palm Springs, Florida. Presented as an oral poster at the annual meeting of the International Urogynecological Association, September 6 to 9, 2006, Athens, Greece. Presented as an oral poster and oral presentation at the annual meeting of the German Association of Gynecology and Obstetrics, September 19 to 22, 2006, Berlin, Germany.     

Loss of β<Subscript>1</Subscript>D-integrin function in human ischemic cardiomyopathy

Integrins play a pivotal role in cardiomyocyte survival and function, with integrin loss leading to myocyte apoptosis and heart failure. The aim of this study was to characterize whether regulation of integrins may contribute to cardiac remodeling in human ischemic cardiomyopathy (ICM). Myocardial tissues of the left ventricle were obtained from patients with ICM (n = 8) undergoing cardiac transplantation and from unused donor hearts (NF, n = 8). In addition, tissue samples from patients with dilated cardiomyopathy (DCM, n = 5) were analyzed. Expression of integrins β₁D and β₃, the effector proteins focal adhesion kinase (FAK) and melusin, and FAK phosphorylation were examined by Western blotting, real-time-PCR and immunofluorescence analysis, respectively. β₁D-integrin protein was decreased in ICM vs. NF by 36%. β₁D-integrin mRNA levels and β₁D-integrin shedding were unchanged. Corresponding to β₁D-integrin regulation, FAK and phosphorylated FAK were decreased in ICM vs. NF by 54% and 49%, respectively. β₃-integrin and melusin were not altered in ICM. As a mediator of integrin effects, AKT kinase activity was examined. In parallel to β₁D-integrin and FAK, AKT activity was decreased in ICM by 44%. In contrast, none of the proteins were significantly altered in DCM compared to NF. Integrins and integrin signaling are regulated differentially in ICM and DCM with a decrease of β₁D-integrin and FAK in ICM. The loss of the β₁Dintegrin-FAK-complex in ICM was paralleled by a reduced AKT activity supporting in vitro data which demonstrate the pivotal role of intact integrin function in anti-apoptotic signaling and cell survival.     

Structure and function of murine cytomegalovirus MHC-I-like molecules: how the virus turned the host defense to its advantage

Immunologic Research - The mouse cytomegalovirus (CMV), a β-herpesvirus, exploits its large (~230&nbsp;kb) double-stranded DNA genome for both essential and non-essential functions. Among...