Molecular markers of cardiomyopathy in cyanotic pediatric heart disease

Cyanotic congenital heart disease (CHD) accounts for approximately 25% of all types of CHD, encompassing a variety of cardiac anomalies. Children with cyanotic CHD are at risk for heart failure, cardiomyopathy, and arrhythmias. In addition to the hemodynamic burden, recent data suggest that hypoxia may contribute to heart failure. Previous studies have shown that neonatal hypoxia results in significant myocardial gene expression alterations that persist in adulthood after the termination of the hypoxic stimulus in the neonatal period or early infancy. In this article we review the current knowledge on molecular biomarkers of cyanotic CHD pathobiology, and expand on how the current knowledge establishes the basis for future studies to further define the role of molecular tools in cyanotic CHD to improve diagnostic, prognostic and therapeutic strategies.     

Heterozygous Mutations in Natriuretic Peptide Receptor‐B (NPR2) Gene as a Cause of Short Stature

Based on the observation of reduced stature in relatives of patients with acromesomelic dysplasia, Maroteaux type (AMDM), caused by homozygous or compound heterozygous mutations in natriuretic peptide receptor‐B gene (NPR2), it has been suggested that heterozygous mutations in this gene could be responsible for the growth impairment observed in some cases of idiopathic short stature (ISS). We enrolled 192 unrelated patients with short stature and 192 controls of normal height and identified seven heterozygous NPR2 missense or splice site mutations all in the short stature patients, including one de novo splice site variant. Three of the six inherited variants segregated with short stature in the family. Nine additional rare nonsynonymous NPR2 variants were found in three additional cohorts. Functional studies identified eight loss‐of‐function mutations in short individuals and one gain‐of‐function mutation in tall individuals. With these data, we were able to rigorously verify that NPR2 functional haploinsufficiency contributes to short stature. We estimate a prevalence of NPR2 haploinsufficiency of between 0 and 1/26 in people with ISS. We suggest that NPR2 gain of function may be a more common cause of tall stature than previously recognized.     

Rapid Response Events in Hospitalized Patients: Patient Symptoms and Clinician Communication

Context

Patients triggering rapid response team (RRT) intervention are at high risk for adverse outcomes. Data on symptom burden of these patients do not currently exist, and current symptom management and communication practices of RRT clinicians are unknown.

中国的卫生人力医学教育

近年来,中国经济发展取得长足进步,但在卫生领域还面临诸多挑战。人口老龄化以及不断加重的慢性非传染性疾病负担,是当前中国亟待解决的卫生问题。然而,和世界上大多数国家一样,中国也面临着卫生人力短缺以及分配不均的问题。本文认为,中国卫生人力的发展需要重点关注三个方面:通过技能组合改善医护比;医学教育现代化,尤其是对教学目标及其内容进行改革;研究生教育和继续医学教育的标准化及推广。     

Comparison of Escherichia coli from bacteriuric patients with those from feces of healthy schoolchildren.

The properties of 709 strains of Escherichia coli isolated from feces of healthy schoolchildren were compared with those of 115 strains from the urine of girls with asymptomatic bacteriuria (ABU) detected in a screening program. These fecal strains were also compared with 45 strains that caused asymptomatic reinfections and 10 that caused symptomatic reinfections in the same group of girls. Typing of O antigen was done by direct bacterial agglutination, and K typing was done with a serum agar technique. Hemolytic capacity was assessed in solid medium. Sensitivity to the bactericidal effect of normal serum and minimal inhibitory concentrations of ampicillin were also determined. The strains isolated from girls who had reinfections of ABU were found to be a random sample of the fecal flora, but the strains from children with symptomatic reinfection were not. Strains from index patients with ABU differed from the other groups in a way that was indicative of adaptive changes in the structure of cell envelopes.     

Mechanism of platelet inhibition by nitric oxide: In vivo phosphorylation of thromboxane receptor by cyclic GMP-dependent protein kinase

Nitric oxide (NO) is a potent vasodilator and inhibitor of platelet activation. NO stimulates production of cGMP and activates cGMP-dependent protein kinase (G kinase), which by an unknown mechanism leads to inhibition of Gα_q-phospholipase C-inositol 1,4,5-triphosphate signaling and intracellular calcium mobilization for several important agonists, including thromboxane A₂ (TXA₂). To explore the mechanism of platelet inhibition by NO, activation of platelet TXA₂ receptors in the presence of cGMP was studied. The nonhydrolyzable analog 8-bromo-cyclic GMP (8-Br-cGMP) potently inhibited activation of the TXA₂-specific GTPase in platelet membranes in a concentration-dependent fashion, suggesting that G kinase catalyzes the phosphorylation of some proximal component of the receptor–G protein signaling pathway. Nanomolar concentrations of G kinase were found to catalyze the phosphorylation of platelet TXA₂ receptors in vitro, but not Gα_q copurifying with the TXA₂ receptors in these experiments. Using immunoaffinity methods, in vivo phosphorylation of TXA₂ receptors by cyclic GMP was demonstrated from ³²P-labeled cells treated with 8-Br-cGMP. Peptide mapping studies of in vivo phosphorylated TXA₂ receptors demonstrated cGMP mediates phosphorylation of the carboxyl terminus of the TXA₂ receptor. G kinase also catalyzed the phosphorylation of peptides corresponding to the cytoplasmic tails of both α and β forms of the receptor but not control peptide or a peptide corresponding to the third intracytoplasmic loop of the TXA₂ receptor. These data identify TXA₂ receptors as cGMP-dependent protein kinase substrates and support a novel mechanism for the inhibition of cell function by NO in which activation of G kinase inhibits signaling by G protein-coupled receptors by catalyzing their phosphorylation.