Endothelial ILK induces cardioprotection by preventing coronary microvascular dysfunction and endothelial-to-mesenchymal transition.

Endothelial dysfunction is an early event in coronary microvascular disease. Integrin-linked kinase (ILK) prevents endothelial nitric oxide synthase (eNOS) uncoupling and, thus, endothelial dysfunction. However, the specific role of endothelial ILK in cardiac function remains to be fully elucidated. We hypothesised that endothelial ILK plays a crucial role in maintaining coronary microvascular function and contractile performance in the heart. We generated an endothelial cell-specific ILK conditional knock-out mouse (ecILK cKO) and investigated cardiovascular function. Coronary endothelial ILK deletion significantly impaired cardiac function: ejection fraction, fractional shortening and cardiac output decreased, whilst left ventricle diastolic internal diameter decreased and E/A and E/E' ratios increased, indicating not only systolic but also diastolic dysfunction. The functional data correlated with extensive extracellular matrix remodelling and perivascular fibrosis, indicative of adverse cardiac remodelling. Mice with endothelial ILK deletion suffered early ischaemic-like events with ST elevation and transient increases in cardiac troponins, which correlated with fibrotic remodelling. In addition, ecILK cKO mice exhibited many features of coronary microvascular disease: reduced cardiac perfusion, impaired coronary flow reserve and arterial remodelling with patent epicardial coronary arteries. Moreover, endothelial ILK deletion induced a moderate increase in blood pressure, but the antihypertensive drug Losartan did not affect microvascular remodelling whilst only partially ameliorated fibrotic remodelling. The plasma miRNA profile reveals endothelial-to-mesenchymal transition (endMT) as an upregulated pathway in endothelial ILK conditional KO mice. Our results show that endothelial cells in the microvasculature in endothelial ILK conditional KO mice underwent endMT. Moreover, endothelial cells isolated from these mice and ILK-silenced human microvascular endothelial cells underwent endMT, indicating that decreased endothelial ILK contributes directly to this endothelial phenotype shift. Our results identify ILK as a crucial regulator of microvascular endothelial homeostasis. Endothelial ILK prevents microvascular dysfunction and cardiac remodelling, contributing to the maintenance of the endothelial cell phenotype.

Should all children receive two measles vaccinations? A study of measles susceptibility in a suburban New Jersey private practice.

Because of the rising incidence of rubeola, we tested all our patients who were vaccinated prior to 15 months of age and those vaccinated after 15 months, if requested, for susceptibility to measles (IgG, ELISA). Those found to be susceptible were revaccinated. Of 1,228 tested, 264 (21.5%) were susceptible. In the group vaccinated before 1980, 237 of 901 (26.3%) were susceptible, whereas only 27 of 327 (8.3%) vaccinated after 1980 were not immune. Susceptibility was sharply divided by month of age at vaccination at the 14-month mark. Less than 5% of those vaccinated after age 15 months in the 1980s (one of 22, or 4.5%) were susceptible. Waning immunity (secondary vaccine failure) was not found to be a factor in our patients. Despite outbreaks of measles in surrounding communities and in our area, none of our patients developed measles. Identification of high-risk groups and selective measles revaccination should be considered as an alternative to universal revaccination in populations such as ours, since it is more cost-effective and may prove equally successful.

Factors affecting outcome in meningococcal infections.

A prognostic score for evaluating meningococcal infections in patients consists of the following five features that indicate a poor prognosis: onset of petechiae within 12 hours of presentation; shock; normal or low peripheral leukocyte count; normal or low erythrocyte sedimentation rate; and absence of meningitis. Based on our experience and some published data, we suspected that the score may no longer be reliable. We reviewed the charts of 73 children with meningococcal infection from December 19, 1979 to December 19, 1987 and applied the prognostic score mentioned previously. Our findings indicate that although a low score is generally associated with a good outcome, a higher score is less predictive of poor outcome than previously suggested. A rash with petechiae or purpura, the presence of shock, and a normal or low peripheral leukocyte count continue to be predictors of poor outcome. Erythrocyte sedimentation rate was not evaluated owing to a limited amount of data. The absence of meningitis did not correlate with a worse outcome in our patients. Most patients who died had evidence of meningeal involvement at the time of presentation. Instead, altered mental status at presentation, particularly obtundation or coma, was an ominous sign. We conclude that absence of meningitis is not a good predictor of outcome, as was previously thought. Altered mental status at the time of presentation may prove to be a stronger indicator of poor outcome.