Interleukin 10 knockout frail mice develop cardiac and vascular dysfunction with increased age

Cardiovascular dysfunction is a primary independent predictor of age-related morbidity and mortality. Frailty is associated with activation of inflammatory pathways and fatigue that commonly presents and progresses with age. Interleukin 10 (IL-10), the cytokine synthesis inhibitory factor, is an anti-inflammatory cytokine produced by immune and non-immune cells. Homozygous deletion of IL-10 in mice yields a phenotype that is consistent with human frailty, including age-related increases in serum inflammatory mediators, muscular weakness, higher levels of IGF-1 at midlife, and early mortality. While emerging evidence suggests a role for IL-10 in vascular protection, a clear mechanism has not yet been elucidated.     

Aging impairs the beneficial effect of granulocyte colony-stimulating factor and stem cell factor on post-myocardial infarction remodeling

Granulocyte colony-stimulating factor (G-CSF) and stem cell factor (SCF) are potential new therapies to ameliorate post-myocardial infarction (post-MI) remodeling, as they enhance endogenous cardiac repair mechanisms and decrease cardiomyocyte apoptosis. Because both of these pathways undergo alterations with increasing age, we hypothesized that therapeutic efficacy of G-CSF and SCF is impaired in old versus young adult rats. MI was induced in 6- and 20-month-old rats by permanent ligation of the left coronary artery. In young animals, G-CSF/SCF therapy stabilized and reversed a decline in cardiac function, attenuated left ventricular dilation, decreased infarct size, and reduced cardiomyocyte hypertrophy. Remarkably, these effects on cardiac structure and function were absent in aged rodents. This could not be attributed to ineffective mobilization of bone marrow cells or decreased quantity of c-Kit(+) cells within the myocardium with aging. However, whereas the G-CSF/SCF cocktail reduced cardiac myocyte apoptosis in old as well as in young hearts, the degree of reduction was substantially less with age and the rate of cardiomyocyte apoptosis in old animals remained high despite cytokine treatment. These findings demonstrate that G-CSF/SCF lacks therapeutic efficacy in old animals by failing to offset periinfarct apoptosis and therefore raise important concerns regarding the efficacy of novel cytokine therapies in elderly individuals at greatest risk for adverse consequences of MI.     

Combined effects of aging and inflammation on renin-angiotensin system mediate mitochondrial dysfunction and phenotypic changes in cardiomyopathies

Although the effects of aging and inflammation on the health of the cardiac muscle are well documented, the combined effects of aging and chronic inflammation on cardiac muscle are largely unknown. The renin-angiotensin system (RAS) has been linked independently to both aging and inflammation, but is understudied in the context of their collective effect. Thus, we investigated localized cardiac angiotensin II type I and type II receptors (AT₁R, AT₂R), downstream effectors, and phenotypic outcomes using mouse models of the combination of aging and inflammation and compared it to a model of aging and a model of inflammation. We show molecular distinction in the combined effect of aging and inflammation as compared to each independently. The combination maintained an increased AT₁R:AT₂R and expression of Nox2 and exhibited the lowest activity of antioxidants. Despite signaling pathway differences, the combined effect shared phenotypic similarities with aging including oxidative damage, fibrosis, and hypertrophy. These phenotypic similarities have dubbed inflammatory conditions as premature aging, but they are, in fact, molecularly distinct. Moreover, treatment with an AT₁R blocker, losartan, selectively reversed the signaling changes and ameliorated adverse phenotypic effects in the combination of aging and inflammation as well as each independently.     

Drug-resistant malaria parasites introduced into Madagascar from Comoros Islands

To determine risk for drug-resistant malaria parasites entering Madagascar from Comoros Islands, we screened travelers. For the 141 Plasmodium falciparum isolates detected by real-time PCR, frequency of mutant alleles of genes associated with resistance to chloroquine and pyrimethamine was high. International-level antimalarial policy and a regional antimalarial forum are needed.     

Factors of Stress Concentration around Spherical Cavity Embedded in Cylinder Subjected to Internal Pressure

In this paper, an accurate distribution of stress as well as corresponding factors of stress concentration determination around a spherical cavity, which is considered as embedded in a cylinder exposed to the internal pressure only, is presented. This approach was applied at three main meridians of the porosity by combining the Eshelby’s equivalent inclusion method with Mura and Chang’s methodology employing the jump condition across the interface of the cavity and matrix, respectively. The distribution of stresses around the spherical flaw and their concentration factors were formulated in the form of newly formulated analytical relations involving the geometric ratio of the cylinder, such as external radius and thickness, the angle around the cavity, depth of the porosity, as well as the material Poisson ratio. Subsequently, a comparison of the analytical results and the numerical simulation results is applied to validate obtained results. The results show that the stress concentration factors (SCFs) are not constant for an incorporated flaw and vary with both the porosity depth and the Poisson ratio, regardless of whether the cylinder geometric ratio is thin or thick.