Systemic Hypoxemia Induces Cardiomyocyte Hypertrophy and Right Ventricular Specific Induction of Proliferation.

BACKGROUND: A recent study suggests that systemic hypoxemia in adult male mice can induce cardiac myocytes to proliferate. The goal of the present experiments was to confirm these results, provide new insights on the mechanisms that induce adult cardiomyocyte cell cycle reentry, and to determine if hypoxemia also induces cardiomyocyte proliferation in female mice. METHODS: EdU-containing mini pumps were implanted in 3-month-old, male and female C57BL/6 mice. Mice were placed in a hypoxia chamber, and the oxygen was lowered by 1% every day for 14 days to reach 7% oxygen. The animals remained in 7% oxygen for 2 weeks before terminal studies. Myocyte proliferation was also studied with a mosaic analysis with double markers mouse model. RESULTS: Hypoxia induced cardiac hypertrophy in both left ventricular (LV) and right ventricular (RV) myocytes, with LV myocytes lengthening and RV myocytes widening and lengthening. Hypoxia induced an increase (0.01±0.01% in normoxia to 0.11±0.09% in hypoxia) in the number of EdU+ RV cardiomyocytes, with no effect on LV myocytes in male C57BL/6 mice. Similar results were observed in female mice. Furthermore, in mosaic analysis with double markers mice, hypoxia induced a significant increase in RV myocyte proliferation (0.03±0.03% in normoxia to 0.32±0.15% in hypoxia of RFP+ myocytes), with no significant change in LV myocyte proliferation. RNA sequencing showed upregulation of mitotic cell cycle genes and a downregulation of Cullin genes, which promote the G1 to S phase transition in hypoxic mice. There was significant proliferation of nonmyocytes and mild cardiac fibrosis in hypoxic mice that did not disrupt cardiac function. Male and female mice exhibited similar gene expression following hypoxia. CONCLUSIONS: Systemic hypoxia induces a global hypertrophic stress response that was associated with increased RV proliferation, and while LV myocytes did not show increased proliferation, our results minimally confirm previous reports that hypoxia can induce cardiomyocyte cell cycle activity in vivo.

Dengue Patients Treated with Doxycycline Showed Lower Mortality Associated to a Reduction in IL-6 and TNF Levels.

OBJECTIVE: To determine the effect of doxycycline treatment on cytokine levels, including tumor necrosis factor (TNF) and interleukin 6 (IL-6), and mortality in dengue patients at high risk of complication. METHODS: A group of dengue hemorrhagic fever patients (n=231) were randomized to receive either standard supportive care or supportive care in addition to oral doxycycline twice daily for 7 days. Dengue virus infection was confirmed by PCR using multiple primers. Serum samples were obtained at days 0, 3, 5 and 7 and tested for levels of TNF and IL-6. RESULTS: Doxycycline-treated group presented a 46% lower mortality than that observed in the untreated group (11.2% [13/116] vs 20.9% [24/115], respectively, p=0.05). Moreover, administration of doxycycline resulted in a significant (p<0.01) decrease in levels of TNF and IL-6 versus controls in the tests performed during follow-up (day 3, 5 and 7). Patients who died in both groups possessed significantly (p<0.01) higher levels of TNF and IL-6 compared to those who survived at all-time points. CONCLUSION: The above findings suggest that doxycycline can provide a clinical benefit to dengue patients at high risk of complications. This effect could be mediated by decreasing pro-inflammatory cytokine levels.

Phthalate exposure and precocious puberty in females.

OBJECTIVE: To determine whether phthalate exposure is associated with precocious puberty in girls. STUDY DESIGN: This was a multicenter cross-sectional study in which 28 girls with central precocious puberty (CPP) and 28 age- and race-matched prepubertal females were enrolled. Nine phthalate metabolites and creatinine were measured in spot urine samples from these 56 children. RESULTS: Levels of 8 of the 9 phthalate metabolites were above the limit of detection (LOD) in all 56 subjects. Mono (2-ethylhexyl) phthalate (MEHP) was below the LOD in 25/56 samples (14 subjects with precocious puberty and 11 controls). No significant differences between the children with CPP and the controls in either absolute or creatinine-normalized concentrations of any of the 9 phthalate metabolites were measured. CONCLUSIONS: Although phthalates may be associated with certain other toxicities in humans, our study suggests that their exposure is not associated with precocious puberty in female children.