AMPK regulates basal skeletal muscle capillarization and VEGF expression, but is not necessary for the angiogenic response to exercise

5 -AMP-activated protein kinase(AMPK)is a metabolic fuel sensor that monitors cellular energy charge, while the vasculature is important for maintaining cellular energy homeostasis. Mice with muscle-specific inactive AMPK (AMPK DN) were used to investigate if AMPK regulates skeletal muscle capillarization and the angiogenic responses to exercise. Two hours of the AMP analogueAICAR(1.0 g kg - 1)or systemichypoxia (6%O2) increased vascular endothelial growth factor (VEGF) mRNA in wild-type (WT), but not in AMPK DN mice. In contrast, the increase in VEGF mRNA with acute exercise (1 h at 20m min - 1, 10% gradient) was greater in AMPK DN compared to WT mice. Nuclear run-on assay demonstrated that exercise increased VEGF transcription, while hypoxia decreased VEGF transcription. There was no difference in VEGF transcription between WT and AMPK DN. There was a strong correlation between VEGF transcription and VEGF mRNA at rest and with exercise. Resting capillarization was lower in AMPK DN compared to WT. Wheel running (28 days) increased capillarization and this response was AMPK independent. Significant correlations between VEGF protein and muscle capillarization are consistent with VEGF being an important determinant of skeletal muscle capillarization. These data are to our knowledge the first to demonstrate in skeletal muscle in vivo that: (1) AMPK is necessary for hypoxia-induced VEGF mRNA stabilization, (2) acute exercise increases VEGF transcription, (3) inhibition of AMPK augments the VEGF mRNA response to acute exercise, and (4) AMPK regulates basal VEGF expression and capillarization, but is not necessary for exercise-induced angiogenesis. Originally published Journal of Physiology, Vol. 586, No. 24, Dec 200

Community-based directly observed therapy (DOT) versus clinic DOT for tuberculosis: a systematic review and meta-analysis of comparative effectiveness.

Background: Directly observed therapy (DOT), as recommended by the World Health Organization, is used in many countries to deliver tuberculosis (TB) treatment. The effectiveness of community-based (CB DOT) versus clinic DOT has not been adequately assessed to date. We compared TB treatment outcomes of CB DOT (delivered by community health workers or community volunteers), with those achieved through conventional clinic DOT. Methods: We performed a systematic review and meta-analysis of studies before 9 July 2014 comparing treatment outcomes of CB DOT and clinic DOT. The primary outcome was treatment success; the secondary outcome was loss to follow-up. Results: Eight studies were included comparing CB DOT to clinic DOT, one a randomised controlled trial. CB DOT outperformed clinic DOT treatment success (pooled odds ratio (OR) of 1.54, 95% confidence interval (CI) 1.01 – 2.36, p = 0.046, I2 heterogeneity 84%). No statistically significant difference was found between the two DOT modalities for loss to follow-up (pooled OR 0.86, 95% CI 0.48 to 1.55, p = 0.62, I2 83%). Conclusions: Based on this systematic review, CB DOT has a higher treatment success compared to clinic DOT. However, as only one study was a randomised controlled trial, the findings have to be interpreted with caution

AMPK regulates basal skeletal muscle capillarization and VEGF expression but is not necessary for the angiogenic response to exercise

5 -AMP-activated protein kinase(AMPK)is a metabolic fuel sensor that monitors cellular energy charge while the vasculature is important for maintaining cellular energy homeostasis. Mice with muscle-specific inactive AMPK (AMPK DN) were used to investigate if AMPK regulates skeletal muscle capillarization and the angiogenic responses to exercise. Two hours of the AMP analogueAICAR(1.0 g kg - 1)or systemichypoxia (6%O2) increased vascular endothelial growth factor (VEGF) mRNA in wild-type (WT) but not in AMPK DN mice. In contrast the increase in VEGF mRNA with acute exercise (1 h at 20m min - 1 10% gradient) was greater in AMPK DN compared to WT mice. Nuclear run-on assay demonstrated that exercise increased VEGF transcription while hypoxia decreased VEGF transcription. There was no difference in VEGF transcription between WT and AMPK DN. There was a strong correlation between VEGF transcription and VEGF mRNA at rest and with exercise. Resting capillarization was lower in AMPK DN compared to WT. Wheel running (28 days) increased capillarization and this response was AMPK independent. Significant correlations between VEGF protein and muscle capillarization are consistent with VEGF being an important determinant of skeletal muscle capillarization. These data are to our knowledge the first to demonstrate in skeletal muscle in vivo that: (1) AMPK is necessary for hypoxia-induced VEGF mRNA stabilization (2) acute exercise increases VEGF transcription (3) inhibition of AMPK augments the VEGF mRNA response to acute exercise and (4) AMPK regulates basal VEGF expression and capillarization but is not necessary for exercise-induced angiogenesis. Originally published Journal of Physiology Vol. 586 No. 24 Dec 200