Vascular adenosine monophosphate‐activated protein kinase: Enhancer,brake or both?

Adenosine monophosphate‐activated protein kinase (AMPK), expressed/present ubiquitously in the body, contributes to metabolic regulation. In the vasculature, activation of AMPK is associated with several beneficial biological effects including enhancement of vasodilatation, reduction of oxidative stress and inhibition of inflammatory reactions. The vascular protective effects of certain anti‐diabetic (metformin and sitagliptin) or lipid‐lowering (simvastatin and fenofibrate) therapeutic agents, of active components of Chinese medicinal herbs (resveratrol and berberine) and of pharmacological agents (AICAR, A769662 and PT1) have been attributed to the activation of AMPK (in endothelial cells, vascular smooth muscle cells and/or perivascular adipocytes), independently of changes in the metabolic profile (eg glucose tolerance and/or plasma lipoprotein levels), leading to improved endothelium‐derived nitric oxide‐mediated vasodilatation and attenuated endothelium‐derived cyclooxygenase‐dependent vasoconstriction. By contrast, endothelial AMPK activation with pharmacological agents or by genetic modification is associated with reduced endothelium‐dependent relaxations in small blood vessels and elevated systolic blood pressure. Indeed, AMPK activators inhibit endothelium‐dependent hyperpolarization (EDH)‐type relaxations in superior mesenteric arteries, partly by inhibiting endothelial calcium‐activated potassium channel signalling. Therefore, AMPK activation is not necessarily beneficial in terms of endothelial function. The contribution of endothelial AMPK in the regulation of vascular tone, in particular in the microvasculature where EDH plays a more important role, remains to be characterized.     

Muscle fiber dysfunction contributes to weakness in inclusion body myositis

Atrophy and fatty infiltration are important causes of muscle weakness in inclusion body myositis (IBM). Muscle weakness can also be caused by reduced specific force; i.e. the amount of force generated per unit of residual muscle tissue. This study investigates in vivo specific force of the quadriceps and ex vivo specific force of single muscle fibers in patients with IBM. We included 8 participants with IBM and 12 healthy controls, who all underwent quantitative muscle testing, quantitative MRI of the quadriceps and paired muscle biopsies of the quadriceps and tibialis anterior. Single muscle fibers were isolated to measure muscle fiber specific force and contractile properties. Both in vivo quadriceps specific force and ex vivo muscle fiber specific force were reduced. Muscle fiber dysfunction was accompanied by reduced active stiffness, which reflects a decrease in the number of attached actin-myosin cross-bridges during activation. Myosin concentration was reduced in IBM fibers. Because reduced specific force contributes to muscle weakness in patients with IBM, therapeutic strategies that augment muscle fiber strength may provide benefit to patients with IBM.     

Monitoring antimalarial drug resistance in India via sentinel sites: outcomes and risk factors for treatment failure, 2009–2010

Objective

To describe India’s National Antimalarial Drug Resistance Monitoring System, measure the efficacy of first-line malaria treatments, and determine risk factors for treatment failure.

Methods

In 2009–2010, prospective studies with 28 days of follow-up were conducted at 25 sentinel sites. Patients infected with Plasmodium falciparum were given artesunate plus sulfadoxine-pyrimethamine (AS+SP); those infected with P. vivax were given chloroquine. Polymerase chain reaction was used to distinguish post-treatment reinfection from treatment failure. Isolates of P. falciparum were checked for dhfr and dhps mutations.

Findings

Overall, 1664 patients were enrolled. Kaplan–Meier survival analysis showed an efficacy of 98.8% for AS+SP. Most patients with P. falciparum parasitaemia cleared their parasitaemias within 24 hours of treatment initiation, but six, including four with treatment failure, remained parasitaemic after 72 hours. Double mutants in dhfr were found in 68.4% of the genotyped isolates. Triple or quadruple mutants in dhfr and mutations in dhps were rare. A daily dose of artesunate of < 3 mg per kg of body weight, age of less than 5 years, and fever at enrolment were associated with an increased risk of treatment failure. Chloroquine remained 100% efficacious and generally cleared P. vivax parasitaemias within 48 hours. Vomiting (seen in 47 patients) was the most common adverse event.

Conclusion

India’s National Antimalarial Drug Resistance Monitoring System provides wide coverage. The first-line antimalarials used in the country remain safe and efficacious. The treatment of malaria in young children and the relative benefits of age- and weight-based dosing need further exploration.