Inhibition of cerebrovascular raf activation attenuates cerebral blood flow and prevents upregulation of contractile receptors after subarachnoid hemorrhage

<p>Abstract</p> <p>Background</p> <p>Late cerebral ischemia carries high morbidity and mortality after subarachnoid hemorrhage (SAH) due to reduced cerebral blood flow (CBF) and the subsequent cerebral ischemia which is associated with upregulation of contractile receptors in the vascular smooth muscle cells (SMC) via activation of mitogen-activated protein kinase (MAPK) of the extracellular signal-regulated kinase (ERK)1/2 signal pathway. We hypothesize that SAH initiates cerebrovascular ERK1/2 activation, resulting in receptor upregulation. The raf inhibitor will inhibit the molecular events upstream ERK1/2 and may provide a therapeutic window for treatment of cerebral ischemia after SAH.</p> <p>Results</p> <p>Here we demonstrate that SAH increases the phosphorylation level of ERK1/2 in cerebral vessels and reduces the neurology score in rats in additional with the CBF measured by an autoradiographic method. The intracisternal administration of SB-386023-b, a specific inhibitor of raf, given 6 h after SAH, aborts the receptor changes and protects the brain from the development of late cerebral ischemia at 48 h. This is accompanied by reduced phosphorylation of ERK1/2 in cerebrovascular SMC. SAH per se enhances contractile responses to endothelin-1 (ET-1), 5-carboxamidotryptamine (5-CT) and angiotensin II (Ang II), upregulates ET_B, 5-HT_1Band AT₁receptor mRNA and protein levels. Treatment with SB-386023-b given as late as at 6 h but not at 12 h after the SAH significantly decreased the receptor upregulation, the reduction in CBF and the neurology score.</p> <p>Conclusion</p> <p>These results provide evidence for a role of the ERK1/2 pathway in regulation of expression of cerebrovascular SMC receptors. It is suggested that raf inhibition may reduce late cerebral ischemia after SAH and provides a realistic time window for therapy.</p

Mitochondrial respiratory states and rate

As the knowledge base and importance of mitochondrial physiology to human health expands, the necessity for harmonizing the terminologyconcerning mitochondrial respiratory states and rates has become increasingly apparent. Thechemiosmotic theoryestablishes the mechanism of energy transformationandcoupling in oxidative phosphorylation. Theunifying concept of the protonmotive force providestheframeworkfordeveloping a consistent theoretical foundation ofmitochondrial physiology and bioenergetics.We followguidelines of the International Union of Pure and Applied Chemistry(IUPAC)onterminology inphysical chemistry, extended by considerationsofopen systems and thermodynamicsof irreversible processes.Theconcept-driven constructive terminology incorporates the meaning of each quantity and alignsconcepts and symbols withthe nomenclature of classicalbioenergetics. We endeavour to provide a balanced view ofmitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes.Uniform standards for evaluation of respiratory states and rates will ultimatelycontribute to reproducibility between laboratories and thussupport the development of databases of mitochondrial respiratory function in species, tissues, and cells.Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

An assessment of the likely acceptability of vaginal microbicides for HIV prevention among women in rural Ghana.

BACKGROUND: The findings of the CAPRISA tenofovir studies have raised expectations that soon an approved microbicide would be available. However it is in only a limited number of countries in sub-Saharan Africa that the acceptability of microbicides has been evaluated. We conducted a study to assess the acceptability of vaginal microbicides among women in rural Ghana. METHODS: The study employs a mixed method design, using cross-sectional survey and focus group discussions to further understand issues related to awareness and attitudes towards microbicide development, acceptability and perceived partner attitudes among pregnant women attending antenatal clinic in two health facilities in the Kintampo North municipality of Ghana. We used logistic regression to identify possible predictors of microbicide acceptability among the women surveyed. RESULTS: Although only 2% of the 504 women were aware of the development of microbicides, 95% were willing to use one when it became available. The cost of a microbicide that will be considered affordable to 50% of women was US$0.75. Although there were concerns about possible wetting effect, gel or creams were the most preferred (68% of women) formulation. Although 71% thought their partners will find microbicide acceptable, apprehensions about the feasibility of and consequences of failed discreet use were evident. 49% of women were concerned about possible negative effect of microbicide on sexual pleasure. Perceived partner acceptability (O.R. =17.7; 95%C.I. 5.03-62.5) and possibility of discreet use (O.R. =8.9 95%C.I. 2.63-30.13) were the important predictors of microbicide acceptability. CONCLUSION: Achieving microbicide acceptability among male partners should be made a part of the promotive interventions for ensuring effective use among women in rural Ghana