Obesity as a determinant for response to antihypertensive treatment.

OBJECTIVE--To test the hypothesis that beta blockers lower blood pressure more effectively than calcium entry blockers in obese hypertensive patients and that calcium entry blockers are more effective in lean patients. DESIGN--Double blind, randomised controlled trial of treatment over six weeks. SETTING--Tertiary referral centre. SUBJECTS--42 white men with uncomplicated mild to moderate essential hypertension (World Health Organisation stage I or II); 36 completed the study. INTERVENTION--Patients were randomised to metoprolol 50-100 mg twice daily or isradipine 2.5-5.0 mg twice daily for six weeks after a two week run in phase. MAIN OUTCOME MEASURE--Blood pressure after six weeks of treatment. RESULTS--When stratified according to treatment and presence of obesity (body mass index < or = 27 kg/m2), the mean (SD) fall in blood pressure in the beta blocker group was 24 (13)/18 (10) mm Hg in obese patients and 18 (19)/12 (13) mm Hg in lean patients. In the calcium entry blocker group, the fall in blood pressure was 21 (15)/17 (6) mm Hg in lean patients and 18 (11)/8 (10) mm Hg in obese patients. After taking age and blood pressure before treatment into account there was a significant interaction between obesity and drug therapy (p = 0.019) with a better diastolic blood pressure response to calcium entry blockers in lean patients and to beta blockers in obese hypertensive patients. CONCLUSION--Obesity affects the efficacy of metoprolol and isradipine in reducing blood pressure.     

The actomyosin cytoskeleton of amoebae of the cellular slime molds acrasis rosea and protostelium mycophaga: structure, biochemical properties, and function

In amoebae of the cellular slime molds (mycetozoans) Acrasis rosea and Protostelium mycophaga, bundles of F-actin radiate from the endoplasm-ectoplasm interface into the pseudopodia, where G-actin is also located. We conclude that these actin bundles form a core scaffold driving pseudopod extension which is subsequently completed by filling with a more loosely organized meshwork of F-actin. Some bipolar, elongate amoebae of A. rosea also contained long bundles of F-actin that traverse the cells lengthwise and remotely resemble stress fibers. Rodlets of F-actin were scattered in the body of amoebae of A. rosea or formed star-shaped or polygonal complexes near or around contractile vacuoles, where they may play a role in contraction. In total protein extracts analyzed by SDS-PAGE and immunoblots the actins migrated like the rabbit skeletal muscle control. The relative proportion of actin in total protein extracts was 7.9% for A. rosea and 34.5% for P. mycophaga. We detected four or five isoactins in extracts of both species and we determined that the genome of each species contains approximately six actin genes. Whether they are all expressed or if posttranslational modifications occur remains to be determined. Myosin II was enriched in actomyosin extracts; its Mr was 187.8 kDa for A. rosea and 220.7 kDa for P. mycophaga. Cell models ("ghosts") contracted upon the addition of ATP. We conclude that amoebae of A. rosea and P. mycophaga, although behaving differently from those of Dictyostelium discoideum, contain the basic repertoire of molecules that enable pseudopod extension by actin polymerization and ATP-induced contraction of the cell cortex. Copyright 1998 Academic Press.     

A pathophysiological framework of hippocampal dysfunction in ageing and disease

The hippocampal formation has been implicated in a growing number of disorders, from Alzheimer's disease and cognitive ageing to schizophrenia and depression. How can the hippocampal formation, a complex circuit that spans the temporal lobes, be involved in a range of such phenotypically diverse and mechanistically distinct disorders? Recent neuroimaging findings indicate that these disorders differentially target distinct subregions of the hippocampal circuit. In addition, some disorders are associated with hippocampal hypometabolism, whereas others show evidence of hypermetabolism. Interpreted in the context of the functional and molecular organization of the hippocampal circuit, these observations give rise to a unified pathophysiological framework of hippocampal dysfunction.     

New donor-acceptor pair for fluorescent immunoassays by energy transfer

A novel F?rster donor-acceptor dye pair for an immunoassay based on resonance energy transfer (RET) is characterized with respect to its photophysical properties. As donor and acceptor, we chose the long-wavelength excitable cyanine dyes Cy5 and Cy5.5, respectively. Due to the perfect spectral overlap, an exceptionally high R(0) value of 68.7 A is obtained in solution. For biochemical applications, antibodies (IgG) are labeled with Cy5, while a tracer for competitive binding is synthesized by labeling bovine serum albumin (BSA) with an analyte derivative and Cy5.5. Binding the dyes to proteins at a low dye/protein ratio increases the fluorescence lifetimes and quantum yields, leading to an enhanced R(0) value of 85.2 A. At higher dye/protein ratios, the formation of nonfluorescent dimeric species causes a decrease in the fluorescence lifetime and quantum yield due to RET from monomeric dyes to dimers within one protein molecule. The F?rster distances could be calculated using the dimer absorption spectra to 83.9 and 83.6 A for Cy5 and Cy5.5, respectively. Upon binding of the Cy5-labeled IgG to the tracer, efficient quenching of Cy5 fluorescence is observed. Steady-state and time-resolved measurements reveal that approximately 50% of the quenching results in F?rster-type RET, while the residual quenching effect is caused by static quenching processes. The applicability of this dye pair is demonstrated in a homogeneous competitive immunoassay for the pesticide simazine.