Angiotensinogen in human essential hypertension

The candidacy of angiotensinogen for a role in the genetic basis of hypertension is supported by the observation that plasma angiotensinogen levels track with raised blood pressure through families. In addition, transgenic mice with overexpression of a rat angiotensinogen gene develop hypertension, and knockout mice with a disrupted gene and absent angiotensinogen production develop low blood pressure. There are now two studies in populations of white European origin and one in African Caribbeans providing support for a role of the angiotensinogen gene locus in human essential hypertension.     

Mapping of a yeast G protein betagamma signaling interaction

The mating pathway of Saccharomyces cerevisiae is widely used as a model system for G protein-coupled receptor-mediated signal transduction. Following receptor activation by the binding of mating pheromones, G protein betagamma subunits transmit the signal to a MAP kinase cascade, which involves interaction of Gbeta (Ste4p) with the MAP kinase scaffold protein Ste5p. Here, we identify residues in Ste4p required for the interaction with Ste5p. These residues define a new signaling interface close to the Ste20p binding site within the Gbetagamma coiled-coil. Ste4p mutants defective in the Ste5p interaction interact efficiently with Gpa1p (Galpha) and Ste18p (Ggamma) but cannot function in signal transduction because cells expressing these mutants are sterile. Ste4 L65S is temperature-sensitive for its interaction with Ste5p, and also for signaling. We have identified a Ste5p mutant (L196A) that displays a synthetic interaction defect with Ste4 L65S, providing strong evidence that Ste4p and Ste5p interact directly in vivo through an interface that involves hydrophobic residues. The correlation between disruption of the Ste4p-Ste5p interaction and sterility confirms the importance of this interaction in signal transduction. Identification of the Gbetagamma coiled-coil in Ste5p binding may set a precedent for Gbetagamma-effector interactions in more complex organisms.     

What if socioeconomics made no difference?: access to a cadaver kidney transplant as an example

OBJECTIVES: Several studies have noted the impact of socioeconomic factors on access to expensive medical care, but none of those studies controlled for self-reported health and functional status or attitudes about treatment alternatives when analyses were completed. Because these factors may be correlated with socioeconomic status, the failure to control for them may have led to bias in other studies. The authors merged data from secondary sources with telephone survey data from a national sample of 456 end-stage renal disease patients to show how estimates of the effects of socioeconomic factors change when self-reported health and functional status and attitudes about treatment are incorporated into statistical models. The authors also showed how kidney transplant rates would change if socioeconomic factors no longer influences organ allocation decisions. METHODS: Weibull proportional hazard analyses were used to show relationships between socioeconomic measures and waiting list entry and kidney transplant rates, before versus after accounting for self-reported health and functional status, attitudes about treatment, and other variables. Simulation analyses were used to estimate the number of waiting list spots and transplant operations that would move from economically advantaged to disadvantaged persons if socioeconomics no longer influenced organ allocation decisions. RESULTS: Incorporating information about health and functional status, attitudes about treatment, and other factors into the hazard models often reduced the estimated impact of socioeconomic measures on the odds of (1) being on a waiting list for a cadaver kidney transplant and (2) receiving a transplant. Simulations showed that 30 to 65 waiting list spots or transplant operations per 1,000 patients would shift from economically advantaged to disadvantaged persons if socioeconomics no longer influenced organ allocation decisions. CONCLUSIONS: Successful efforts to level the playing field would result in substantial redistributions of kidney transplants from economically advantaged to disadvantaged persons.     

Management of allergic bronchopulmonary aspergillosis without maintenance oral corticosteroids: a fifteen-year follow-up

Five non-smoking patients were diagnosed as having allergic bronchopulmonary aspergillosis in 1978/9. All have been treated since then with inhaled corticosteroids, using short courses of self-administered oral corticosteroids for symptomatic exacerbations. Over a mean 15 years of follow-up, they have required on average less than one course of oral drugs per annum. Regular monitoring of spirometry has shown no evidence of deterioration, and all have close to normal gas transfer. All have some localized bronchiectasis on CT scanning, in two cases probably occurring after treatment started, but in no case is there any respiratory disability. We conclude that this is a safe and effective method for the management of allergic bronchopulmonary aspergillosis when diagnosed before persistent hyphal colonization of the airways has occurred.     

Time-resolved FTIR studies of the GTPase reaction of H-ras p21 reveal a key role for the beta-phosphate

FTIR difference spectroscopy has been established as a new tool to study the GTPase reaction of H-ras p21 (Ras) in a time-resolved mode at atomic resolution without crystallization. The phosphate vibrations were analyzed using site specifically 18O-labeled caged GTP isotopomers. One nonbridging oxygen per nucleotide was replaced for an 18O isotope in the alpha-, beta-, or gamma-position of the phosphate chain. In photolysis experiments with free caged GTP, strong vibrational coupling was observed among all phosphate groups. The investigation of Ras*caged GTP photolysis and the subsequent hydrolysis reaction of Ras*GTP showed that the phosphate vibrations are largely decoupled by interaction with the protein in contrast to free GTP. The characteristic isotope shifts allow band assignments to isolated alpha-, beta-, and gamma-phosphate vibrations of caged GTP, GTP, and the liberated inorganic phosphate. The unusually low frequency of the beta (PO2-) vibration of Ras-bound GTP, as compared to free GTP, indicates a large decrease in the P-O bond order. The bond order decrease reveals that the oxygen atoms of the beta (PO2-) group interact much more strongly with the protein environment than the gamma-oxygen atoms. Thereby, electrons are withdrawn from the beta-phosphorus, and thus also from the beta/gamma-bridging oxygen. This leads to partial bond breakage or at least weakening of the bond between the beta/gamma-bridging oxygen and the gamma-phosphorus atom as a putative early step of the GTP hydrolysis. Based on these results, we propose a key role of the beta-phosphate for GTP hydrolysis. The assignments of phosphate bands provide a crucial marker for further time-resolved FTIR studies of the GTPase reaction of Ras.