Renal transport of urate during diuretic-induced hypouricemia

The effect of two weeks administration of a uricosuric diuretic (SKF-62698) on renal urate handling has been examined in 11 normal men. Plasma urate concentrations had declined by more than 60 per cent after two weeks. Urate excretion per unit of glomerular filtration rate and urate clearance (Curate) per unit of glomerular filtration rate were increased after the administration of SKF-62698. The importance of intact tubular secretion of urate in producing these changes was assessed by administering pyrazinamide, an agent that curtails urate secretion, to each participant. The decrements in urate excretion and clearance produced by pyrazinamide both increased significantly, whereas the residual urate excretion rates and clearances not suppressible by pyrazinamide were only minimally altered by SKF-62698 treatment. These results suggest that the excretion of secreted urate was enhanced by prolonged administration of SKF-62698, probably secondary to the inhibition of postsecretory urate reabsorption. In addition, because the nonsuppressible urate excretion did not decline despite a 63 per cent reduction in the plasma urate, it is likely that the reabsorption of filtered urate also was impaired by SKF-62698.     

3D space-varying coefficient models with application to diffusion tensor imaging

The present methodological development and the primary application field originate from diffusion tensor imaging (DTI), a powerful nuclear magnetic resonance technique which enables the quantification of microscopical tissue properties. The current analysis framework of separate voxelwise regressions is reformulated as a 3D space-varying coefficient model (SVCM) for the entire set of diffusion tensor images recorded on a 3D voxel grid. The SVCM unifies the three-step cascade of standard data processing (voxelwise regression, smoothing, interpolation) into one framework based on B-spline basis functions. Thereby strength is borrowed from spatially correlated voxels to gain a regularization effect right at the estimation stage. Two SVCM variants are conceptualized: a full tensor product approach and a sequential approximation, rendering the SVCM numerically and computationally feasible even for the huge dimension of the joint model in a realistic setup. A simulation study shows that both approaches outperform the standard method of voxelwise regression with subsequent regularization. Application of the fast sequential method to real DTI data demonstrates the inherent ability to increase the grid resolution by evaluating the incorporated basis functions at intermediate points. The resulting continuous regularized tensor field may serve as basis for multiple applications, yet, ameloriation of local adaptivity is desirable.     

The membrane protein alkaline phosphatase is delivered to the vacuole by a route that is distinct from the VPS-dependent pathway

Membrane trafficking intermediates involved in the transport of proteins between the TGN and the lysosome-like vacuole in the yeast Saccharomyces cerevisiae can be accumulated in various vps mutants. Loss of function of Vps45p, an Sec1p-like protein required for the fusion of Golgi-derived transport vesicles with the prevacuolar/endosomal compartment (PVC), results in an accumulation of post-Golgi transport vesicles. Similarly, loss of VPS27 function results in an accumulation of the PVC since this gene is required for traffic out of this compartment. The vacuolar ATPase subunit Vph1p transits to the vacuole in the Golgi-derived transport vesicles, as defined by mutations in VPS45, and through the PVC, as defined by mutations in VPS27. In this study we demonstrate that, whereas VPS45 and VPS27 are required for the vacuolar delivery of several membrane proteins, the vacuolar membrane protein alkaline phosphatase (ALP) reaches its final destination without the function of these two genes. Using a series of ALP derivatives, we find that the information to specify the entry of ALP into this alternative pathway to the vacuole is contained within its cytosolic tail, in the 13 residues adjacent to the transmembrane domain, and loss of this sorting determinant results in a protein that follows the VPS-dependent pathway to the vacuole. Using a combination of immunofluorescence localization and pulse/chase immunoprecipitation analysis, we demonstrate that, in addition to ALP, the vacuolar syntaxin Vam3p also follows this VPS45/27-independent pathway to the vacuole. In addition, the function of Vam3p is required for membrane traffic along the VPS-independent pathway.     

The depolarization near-field scanning optical microscope: comparison of experiment and theory

The depolarization near-field scanning optical microscope allows for sub-wavelength optical resolution with uncoated optical fibre tips. We show by a simple thought experiment, by numerical solution of the Maxwell equations for a realistic geometry, and by direct experiments, that this novel apparatus images gradients of the dielectric function of a sample in the direction of the incident electric field vector. The near-field images obtained from experiment and theory agree well.     

A molecular mechanism for electrical tuning of cochlear hair cells

Cochlear frequency selectivity in lower vertebrates arises in part from electrical tuning intrinsic to the sensory hair cells. The resonant frequency is determined largely by the gating kinetics of calcium-activated potassium (BK) channels encoded by the slo gene. Alternative splicing of slo from chick cochlea generated kinetically distinct BK channels. Combination with accessory beta subunits slowed the gating kinetics of alpha splice variants but preserved relative differences between them. In situ hybridization showed that the beta subunit is preferentially expressed by low-frequency (apical) hair cells in the avian cochlea. Interaction of beta with alpha splice variants could provide the kinetic range needed for electrical tuning of cochlear hair cells.     

Incremental value of rubidium-82 positron emission tomography for prognostic assessment of known or suspected coronary artery disease

Myocardial perfusion imaging using positron emission tomography (PET) may be more accurate for the diagnosis of coronary artery disease (CAD) than conventional imaging. The purpose of this study was to evaluate the prognostic implications of perfusion abnormalities in 685 patients (age 62 +/- 11 years, 199 women) studied by PET, and to assess the incremental value of these data in relation to prognostic implications of clinical and angiographic findings. Rubidium (Rb)-82 PET was performed before and after dipyridamole stress. Transient defects were detected in 227 patients (33%), and were moderate or greater in severity (> 15% of the left ventricle) in 84 (12%). Resting defects were present in 435 (64%) and were moderate or greater in severity in 216 (32%). The total extent of abnormally perfused myocardium was small (< 15% of the left ventricle) in 198 (29%), moderate in 216 (32%), and extensive in 105 (15%). Clinic review or standardized phone interview in 657 patients (96%) identified 151 cardiac events, including 81 cardiac deaths, 16 patients with myocardial infarction, 7 with unstable angina, and 47 with late revascularization (> 3 months after PET). Normal scans had a 90% event-free survival, compared with 87% in patients with small, 75% with moderate, and 76% with extensive defects (log rank chi-square 30, p <0.0001). Functional class, extent of CAD, and the presence and extent of perfusion defects (both at rest and during stress) were independent predictors of cardiac death and total cardiac events. In sequential Cox proportional-hazards models, the results of PET were incremental to those of clinical and angiographic evaluation. Thus, the presence and extent of damaged and jeopardized myocardium are independent and incremental predictors of outcome in patients undergoing Rb-82 PET.