The pathogenesis of glomerular injury in the remnant kidney (RK) model remains controversial. Increased glomerular transmission of systemic hypertension has been postulated to be an important pathogenic mechanism, but the precise relationship between systemic pressures and glomerular injury has not been defined because of the limitations of the tail-cuff method. Systolic blood pressure (BP) was continuously recorded radiotelemetrically at 10-min intervals for 6 wk in rats after approximately 5/6 renal ablation (n = 16) or sham ablation (n = 7). Overall mean systolic BP in RK rats was significantly higher than sham (138 +/- 3.3 vs. 117 +/- 1.3 mmHg, P < 0.01). Additionally, marked lability of systolic BP was observed in RK rats as compared with sham rats. Glomerular injury was essentially confined to RK rats, but the percentage of injured glomeruli ranged between 1 and 55%. Glomerular injury in individual animals was strongly correlated (r = 0.88) with the mean systolic BP during the last approximately 4 wk and with the frequency of systolic BP readings of > 140 mmHg. These data strongly suggest that transmission of systemic hypertension to the renal microvasculature plays a predominant role in the pathogenesis of glomerular injury in the RK model and also support the potential usefulness of the radiotelemetric technique to investigate hypertensive target organ injury.
A novel strategy for anti-viral intervention of hepatitis B virus (HBV) through the disruption of the proper folding and transport of the hepadnavirus glycoproteins is described. Laboratory reared woodchucks chronically infected with woodchuck hepatitis virus (WHV) were treated with N-nonyl-deoxynojirimycin (N-nonyl-DNJ), an inhibitor of the endoplasmic reticulum (ER) alpha-glucosidases. The woodchucks experienced significant dose dependent decreases in enveloped WHV, resulting in undetectable amounts in some cases. The reduction in viremia correlated with the levels of hyperglucosylated glycan in the serum of treated animals. This correlation supports the mechanism of action associated with the drug and highlights the extreme sensitivity of the virus to this type of glycan inhibitor. At N-nonyl-DNJ concentrations that prevented WHV secretion, the glycosylation of most serum glycoproteins appeared unaffected, suggesting great selectivity for this class of therapeutics. Indeed, this may account for the low toxicity of the compound over the treatment period. We provide the first evidence that glucosidase inhibitors can be used in vivo to alter specific steps in the N-linked glycosylation pathway and that this inhibition has anti-viral effects.
The development and validation of ligand binding assays used in the support of pharmacokinetic studies has been the focus of various workshops and publications in recent years, all in an effort to establish a guidance document for standardization of these bioanalytical methods. This summary report of the workshop from 2003 focuses on the issues discussed in presentations and notes points of discussion and areas of consensus among the participants.
The anthrax lethal toxin neutralization assay (TNA) will likely be used to correlate the protection offered by new anthrax vaccines in animal models to the immunogenicity that will be provided in humans. TNA data are being generated in several different laboratories to measure the immune responses in rabbits, nonhuman primates, and humans. In order to compare data among species and laboratories, a collaborative study was conducted in which 108 samples from the three species were analyzed in seven independent laboratories. Six of the seven laboratories had participated in an interlaboratory technology transfer of the TNA. Analysis of the titration curves generated by samples from each species indicated that the behaviors of the samples from all species were similar; the upper and lower asymptotes and the slopes of the curves were less than 30% divergent from those for human reference material. Dilutional linearity was consistent among samples from each species, with spike to effective dilution at 50% inhibition (ED 50 ) slopes of less than 1.2 for all species. Agreement among the laboratories with consensus values was within 10% of the ED 50 s for all samples and within 7.5% of the quotients of the test sample ED 50 and the reference standard ED 50 (NF 50 s) for all samples. The relative standard deviations obtained when data from all laboratories and for all species were combined were 45% for the ED 50 s and 35% for the NF 50 s. These precision data suggest that the NF 50 readout may normalize the values generated by different laboratories. This study demonstrates that the TNA is a panspecies assay that can be performed in several different laboratories with a high degree of quantitative agreement and precision.
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