Time-dependent effect of an oral hypoglycemic agent upon serum glucose levels

Summary A constant dosage of glibenclamide (50 μg/kg i.p.) was administered to normal mice at 4-h intervals during the day. Blood samples were collected up to 360 min after the injection, for glucose determination. It was found that neither the depth nor the duration of the glibenclamide-induced hypoglycemia was constant throughout the day. These results demonstrate the existence of a circadian rhythm of the glibenclamide effect on serum glucose levels. They also suggest that a day-time schedule of therapy with this drug should result in improved control of serum glucose. Traduzione a cura di G.U.     

Reducing diarrhea through the use of household-based ceramic water filters: a randomized, controlled trial in rural Bolivia

Ceramic water filters have been identified as one of the most promising and accessible technologies for treating water at the household level. In a six-month trial, water filters were distributed randomly to half of the 50 participating households in a rural community in Bolivia; the remaining households continued to use customary water handling practices and served as controls. In four rounds of sampling following distribution of the filters, 100% of the 96 water samples from the filter households were free of thermotolerant coliforms compared with 15.5% of the control household samples. Diarrheal disease risk for individuals in intervention households was 70% lower than for controls (95% confidence interval [CI] = 53-80%; P < 0.001). For children less than five years old, the reduction in risk was 83% (95% CI = 51-94%; P < 0.001). These results show that affordable ceramic water filters enable low-income households to treat and maintain the microbiologic quality of their drinking water.     

Multichannel data acquisition system for mapping the electrical activity of the heart

BACKGROUND: Details of the electrical conduction pattern of the heart are revealed to the electrophysiologist when multichannel data are used for activation mapping. Commercial electronic systems are available for simultaneous acquisition of many surface electrograms; however, the cost of these systems may be prohibitive and they can be mostly inflexible for adaptation to other research projects. Furthermore, the hardware and software design is often proprietary. In this article we describe the in-house design and implementation of a 320-multichannel acquisition system for animal electrophysiologic research. METHOD AND RESULTS: Several modules comprise this system. The multichannel data are first preprocessed by amplification, filtering, and analog multiplexing. An algorithm for automatic adjustment of signal gains is implemented to maximize the voltage resolution and minimize noise pickup. Signals are then digitized, and sequenced to order the multichannel data and to add markers required for analysis. The digital data are streamed to archival storage media. Additionally, the electrocardiogram (ECG), blood pressure, and stimulus channel signals are stored simultaneously. Selected signals are then displayed in real-time for measurement and analysis and as a check of the system integrity. Examples of multielectrode arrays and surface recordings are provided. Costs for building such a system are estimated. CONCLUSIONS: Multichannel data acquisition systems that are designed and constructed in-house have several advantages over turnkey commercial systems, including the potential for considerable cost savings, flexibility in acquiring data, and the ability to subsequently add additional components.     

Advantage of high-resolution melting curve analysis over conformation-sensitive gel electrophoresis for mutational screening of BRCA1 and BRCA2 genes

BackgroundMutation screening of BRCA1 and BRCA2 (BRCAs) genes is a time-consuming and costly procedure that demands faster and cheaper alternative methods for routine diagnostics. The present study is aimed at comparing the results obtained with screening mutations methods, conformation sensitive gel electrophoresis (CSGE) and high-resolution melting analysis (HRMA), for BRCAs attending to their specificity, sensitivity, reliability and cost-efficiency.MethodsWe included 52 DNA samples of index patients from high-risk families. The mutational screening was performed by CSGE according to the Ganguly (1993) method and HRMA according to a modified De Leeneer (2008) method. The assays were performed in 384 well plates in the LightCycler 480 (Roche). All PCR products showing altered patterns were confirmed by sequencing.ResultsThe results obtained with the mutational study of BRCAs genes showed that HRMA exhibited higher sensitivity than CSGE as it was able to detect a wide mutational spectra of genetic variants in a larger number of samples. Aditionally, the combination of HRMA with hybiridization probes in a second step of the assay allows the specific confirmation of mutations. Furthermore, HRMA use less time, allowing the reduction of analysis time.ConclusionsHRMA offers clear advantages over CSGE for the mutation screening of BRCAs genes as it has greater sensitivity and higher efficiency and it is less time-consuming.     

Constrained reverse diffusion for thick slice interpolation of 3D volumetric MRI images

Due to physical limitations inherent in magnetic resonance imaging scanners, three dimensional volumetric scans are often acquired with anisotropic voxel resolution. We investigate several interpolation approaches to reduce the anisotropy and present a novel approach - constrained reverse diffusion for thick slice interpolation. This technique was compared to common methods: linear and cubic B-Spline interpolation and a technique based on non-rigid registration of neighboring slices. The methods were evaluated on artificial MR phantoms and real MR scans of human brain. The constrained reverse diffusion approach delivered promising results and provides an alternative for thick slice interpolation, especially for higher anisotropy factors.     

Model-based prediction of the acute and long-term safety profile of naproxen in rats

Background and Purpose

Despite the increasing importance of biomarkers as predictors of drug effects, toxicology protocols continue to rely on the experimental evidence of adverse events (AEs) as a basis for establishing the link between indicators of safety and drug exposure. Furthermore, biomarkers may facilitate the translation of findings from animals to humans. Combined with a model-based approach, biomarker data have the potential to predict long-term effects arising from prolonged drug exposure. Here, we used naproxen as a paradigm to explore the feasibility of a biomarker-guided approach for the prediction of long-term AEs in humans.

Experimental Approach

An experimental toxicology protocol was set up for evaluating the effects of naproxen in rats, in which four active doses were tested (7.5, 15, 40 and 80 mg·kg⁻¹). In addition to AE monitoring and histology, a few blood samples were also collected for the assessment of drug exposure, TXB₂ and PGE₂ levels. Non-linear mixed effects modelling was used to analyse the data and identify covariate factors on the incidence and severity of AEs.

Key Results

Modelling results showed that besides drug exposure, maximum PGE₂ inhibition and treatment duration were also predictors of gastrointestinal ulceration. Although PGE₂ levels were clearly linked to the incidence rates, it appeared that ulceration severity is better predicted by measures of drug exposure.

Conclusions and Implications

These results show that the use of a model-based approach provides the opportunity to integrate pharmacokinetics, pharmacodynamics and toxicity data, enabling optimization of the design, analysis and interpretation of toxicology experiments.