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Testing Paradigm (testing + paradigm)

Distribution by Scientific Domains

Medical Sciences	50%

Selected Abstracts

Electroconvulsive seizure thresholds and kindling acquisition rates are altered in mouse models of human KCNQ2 and KCNQ3 mutations for benign familial neonatal convulsions

EPILEPSIA, Issue 7 2009
James F. Otto
Summary Purpose:, Benign familial neonatal convulsions (BFNC) is caused by mutations in the KCNQ2 and KCNQ3 genes, which encode subunits of the M-type potassium channel. The purpose of this study was to examine the effects of orthologous BFNC-causing mutations on seizure thresholds and the acquisition of corneal kindling in mice with heterozygous expression of the mutations. Methods:, The effects of the Kcnq2 gene A306T mutation and the Kcnq3 gene G311V mutation were determined for minimal clonic, minimal tonic hindlimb extension, and partial psychomotor seizures. The rate of corneal kindling acquisition was also determined for Kcnq2 A306T and Kcnq3 G311V mice. Results:, Seizure thresholds were significantly altered relative to wild-type animals in the minimal clonic, minimal tonic hindlimb extension, and partial psychomotor seizure models. Differences in seizure threshold were found to be dependent on the mutation expressed, the seizure testing paradigm, the genetic background strain, and the gender of the animal. Mutations in Kcnq2 and Kcnq3 were associated with an increased rate of corneal kindling. In the Kcnq2 A306T mice, an increased incidence of death occurred during and immediately following the conclusion of the kindling acquisition period. Conclusions:, These results suggest that genetic alterations in the subunits that underlie the M-current and cause BFNC alter seizure susceptibility in a sex-, mouse strain-, and seizure-test dependent manner. Although the heterozygous mice do not appear to have spontaneous seizures, the increased seizure susceptibility and incidence of death during and after kindling suggests that these mutations lead to altered excitability in these animals. [source]

Bayesian Detection and Modeling of Spatial Disease Clustering

BIOMETRICS, Issue 3 2000
Ronald E. Gangnon
Summary. Many current statistical methods for disease clustering studies are based on a hypothesis testing paradigm. These methods typically do not produce useful estimates of disease rates or cluster risks. In this paper, we develop a Bayesian procedure for drawing inferences about specific models for spatial clustering. The proposed methodology incorporates ideas from image analysis, from Bayesian model averaging, and from model selection. With our approach, we obtain estimates for disease rates and allow for greater flexibility in both the type of clusters and the number of clusters that may be considered. We illustrate the proposed procedure through simulation studies and an analysis of the well-known New York leukemia data. [source]

Olfactory deficits in mice overexpressing human wildtype ,-synuclein

EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 2 2008
Sheila M. Fleming
Abstract Accumulation of ,-synuclein in neurons of the central and peripheral nervous system is a hallmark of sporadic Parkinson's disease (PD) and mutations that increase ,-synuclein levels cause familial PD. Transgenic mice overexpressing ,-synuclein under the Thy1 promoter (Thy1-aSyn) have high levels of ,-synuclein expression throughout the brain but no loss of nigrostriatal dopamine neurons up to 8 months, suggesting that they may be useful to model pre-clinical stages of PD. Olfactory dysfunction often precedes the onset of the cardinal motor symptoms of PD by several years and includes deficits in odor detection, discrimination and identification. In the present study, we measured olfactory function in 3- and 9-month-old male Thy1-aSyn mice with a buried pellet test based on latency to find an exposed or hidden odorant, a block test based on exposure to self and non-self odors, and a habituation/dishabituation test based on exposure to non-social odors. In a separate group of mice, ,-synuclein immunoreactivity was assessed in the olfactory bulb. Compared with wildtype littermates, Thy1-aSyn mice could still detect and habituate to odors but showed olfactory impairments in aspects of all three testing paradigms. Thy1-aSyn mice also displayed proteinase K-resistant ,-synuclein inclusions throughout the olfactory bulb. These data indicate that overexpression of ,-synuclein is sufficient to cause olfactory deficits in mice similar to that observed in patients with PD. Furthermore, the buried pellet and block tests provided sufficient power for the detection of a 50% drug effect, indicating their usefulness for testing novel neuroprotective therapies. [source]

First Exposure in Man: Toxicological Considerations

BASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 2000
Per Spindler
Recommendations on the type and extent of preclinical safety studies that should be conducted prior to first dose in man have been developed by the International Conference on Harmonisation, and the European Committee for Proprietary Medicinal Products. These recommendations include studies designed to characterise local tolerance and general toxicity of the drug candidate as well as its genotoxic potential and ability to interfere with reproduction. For trials which can be categorised as low dose PK screening trials and trials with products where rodent and non-rodent (primarily dog) models do not show any biological response (e.g. some biotechnology-derived hormones and cytokines) other testing paradigms should be used. The present recommendations for preclinical testing have had an important impact on the documented impressive safety record of phase I clinical trials. In this spirit we extend our warmest and sincerest thanks to Professor Jens S. Schou for his long and deep engagement in European and International harmonisation of preclinical test recommendations. His efforts have had a substantial impact on the present testing recommendations, which are of obvious benefit to the safety of the patient. [source]