The clinical development of a 5 alpha-reductase inhibitor, finasteride.

Finasteride, a 4-aza steroid compound, is an orally active inhibitor of the 5 alpha-reductase enzyme. 5 alpha-Reductase is necessary for the metabolism of testosterone (T) to dihydrotestosterone (DHT) and is found in high levels only in certain tissues such as the prostate. Finasteride has been shown to markedly suppress serum DHT levels in man without lowering testosterone levels. In patients with benign prostate hyperplasia (BPH), finasteride was found to decrease prostate volume by a mean of 28% over a period of 6 months, without causing clinically significant adverse effects. DHT appears to be the primary androgen for prostatic growth. Selective inhibition of 5 alpha-reductase by finasteride may provide a novel approach to BPH therapy by reducing prostate size without affecting T-dependent processes such as fertility, muscle strength, and libido. The clinical development of finasteride for the treatment of benign prostate hyperplasia is reviewed.     

Effect of pretest temperature on aerosol penetration and clearance in donkeys.

Pretest temperature and humidity were correlated with tracheobronchial particle penetration and clearance data from donkeys housed in unheated outdoor facilities and tested after spending 1-2 h in a temperature- and humidity-controlled laboratory. The animals inhaled an inert insoluble radioisotope-labeled monodisperse aerosol for several minutes. Its retention was monitored continuously for 3 h by external gamma detection. Aerosol deposition pattern and bronchial clearance were linearly correlated with pretest outdoor temperature which ranged from -10 to 30 degrees C. The fraction depositing in the unciliated regions of the lung decreased 0.6% per degrees C drop in outdoor temperature. Overall bronchial transport decreased at least 1.5% per degrees C decrease. Multiple linear regression analysis and correction for the positive correlation between temperature and humidity left no significant residual humidity dependence. Acclimatization of the animals in the laboratory for 6 h before testing significantly reduced these effects.     

The role of the Cdk5--p35 kinase in neuronal development.

Cyclin-dependent kinase 5 (Cdk5) plays a key role in proper development of the nervous system. To be activated, Cdk5 associates with regulatory subunits not related to cyclins, such as p35 (the regulatory subunit of Cdk5). In this article, we review some of the experimental evidence supporting a central role for the Cdk5/p35 kinase in neuronal migration and process formation.     

The Children's Treatment of Animals Questionnaire: A Rasch Analysis

ABSTRACT

The study of human–animal interactions is limited by a paucity of empirically validated measures of humane treatment of companion animals. The current study reports findings from a psychometric analysis of the Children's treatment of animals Questionnaire (CTAQ; thompson and Gullone 2003), an instrument that assesses children's humane interactions with nonhuman animals. Specifically, the current study extends what is known about the psychometric properties of the CTAQ by using traditional and item response theory analyses. The CTAQ was administered to a sample of 217 school-age children whose mothers were currently receiving residential or non-residential domestic violence services. Item-analysis, exploratory factor analysis, and parallel analysis were conducted to replicate previous psychometric evaluations of the CTAQ. Rasch analysis of the CTAQ was also conducted to provide a stringent test of unidimensionality and to identify potential invariance in item functioning across various demographic variables. The CTAQ showed adequate fit to the Rasch model; one modification, removal of item 5, was required. A Rasch principal components analysis of residuals indicated a single latent dimension among the remaining 12 items. Scale use was appropriate; Rasch-andrich thresholds increased with category values and no disordering of categories was evident. Examination of item-person maps indicated the sample was also well-targeted. Notably, evidence of differential item function was found across Spanish and English translations. Overall, findings indicate that the CTAQ is an appropriate unidimensional measure of children's humane treatment of animals. The measure is particularly well-suited for children ages 7 to 12 years who are at risk for exposure to and perpetration of animal cruelty. We recommend use of a 12-item version of the CTAQ to enhance the utility of the total score as a latent measure of children's humane treatment of companion animals.     

The alpha 5 beta 1 integrin associates with a dystrophin-containing lattice during muscle development.

The organization of the alpha 5 beta 1 integrin on skeletal muscle was studied in culture and in sections from adult and embryonic tissue using monoclonal antibodies specific for the alpha 5 subunit. The alpha 5 beta 1 integrin showed changes in organization and in the molecules with which it colocalizes. On early myoblasts, possessing a fibroblast-like morphology, the alpha 5 integrin organization was indistinguishable from that on fibroblasts; it was expressed prominently and localized in numerous focal contacts around the cell periphery. In bipolar myoblasts and early myotubes, the alpha 5 integrin was expressed only weakly and localized in a small number of focal contact-like structures. As myogenesis proceeded there was an apparent increase in integrin expression and a change in organization. In addition to the focal contact-like structures that persist throughout myogenesis in vitro, a dense lattice-like structure of integrin appeared. Fibrillar fibronectin, talin, and non-muscle alpha-actinin did not colocalize with the alpha 5 beta 1 integrin in the lattice structure as they did in the focal contact-like structures. However, dystrophin, which displayed a diffuse distribution earlier, now colocalized with the alpha 5 beta 1 integrin in the punctate lattice. Coincident with the registration of myofibrils into visible sarcomeres, the prominent dense, lattice structure disappeared leaving the focal contact-like structures as the only regions of organized alpha 5 beta 1 integrin. Despite the presence of the beta 1 integrin in neuromuscular or myotendinous junctions in vivo and on myotubes in vitro, the alpha 5 beta 1 integrin was not present in either junction. These observations suggest that the alpha 5 beta 1 integrin is involved in the adhesion of muscle to the extracellular matrix, the organization of the dystrophin-containing lattice, and the organization of nascent myofibrils which emanate from the focal contact- and stress fiber-like structures in muscle. Other integrins appear to anchor myofibrils at the myotendinous and neuromuscular junctions.     

CCN5 Expression in mammals. III. Early embryonic mouse development

CCN proteins play crucial roles in development, angiogenesis, cell motility, matrix turnover, proliferation, and other fundamental cell processes. Early embryonic lethality in CCN5 knockout and over-expressing mice led us to characterize CCN5 distribution in early development. Previous papers in this series showed that CCN5 is expressed widely in mice from E9.5 to adult; however, its distribution before E9.5 has not been studied. To fill this gap in our knowledge of CCN5 expression in mammals, RT-PCR was performed on preimplantation murine embryos: 1 cell, 2 cell, 4 cell, early morula, late morula, and blastocyst. CCN5 mRNA was not detected in 1, 2, or 4 cell embryos. It was first detected at the early morula stage and persisted to the preimplantation blastocyst stage. Immunohistochemical staining showed widespread CCN5 expression in post-implantation blastocysts (E4.5), E5.5, E6.5, and E7.5 stage embryos. Consistent with our previous study on E9.5 embryos, this expression was not limited to a particular germ layer or cell type. The widespread distribution of CCN5 in early embryos suggests a crucial role in development.     

Cortical development: Cdk5 gets into sticky situations

Cyclin-dependent kinase 5 (Cdk5) is much more than its name implies; it plays a role in neuronal migration, neurite outgrowth and degeneration. Recent evidence suggests that Cdk5 regulates neuronal adhesion and cytoskeletal dynamics.