Duchenne dystrophy: alteration in muscle plasma membrane structure

Freeze fracture studies of skeletal muscle from eight patients with Duchenne dystrophy showed nonuniform distribution and depletion of particles on both protoplasmic and extracellular faces of the muscle plasma membrane. The findings support the view that the muscle surface membrane is abnormal in this disorder and indicate that alterations are present in the internal molecular architecture of the membrane.     

Molar polymorphisms and the timing of dentition mineralization

The chronological age, skeletal age, and morphological age at the time of mineralization of 14 stages of the permanent teeth of 121 boys and 111 girls of the serial experimental sample of the Burlington Growth Centre were contrasted according to whether or not the children had 4- or 5-cusped mandibular permanent first molars, and whether or not they had agenesis of one or more third molars. In the boys with 4-cusped mandibular first molars, the mineralization of the teeth occurred at significantly earlier chronological and skeletal ages when they were significantly shorter in stature. Tooth mineralization was not consistently earlier in the girls with 4-cusped molars, but these girls tended to be taller and heavier than those with 5-cusped molars. In contrast, in both sexes with agenesis of third molars, the mineralization of the teeth was significantly delayed according to chronological, skeletal and morphological evaluation. The change in timing of mineralization was greatest for the second premolars and second molars, and least for the first molars.     

Measuring job stressors and strains: where we have been, where we are, and where we need to go

This article examines assessment approaches and specific measures used by job-stress researchers to characterize aspects of work and the working environment (potential job stressors) and workers' reactions to these working conditions (strains). Self-report instruments, observational approaches, and physiological indicators are described. Problematic areas (e.g., the use of overlapping stressor and strain measures) and contemporary issues affecting job stress assessment (e.g., negative affectivity) are discussed. Recommendations regarding instrument selection and measurement improvements are offered. It is concluded that closer attention to measurement-related issues is critical to the advancement of knowledge in the field. Important needs include the identification and more frequent use of objective measures, the increased use of triangulation strategies, and a careful examination of the adequacy of existing constructs and measures for capturing the demands of contemporary work.     

A forecasting approach to accelerate drug development

The clinical phase of drug development should be concluded sooner and at a lower cost if primarily only the pivotal and supportive studies were to be conducted. Such improved efficiency requires development of a decision support system that delivers five new capabilities: (i) it enables one to predict a result of a clinical study and to identify those studies that are expected to have an acceptable probability of success; (ii) it will allow one to optimally utilize available pharmacokinetic and pharmacodynamic (PK/PD) data and improve its predictive capability as more data become available; (iii) it will enable one to project useful population results, not just mean results; (iv) predictions will be accompanied by a measure of reliability; and (v) expected initial clinical results will be predictable from animal and related drug class data. With such a tool population targets could be specified very early in the drug development programme, challenged, and then rationally revised at each step during the development process. This report describes progress in developing and testing a clinical trials Forecaster, a prototype for such a system. The Forecaster generates estimates of the joint density for a population of combined PK/PD parameters. That population then serves as a surrogate for the population of individuals. When the resulting joint density is sampled, the obtained sets of parameters may be used to generate data that is statistically indistinguishable from the original experimental data. Such simulated data can be used to validate assumptions, and make inferences on specified population targets that are accompanied by a measure of prediction reliability. We demonstrate use of the forecaster by employing N = 22 PK/PD parameter sets for an orally administered analgesic.     

Sex differences in hepatic sulfation of taurolithocholate in the rat

Metabolism of the bile salts by formation of sulfate esters is catalyzed by bile salt sulfotransferase, an enzyme isolated from rat liver and kidney. The activity of bile salt sulfotransferase was measured in liver and kidney of male and female rats and in oophorectomized rats with or without estrogen replacement. In vitro sulfotransferase activity was correlated with in vivo sulfation by measuring the percentage of an infused dose (0.03 micron per 100 g per min) of taurolithocholate, which was excreted in bile as the sulfate. The activity of sulfotransferase in liver was higher in females (26.3 +/- 3.0 pmoles per mg of protein per min) than in males (9.6 +/- 3.9) and was lower (12.1 +/- 3.8) after oophorectomy. The decrease in activity was prevented by replacement of estrogen. Renal sulfotransferase activity did not differ between the sexes and was unaffected by oophorectomy. Hepatic sulfotransferase activity measured in vitro correlated with in vivo sulfation of taurolithocholate. This study shows definite sex differences in hepatic bile salt sulfotransferase activity, which in females is affected by the presence of estrogen. The correlation between in vitro sulfotransferase activity and in vivo bile salt sulfation suggests that bile salt sulfotransferase is responsible for bile salt sulfation in vivo.     

Lymphocyte and macrophage responses after vaccinia virus infections

Using a semimicromethod with washed whole blood, in vitro lymphocyte responses of rabbits to intradermal infection with vaccinia virus was studied. Peritoneal exudate macrophages were infected with vaccinia in vitro to determine the time of appearance of activated macrophages. After primary infection, an increase in spontaneous incorporation of thymidine by blood cultures was found as early as 2 days postinfection. This effect was at a maximum at 7 to 10 days, with counts up to 100-fold higher than before infection. Incubation of these cultures with concanavalin A showed a marked decrease in stimulation index as compared with normals. Although only a transient stimulation with vaccinia was found during the acute infection, stimulation indexes of 2 to 3 were obtained during convalescence. Macrophages from rabbits early after infection supported vaccinia replication, whereas those at day 6 or later resisted infection. Macrophage resistance persisted for 2 to 3 weeks. The response of lymphocytes from rabbits reinfected with vaccinia after 15 weeks differed, with a small increase in spontaneous thymidine uptake, a smaller depression in concanavalin A stimulation, and a greater specific response to vaccinia. Macrophage activation occurred earlier and persisted for a longer time after secondary infection.