Limitations of current medical treatments for depression: Disturbed circadian rhythms as a possible therapeutic target

The proportion of diagnosed depressives prescribed antidepressants has increased markedly over the last 20 years, mainly following the introduction of the selective serotonin reuptake inhibitors. However, currently available antidepressants have notable limitations, relating to their only moderate efficacy relative to placebo, relatively slow onset of action, possible withdrawal symptoms, and problems of compliance. Sleep disturbances are often used to identify newly presenting depressive patients, and may be part of a more general alteration of bodily rhythms. There are links between pharmacological treatments and circadian rhythms in depression, which might represent another, new option for the development of a therapeutic approach to depression treatment. Many antidepressants affect sleep, some are sedative, and others have been used specifically in severely insomniac depressives. Disturbances in circadian rhythms may be an integral part of depressive mechanisms, and normalising them via an innovative mechanism of antidepressant action may be a fruitful avenue in the search for improved antidepressant agents.     

P1 blood group antigen expression and epidemic hemolytic uremic syndrome

P1 blood group positivity has been postulated as a host factor which may provide protection against the development of post-enteropathic hemolytic uremic syndrome (HUS). In this study, blood group status in 20 Inuit survivors ofEscherichia coli 0157: H7-associated HUS was compared with age-and sex-matched controls from the same community who had experienced uncomplicated diarrheal illness due to the same pathogen. Of 20 HUS survivors, 6 were P1 antigen positive compared with 8 of the 20 controls (P=0.7). We conclude that P1 antigen positivity was not protective against HUS in this population. Further studies of this condition to clarify the role of host factors in verotoxin-induced endothelial damage are indicated.     

Phospholipase A2-catalyzed conversion of hepatic cytochrome P450 to P420 in microsomal membranes prepared from young and old rats

Previous studies from this Laboratory have revealed few significant age-related changes in either hepatic microsomal cytochrome P₄₅₀ content or NADPH-cytochrome P₄₅₀ reductase activity, prompting the suggestion that the nearly ubiquitous age-associated decline in the hepatic metabolism of xenobiotics by the mixed-function oxidases is a result of alterations in the lipid matrix in which the macromolecular components are organized. In order to examine this postulate, the membrane microenvironment surrounding hepatic microsomal cytochrome P₄₅₀ was enzymatically digested with snake venom phospholipase A₂, and the kinetics of conversion of cytochrome P₄₅₀ to cytochrome P₄₂₀ determined for preparations obtained from rats of varying age. There were no significant differences in the kinetics of conversion of cytochrome P₄₅₀ to cytochrome P₄₂₀, suggesting that there are no significant age-related changes in the lipid microenvironment immediately adjacent to cytochrome P₄₅₀. However, there was a slight difference, independent of age, in the rate of conversion of cytochrome P₄₅₀ to cytochrome P₄₂₀ between smooth and rough microsomes. The results are discussed in terms of general experimental approaches toward understanding drug metabolism in senescent organisms.     

Catabolism of newly synthesized decorin in vitro by human peritoneal mesothelial cells.

OBJECTIVE: Previous studies have shown that decorin and biglycan account for over 70% of the proteoglycans (PGs) synthesized by human peritoneal mesothelial cells (HPMCs). Since these PGs are involved in the control of cell growth, cell differentiation, and matrix assembly, we investigated their turnover in cultured HPMCs. METHODS: Confluent HPMCs were metabolically labeled with [35S]-sulfate and the labeled products isolated from the cell medium and the cell layer characterized by sensitivity to bacterial eliminases. Experiments were undertaken with exogenous labeled decorin, and its metabolic state was studied. RESULTS: In a 24-hour labeling period, 75% of the newly synthesized chondroitin sulfate/dermatan sulfate (CS/DS) PGs appeared in the culture medium, the majority of which (90%) was decorin. In the cell layer, protein-free glycosaminoglycan (GAG) chains accounted for 21% of the total CS/DS at 24 hours and exhibited constant specific activity at 12-16 hours. The latter material was turned over with a half-life of approximately 2.5 hours. Exogenous decorin underwent receptor-mediated endocytosis and subsequent intracellular degradation. Uptake but not degradation could be inhibited by heparin. CONCLUSIONS: HPMCs are distinguished by a rapid turnover of decorin. A characteristic metabolic feature is the existence of a large intracellular pool of protein-free DS-GAGs. Understanding the control of decorin turnover in HPMCs might lead to delineation of its potential role in both the physiology and pathophysiology of the membrane in PD patients.     

Genetic differentiation between and within strains of the saw-toothed grain beetle, Oryzaephilus surinamensis (Coleoptera: Silvanidae) at RAPD loci

Nine strains of Oryzaephilus surinamensis have been kept in laboratory culture for periods ranging from 5 to 30 years (30–180 generations). Two RAPD primers provided sufficient information to separate the strains reliably and unambiguously. The strains are maintained at a population size of 200 breeding adults. The marked divergence between strains is consistent with the small population size, which for the older strains, according to population genetics theory, implies that roughly half the original genetic variation should now be lost from within strains. However, there is no indication that the older strains have less inter-strain variation. The results demonstrate RAPD loci can reliably detect population subdivision, which in field populations of pest species is of fundamental importance in understanding the population genetics of insecticide resistance.