Small effects of valproic acid on the plasma concentrations of clozapine and its major metabolites in patients with schizophrenic or affective disorders.

Two separate studies were carried out to assess the effect of valproic acid on the steady-state plasma concentrations of clozapine and its major metabolites norclozapine and clozapine N-oxide in psychotic patients. In the first study, concentrations of clozapine and metabolites were compared between patients treated with clozapine in combination with sodium valproate (n = 15) and control patients treated with clozapine alone (n = 22) and matched for sex, age, body weight, and antipsychotic dosage. Patients comedicated with valproate tended to have higher clozapine levels and lower norclozapine levels, but the differences did not reach statistical significance. In a subsequent study, plasma concentrations of clozapine and its metabolites were determined in 6 patients with schizophrenia stabilized on clozapine therapy (200-400 mg/d) before and after treatment with sodium valproate (900-1200 mg/d) for 4 weeks. Mean plasma concentrations of clozapine and its metabolites did not change significantly throughout the study, but there was a trend for clozapine levels to be higher and for norclozapine levels to be lower after valproate. Overall, these findings suggest that valproic acid may have an inhibiting effect on the CYP1A2- or CYP3A4-mediated conversion of clozapine to norclozapine. However, the interaction is unlikely to be clinically significant.     

The convergence of carbohydrate active gene repertoires in human gut microbes

The extreme variation in gene content among phylogenetically related microorganisms suggests that gene acquisition, expansion, and loss are important evolutionary forces for adaptation to new environments. Accordingly, phylogenetically disparate organisms that share a habitat may converge in gene content as they adapt to confront shared challenges. This response should be especially pronounced for functional genes that are important for survival in a particular habitat. We illustrate this principle by showing that the repertoires of two different types of carbohydrate-active enzymes, glycoside hydrolases and glycosyltransferases, have converged in bacteria and archaea that live in the human gut and that this convergence is largely due to horizontal gene transfer rather than gene family expansion. We also identify gut microbes that may have more similar dietary niches in the human gut than would be expected based on phylogeny. The techniques used to obtain these results should be broadly applicable to understanding the functional genes and evolutionary processes important for adaptation in many environments and useful for interpreting the large number of reference microbial genome sequences being generated for the International Human Microbiome Project.     

Cannibalism of live lymphocytes by human metastatic but not primary melanoma cells

The phenomenon of cell cannibalism, which generally refers to the engulfment of cells within other cells, was described in malignant tumors, but its biological significance is still largely unknown. In the present study, we investigated the occurrence, the in vivo relevance, and the underlying mechanisms of cannibalism in human melanoma. As first evidence, we observed that tumor cannibalism was clearly detectable in vivo in metastatic lesions of melanoma and often involved T cells, which could be found in a degraded state within tumor cells. Then, in vitro experiments confirmed that cannibalism of T cells was a property of metastatic melanoma cells but not of primary melanoma cells. In particular, morphologic analyses, including time-lapse cinematography and electron microscopy, revealed a sequence of events, in which metastatic melanoma cells were able to engulf and digest live autologous melanoma-specific CD8(+) T cells. Importantly, this cannibalistic activity significantly increased metastatic melanoma cell survival, particularly under starvation condition, supporting the evidence that tumor cells may use the eating of live lymphocytes as a way to "feed" in condition of low nutrient supply. The mechanism underlying cannibalism involved a complex framework, including lysosomal protease cathepsin B activity, caveolae formation, and ezrin cytoskeleton integrity and function. In conclusion, our study shows that human metastatic melanoma cells may eat live T cells, which are instead programmed to kill them, suggesting a novel mechanism of tumor immune escape. Moreover, our data suggest that cannibalism may represent a sort of "feeding" activity aimed at sustaining survival and progression of malignant tumor cells in an unfavorable microenvironment.     

The structure of the trabeculae of cancellous bone. 1. The calcaneus

87 either cylindroid or laminar trabeculae, isolated from the perpendicular or inferior bundles of the human calcaneus, were embedded in methylmatecrylate and serially cut along longitudinal and transversal planes with a rotatory-blade saw. The microscopical study of the sections showed that in 83% of the samples secondary osteons run along the longitudinal axis of the trabeculae and their lumina either form a continuous channel network throughout each trabecula (37% of cases) or are restricted to discrete segments (46% of cases). The trabeculae entirely devoid of osteons (17%) are the thinnest, never exceeding 400 microns in thickness. This value is not even exceeded by the segments devoid of osteons in the trabeculae in which the Haversian canals occur only intermittently; conversely, the segments containing Haversian canals can reach and exceed 600 microns in thickness. The maximum distance of the osteocytic lacunae from filtering surfaces--i.e. outer surface of the trabeculae or inner surface of the Haversian canals--was found to be almost the same in the segments of the trabeculae that enclose or not osteons, even though the average trabecular thickness is greater in the former than in the latter regions. On the basis of these findings the formation of endotrabecular osteons may be viewed as a device that indirectly favours the metabolic exchange of deep-seated osteocytes while increasing the free surface area available for bone tissue reconstruction. It remains doubtful whether the Haversian systems may also contribute to improve the mechanical properties of the trabeculae. The arrangement of the collagen fibrils, which differs between cylindroid and laminar trabeculae, is apparently well suited to ensure the resistance of the trabeculae to mechanical loading through the use of the least amount of building material, in accordance with Wolff's law.     

Effect of hormone replacement therapy on lacrimal fluid peroxidase activity in woman

OBJECTIVE: Lacrimal fluid peroxidase (POD) is an antioxidant and antimicrobial enzyme involved in the protection of the ocular surface. Our recent findings showed the existence of significant cyclic variations in POD activity that were positively correlated with those of 17beta-estradiol plasma levels throughout the menstrual cycle of fertile women. During the menopause, women lacrimal fluid POD activity significantly (P<0.05) decreased according to the natural oestrogen reduction. Since a possible influence of oestrogen on human POD activity was suggested, aim of the present investigation is to evaluate whether hormone replacement therapy (HRT) might influence this enzyme activity. METHODS: Lacrimal fluid POD activities of 10 healthy postmenopausal women (mean age: 52.0) and eight healthy postmenopausal women (mean age: 53.0) treated by oral or transdermal routes containing oestrogen or oestrogen plus progestin were determined. Enzyme activity of each tear sample (5 microl) was spectrophotometrically determined by the 5,5'-dithiobis, 2-nitrobenzoic acid thiocyanate (NBS-SCN) assay; total protein content of tears was determined too. 17beta-Estradiol plasma levels were assayed by ELISA test. RESULTS: HRT significantly (P<0.05) increased tear POD low postmenopausal levels. The significant (P<0.05) rise of 17beta-estradiol plasma levels of treated women was not strictly correlated to the enzyme activity increase in tears. CONCLUSIONS: The suggested estrogen regulation of lacrimal fluid POD activity could be one possible cause for the female gender predilection in some ocular diseases. HRT is able to increase tear POD activity levels of postmenopausal women, probably contributing to the effective relieve of ocular surface complications occurring during menopause.