Modulation of enterotoxin binding and function in vitro and in vivo

The use of the nontoxic B subunits of cholera and Escherichia coli enterotoxins in vitro and in vivo led to a decrease in toxin binding to target cells and a decrease in toxin-induced effects (i.e., morphological effects, adenylate cyclase activation, and fluid secretion). The reduction in toxin binding involves a process of down-regulation of cellular receptors for the toxin and not toxin occupancy of receptors. The extent of inhibition was dependent on the amount of B subunit used and on the duration of time after its use. Thus, in vivo exposure to a single bolus of B subunit was sufficient to block toxin binding and activity for up to 18 h. Because the B subunit binds extensively to the esophagus and the stomach, peroral administration will require a preparation that allows the subunit to reach the small bowel in a protected form. Our data provide a rationale for using B subunit therapy for short-term protection against the effects of enterotoxins, before the development of an immune response.     

Diabetes may increase risk for oral cancer through the insulin receptor substrate-1 and focal adhesion kinase pathway

In light of recent epidemiological studies that associate diabetes mellitus with increased risk for oral cancer, we investigated in diabetic (type I) and normal rats with induced oral squamous cell carcinoma whether the molecular basis for that putative association involves insulin receptor substrate-1 (IRS-1) and focal adhesion kinase (FAK). Fourteen diabetic and 12 normal rats developed cancer after 4-nitroquinoline-N-oxide treatment, while six diabetic and six normal animals were used as controls. Oral sections were studied using monoclonal antibodies against IRS-1 and FAK proteins. Expression of IRS-1 was significantly higher in diabetic than normal rats, but it decreased in diabetic animals with tumor, especially in more advanced stages. FAK expression was significantly higher in rats with cancer in comparison to the ones without it, regardless the diabetes status. These data suggest that the IRS-1/FAK pathway is altered by diabetes resulting in reduced cell adhesion and possibly increasing risk for oral cancer.     

Glycogen synthase kinase-3 (GSK-3) inhibitory activity and structure-activity relationship (SAR) studies of the manzamine alkaloids. Potential for Alzheimer's disease

Manzamine A and related derivatives isolated from a common Indonesian sponge, Acanthostrongylophora, have been identified as a new class of GSK-3beta inhibitors. The semisynthesis of new analogues and the first structure-activity relationship studies with GSK-3beta are also reported. Moreover, manzamine A proved to be effective in decreasing tau hyperphosphorylation in human neuroblastoma cell lines, a demonstration of its ability to enter cells and interfere with tau pathology. Inhibition studies of manzamine A against a selected panel of five different kinases related to GSK-3beta, specifically CDK-1, PKA, CDK-5, MAPK, and GSK-3alpha, show the specific inhibition of manzamine A on GSK-3beta and CDK-5, the two kinases involved in tau pathological hyperphosphorylation. These results suggest that manzamine A constitutes a promising scaffold from which more potent and selective GSK-3 inhibitors could be designed as potential therapeutic agents for Alzheimer's disease.     

Increased male responsibility and participation: a key to improving the reproductive health

This article examines the role of male responsibility and participation in the enhancement of reproductive health in India. Men are recognized to be responsible for the large proportion of reproductive ill health suffered by their female partners. Lack of knowledge, nonavailability of acceptable contraceptives and lack of services with quality of care deter men from sharing the responsibility in reproductive health matters. Misinformation regarding male sexuality and limited availability of scientific data contributed men's less involvement in reproductive health. Thus, various strategies are implemented to increase men's awareness of reproductive health and the accessibility of products and services. These strategies include: 1) increasing contraceptive options for men; 2) supporting women's contraceptive use; 3) improving sexual behavior and safe sex practices; and 4) narrowing the gender gap for better fertility control. Moreover, extensive research is required in order to understand men's perceptions and needs about fertility regulation and sexual behavior as well as services development.     

Access to Money and Relation to Women’s Use of Family Planning Methods Among Young Married Women in Rural India

Objectives The social positioning (i.e. social status and autonomy) of women in the household facilitates women’s access to and decision-making power related to family planning (FP). Women’s access to spending money, which may be an indicator of greater social positioning in the household, may also be greater among women who engage in income generating activities for their families, regardless of women’s status in the household. However, in both scenarios, access to money may independently afford greater opportunity to obtain family planning services among women. This study seeks to assess whether access to money is associated with FP outcomes independently of women’s social positioning in their households. Methods Using survey data from married couples in rural Maharashtra, India (n = 855), crude and adjusted regression was used to assess women’s access to their own spending money in relation to past 3 month use of condoms and other forms of contraceptives (pills, injectables, intrauterine device). Results Access to money (59 %) was associated with condom and other contraceptive use (AORs ranged 1.5–1.8). These findings remained significant after adjusting for women’s FP decision-making power in the household and mobility to seek FP services. Conclusion While preliminary, findings suggest that access to money may increase women’s ability to obtain FP methods, even in contexts where social norms to support women’s power in FP decision-making may not be readily adopted.     

Cell proliferation and apoptosis culminate in early stages of oral oncogenesis

Markers of cell proliferation (Ki-67 antigen) and apoptosis (Bax, Bcl-2) were studied in an experimental system of induced oral carcinogenesis in Syrian golden hamsters. Thirty-seven animals were divided into one control group and three experimental groups, which were treated with a carcinogen and sacrificed at 10, 14 and 19 weeks after treatment. The histological status of the lesions in the three experimental groups corresponded well with tumour advancement (from oral mucosal dysplasia to moderately differentiated squamous cell carcinoma). Tumour sections were studied using monoclonal antibodies against Bax, Bcl-2 and Ki-67 proteins. Pro-apoptotic Bax expression maintained high levels during all stages of oral carcinogenesis. Anti-apoptotic Bcl-2 expression decreased significantly in dysplastic and early invasion lesions and consequently increased almost to normal tissue level in consequent stages. Finally, Ki-67 expression increased sharply in initial stages of oral carcinogenesis, but significantly decreased in later stages.     

Encephalomyocarditis virus can bind to and transfect non-permissive cells

Summary Mouse embryo fibroblasts and mouse adrenal tumor cells support the replication of encephalomyocarditis (EMC) virus, whereas rat glial and rat hepatoma cells are non-permissive. These differences in susceptibility were not due to the lack of virus attachment to rat cells. The finding that rat cells could be transfected with RNA derived from EMC virus indicates that the block in viral replication in these cells occurs at some point between attachment and uncoating of virus, probably at the level of uncoating.With 2 Figures     

Drug removal during continuous arteriovenous hemofiltration: theory and clinical observations

We have discussed the basic principles of pharmacokinetics and convective solute removal in the context of each other. Clinical observations appear to follow the theoretical expectations. For practical purposes plasma and plasma water are not different. In the calculation of drug sieving, venous samples do not contribute enough to warrant their extra costs. We recommend that drug removal in hemofiltration be expressed by the sieving coefficient, UF/A. Drug sieving data in humans undergoing CAVH are tabulated. Recommendations for supplemental dosing are discussed which are applicable to any clinical setting.     

Inhibition of heat-labile cholera and Escherichia coli enterotoxins by brefeldin A.

Cholera enterotoxin and the related heat-labile enterotoxins of Escherichia coli enter their target cells through noncoated vesicles, but how the toxins are processed intracellularly and how they get to their targeted enzyme, adenylate cyclase, remain to be defined. Brefeldin A, an inhibitor of the trans-Golgi network, is shown herein to transiently block the morphologic and enzymatic effects of the toxin at a step distal to the initial binding process but prior to activation of adenylate cyclase by the toxin. It is likely, therefore, that these toxins are processed by the Golgi apparatus before trafficking to the membrane adenylate cyclase.