TNF-alpha and IFN-gamma render microglia sensitive to Fas ligand-induced apoptosis by induction of Fas expression and down-regulation of Bcl-2 and Bcl-xL

The immune response in the central nervous system (CNS) involves microglial cells which represent intraparenchymal antigen-presenting cells (APC). To control immune effector mechanisms it may be required to induce apoptosis of APC and thereby limit reactivation of T cells that have invaded the CNS. In the present study we investigated the susceptibility of primary murine microglia and of the murine microglial cell line BV-2 to undergo Fas-mediated apoptosis. Whereas resting microglia are resistant to Fas ligand (FasL) treatment, induction of FasL-mediated apoptosis was achieved by treatment with TNF-alpha or IFN-gamma. The effect of these cytokines was paralleled by up-regulation of Fas expression and down-regulation of Bcl-2 and Bcl-xL but not Bax. Activation of microglia by TNF-alpha and IFN-gamma was also accompanied by increased amounts of mRNA for the apoptosis inhibitor FLIP, an effect which did not protect the cells from FasL-induced apoptosis. The FasL-induced cell death pathway in microglia involves reactive oxygen intermediates because the antioxidants N-acetylcysteine and glutathione interfere with induction of apoptosis. Surprisingly, microglia constitutively express FasL on the cell surface. However, blocking of endogenous Fas-FasL interaction with Fas-Fc fusion protein did not enhance the survival of microglia, excluding the possibility of suicide or fratricide mechanisms. By their expression of FasL and their TNF-alpha/IFN-gamma-dependent sensitivity to the pro-apoptotic effect of exogenous FasL, microglial cells may influence the course of T cell-mediated diseases of the CNS.     

Apoptosis induced by sulindac sulfide in epithelial and mesenchymal cells from human abdominal neoplasms

A tadpole of bullfrog, Rana catesbeiana, is originally covered with the larval skin over its entire body. Drastic changes arise in both the epidermis and the subcutaneous connective tissue at an early developmental stage, producing the precursor of adult type skin (pre-adult skin). It was found that calcium is a useful probe to detect the region where the precursor formation has occurred because its deposition in the upper part of subcutaneous collagen bundles coincides with the appearance of the pre-adult skin. Whole-mount in situ staining of tadpoles with alizarin red S revealed the initiation site of the premetamorphic transformation of the larval skin into the adult precursor and its ensuing region-dependent expansion. The pre-adult skin first emerged at TK II to III (TK, Taylor and Kollros staging) t lateral sides of the body, which led us to postulate that 'the center for premetamorphic skin transformation' is formed at the specific site in this region. This center moved dorsally and then ventrally, then reached to the most proximal region of the tail, yielding a unique sequential conversion pattern by around TK V when the conversion was completed in the trunk. The present study also visualized the process of the hindlimb skin transformation.     

Glyphosate is an inhibitor of plant cytochrome P450: functional expression of Thlaspi arvensae cytochrome P45071B1/reductase fusion protein in Escherichia coli

Radiofrequency (RF) energy has many advantages in thermal tumor ablation protocols. With the recent development of open MRI systems, interventional MRI procedures, including thermal ablation, have become the focus of great research interest. However, the significant interference between RF generators and MR imagers has prevented simultaneous imaging and RF ablation and, until now, has limited the role of RF-based thermal therapy in interventional MRI. Here, a simple switching circuit designed with consideration of patient safety provides compatibility between open MRI systems and RF thermal lesion generators. The experimental results show that the switching circuit allows imaging during RF ablation and opens new opportunity for MR-guided thermal therapy.     

GB virus C/hepatitis G virus infection among patients with hepatocellular carcinoma in the inshore area of the Yangtze River, China

The latest meeting of the AAMC's Forum on the Future of Academic Medicine, on April 29, 1998, opened with a talk by Francis S. Collins, MD, PhD, director of the National Human Genome Research Institute, who reviewed the significant progress that the Human Genome Project (HGP) has made and speculated on how genetic discoveries and technologies would transform health-related research and ultimately the practice of medicine. The HGP's findings will offer clear improvements in diagnosis and prevention, and eventually in treatments, and the relationship between the academic medical center and the pharmaceutical industry will change--but remain good--as that industry applies the findings of the HGP. He stressed the need for the public and health care providers to develop a greater understanding of genetic issues, and urged changes in medical education to accomplish this. Forum members and Dr. Collins discussed the ethics and economics in patient care resulting from genetic research; forum members also asked whether academic medical centers could profit from genetic research findings. The second speaker was John Eisenberg, MD, administrator of the Agency for Health Care Policy and Research, which fosters health care research and disseminates to clinicians and others the findings of such research. Among other topics, Dr. Eisenberg described the new emphasis on health care outcomes and quality and described how his agency promotes research in these areas. Forum members asked who would pay for the information systems needed to communicate the findings of health services research and also noted that there is an expanding definition of health that places new pressures on already stressed academic medical centers, their missions, and their curricula, which must change. Michael Whitcomb, MD, of the AAMC, noted that the view that medical schools can't change their curricula has been proved wrong, and that 24 medical schools are working with the AAMC's Medical Schools Objectives Project on curricular reform. The forum closed with discussion of a few broader issues affecting academic medical centers.     

Role of glutathione modulation in acrylonitrile-induced gastric DNA damage in rats

Acrylonitrile (VCN) or its reactive metabolites irreversibly interact with gastric DNA in vivo and cause DNA damage. The effect of glutathione (GSH) modulation on VCN-induced genotoxicity and unscheduled DNA repair synthesis (UDRS) in DNA of gastric mucosal tissues was investigated. VCN-induced UDRS was determined: in control rats, rats with depleted gastric GSH contents, and rats treated with sulfhydryl compounds. A single oral dose (23 mg/kg) of VCN induced a time- and dose-dependent increase in gastric UDRS and decrease in GSH levels. While maximal UDRS in gastric mucosa was observed 2 h following oral administration of 23 mg/kg VCN, maximal GSH depletion (50% of control) was detected 4 h following treatment. Increasing the VCN dose to 46 mg/kg caused a further decrease in gastric GSH level (27% of control), while UDRS was elevated. Inhibition of VCN oxidation by treatment of the animals with the cytochrome P450 inhibitor, SKF 525-A, prior to VCN administration caused 65% reduction in VCN-induced UDRS. Treatment of rats with the GSH depletor diethylmaleate (DEM) prior to VCN administration caused 167% increase in UDRS in gastric mucosal tissues. Treatment of the animals with the sulfhydryl compounds, cysteine and penicillamine, prior to VCN administration protected against VCN-induced UDRS. The results demonstrated an inverse and highly significant correlation between gastric GSH levels and VCN-induced UDRS (r = -0.873, P < 0.0001). In conclusion, our study indicates that VCN bioactivation and the homeostasis of gastric GSH may play a major, role in the initial processes underlying VCN-induced gastric carcinogenesis.     

Prospective study of exogenous hormones and risk of pulmonary embolism in women

BACKGROUND: Current use of oral contraceptives (OCs) is a well-recognised risk factor for venous thrombosis and consequent pulmonary embolism (PE). Little is known about residual effects of past OC use. Furthermore, few epidemiological studies have assessed the relation between postmenopausal use of hormones and thrombotic disease. METHODS: In this prospective study information was obtained through questionnaires sent every 2 years (1976-92) to 1125,93 women aged 30-55 in 1976. We excluded women with previously diagnosed cardiovascular disease or cancer in 1976 and at the beginning of each subsequent 2-year follow-up period. FINDINGS: From self-reports and medical records, we documented 123 cases of primary PE (no identified antecedent cancer, trauma, surgery, or immobilisation). Current users of postmenopausal hormones had an increased risk of primary PE (relative risk adjusted for multiple risk factors 2.1 [95% CI 1.2-3.8]). However, past use showed no relation to PE (1.3 [0.7-2.4]). In current users of OCs the risk of primary PE was about twice that in non-users (2.2 [0.8-5.9]), but this finding was based on only five cases who were current OC users. Users of OCs in the past had no increase in risk of PE (0.8 [0.5-1.2]). These relations were consistent irrespective of cigarette-smoking status. INTERPRETATION: Primary PE was uncommon in this cohort. The risk was increased by current though not past use of postmenopausal hormones or OCs.