Blockade of accumbens 5-HT3 receptor down-regulation by ondansetron administered during continuous cocaine administration

The present experiment examined whether ondansetron, co-administered with continuous cocaine, would block the down regulation of accumbens 5-HT3 receptors. Rats were exposed to a 14-day pretreatment regimen that involved the continuous infusion of 40 mg kg(-1) day(-1) cocaine or 0.9% saline via a subcutaneously implanted osmotic minipump. In addition to the continuous cocaine or saline administration, all subjects received daily subcutaneous (s.c.) injections of either vehicle or 0.1 mg kg(-1) ondansetron for the entire 14-day pretreatment regimen. The rats were then withdrawn from this pretreatment regimen for seven days, and slices from the nucleus accumbens obtained. The slices were perfused with 25 mM K+ in the absence and presence of 0, 12.5, 25, or 50 microM m-Chlorophenyl-biguanide HCl (mCPBG). The efflux samples were assayed for dopamine content by high pressure liquid chromatography (HPLC) with electrochemical detection. Continuous cocaine administration significantly attenuated the ability of mCPBG to facilitate K+-induce dopamine overflow compared to saline control rats. In addition, the rats that received ondansetron and cocaine during the 14-day pretreatment period, the ability of mCPBG to enhance K+ stimulated dopamine release was not significantly different from the saline control subjects. For all groups except the cocaine alone group, the effects of mCPBG on K+ stimulated dopamine release were Ca2+ dependent, suggesting that these effects are receptor mediated. These results suggest that continuous cocaine administration functionally down-regulates 5-HT3 receptors in the nucleus accumbens, and that this down-regulation can be blocked by chronic ondansetron administration. Hence, a functional down regulation of accumbens 5-HT3 receptors represents a significant contribution to the tolerance induced by continuous cocaine administration.     

The stability of preferences for life-sustaining care among persons with AIDS in the Boston Health Study

In 1982, the World Health Organization (WHO) identified inadequate relief from cancer pain as an international health problem. WHO recommended that governments develop and implement national policies and programs for cancer pain relief. This report evaluates national health policy and the systems of health care delivery in relation to cancer pain management in the new South Africa. This field study included multiple methods of data collection: analysis of documents, field trips with participant observation in sites of care delivery, focused interviews, and in-depth interviews of key informants. The purposive sample of key informants (n = 33) represented multiple stakeholders in a variety of settings. Strengths of the developing health policy include specific recommendations related to palliative care; the shift to universal primary care; policies to support drug availability; the inclusion of morphine and codeine as essential drug at the primary health care level; and the development of a national standard related to cancer pain management. Health services are characterized by two parallel systems of care (private and public) with numerous vestiges of the inequities of apartheid. The management of pain varies by provider and setting; major problems with access exist in the rural areas. Health services in South Africa have been plagued by inequity and inadequate resources. New health policies have set a path to ensure universal access to health care including palliative care for cancer. Their successful implementation is the next necessary step toward improving health services and alleviating the suffering of increasing numbers of individuals with cancer.     

BMP signaling plays a role in visceral endoderm differentiation and cavitation in the early mouse embryo

At E4.0 the inner cell mass of the mouse blastocyst consists of a core of embryonic ectoderm cells surrounded by an outer layer of primitive (extraembryonic) endoderm, which subsequently gives rise to both visceral endoderm and parietal endoderm. Shortly after blastocyst implantation, the solid mass of ectoderm cells is converted by a process known as cavitation into a pseudostratified columnar epithelium surrounding a central cavity. We have previously used two cell lines, which form embryoid bodies that do (PSA1) or do not (S2) cavitate, as an in vitro model system for studying the mechanism of cavitation in the early embryo. We provided evidence that cavitation is the result of both programmed cell death and selective cell survival, and that the process depends on signals from visceral endoderm (Coucouvanis, E. and Martin, G. R. (1995) Cell 83, 279-287). Here we show that Bmp2 and Bmp4 are expressed in PSA1 embryoid bodies and embryos at the stages when visceral endoderm differentiation and cavitation are occurring, and that blocking BMP signaling via expression of a transgene encoding a dominant negative mutant form of BMP receptor IB inhibits expression of the visceral endoderm marker, Hnf4, and prevents cavitation in PSA1 embryoid bodies. Furthermore, we show that addition of BMP protein to cultures of S2 embryoid bodies induces expression of Hnf4 and other visceral endoderm markers and also cavitation. Taken together, these data indicate that BMP signaling is both capable of promoting, and required for differentiation of, visceral endoderm and cavitation of embryoid bodies. Based on these and other data, we propose a model for the role of BMP signaling during peri-implantation stages of mouse embryo development.     

Sensitivity of the Human Eye to Power Frequency Electric Fields

Reports spanning more than a century have shown that tissues associated with the eye are able to respond to local electric fields with impressions of light called electrophosphenes. A finite element analysis of the field distributions in the head near the receptors shows that the 60 Hz threshold for perception of electrophosphenes is approximately 1 V/m. Thus, tissues associated with the eye appear to be among the most sensitive to power frequency electric fields in the human body.