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 The rats were then withdrawn from this pretreatment regimen for seven days, and slices from the nucleus accumbens obtained.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.     

RBS analyses of xenon-irradiated Ti and TiN films

TiN films of 30–300 nm thickness, deposited onto stainless steel via magnetron sputtering, and 10 μm thick Ti foils were irradiated with 80–360 keV Xe⁺ ions at influences of φ = 10¹⁵–10¹⁷ ions/cm². The Xe content was depth-profiled by means of 900 keV He⁺⁺ Rutherford backscattering. Irradiations of films with a thickness exceeding the ion range (at 80 and 250 keV) led to saturation effects due to sputtering and outdiffusion from the near-surface region. The sputtering yields deduced at low Xe fluences were compared to calculations for mono-elemental and compound sputtering. Surface blistering was observed after 250 keV saturation implantation into Ti. For TiN layers with a thickness comparable to the ion range, precipitation of the mixing gas at the interface was observed which finally led to the destruction of the layers. The dependence of the Xe fraction accumulated in the interface is discussed in terms of thermal-spike calculations.     

Specific recognition of HLA-E, but not classical, HLA class I molecules by soluble CD94/NKG2A and NK cells

The CD94/NKG2 receptors expressed by subpopulations of NK cells and T cells have been implicated as receptors for a broad range of both classical and nonclassical HLA class I molecules. To examine the ligand specificity of CD94/NKG2 proteins, a soluble heterodimeric form of the receptor was produced and used in direct binding studies with cells expressing defined HLA class I/peptide complexes. We confirm that CD94/NKG2A specifically interacts with HLA-E and demonstrate that this interaction is dependent on the association of HLA-E with peptide. Moreover, no interaction between CD94/NKG2A and classical HLA class I molecules was observed, as assayed by direct binding of the soluble receptor or by functional assays using CD94/NKG2A+ NK cells. The role of the peptide associated with HLA-E in the interaction between HLA-E and CD94/NKG2A was also assessed. All class I leader sequence peptides tested bound to HLA-E and were recognized by CD94/NKG2A. However, amino acid variations in class I leader sequences affected the stability of HLA-E. Additionally, not all HLA-E/peptide complexes examined were recognized by CD94/NKG2A. Thus CD94/NKG2A recognition of HLA-E is controlled by peptide at two levels; first, peptide must stabilize HLA-E and promote cell surface expression, and second, the HLA-E/peptide complex must form the ligand for CD94/NKG2A.     

An in vitro tissue culture bilayer model to examine early events in Mycobacterium tuberculosis infection

A tissue culture bilayer system that mimics some aspects of early alveolar infection by Mycobacterium tuberculosis was developed. This model incorporates human lung epithelial type II pneumocyte (A549) (upper chamber) and endothelial cell (lower chamber) layers separated by a microporous membrane. This construction makes it possible to observe and quantify the passage of bacteria through the two layers, to observe the interaction of the bacteria with the various cell types, and to examine the basic mechanisms of immune cell recruitment to the site of infection. After 10(7) organisms were added to the upper chamber we microscopically observed large numbers of bacteria attached to and within the pneumocytes and we determined by viable-cell counting that a small percentage of the inoculum (0.02 to 0.43%) passed through the bilayer into the lower chamber. When peripheral blood mononuclear cells were added to the lower chamber, microscopic examination indicated a migration of the mononuclear cells through the bilayer to the apical surface, where they were seen associated with the mycobacteria on the pneumocytes. The added complexity of the bilayer system offers an opportunity to define more precisely the roles of the various lung cell types in the pathogenesis of early tuberculosis.     

‘Baltimore does not condone profiteering in squalor’: the Baltimore Plan and the problem of housing-code enforcement in an American city

In 1941, the Baltimore City Council passed a law, the Ordinance on the Hygiene of Housing, declaring that all property in the city should be ‘maintained in good repair by the owner or agent, and fit for human habitation’. The campaign of housing-code enforcement that followed, known as the Baltimore Plan, made the city famous. When historians write about American housing-reform efforts during the mid-20th century, they tend to focus on big-ticket federal policies; by contrast, the Baltimore Plan seems too small to be significant. But it is more than a curiosity. First in Baltimore and then across the country, the neat cause-and-effect it posited between good stewardship and good housing crowded out more challenging ways of thinking about the problem. Eventually, the Baltimore Plan turned into a policy tool that reinforced the interests of the real estate industry at the expense of poor people. In that regard, the Baltimore Plan laid the foundations for federal disinvestment in the provision of decent housing and the midcentury tragedy of urban renewal.     

Representation of change in controlled medical terminologies

Computer-based systems that support health care require large controlled terminologies to manage names and meanings of data elements. These terminologies are not static, because change in health care is inevitable. To share data and applications in health care, we need standards not only for terminologies and concept representation, but also for representing change. To develop a principled approach to managing change, we analyze the requirements of controlled medical terminologies and consider features that frame knowledge-representation systems have to offer. Based on our analysis, we present a concept model, a set of change operations, and a change-documentation model that may be appropriate for controlled terminologies in health care. We are currently implementing our modeling approach within a computational architecture.     

Effects of temperature and volatile anesthetics on GABA(A) receptors

BACKGROUND: Potentiation of the activity of the gamma-aminobutyric acid type A (GABA(A)) receptor channel by volatile anesthetic agents is usually studied in vitro at room temperature. Systematic variation of temperature can be used to assess the relevance of this receptor to general anesthesia and to characterize the modulation of its behavior by volatile agents at normal body temperature. METHODS: Potentiation of the GABA(A) receptor by halothane, sevoflurane, isoflurane, and methoxyflurane was studied at six temperatures in the range 10-37 degrees C using the whole-cell patch-clamp technique and mouse fibroblast cells stably transfected with defined GABA(A) receptor subunits. RESULTS: Control GABA concentration-response plots showed small and physically reasonable changes in the GABA concentration required for a half-maximal effect, the Hill coefficient, and maximal response over the range 10-30 degrees C. Potentiations of GABA (1 microM) responses by aqueous minimum alveolar concentrations of the volatile anesthetic agents decreased with increasing temperature from 10-37 degrees C in an agent-specific manner (methoxyflurane > isoflurane > sevoflurane > halothane) but tended to equalize at normal body temperature (37 degrees C). These findings are in line with published results on the temperature dependence of anesthetic potencies in animals. CONCLUSIONS: These results are consistent with direct binding of volatile anesthetic agents to the GABA(A) receptor channel playing an important role in general anesthesia. The finding that the degree of anesthetic potentiation was agent-specific at low temperatures but not at 37 degrees C emphasizes the importance of doing in vitro experiments at normal body temperature.     

Depression of young and elderly patients

OBJECTIVE: To compare the presentation and outcome of depression between young and elderly patients. DESIGN: The clinical presentation, treatment and outcome of 47 young patients (21 to 64 years) were compared with 58 elderly (65 years and older) patients admitted to a general hospital psychiatric ward for the treatment of depressive disorders (based on ICD-10). SUBJECTS: There was no significant difference between the sexes in each age group. The majority of the elderly were either widowed (36%) or married (53%) while 45% of the young were single and 51% married. Seventy per cent of the elderly had retired while 64% of the young were in full-time employment. Most patients lived with their families (87% young and 96% elderly). All but one elderly suffered at least one physical disorder with two-thirds having two or more physical disorders; this contrasts greatly to young patients who were physically healthier (p < 0.001). RESULTS: In clinical presentation and symptomatology, the young patients had significantly more suicide ideation (p < 0.003) and psychomotor retardation (p < 0.001) but there was no difference in suicidal attempt, delusion, hallucination or agitation. More young patients (36%) had a past psychiatric illness (often depressive disorders) than elderly patients (8%) (p < 0.001), more elderly patients (88%) were treated with antidepressants than the young patients (62%) (p < 0.002). At one year follow-up, more elderly patients (46%) recovered compared with the young patients (23%) (p < 0.05). CONCLUSION: There were some differences in the symptomatology of depression between young and elderly patients, but the prognosis was better for elderly patients.