Dental care access and use among HIV-infected women.

OBJECTIVES: This study sought to identify predictors of dental care use in HIV-infected women. METHODS: In a cross-sectional survey of HIV-infected women enrolled in the northern California site of the Women's Interagency HIV Study, dental care use and unmet need were assessed in relation to selected variables. RESULTS: Among 213 respondents, who were predominantly Black and younger than 45 years, 43% had not seen a dentist and 53% (among dentate women) reported no dental cleaning in more than a year (although 67% had dental insurance coverage, mainly state Medicaid). Nine percent were edentulous. Among nonusers of dental care, 78% reported that they wanted care but failed to get it. Barriers included fear of and discomfort with dentists, not getting around to making an appointment, and not knowing which dentist to visit. Multivariate analysis showed that lack of past-year dental care was associated mainly with unemployment, a perception of poor oral health, and edentulism. CONCLUSIONS: HIV-positive women appear to be underusing dental care services. Fear and lack of information regarding available resources, in addition to unemployment and perception of poor oral health, may be important barriers.     

Self-administration of cocaine analogs by rats

  Rationale: A novel scheme for the synthesis of cocaine analogs from vinylcarbenoid precursors has made available compounds that have a diverse range of affinities for the DA and 5-HT transporters. These compounds were used to explore the relationship between their biochemical properties and their reinforcing effects. Objectives: The objective was to assess the reinforcing efficacy of selected cocaine analogs and compare the results with their selectivity in binding to DA and 5-HT transporters. Methods: Rats were prepared with chronically indwelling intravenous cannulae and trained to self-administer cocaine on a progressive ratio (PR) schedule. A range of doses of seven cocaine analogs were substituted for cocaine in separate groups of animals. Results: The results demonstrate a wide range of reinforcing efficacies and potencies among the seven selected drugs. Four tropane analogs (WF-11, WF-23, WF-24, WF-55) were found to support self-administration behavior on a PR schedule while three did not (WF-31, WF-54 and WF-60). The DA/5-HT selectivity ratio was found to be a better predictor of self-administration behavior than affinity at the DA transporter alone. Conclusion: These data suggest that drugs with a higher affinity for the DA versus the 5-HT transporter are more likely to be self-administered. Received: 29 October 1998 / Final version: 5 February 1999     

Antibody-based profiling of the phosphoinositide 3-kinase pathway in clinical prostate cancer.

PURPOSE: As kinase inhibitors transition from the laboratory to patients, it is imperative to develop biomarkers that can be used in the clinic. The primary objectives are to identify patients most likely to benefit from molecularly targeted therapies and to document modulation of the drug target. Constitutive activation of the phosphoinositide 3-kinase (PI3K) pathway and its downstream effectors, as a result of PTEN loss or by other mechanisms, occurs in a high proportion of prostate cancers, making it an ideal template for the design of clinical trials involving PI3K pathway inhibitors. Prostate cancers also present unique organ-specific challenges, in that tumors are heterogeneous and diagnostic tissue is extremely limited. EXPERIMENTAL DESIGN: Working within these limitations, we have developed a set of immunohistochemical assays that define activation of the PI3K pathway in clinical samples. Results and CONCLUSIONS: Using both univariate and multivariate analyses, we show that loss of PTEN is highly correlated with the activation of AKT, and this, in turn, is associated with the phosphorylation of S6, one of its main effectors. These three antibodies are potentially able to define a molecular signature of PTEN loss and/or AKT pathway activation in prostate cancer.     

Vaccination with irradiated autologous tumor cells engineered to secrete granulocyte-macrophage colony-stimulating factor augments antitumor immunity in some patients with metastatic non-small-cell lung carcinoma.

PURPOSE: We demonstrated that vaccination with irradiated tumor cells engineered to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates potent, specific, and long-lasting antitumor immunity in multiple murine models and patients with metastatic melanoma. To test whether this vaccination strategy enhances antitumor immunity in patients with metastatic non-small-cell lung cancer (NSCLC), we conducted a phase I clinical trial. PATIENTS AND METHODS: Resected metastases were processed to single-cell suspension, infected with a replication-defective adenoviral vector encoding GM-CSF, irradiated, and cryopreserved. Individual vaccines consisted of 1 x 10(6), 4 x 10(6), or 1 x 10(7) cells, depending on overall yield, and were administered intradermally and subcutaneously at weekly and biweekly intervals. RESULTS: Vaccines were successfully manufactured for 34 (97%) of 35 patients. The average GM-CSF secretion was 513 ng/10(6) cells/24 h. Toxicities were restricted to grade 1 to 2 local skin reactions. Nine patients were withdrawn early because of rapid disease progression. Vaccination elicited dendritic cell, macrophage, granulocyte, and lymphocyte infiltrates in 18 of 25 assessable patients. Immunization stimulated the development of delayed-type hypersensitivity reactions to irradiated, dissociated, autologous, nontransfected tumor cells in 18 of 22 patients. Metastatic lesions resected after vaccination showed T lymphocyte and plasma cell infiltrates with tumor necrosis in three of six patients. Two patients surgically rendered as having no evidence of disease at enrollment remain free of disease at 43 and 42 months. Five patients showed stable disease durations of 33, 19, 12, 10, and 3 months. One mixed response was observed. CONCLUSION: Vaccination with irradiated autologous NSCLC cells engineered to secrete GM-CSF enhances antitumor immunity in some patients with metastatic NSCLC.     

ZD1839, a specific epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, induces the formation of inactive EGFR/HER2 and EGFR/HER3 heterodimers and prevents heregulin signaling in HER2-overexpressing breast cancer cells.

PURPOSE: ZD1839 is a tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR) that has shown clinical activity against EGFR-expressing tumors. Our aim was to explore the effects of ZD1839 in breast cancer cell lines expressing different levels of EGFR and the closely related HER2 receptor. EXPERIMENTAL DESIGN: We studied the growth-inhibitory effects of ZD1839 in a series of breast carcinoma cell lines. In HER2-overexpressing BT-474 breast cancer cells, we studied the effects of ZD1839 on cell growth and heterodimerization of receptors under basal and ligand-stimulated conditions. RESULTS: ZD1839 was an equally potent inhibitor of growth in breast cancer cells expressing high levels of EGFR and HER2. In BT-474 breast cancer cells, ZD1839 abolished EGF- and heregulin-induced activation of ErbB receptors and downstream signaling molecules. Because ZD1839 does not inhibit the HER2 tyrosine kinase in vitro, and because heregulin is a ligand that activates HER2 by binding to HER3 and HER4 but does not bind to the EGFR, our findings suggested that ZD1839 interfered with HER2 function in intact cells. Searching for mechanisms, we report that ZD1839 induces the formation of inactive unphosphorylated EGFR/HER2 and EGFR/HER3 heterodimers. Furthermore, ZD1839 completely abolishes basal and heregulin-induced formation of active phosphorylated HER2/HER3 heterodimers. CONCLUSIONS: ZD1839 inhibits the growth of HER2-overexpressing breast cancer cells, possibly by sequestration of HER2 and HER3 receptors in an inactive heterodimer configuration with the EGFR. Our findings suggest that there is a strong rationale to conduct clinical trials of ZD1839 in patients with HER2-overexpressing breast tumors.     

Training Staff in an Adolescent Inpatient Psychiatric Unit in Positive Approaches to Managing Aggressive and Harmful Behaviour: Does it Improve Confidence and Knowledge?

This study examined the implementation of a model of managing aggressive and harmful behaviour in an adolescent in-patient psychiatric unit. This model, Positive Behaviour Management, replaced a previous model, Control and Restraint, which was considered unsuitable. Both models included the use of physical interventions, and the research into such techniques is considered. The aims of the study were to evaluate the effects of three training courses on staff confidence in managing aggressive behaviour, knowledge about good practice and staff satisfaction with the new model. A multiple baseline design was used to examine change before, during and after the training period, and at one-year follow-up. The study found that staff confidence increased significantly following training but had returned to baseline levels by the time of follow-up. Staff knowledge significantly increased during the study periods but did not appear to be directly linked to the training courses, and was maintained at one-year follow-up. Staff reported significantly higher levels of satisfaction with the new model than with the previous model, which were maintained at follow-up. The findings of the study and the difficulties encountered are discussed in relation to similar findings elsewhere.     

Social work, general practice and evidence-based policy in the collaborative care of older people: current problems and future possibilities

While collaborative (or joint) working between social services and primary healthcare continues to rise up the policy agenda, current policy is not based on sound evidence of benefit to either patients or the wider community. Both sets of practitioners report benefits for their own work from adopting new arrangements for collaboration. The underlying assumption behind much of this activity is that a greater degree of integration provides benefits to both users and their carers, a perspective that at times obscures the issue of resource availability, especially in the form of practical community services such as district nursing and home help. At the present time there is insufficient evidence to demonstrate that formal arrangements for collaborative working (CW) are better than those forged informally between committed individuals or teams. Furthermore, arrangements for CW have not hitherto been widely evaluated in systematic studies with a comparative design and focus on outcomes for users and carers rather than on processes. In this paper we propose a number of process measures for future evaluation of CW: (1) study populations must be comparable; (2) details of how services are actually delivered must be obtained and colocation should not be assumed to mean collaboration; (3) care packages in areas of comparable resources should be examined; (4) both destinational outcomes and user‐defined evaluations of benefit should be considered; (5) possible disadvantages of integrated care also need to be actively considered; (6) evaluations should include an economic analysis. Those implementing new policies in Primary Care Trusts have, at present, little sound evidence to guide them in their innovative work. However, they should take the opportunity to rigorously test the advantages and disadvantages of collaboration.