p53 mutations in leukemia and myelodysplastic syndrome after ovarian cancer.

PURPOSE: Although p53 mutations occur in alkylating agent-related leukemias, their frequency and spectrum in leukemias after ovarian cancer have not been addressed. The purpose of this study was to examine p53 mutations in leukemias after ovarian cancer, for which treatment with platinum analogues was widely used. EXPERIMENTAL DESIGN: Adequate leukemic or dysplastic cells were available in 17 of 82 cases of leukemia or myelodysplastic syndrome that occurred in a multicenter, population-based cohort of 23,170 women with ovarian cancer. Eleven of the 17 received platinum compounds and other alkylating agents with or without DNA topoisomerase II inhibitors and/or radiation. Six received other alkylating agents, in one case, with radiation. Genomic DNA was extracted and p53 exons 5, 6, 7, and 8 were amplified by PCR. Mutations and loss of heterozygosity were analyzed on the WAVE instrument (Transgenomic) followed by selected analysis by sequencing. RESULTS: Eleven p53 mutations involving all four exons studied and one polymorphism were identified. Genomic DNA analyses were consistent with loss of heterozygosity for four of the mutations. The 11 mutations occurred in 9 cases, such that 6 of 11 leukemias after platinum-based regimens (55%) and 3 of 6 leukemias after other treatments (50%) contained p53 mutations. Two leukemias that occurred after treatment with platinum analogues contained two mutations. Among eight mutations in leukemias after treatment with platinum analogues, there were four G-to-A transitions and one G-to-C transversion. CONCLUSIONS: p53 mutations are common in leukemia and myelodysplastic syndrome after multiagent therapy for ovarian cancer. The propensity for G-to-A transitions may reflect specific DNA damage in leukemias after treatment with platinum analogues.     

GAIP, GIPC and Galphai3 are concentrated in endocytic compartments of proximal tubule cells: putative role in regulating megalin's function

Megalin is the most abundant endocytic receptor in the proximal tubule epithelium (PTE), where it is concentrated in clathrin-coated pits (CCPs) and vesicles in the brush border region. The heterotrimeric G protein alpha subunit, Galphai3, has also been localized to the brush border region of PTE. By immunofluorescence GIPC and GAIP, components of G protein-mediated signaling pathways, are also concentrated in the brush border region of PTE and are present in megalin-expressing cell lines. By cell fractionation, these signaling molecules cosediment with megalin in brush border and microvillar fractions. GAIP is found by immunoelectron microscopy in CCPs, and GIPC is found in CCPs and apical tubules of endocytic compartments in the renal brush border. In precipitation assays, GST-GIPC specifically binds megalin. The concentration of Galphai3, GIPC, and GAIP with megalin in endocytic compartments of the proximal tubule, where extensive endocytosis occurs, and the interaction between GIPC and the cytoplasmic tail of megalin suggest a model whereby G protein-mediated signaling may regulate megalin's endocytic function and/or trafficking.     

Twelve tips for undertaking a systematic review

The need to underpin health and education with a firm evidence base is of increasing significance. Systematic review offers an effective approach to critically assessing research in order to understand its overall impact on practice. Based on 5 years' experience undertaking systematic reviews of interprofessional education, this paper offers guidance for researchers and practitioners about to embark upon systematic review work.     

Deconstructing relative reinforcing efficacy and situating the measures of pharmacological reinforcement with behavioral economics: a theoretical proposal

BACKGROUND: Relative reinforcing efficacy has been assumed to be a homogeneous phenomenon referring to the behavior-strengthening or behavior-maintaining effects of a drug reinforcer. However, a variety of studies suggest that relative reinforcing efficacy may be heterogeneous. OBJECTIVES: The purpose of this theoretical proposal is to examine the difficulties associated with this conception of reinforcing efficacy and to explore whether relative reinforcing efficacy is a homogenous concept or whether it is composed of several functionally related heterogeneous phenomena. In examining this issue, we explore whether behavioral economic theory may address some of the challenges to the current conception of relative reinforcing efficacy and use this theory to suggest how the differing measures of reinforcing efficacy may relate to one another. RESULTS: Results indicate that peak-response rate and breakpoint are related to the economic measure of maximal output and elasticity of demand, respectively. Preference is related to and predicted by the relative location of the demand curves obtained under single schedule conditions. This behavioral economic analysis may provide a theoretical understanding of reinforcement that can reconcile results of studies that both support and fail to support the notion of reinforcing efficacy as a homogenous phenomenon. CONCLUSIONS: If this theoretical proposal is validated by additional studies, then like other natural phenomena found to be heterogeneous, the study of drug reinforcers may require the adoption of several new scientific terms, such as those used in behavioral economics, each of which has analytical precision and refers to homogeneous phenomena.     

Cisplatin disposition in children and adolescents with cancer

Summary The disposition of cisplatin was evaluated in 28 children and adolescents with cancer, as part of a phase II clinical trial. Patients received either 30 mg/m² (11) or 90 mg/m² (17) of cisplatin as a 6-h IV infusion. Serum samples and divided urine collections were obtained over 48 h following completion of the cisplatin infusion, and were assayed in duplicate for total platinum by atomic absorption spectrophotometry. Serum samples obtained up to 4 h after three cisplatin infusions were assayed for parent (free) cisplatin following ultrafiltration. The mean (±SE) elimination half-life of free cisplatin in serum was 1.3 (±0.4) h. Serial serum concentrations of total platinum following 90 mg/m² dosages were adequately described by a biexponential equation. The mean (±SE) serum T_1/2 of total platinum was 0.42 (±0.10) h and the mean (±SE) T_1/2 was 44.43 (±8.24) h. The intercompartment distribution rate constants of a two-compartment kinetic model indicate extensive tissue accumulation of total platinum, with a rate of transport into tissue compartments (K₁₂) that is about six times the rate of transport out of tissues (K₂₁). The mean (±SE) renal clearance of total platinum from 0–3 h was 37.36 (±11.96) ml/min/m² and 35.8 (±13.6) ml/min/m² for the 30 mg/m² and 90 mg/m² groups, respectively. This value decreased to 3.25 (±0.94) and 2.16 (±0.4) ml/min/m² for the two groups by the 6–12 h interval, and remained between 1 and 3 ml/min/m² for the duration of the observation period. The ratio of total plantinum clearance to creatinine clearance decreased significantly(P<0.05) beginning 3 h post-infusion. The change in renal clearance of total platinum is apparently a function of two independent first-order processes for renal clearance of parent drug and cisplatin metabolites.     

Injection drug use, multiple hepatitis virus infections, and migration: a German study

This article examines infection with viral hepatitis A, B, and C and socioethnic factors in a population of injection drug users seeking treatment. The study was conducted between 2001 and 2003 in a rural German hospital; selected sociodemographic and drug-related data as well as a serology for hepatitis A, B, and C were obtained from 1499 patients. Statistical analyses were performed by univariate analysis of variance and post hoc Scheffé tests or with the chi(2) test and Bonferroni adjustment. Ethnic minority patients manifested a more severe course of addiction and showed a higher frequency of infection with hepatitis A, B, and C. Low-threshold culture-sensitive drug user treatment programs should be implemented and evaluated. The study's limitations are noted.     

Moving from a culture of blame to a culture of safety in the nursing home setting

TOPIC: A culture of safety. PURPOSE: To explore the current culture of blame and what organizational elements must be impacted to move toward a culture of safety in the nursing home setting. METHODS: A mixed-method approach incorporating a case study and staff member survey results were used to explicate the organizational elements impacting the current nursing home culture. CONCLUSION: Nurse leaders can create an environment in which every member of the team feels a responsibility and an ability to insure that residents are safe by improving communication and participation in decision making.     

Integrated health practices: development of a graduate nursing program

This article describes pedagogical issues in the development of a graduate nursing program in Integrated Health Practices (IHP), reports early experiences in the program, and asserts the importance of a graduate program in the specialty. The experience is described, and unique pedagogical issues encountered are discussed. While noting the contributions made to health and health care by Western medicine and nursing practice, the authors elaborate on the benefits of integrating western health care with less technological, less invasive, and less expensive holistic approaches. Diverse populations often require attention to specific chronic conditions, rather than to acute conditions, and constitutional requirements for overall health may be influenced by diverse health philosophies and practices. These requirements may be grounded in cultural and religious beliefs that must be incorporated into culturally sensitive plans of care. Clinical nurse specialists in IHP can offer knowledge and leadership to nursing practice, which address these complex, yet subtle health care issues.