Previous exposure to VTA amphetamine enhances cocaine self-administration under a progressive ratio schedule in an NMDA, AMPA/kainate, and metabotropic glutamate receptor-dependent manner.

Previous exposure to amphetamine (AMPH) in the ventral tegmental area (VTA) enhances cocaine self-administration in a D(1) dopamine receptor-dependent manner. The present study examined the contribution of VTA NMDA, AMPA/kainate, and metabotropic glutamate (mGlu) receptors to this effect. Rats in different groups received three intra-VTA injections, one every third day, of either saline (0.5 microl/side), AMPH (2.5 microg/0.5 microl/side), AMPH+CPP (NMDA receptor antagonist; 10 microM or 100 microM/0.5 microl/side), AMPH+CNQX (AMPA/kainate receptor antagonist; 0.3 mM or 1 mM/0.5 microl/side), AMPH+MCPG (mGlu receptor antagonist; 0.5 mM or 50 mM/0.5 microl/side), or the glutamate receptor antagonists alone. Starting 7-10 days after the last pre-exposure injection, rats were trained to self-administer cocaine (0.3 mg/kg/infusion) and then tested under a progressive ratio (PR) schedule of reinforcement for 6 consecutive days. As reported previously, VTA AMPH pre-exposed rats worked more and obtained more infusions of cocaine than saline pre-exposed animals. Coadministration of CPP, CNQX, or MCPG with AMPH during pre-exposure dose-dependently blocked this enhancement of cocaine self-administration. Rats pre-exposed to the glutamate receptor antagonists alone did not differ on the test days from the saline pre-exposed controls. These results indicate that, in a manner paralleling the induction of sensitization of the locomotor stimulating effects of AMPH, activation of NMDA, AMPA/kainate, and mGlu receptors during pre-exposure to AMPH in the VTA is necessary for the enhancement of cocaine self-administration to develop.     

Phase II trial of gefitinib in recurrent glioblastoma.

PURPOSE: To evaluate the efficacy and tolerability of gefitinib (ZD1839, Iressa; AstraZeneca, Wilmington, DE), a novel epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma. PATIENTS AND METHODS: This was an open-label, single-center phase II trial. Fifty-seven patients with first recurrence of a glioblastoma who were previously treated with surgical resection, radiation, and usually chemotherapy underwent an open biopsy or resection at evaluation for confirmation of tumor recurrence. Each patient initially received 500 mg of gefitinib orally once daily; dose escalation to 750 mg then 1,000 mg, if a patient received enzyme-inducing antiepileptic drugs or dexamethasone, was allowed within each patient. RESULTS: Although no objective tumor responses were seen among the 53 assessable patients, only 21% of patients (11 of 53 patients) had measurable disease at treatment initiation. Seventeen percent of patients (nine of 53 patients) underwent at least six 4-week cycles, and the 6-month event-free survival (EFS) was 13% (seven of 53 patients). The median EFS time was 8.1 weeks, and the median overall survival (OS) time from treatment initiation was 39.4 weeks. Adverse events were generally mild (grade 1 or 2) and consisted mainly of skin reactions and diarrhea. Drug-related toxicities were more frequent at higher doses. Withdrawal caused by drug-related adverse events occurred in 6% of patients (three of 53 patients). Although the presence of diarrhea positively predicted favorable OS from treatment initiation, epidermal growth factor receptor expression did not correlate with either EFS or OS. CONCLUSION: Gefitinib is well tolerated and has activity in patients with recurrent glioblastoma. Further study of this agent at higher doses is warranted.     

Intensive methotrexate and cytarabine followed by high-dose chemotherapy with autologous stem-cell rescue in patients with newly diagnosed primary CNS lymphoma: an intent-to-treat analysis.

PURPOSE: To assess the safety and efficacy of intensive methotrexate-based chemotherapy followed by high-dose chemotherapy (HDT) with autologous stem-cell rescue in patients with newly diagnosed primary CNS lymphoma (PCNSL). PATIENTS AND METHODS: Twenty-eight patients received induction chemotherapy using high-dose systemic methotrexate (3.5 g/m2) and cytarabine (3 g/m2 daily for 2 days). Fourteen patients with chemosensitive disease evident on neuroimaging then received high-dose therapy using carmustine, etoposide, cytarabine, and melphalan with autologous stem-cell rescue. RESULTS: The objective response rate to the induction-phase chemotherapy was 57%, and median overall survival is not yet assessable, with a median follow-up time of 28 months. The overall median event-free survival time is 5.6 months for all patients and 9.3 months for 14 patients who underwent transplantation. Six of these 14 patients (43%) remained disease-free at last follow-up. Treatment was well tolerated; there was one transplantation-related death. Prospective neuropsychologic evaluations have revealed no evidence of treatment-related neurotoxicity. CONCLUSION: This treatment approach is feasible in patients with newly diagnosed PCNSL without evidence of significant related neurotoxicity. Although the transplantation results are similar to those achieved in patients with aggressive or poor-prognosis systemic lymphoma, the low response rate to induction chemotherapy and the significant number of patients who experienced relapse soon after HDT suggest that more aggressive induction chemotherapy may be warranted.     

Is there a relationship between overweight and obesity and mental health problems in 4- to 5-year-old Australian children?

OBJECTIVE: To investigate the relationship between overweight and obesity, and mental health problems in Australian 4- to 5-year-old children. METHODS: The study used data from wave 1 (2004) of the Longitudinal Study of Australian Children (LSAC). The participants were 4983 4- to 5-year-old children (2537 boys and 2446 girls) with a mean age of 56.9 months (standard deviation 2.6 months; range 51-67 months). Children were classified as nonoverweight, overweight, and obese on the basis of International Obesity Task Force definitions. Mental health problems were assessed by the Strengths and Difficulties Questionnaire (SDQ) completed by parents and teachers. RESULTS: Although obese 4- to 5-year-old boys had more mental health problems than nonoverweight boys, differences between the groups were small and substantially reduced when analyses controlled for children's sociodemographic characteristics. Parents reported that overweight/obese girls had more peer problems, whereas teachers reported they had more conduct problems. Children in all weight groups had mean scores within the normal range of scores on all the SDQ subscales. CONCLUSIONS: Differences in rates of mental health problems experienced by young children of different weight status appear relatively small. Higher rates of mental health problems experienced by more obese boys may reflect differences in their sociodemographic characteristics rather than their weight status per se. Policies that reduce the number of young children living in poverty or experiencing other adverse social circumstances have the potential to reduce rates of mental health problems experienced by older children with overweight/obesity.     

Phase I trial of tipifarnib in patients with recurrent malignant glioma taking enzyme-inducing antiepileptic drugs: a North American Brain Tumor Consortium Study.

PURPOSE: To determine the maximum-tolerated dose (MTD), toxicities, and clinical effect of tipifarnib, a farnesyltransferase (FTase) inhibitor, in patients with recurrent malignant glioma taking enzyme-inducing antiepileptic drugs (EIAEDs). This study compares the pharmacokinetics and pharmacodynamics of tipifarnib at MTD in patients on and off EIAEDs. PATIENTS AND METHODS: Recurrent malignant glioma patients were treated with tipifarnib using an interpatient dose-escalation scheme. Pharmacokinetics and pharmacodynamics were assessed. RESULTS: Twenty-three assessable patients taking EIAEDs received tipifarnib in escalating doses from 300 to 700 mg bid for 21 of 28 days. The dose-limiting toxicity was rash, and the MTD was 600 mg bid. There were significant differences in pharmacokinetic parameters at 300 mg bid between patients on and not on EIAEDs. When patients on EIAEDs and not on EIAEDs were treated at MTD (600 and 300 mg bid, respectively), the area under the plasma concentration-time curve (AUC)(0-12 hours) was approximately two-fold lower in patients on EIAEDs. Farnesyltransferase inhibition was noted at all tipifarnib dose levels, as measured in peripheral-blood mononuclear cells (PBMC). CONCLUSION: Toxicities and pharmacokinetics differ significantly when comparing patients on or off EIAEDs. EIAEDs significantly decreased the maximum concentration, AUC(0-12 hours), and predose trough concentrations of tipifarnib. Even in the presence of EIAEDs, the levels of tipifarnib were still sufficient to potently inhibit FTase activity in patient PBMCs. The relevance of these important findings to clinical activity will be determined in ongoing studies with larger numbers of patients.     

Feasibility and acceptability of a motivational interviewing breastfeeding peer support intervention

An uncontrolled study with process evaluation was conducted in three U.K. community maternity sites to establish the feasibility and acceptability of delivering a novel breastfeeding peer‐support intervention informed by motivational interviewing (MI; Mam‐Kind). Peer‐supporters were trained to deliver the Mam‐Kind intervention that provided intensive one‐to‐one peer‐support, including (a) antenatal contact, (b) face‐to‐face contact within 48 hr of birth, (c) proactive (peer‐supporter led) alternate day contact for 2 weeks after birth, and (d) mother‐led contact for a further 6 weeks. Peer‐supporters completed structured diaries and audio‐recorded face‐to‐face sessions with mothers. Semistructured interviews were conducted with a purposive sample of mothers, health professionals, and all peer‐supporters. Interview data were analysed thematically to assess intervention acceptability. Audio‐recorded peer‐support sessions were assessed for intervention fidelity and the use of MI techniques, using the MITI 4.2 tool. Eight peer‐supporters delivered the Mam‐Kind intervention to 70 mothers in three National Health Service maternity services. Qualitative interviews with mothers (n = 28), peer‐supporters (n = 8), and health professionals (n = 12) indicated that the intervention was acceptable, and health professionals felt it could be integrated with existing services. There was high fidelity to intervention content; 93% of intervention objectives were met during sessions. However, peer‐supporters reported difficulties in adapting from an expert‐by‐experience role to a collaborative role. We have established the feasibility and acceptability of providing breastfeeding peer‐support using a MI‐informed approach. Refinement of the intervention is needed to further develop peer‐supporters' skills in providing mother‐centred support. The refined intervention should be tested for effectiveness in a randomised controlled trial.     

An Analysis of the Acoustic Input Impedance of the Ear

Ear canal acoustics was examined using a one-dimensional lossy transmission line with a distributed load impedance to model the ear. The acoustic input impedance of the ear was derived from sound pressure measurements in the ear canal of healthy human ears. A nonlinear least squares fit of the model to data generated estimates for ear canal radius, ear canal length, and quantified the resistance that would produce transmission losses. Derivation of ear canal radius has application to quantifying the impedance mismatch at the eardrum between the ear canal and the middle ear. The length of the ear canal was found, in general, to be longer than the length derived from the one-quarter wavelength standing wave frequency, consistent with the middle ear being mass-controlled at the standing wave frequency. Viscothermal losses in the ear canal, in some cases, may exceed that attributable to a smooth rigid wall. Resistance in the middle ear was found to contribute significantly to the total resistance. In effect, this analysis “reverse engineers” physical parameters of the ear from sound pressure measurements in the ear canal.