Serum and Cerebrospinal Fluid Pharmacokinetics of Intravenous and Oral Lamivudine in Human Immunodeficiency Virus-Infected Children

We studied the pharmacokinetics of intravenously and orally administered lamivudine at six dose levels ranging from 0.5 to 10 mg/kg of body weight in 52 children with human immunodeficiency virus infection. A two-compartment model with first-order elimination from the central compartment was simultaneously fitted to the serum drug concentration-time data obtained after intravenous and oral administration. The maximal concentration at the end of the 1-h intravenous infusion and the area under the concentration-time curve after oral and intravenous administration increased proportionally with the dose. The mean clearance of lamivudine (± standard deviation) in the children was 0.53 ± 0.19 liter/kg/h (229 ± 77 ml/min/m² of body surface area), and the mean half-lives at the distribution and elimination phases were 0.23 ± 0.18 and 2.2 ± 2.1 h, respectively. Clearance was age dependent when normalized to body weight but age independent when normalized to body surface area. Lamivudine was rapidly absorbed after oral administration, and 66% ± 25% of the oral dose was absorbed. Serum lamivudine concentrations were maintained above 1 μM for ≥8 h of 24 h on the twice daily oral dosing schedule with doses of ≥2 mg/kg. The cerebrospinal fluid drug concentration measured 2 to 4 h after the dose was 12% (range, 0 to 46%) of the simultaneously measured serum drug concentration. A limited-sampling strategy was developed to estimate the area under the concentration-time curve for concentrations in serum at 2 and 6 h.     

Accuracy of women's recall of opportunistic recruitment for cervical cancer screening in general practice

Abstract: Evaluation of strategies to improve opportunistic recruitment via general practice of women overdue for a cervical smear requires an accurate behavioural measure. As part of an experimental trial to evaluate the effect of a postgraduate workshop on preventive care, we conducted this methodological study to determine the accuracy of women's recall of an opportunistic discussion about cervical screening, by comparing it against audiotapes ( n = 524). Taking the taped evidence of the trainee's verbal behaviour as the gold standard, sensitivity was 85 per cent (95 per cent confidence interval (CI) 73.1 to 92.0 per cent) and specificity was 78 per cent (CI 73.9 to 81.6 per cent). Given the low rate of opportunistic recruitment by trainees in the main study, only one–third of positive recollections by women of an opportunistic discussion about cervical screening were correct. Until other measures have been validated, women's recall may continue to be used to measure general practitioners' behaviour, but an appreciation of likely bias is recommended.     

Total synthesis of the four stereoisomers of dihexadecanoyl phosphatidylinositol and the substrate stereospecificity of human erythrocyte membrane phosphatidylinositol 4-kinase

A new and convenient method for the preparation of the four stereoisomers of dihexadecanoyl phosphatidylinositol has been developed. An enantiomeric pair of acid-labile, pentaprotected myo-inositol building blocks was synthesized in high yield and coupled with chiral phenyl dihexadecanoylglyceryl phosphates to give the fully protected phosphatidylinositols. These were subsequently deprotected by hydrogenolysis and self-hydrolysis in aqueous ethanol to give the desired pure products. Comparison of these compounds as potential substrates for a partially purified phosphatidylinositol 4-kinase (EC 2.7.1.67) derived from human erythrocyte membranes revealed that the chirality of the inositol ring is crucial for efficient phosphorylation, whereas the chirality of the glycerol moiety is relatively unimportant. Moreover, the similarity in phosphorylation rates of the naturally occurring mammalian phospholipid, I, and its synthetic stereochemical counterpart, compound 10a, suggests that the enzyme is relatively tolerant to changes in fatty acid composition.     

Deliberating about Bioethics

In some sense, bioethics was built on conflicts. Abortion, physician-assisted suicide, patients’ demand for autonomy all are staple and contentious issues. And the controversies continue to proliferate. What forum best serves such debates? A look at political theories of democracy can help answer that question. The most promising for bioethics debates are theories that ask citizens and officials to justify any demands for collective action by giving reasons that can be accepted by those who are bound by the action. This conception has come to be known as deliberative democracy.     

Using a supervisory framework to support and evaluate a multiproject practice development programme

? The paper describes a multiproject practice development programme undertaken over a period of 1 year. ? The background and development of the programme are outlined, whilst attention is paid to the innovatory nature of the work, particularly the use of inductive, deductive and integrated approaches to both change implementation and project supervision. ? The programme was monitored throughout using different data sources and the paper uses evaluative material retrospectively to provide answers to organizational and professional difficulties which arose during the course of the programme. ? The authors conclude that the use of combinations of different models for practice development has potential, but requires careful supervision. ? They also recommend that those involved in practice development are made fully aware of its local or micropolitics, and develop strategies to deal with change before it occurs, not after it has taken place.     

Repeated treatment with ascorbate or haloperidol,but not clozapine,elevates extracellular ascorbate in the neostriatum of freely moving rats

Acute administration of neuroleptic drugs alters the extracellular level of ascorbate in the neostriatum, and increasing evidence suggests a role for this vitamin in the behavioral, and possibly therapeutic, effects of these drugs. To shed further light on this issue, extracellular ascorbate was recorded in the neostriatum and nucleus accumbens of awake, behaving rats following chronic treatment with either classical (haloperidol) or atypical (clozapine) neuroleptics or ascorbate itself. Electrochemically modified, carbon-fiber microelectrodes were lowered in place the day after the last of 21 daily injections of either haloperidol (0.5 mg/kg, SC), clozapine (20 mg/kg, IP), sodium ascorbate (500 mg/kg, IP) or vehicle. Voltammetric measurements were obtained during quiet rest and following administration ofd-amphetamine (2.5 mg/kg). Repeated treatment with either haloperidol or ascorbate elevated basal extracellular ascorbate and potentiated the amphetamine-induced increase in ascorbate release in neostriatum but not nucleus accumbens. Both treatment groups also showed a significant increase in amphetamine-induced sniffing and repetitive head movements compared to vehicle-treated animals. In contrast, repeated clozapine had no effect on extracellular ascorbate in either neostriatum or nucleus accumbens, but increased the locomotor response to an amphetamine challenge. Thus, to the extent that increases in neostriatal ascorbate exert neuroleptic-like effects, such effects are likely to parallel haloperidol rather than clozapine.     

Mechanism of persistent infection associated with peritoneal implants.

The ability of rabbits to clear an intraperitoneal injection of Pseudomonas aeruginosa in the presence or absence of a surgically implanted peritoneal device was investigated. Sham-operated rabbits without an implant eliminated a P. aeruginosa challenge of 5 x 10(6) cfu/ml; lavage fluid and peritoneal tissues became culture-negative within 96 h. However, peritonitis developed in rabbits that were given the same number of bacteria in the presence of an implant; high bacterial counts were recovered from the lavage fluid and the device itself. Scanning and transmission electronmicroscopy revealed bacterial biofilms on the surface of the device. Insertion of pre-colonised devices demonstrated a rapid multiplication of sessile organisms within the resulting bacterial biofilm. Counts reached a plateau of about 1 x 10(7) cfu/cm2 of Silastic by day 16 and fluctuated around this level until the end of the study. Pre-immunisation with formalin-killed whole cells of P. aeruginosa did not reduce this bacterial growth despite high levels of specific IgG. The results confirm the failure of peritoneal defences to clear an infection in the presence of an implant following either challenge with planktonic bacteria or insertion of a pre-colonised device, and demonstrate the rapid development of bacterial biofilms on the surface of the implant which appear to protect the bacteria from host defences, even when primed by pre-immunisation.     

Different effects of unilateral versus bilateral subthalamic nucleus stimulation on walking and reaching in Parkinson's disease.

The purpose of this study was to determine the effects of unilateral versus bilateral subthalamic nucleus (STN) stimulation on quantitative measures of walking and reaching in Parkinson's disease (PD). We used kinematic measures and the Unified Parkinson's Disease Rating Scale (UPDRS) motor subscale (subscale III) to evaluate the movement of 6 people with PD who had bilateral STN stimulators implanted for at least 6 months and withheld their anti-parkinson medication for at least 8 hours. Subjects were studied with both stimulators off, one on, and both on. Kinematic data were collected as subjects walked, reached to a target, and were rated using the UPDRS motor subscale. STN stimulation improved walking speed and stride length, with the greatest benefit from bilateral stimulation. Reaching speed was improved by unilateral STN stimulation alone, with no additive effect of bilateral stimulation. UPDRS motor subscale ratings paralleled the kinematic findings. STN stimulation did not restore PD subjects' movements to the level of age-matched controls. Overall, these results provide further evidence that the basal ganglia pathways involved in control of walking and reaching may be distinct. We speculate that basal ganglia may influence walking through bilateral pedunculopontine projections and reaching through ipsilateral thalamocortical projections. Our findings also suggest that maximal improvement of walking requires bilateral rather than unilateral STN stimulation.