Simultaneous administration of a cocktail of markers to measure renal drug elimination pathways: absence of a pharmacokinetic interaction between fluconazole and sinistrin, p-aminohippuric acid and pindolol

Aims Previous studies suggest that estimated creatinine clearance, the conventional measure of renal function, does not adequately reflect charges in renal drug handling in some patients, including the immunosuppressed. The aim of this study was to develop and validate a cocktail of markers. to be given in a single administration, capable of detecting alterations in the renal elimination pathways of glomerular filtration, tubular secretion and tubular reabsorption. Methods Healthy male subjects (n = 12) received intravenously infused 2500 mg sinistrin (glomerular filtration) and 440 mg p-aminohippuric acid (PAH; anion secretion), and orally administered 100 mg fluconazole (reabsorption) and 15 mg rac-pindolol (cation secretion). The potential interaction between these markers was investigated in a pharmacokinetic study where markers (M) or fluconazole (F) were administered alone or together (M + F). Validated analytical methods were used to measure plasma and urine concentrations in order to quantify the renal handling of each marker. Plasma protein binding of fluconazole was measured by ultrafiltration. All subjects had an estimated creatinine clearance within the normal range. The renal clearance of each marker (Mean +/- s.d.) was calculated as the ratio of the amount excreted in urine and thearea-under-the-concentration-time curve. Statistical comparisons were made using a paired t-test and 95% confidence intervals were reported. Results The renal clearances of sinistrin (M: 119 +/- 31 ml min(-1); M + F: 130 +/- 40 ml min(-1); P = 0.32), PAH (M: 469 +/- 145 ml min(-1); M + F: 467 +/- 146 ml min(-1); P = 0.95), R-pindolol (M: 204 +/- 41 ml min(-1); M + F: 190 +/- 41 ml min(-1); P = 0.39; n = 11), S-pindolol (M: 225 +/- 55 ml min(-1); M + F: 209 +/- 60 ml min(-1); P = 0.27; n = 11) and fluconazole (F: 14.9 +/-3.8 ml min(-1); M + F: 13.6 +/- 3.4 ml min(-1); P = 0.16) were similar when the markers or fluconazole were administered alone (M or F) or as a cocktail (M + F). Conclusions This study found no interaction between markers and fluconazole in healthy male subjects, suggesting that a single administration of this cocktail of markers of different renal processes call be used to simultaneously investigate pathways of renal drug elimination.

Early rise in blood pressure following administration of adrenocorticotropic hormone-[1-24] in humans

1. An elevation in blood pressure has been consistently observed 24 h after adrenocorticotropic hormone (ACTH) administration and is caused by increased ACTH-stimulated cortisol secretion, in association with increased cardiac output. The aim of the present study was to investigate the previously undefined time of onset of this increase in blood pressure in normal humans. 2. Ten normal healthy volunteers received 250 mug ACTH-[1-24], in 500 mL normal saline, infused at a constant rate over 8 h. Six subjects also received a placebo infusion (normal saline only). Blood pressure, heart rate and cortisol levels were determined hourly. Adrenocorticotropic hormone (ACTH-[1-24] plus native ACTH) was measured at 0, 1, 7 and 8 h. 3. Infusion of ACTH-[1-24] produced maximal secretion rates of cortisol, resulting in a mean peak plasma level of 985 +/- 46 nmol/L at 8 h. In response, blood pressure and heart rate rose significantly by 2 h and remained generally elevated for the duration of the infusion. 4. The early onset of haemodynamic responses is consistent with classical steroid receptor-mediated genomic mechanisms, but could be due non-genomic mechanisms. 5. The cardiovascular consequences of therapeutic use of ACTH are well recognized. This results of the present study suggest that even diagnostic administration of ACTH, delivered over a few hours, may raise blood pressure.

Route of administration of chimeric BPV1VLP determines the character of the induced immune responses

To examine the mucosal immune response to papillomavirus virus-like particles (PV-VLP), mice were immunized with VLP intrarectally (i.r.), intravaginally (i.va.) or intramuscularly (i.m.) without adjuvant. PV-VLP were assembled with chimeric BPV-1 L1 proteins incorporating sequence from HIV-1 gp 120, either the V3 loop or a shorter peptide incorporating a known CTL epitope (HIVP18I10). Antibody specific for BPV-1 VLP and P18 peptide was detected in serum following i.m., but not i.r. or i.va. immunization. Denatured VLP induced a much reduced immune response when compared with native VLP, Immune responses following mucosal administration of VLP were generally weaker than following systemic administration. VLP specific IgA was higher in intestine washes following i.r. than i.va. immunization, and higher in vaginal washes following i.m. than i.r. or i.va. immunization. No differences in specific antibody responses were seen between animals immunized with BPV-1 P18 VLP or with BPV-1 V3 VLP. Cytotoxic T lymphocyte precursors specific for the P18 CTL epitope were recovered from the spleen following i.m., i.va. or i.r. immunization with P18 VLP, and were similarly detected in Peyer's patches following i.m. or i.r. immunization. Thus, mucosal or systemic immunization with PV VLP induces mucosal CTL responses and this may be important for vaccines for mucosal infection with human papillomaviruses and for other viruses.

The global sports-media nexus: Reflections on the 'Super League Saga' in Australia

Despite the social and (increasingly) commercial significance of sport and sporting bodies worldwide, they remain under-represented in the mainstream management literature. One of the more recent and dramatic examples of the global sports-media nexus is the 'Super League saga' in Australia. This paper recounts the tale of the Super League saga, providing a holistic analysis of the events and competitive issues arising by drawing on literatures concerning the economic nature and value of sports leagues, the resource-based view of the firm and the nature of psychological contracts in changing environments. The analysis confirms the general monopolistic tendencies of professional sports leagues in an increasingly global industry driven by the sports-media nexus, in accord with a number of comparable cases internationally. The particular conditions of the Australian marketplace that exacerbate this tendency beyond, for example, that found in the USA, and differences in the outcomes of battles between rival leagues are also considered. The Super League saga portrays the importance of effective management of resources key to the production of the 'rugby league product' including, among others, the often over-looked importance of careful management of local resources for the success of global strategies, and, where human resources are key, the importance of psychological contracting. The holistic analysis of the Super League saga in Australia affords lessons that extend well beyond the realm of sports.

Oral administration of a 12% sucrose solution did not decrease behavioural indicators of distress in piglets undergoing tail docking, teeth clipping and ear notching

Sucrose has been shown to attenuate the behavioural response to painful procedures in human infants undergoing circumcision or blood collection via heelstick. Sucrose has also been found to have a behaviour-modifying effect in neonatal rats exposed to a hot plate. The effect was abolished in neonatal rats by injection of the opioid antagonist naltrexone, suggesting that it was mediated by endogenous opioids. In this experiment, the behaviour of 571 newborn Large White x Landrace hybrid piglets in a specific-pathogen-free piggery of the University of Queensland was recorded during and after the routine management practices of tail docking, ear notching and teeth clipping. Piglets were randomly assigned to receive 1.0 ml of a 12% sucrose solution (treatment group) or a placebo (1.0 ml of air) administered via syringe in the mouth, 60 s before commencement of one of the management procedures. Behaviours were recorded at the time of the procedure, and then 2 min after completion of the procedure. Piglets that received the sucrose solution did not behave significantly differently from piglets receiving the placebo. Regardless of whether sucrose or placebo was administered, piglets undergoing the routine management procedures showed significantly greater behavioural responses than piglets undergoing no procedure. It was concluded that under commercial conditions, a 12% sucrose solution administered I min prior to surgery was not effective in decreasing the behavioural indicators of distress in piglets undergoing routine management procedures, Further research into methods of minimising distress caused to piglets by these procedures is recommended.

Severity of sports-related concussion and neuropsychological test performance

Concussion severity grades according to the Cantu, Colorado Medical Society, and American Academy of Neurology systems were not clearly related to the presence or duration of impaired neuropsychological test performance in 21 professional rugby league athletes. The use of concussion severity guidelines and neuropsychological testing to assist return to play decisions requires further investigation.

Immunity to malaria after administration of ultra-low doses of red cells infected with Plasmodium falciparum

Background The ability of T cells, acting independently of antibodies, to control malaria parasite growth in people has not been defined. If such cell-mediated immunity was shown to be effective, an additional vaccine strategy could be pursued. Our aim was to ascertain whether or not development of cell-mediated immunity to Plasmodium falciparum blood-stage infection could be induced in human beings by exposure to malaria parasites in very low density. Methods We enrolled five volunteers from the staff at our research institute who had never had malaria. We used a cryopreserved inoculum of red cells infected with P falciparum strain 3D7 to give them repeated subclinical infections of malaria that we then cured early with drugs, to induce cell-mediated immune responses. We tested for development of immunity by measurement of parasite concentrations in the blood of volunteers by PCR of the multicopy gene STEVOR and by following up the volunteers clinically, and by measuring antibody and cellular immune responses to the parasite. Findings After challenge and a extended period without drug cure, volunteers were protected against malaria as indicated by absence of parasites or parasite DNA in the blood, and absence of clinical symptoms. Immunity was characterised by absence of detectable antibodies that bind the parasite or infected red cells, but by the presence of a proliferative T-cell response, involving CD4+ and CD8+ T cells, a cytokine response, consisting of interferon gamma but not interleukin 4 or interleukin 10, induction of high concentrations of nitric oxide synthase activity in peripheral blood mononuclear cells, and a drop in the number of peripheral natural killer T cells. Interpretation People can be protected against the erythrocytic stage of malaria by a strong cell-mediated immune response, in the absence of detectable parasite-specific antibodies, suggesting an additional strategy for development of a malaria vaccine.

Human peripheral blood V alpha 24(+) V beta 11(+) NKT cells expand following administration of alpha-galactosylceramide-pulsed dendritic cells

Background and Objectives We have undertaken the first clinical trial involving the administration of alpha-GalactosylCeramine (alpha-GalCer)-pulsed dendritic cells (DCs) to human subjects, to determine safety, optimal dose, optimal administration route and immunological effects. Materials and Methods Subjects (n = 4) with metastatic malignancy received two infusions of alpha-GalCer-pulsed DCs intravenously, and two infusions intradermally. The percentages of Valpha24 Vbeta11 NKT cells in peripheral blood (PB) were determined by three-colour flow cytometry and the PB NKT cell numbers were calculated using the total number of PB lymphocytes/ml determined by automated full-blood counts. Results No serious treatment related adverse events were observed during the study period. Administration of alpha-GalCer-pulsed DCs in vivo can significantly (P < 0.03) increase PB Valpha24(+) Vbeta11(+) NKT cell numbers above pretreatment baseline levels after the transient fall in the NKT numbers within 48 h. Conclusions Administration of alpha-GalCer-pulsed DCs is well tolerated, modulates PB Valpha24(+) Vbeta11(+) NKT cells and may have a role in the therapy of malignancies sensitive to activities of Valpha24(+) Vbeta11(+) NKT cells, or for autoimmune diseases.

Systemic administration of interleukin-1 beta activates select populations of central amygdala afferents

The central nucleus of the amygdala (CeA) is activated robustly by an immune challenge such as the systemic administration of the proinflammatory cytokine interleukin-1beta (IL-1beta). Because IL-1beta is not believed to cross the blood-brain barrier in any significant amount, it is likely that IL-1beta elicits CeA cell recruitment by means of activation of afferents to the CeA. However, although many studies have investigated the origins of afferent inputs to the CeA, we do not know which of these also respond to IL-1beta. Therefore, to identify candidate neurons responsible for the recruitment of CeA cells by an immune challenge, we iontophoretically deposited a retrograde tracer, cholera toxin b-subunit (CTb), into the CeA of rats 7 days before systemic delivery of IL-1beta (1 mug/kg, i.a.). By using combined immunohistochemistry, we then quantified the number of Fos-positive CTb cells in six major regions known to innervate the CeA. These included the medial prefrontal cortex, paraventricular thalamus (PVT), ventral tegmental area, parabrachial nucleus (PB), nucleus tractus solitarius, and ventrolateral medulla. Our results show that after deposit of CTb into the CeA, the majority of double-labeled cells were located in the PB and the PVT, suggesting that CeA cell activation by systemic IL-1beta is likely to arise predominantly from cell bodies located in these regions. These findings may have significant implications in determining the central pathways involved in generating acute central responses to a systemic immune challenge. J. Comp. Neurol. 452:288-296, 2002. (C) 2002 Wiley-Liss, Inc.

The over-production of US sports and the new International Division of Cultural Labor

This article focuses on how US professional sports utilize the New International Division of Cultural Labor to supplement an overly costly local labor pool and over-supplied local market. We argue that while the classic problem of over-production is slowly eroding the sealed-off nature of US culture, the forces of its hyper-protectionist capitalism continue to characterize sports, precluding equal exchange.

Sport-specific practice and the development of expert decision-making in team ball sports

The role of sport-specific practice in the development of decision-making expertise in the sports of field hockey, netball, and basketball was examined. Fifteen expert decision-makers and 13 experienced non-expert athletes provided detailed information about the quantity and type of sport-specific and other related practice activities they had undertaken throughout their careers. Experts accumulated more hours of sport-specific practice from age 12 years onwards than did non-experts, spending on average some 13 years and 4,000 hours on concentrated sport-specific practice before reaching international standard. A significant negative correlation existed between the number of additional activities undertaken and the hours of sportspecific training required before attaining expertise, suggesting a functional role for activities other than sport-specific training in the development of expert decision-making.