Outcome data from the LEAP (Live, Eat and Play) trial: a randomized controlled trial of a primary care intervention for childhood overweight/mild obesity

OBJECTIVES: To reduce gain in body mass index (BMI) in overweight/mildly obese children in the primary care setting.
DESIGN: Randomized controlled trial (RCT) nested within a baseline cross-sectional BMI survey.
SETTING: Twenty nine general practices, Melbourne, Australia.
PARTICIPANTS: (1) BMI survey: 2112 children visiting their general practitioner (GP) April-December 2002; (2) RCT: individually randomized overweight/mildly obese (BMI z-score <3.0) children aged 5 years 0 months-9 years 11 months (82 intervention, 81 control).
INTERVENTION: Four standard GP consultations over 12 weeks, targeting change in nutrition, physical activity and sedentary behaviour, supported by purpose-designed family materials.
MAIN OUTCOME MEASURES: Primary: BMI at 9 and 15 months post-randomization. Secondary: Parent-reported child nutrition, physical activity and health status; child-reported health status, body satisfaction and appearance/self-worth.
RESULTS: Attrition was 10%. The adjusted mean difference (intervention-control) in BMI was -0.2 kg/m(2) (95% CI: -0.6 to 0.1; P=0.25) at 9 months and -0.0 kg/m(2) (95% CI: -0.5 to 0.5; P=1.00) at 15 months. There was a relative improvement in nutrition scores in the intervention arm at both 9 and 15 months. There was weak evidence of an increase in daily physical activity in the intervention arm. Health status and body image were similar in the trial arms.
CONCLUSIONS: This intervention did not result in a sustained BMI reduction, despite the improvement in parent-reported nutrition. Brief individualized solution-focused approaches may not be an effective approach to childhood overweight. Alternatively, this intervention may not have been intensive enough or the GP training may have been insufficient; however, increasing either would have significant cost and resource implications at a population level.

Pharmacokinetics of recombinant human endostatin in rats

The pharmacokinetics of recombinant human endostatin (rh-Endo) has not been established in the rat, although this species of animal is commonly used in the pharmacological studies of rh-Endo. This study aimed to investigate the pharmacokinetics, tissue distribution, and excretion of rh-Endo in rats. 125I-radiolabeled rh-Endo was administered to healthy rats by intravenous (i.v) bolus injection at 1.5, 4.5 and 13.5 mg/kg. The maximum plasma concentration (Cmax) and area under the plasma concentration versus time curve (AUC) of rh-Endo increased proportionally with the increase of the dosage. There were no significant differences in total body clearance (CL) and elimination half-life (t1/2beta) of rh-Endo among the three dosages used. A 93.5% and 2.2% of the radioactivity was recovered in the urine and feces, respectively, in bile-duct intact rats; whereas only 0.1% of the total radioactivity was excreted into the bile in bile-duct cannulated rats. rh-Endo was rapidly and widely distributed in the liver, kidneys, spleen and lungs. Furthermore, a significant allometric relationship between CL, but not volume of distribution (Vd) and t1/2beta of rh-Endo, and the body weight was observed across mouse, rat and monkey, with the predicted values in humans significantly lower than those observed in cancer patients. rh-Endo exhibited a linear pharmacokinetics in rats and it is mainly excreted through the urine.

Pharmacokinetic mechanisms for reduced toxicity of irinotecan by coadministered Thalidomide

The clinical use of irinotecan (CPT-11) is hindered by dose-limiting diarrhea and myelosuppression. Recent clinical studies indicate that thalidomide, a known tumor necrosis factor-alpha inhibitor, ameliorated the toxicities induced by CPT-11. However, the mechanisms for this are unknown. This study aimed to investigate whether combination of thalidomide modulated the toxicities of CPT-11 using a rat model and the possible role of the altered pharmacokinetic component in the toxicity modulation using in vitro models. The toxicity model was constructed by treatment of healthy rats with CPT-11 at 60 mg/kg per day by intravenous (i.v.) injection. Body weight, acute and delayed-onset diarrhea, blood cell counts, and macroscopic and microscopic intestinal damages were monitored in rats treated with CPT-11 alone or combined therapy with thalidomide at 100 mg/kg administered by intraperitoneal (i.p.) injection. Single dose and 5-day multiple-dose studies were conducted in rats to examine the effects of concomitant thalidomide on the plasma pharmacokinetics of CPT-11 and its major metabolites SN-38 and SN-38 glucuronide (SN-38G). The effect of CPT-11 on thalidomide's pharmacokinetics was also checked. Rat liver microsomes and a rat hepatoma cell line, H4-II-E cells, were used to study the in vitro metabolic interactions between these two drugs. H4-II-E cells were also used to investigate the effect of thalidomide and its hydrolytic products on the transport of CPT-11 and SN-38. In addition, the effect of thalidomide and its hydrolytic products on rat plasma protein binding of CPT-11 and SN-38 was examined. Administration of CPT-11 by i.v. for 4 consecutive days to rats induced significant body weight loss, decrease in neutrophil and lymphocyte counts, severe acute- and delayed-onset diarrhea, and intestinal damages. These toxicities were alleviated when CPT-11 was combined with thalidomide. In both single-dose and 5-day multiple-dose pharmacokinetic study, coadministered thalidomide significantly increased the area under the plasma concentration-time curve (AUC) of CPT-11, but the AUC and elimination half-life (t(1/2)) of SN-38 were significantly decreased. However, CPT-11 did not significantly alter the pharmacokinetics of thalidomide. Thalidomide at 25 and 250 microM and its hydrolytic products at a total concentration of 10 microM had no significant effect on the plasma protein binding of CPT-11 and SN-38, except for that thalidomide at 250 microM caused a significant increase in the unbound fraction (f(u)) of CPT-11 by 6.7% (P < 0.05). The hydrolytic products of thalidomide (total concentration of 10 microM), but not thalidomide, significantly decreased CPT-11 hydrolysis by 16% in rat liver microsomes (P < 0.01). The formation of both SN-38 and SN-38G from CPT-11, SN-38 glucuronidation, or intracellular accumulation of both CPT-11 and SN-38 in H4-II-E cells followed Michaelis-Menten kinetics with the one-binding site model being the best fit for the kinetic data. Coincubation or 2-hr preincubation of thalidomide at 25 microM and 250 microM and its hydrolytic products at 10 microM did not show any significant effects on CPT-11 hydrolysis and SN-38 glucuronidation. However, preincubation of H4-II-E cells with thalidomide (250 microM), its hydrolytic products (total concentration of 10 microM), or phthaloyl glutamic acid (one major thalidomide hydrolytic product, 10 microM) significantly increased the intracellular accumulation of SN-38, but not CPT-11 (P < 0.01). The dose-limiting toxicities of CPT-11 were alleviated by combination with thalidomide in rats and the pharmacokinetic modulation by thalidomide may partially explain its antagonizing effects on the toxicities of CPT-11. The hydrolytic products of thalidomide, instead of the parental drug, modulated the hepatic hydrolysis of CPT-11 and intracellular accumulation of SN-38, probably contributing to the altered plasma pharmacokinetics of CPT-11 and SN-38. Further studies are needed to explore the role of both pharmacokinetics and pharmacodynamic components in the protective effect of thalidomide against the toxicities of CPT-11.

Mechanism-based inhibition of cytochrome P450 3A4 by therapeutic drugs

Consistent with its highest abundance in humans, cytochrome P450 (CYP) 3A is responsible for the metabolism of about 60% of currently known drugs. However, this unusual low substrate specificity also makes CYP3A4 susceptible to reversible or irreversible inhibition by a variety of drugs. Mechanism-based inhibition of CYP3A4 is characterised by nicotinamide adenine dinucleotide phosphate hydrogen (NADPH)-, time- and concentration-dependent enzyme inactivation, occurring when some drugs are converted by CYP isoenzymes to reactive metabolites capable of irreversibly binding covalently to CYP3A4. Approaches using in vitro, in silico and in vivo models can be used to study CYP3A4 inactivation by drugs. Human liver microsomes are always used to estimate inactivation kinetic parameters including the concentration required for half-maximal inactivation (K(I)) and the maximal rate of inactivation at saturation (k(inact)).Clinically important mechanism-based CYP3A4 inhibitors include antibacterials (e.g. clarithromycin, erythromycin and isoniazid), anticancer agents (e.g. tamoxifen and irinotecan), anti-HIV agents (e.g. ritonavir and delavirdine), antihypertensives (e.g. dihydralazine, verapamil and diltiazem), sex steroids and their receptor modulators (e.g. gestodene and raloxifene), and several herbal constituents (e.g. bergamottin and glabridin). Drugs inactivating CYP3A4 often possess several common moieties such as a tertiary amine function, furan ring, and acetylene function. It appears that the chemical properties of a drug critical to CYP3A4 inactivation include formation of reactive metabolites by CYP isoenzymes, preponderance of CYP inducers and P-glycoprotein (P-gp) substrate, and occurrence of clinically significant pharmacokinetic interactions with coadministered drugs.Compared with reversible inhibition of CYP3A4, mechanism-based inhibition of CYP3A4 more frequently cause pharmacokinetic-pharmacodynamic drug-drug interactions, as the inactivated CYP3A4 has to be replaced by newly synthesised CYP3A4 protein. The resultant drug interactions may lead to adverse drug effects, including some fatal events. For example, when aforementioned CYP3A4 inhibitors are coadministered with terfenadine, cisapride or astemizole (all CYP3A4 substrates), torsades de pointes (a life-threatening ventricular arrhythmia associated with QT prolongation) may occur.However, predicting drug-drug interactions involving CYP3A4 inactivation is difficult, since the clinical outcomes depend on a number of factors that are associated with drugs and patients. The apparent pharmacokinetic effect of a mechanism-based inhibitor of CYP3A4 would be a function of its K(I), k(inact) and partition ratio and the zero-order synthesis rate of new or replacement enzyme. The inactivators for CYP3A4 can be inducers and P-gp substrates/inhibitors, confounding in vitro-in vivo extrapolation. The clinical significance of CYP3A inhibition for drug safety and efficacy warrants closer understanding of the mechanisms for each inhibitor. Furthermore, such inactivation may be exploited for therapeutic gain in certain circumstances.

Enough energy to get half way to the moon

A proposal to abandon Melbourne's Supreme Court for a new high-tech facility prompted quite an outcry of dismay when it was reported in the Melbourne press earlier this year, and has highlighted sustainability issues in relation to heritage buildings in Victoria.

Dance card : light : sound : space : moves : a live-performance mix-re-mix event

12 minute solo within an hour-long work, performed 18 - 22 February 2004  at the Dancehouse, Melbourne

Pharmaceutical ecomonics and politics vs. patient safety : Lumiracoxib in Australia

Lumiracoxib (Prexige©) 200 mg was listed in Australia’s Pharmaceutical Benefits Scheme (PBS) schedules on 01 August 2006. The listing was intended as a cost-minimisation strategy, as lumiracoxib 200 mg was deemed equivalent in therapeutic effect to celecoxib (Celebrex©) 200 mg, and was available at a lower cost. By the time of listing on the PBS, a safety re-evaluation of the recommended daily dose of lumiracoxib was being considered in other national regulatory jurisdictions. Within 3 months of listing, the manufacturer revised the recommended dosage to half that of the PBS-listed dosage. However, the PBS listing was neither revoked nor modified. At the time of listing on the PBS, lumiracoxib was known to be 17 times as biochemically selective in inhibiting the COX-2 isoform as celecoxib, and twice as selective as rofecoxib, already withdrawn for safety reasons. Safety concerns had already been raised about adverse hepatic outcomes on daily doses of lumiracoxib 200 mg. Communication of information about the risk potential of lumiracoxib was inadequate. Economic and political considerations were prioritised over patient safety, and lumiracoxib 200 mg remained available via the PBS until 10 August 2007, when it was withdrawn for safety reasons following cases of hepatic morbidity and mortality.

An evaluation of three field techniques for sexing live Gould's petrels (Pterodroma leucoptera) (Procellariidae)

Many petrels show no obvious sex-linked dimorphism in plumage or size and consequently many researchers fail to sex the living individuals they study. Several methods of sex discrimination that do not rely on plumage- or obvious size-dimorphism can be used to sex live petrels. The effectiveness of three such techniques was evaluated: body condition at the time of laying, cloacal inspection, and discriminant function analysis (DFA) of external morphometrics. Gould’s Petrel (Pterodroma leucoptera leucoptera) was used as the subject species. Sexing of breeding adults on the basis of body condition at laying proved to be highly accurate (100% of birds sexed correctly) but required detailed knowledge of the breeding biology. Following training, cloacal inspection proved to be an accurate (96%) method of determining the sex of breeding adults, but not of chicks. Unlike molecular sexing, the latter two methods of sex discrimination provide immediate knowledge of the sex of individuals in the field. DFA of external morphometrics predicted the sex of adults with an accuracy of 73% and the sex of near-fledged chicks with an accuracy of 66%. However, the probability of correct assignment of sex was low in most cases and, therefore, this is the least useful of the three techniques assessed here.

Mineral rights are dead! Long live mineral rights!

Whilst being mindful of the eventual extinction of the legal notion of mineral rights in South Africa upon expiry of the transitional measures in terms of schedule II of the Mineral and Petroleum Resources Development Act 28 of 2002 on 30 April 2009, the classification of mineral rights by the supreme court of appeal in the Anglo decision is to be welcomed, even though it is somewhat ironic at this stage. (As to the extinction of the notion of mineral rights, see Badenhorst "Mineral rights : 'year zero cometh?'" 2001 Obiter 119; "Exodus of 'mineral rights' from South African mineral law" 2004 Journal of Energy and Natural Resources Law 218.) It will, however, be shown in this discussion that the decision of the supreme court of appeal will extend beyond the statutory transitional period and will also have an impact on rights to minerals or rights to petroleum as created in terms of the Mineral and Petroleum Resources Development Act (hereafter referred to as the act). For purposes of this discussion, one can simply continue to refer to mineral rights that developed from the common law as "mineral rights", whilst referring to the new rights created in terms of the act as "rights to minerals and petroleum". The present decision only deals with coal as "minerals".

Cadaveric vs. live-donor kidney transplants : theoretical foundations of interaction between institutions and inequality

In 1991, the World Health Assembly approved a set of Guiding Principles which emphasize voluntary donation, non-commercialization and a preference for cadavers over living donors” (World Health Organization). The objective of this paper is to identify the factors that affect the ratio of cadaveric transplants to all transplants. This paper first provides informational background on problems surrounding kidney transplants and then uses a theoretical framework which employs standard economic assumptions but incorporates a setup where the persons needing kidneys can obtain it from their compatible relatives or purchase it from individuals who are willing to sell one of their kidneys. The methods of economic theoretical analyses are used where following definitions and assumptions some conclusions are drawn. This paper finds that factors such as inequality, rule of law and religion have significant effect on the ratio of cadaveric transplants to all transplants. The paper concludes that improvement in equality and in rule of law will increase the use of cadaveric kidney transplants. In addition, fighting religious beliefs against cadaveric kidney transplants too will lead to a higher ratio of cadaveric transplants to all transplants.

Studies on Australian hydroids : the genus Eudendrium and the fauna of the seagrass Amphibolis

An important Athecate genus, Eudendrium, and a group of species of the Thecata, the latter ecologically related by life on a common substrate, are reviewed. Eudendrium, hitherto poorly known in Australia, comprises 17 species, including 10 undescribed species with 71% Australian, and high provincial endemicity. Eudendrium may be a shelf genus avoiding turbulent oceanic waters. Species of Eudendrium are predominantly epizoic and some gregariously settling colonies may live for five years. Identification of sterile material is refined by using the cnidome in a key to classification. The species and population dynamics of hydroid epiphytes of the endemic southern Australian marine angiosperm Amphibolis were investigated with revision of historically vexatious taxa. In contrast with the northern hemisphere, no Athecata are associated with southern Australian seagrasses. Seventeen species from eight thecate families are associated with the two species of Amphibolis, including one undescribed species, H&lecium amphibolum, and one new record for Australia, Aglaophenia postdentata. The Lineolariidae is revised and a new genus, Millardaria, erected for a species from seagrass in Madagascar. The high endemicity (58%) and host-specificity of hydroids to Amphibolis is an evolutionary consequence of isolation of the seagrass dating from break-up of the Tethyan Sea. Hydroids occur throughout the year in the Amphibolis leaf canopy with a mean annual epiphytism of 44% on A. antarctica in the eastern continent and 86% in the western continent; epiphytism is 52% on A. griffithii in the western continent. Half of the eight important species are dominant epiphytes across the southern continent but the species and order of abundance varies regionally. Most are pioneer colonists with short, repetetive life-cycles lasting from weeks to a few months. Three species epiphytise the seagrass stems but only one is a leaf-canopy dominant. The canopy community comprises small, fast-growing species or dwarfed variants of species larger in other habitats: these ecomorphically constant forms are associated only with seagrass. Strategies for survival in the harsh Amphibolis environment include adnate colonies and gonothecae adnate or recumbent to the substrate, marked strengthening of the hydrorhiza, various hydrodynamic adaptations of the hydrotheca, early maturation and production of numerous small ova.