Hepatic disposition and metabolite kinetics of a homologous series of diflunisal esters

The hepatic disposition and metabolite kinetics of a homologous series of diflunisal O-acyl esters (acetyl, butanoyl, pentanoyl, anti hexanoyl) were determined using a single-pass perfused in situ rat liver preparation. The experiments were conducted using 2% BSA Krebs-Henseleit buffer (pH 7.4), and perfusions were performed at 30 mL/min in each liver. O-Acyl esters of diflunisal and pregenerated diflunisal were injected separately into the portal vein. The venous outflow samples containing the esters and metabolite diflunisal were analyzed by high performance liquid chromatography (HPLC). The normalized outflow concentration-time profiles for each parent ester and the formed metabolite, diflunisal, were analyzed using statistical moments analysis and the two-compartment dispersion model. Data (presented as mean +/- standard error for triplicate experiments) was compared using ANOVA repeated measures, significance level P < 0.05. The hepatic availability (AUC'), the fraction of the injected dose recovered in the outflowing perfusate, for O-acetyldiflunisal (C2D = 0.21 +/- 0.03) was significantly lower than the other esters (0.34-0.38). However, R-N/f(u), the removal efficiency number R-N divided by the unbound fraction in perfusate f(u), which represents the removal efficiency of unbound ester by the liver, was significantly higher for the most lipophilic ester (O-hexanoyldiflunisal, C6D = 16.50 +/- 0.22) compared to the other members of the series (9.57 to 11.17). The most lipophilic ester, C6D, had the largest permeability surface area (PS) product (94.52 +/- 38.20 mt min-l g-l liver) and tissue distribution value VT (35.62 +/- 11.33 mL g(-1) liver) in this series. The MTT of these O-acyl esters of diflunisal were not significantly different from one another. However, the metabolite diflunisal MTTs tended to increase with the increase in the parent ester lipophilicity (11.41 +/- 2.19 s for C2D to 38.63 +/- 9.81 s for C6D). The two-compartment dispersion model equations adequately described the outflow profiles for the parent esters and the metabolite diflunisal formed from the O-acyl esters of diflunisal in the liver.

Determination of the stability constants of mercury(II) complexes of mixed donor macrobicyclic encapsulating ligands

The reactions of mercury(II) with the mixed donor encapsulating ligands 3,6,16-trithia-6,11,19-triazabicyclo[6.6.6]icosane (AMN(3)S(3)sar) and 1-amino-8-methyl-6,19-dithia-3,10,13,16-tetraazabicyclo[6.6.6]icosane (AMN(4)S(2)sar) have been studied. NMR ligand-ligand competition experiments with the ligands 1,4,8,11-tetraazaeyclotetradecane ([14]aneN(4)), 1-thia-4,7,10-triazacyclododecane ([12]aneN(3)S) and ethylenediaminetetraacetic acid (EDTA) with AMN(3)S(3)sar and Hg(II) indicated that [14]aneN(4) would be an appropriate competing ligand for the, determination of the Hg(II) stability constant. Calculations indicated the ratio of concentrations of AMN3S3sar, [14]aneN(4) and Hg(II) required for the determination of the stability constant ranged from 1:1:1 to 1:5:1. Refinement of the titration curves yielded log(10)K[Hg(AMN(3)S(3)sar)](2+) = 17.7. A similar competition titration resulted in the determination of the stability constant for the AMN(4)S(2)sar system as log(10)K[Hg(AMN(4)S(2)sar)](2+) = 19.5. The observed binding constants for the mixed N/S donor systems and the hexaaza analogues sar (3,6,10,13,16,19-hexaazabicyclo [6.6.6]icosane) and diamsar (1,8-diamino-3,6,10,13,16,19 -hexazabicyclo [6.6.6] icosane (log(10)K-[Hg(diamsar)](2+) = 26.4; log(10)K[Hg(sar)](2+) = 28.1) differ by approximately ten orders of magnitude. The difference is ascribed not to a cryptate effect but to a mismatch in the Hg-N and Hg-S bond lengths in the N/S systems.

The ecological significance of the combtoothed blenny in a coral reef ecosystem

At Heron Island reef, Great Barrier Reef Australia, biomass densities and mean wet mass of Ward's damselfish Pomacentrus wardi and the jewelled blenny Salarias fasciatus were not significantly different at 2-37 v. 2-95 g m(-2) and 8-7 v. 7-9 g, respectively. Whereas S. fasciatus significantly exceeded P. wardi in (1) total number of bites per day (3427 v. 1155), (2) the mass of epilithic algal community consumed per bite (2-19 1,. 0-14mg) and (3) total organic carbon consumed per day (487-31 v. 35-46 mg C m(-2) day(-1)). Territorial behaviour differed also between the two species. Pomacentrus wardi chased from their territories a smaller proportion of blennies than roving grazers (i.e. scarids, acanthurids, siganids and pomacentrids) relative to S. fasciatus. Salarias fasciatus chased c. 90% of other blennies from their territories, while chasing only c. 20% of all damsels that entered. Both P. wardi and S. fasciatus rarely chased non-grazers. The chasing behaviour of S. fascialus was size dependent, with resident fish chasing only individuals of its own family (i.e. Blenniidae) that were the same or smaller size. Pomacentrus wardi may have tolerated S. fasciatus grazing within its territory, as it contributes to territory defence from other blennies. The possibility that the interaction between the two species is facilitative, rather than competitive, is discussed. It was concluded that salariine blennies play an important, and previously underestimated role in coral reef trophodynamics. (C) 2004 The Fisheries Society of the British Isles.

Elucidating the specificity of binding of sulfonylurea herbicides to acetohydroxyacid synthase

Acetohydroxyacid synthase (AHAS, EC 2.2.1.6) is the target for the sulfonylurea herbicides, which act as potent inhibitors of the enzyme. Chlorsulfuron (marketed as Glean) and sulforneturon methyl (marketed as Oust) are two commercially important members of this family of herbicides. Here we report crystal structures of yeast AHAS in complex with chlorsulfuron (at a resolution of 2.19 Angstrom), sulforneturon methyl (2.34 Angstrom), and two other sulfonylureas, metsulfuron methyl (2.29 Angstrom) and tribenuron methyl (2.58 Angstrom). The structures observed suggest why these inhibitors have different potencies and provide clues about the differential effects of mutations in the active site tunnel on various inhibitors. In all of the structures, the thiamin diphosphate cofactor is fragmented, possibly as the result of inhibitor binding. In addition to thiamin diphosphate, AHAS requires FAD for activity. Recently, it has been reported that reduction of FAD can occur as a minor side reaction due to reaction with the carbanion/enamine of the hydroxyethyl-ThDP intermediate that is formed midway through the catalytic cycle. Here we report that the isoalloxazine ring has a bent conformation that would account for its ability to accept electrons from the hydroxyethyl intermediate. Most sequence and mutation data suggest that yeast AHAS is a high-quality model for the plant enzyme.

Australian and New Zealand practice in intensive care (ANZPIC II: The spectrum of practice in the diagnosis and management of pneumonia in patients requiring mechanical ventilation

This study of ventilated patients investigated current clinical practice in 476 episodes of pneumonia (48% community-acquired pneumonia, 24% hospital-acquired pneumonia, 28% ventilator-associated pneumonia) using a prospective survey in 14 intensive care units (ICUs) within Australia and New Zealand. Diagnostic methods and confidence, disease severity, microbiology and antibiotic use were assessed. All pneumonia types had similar mortality (community-acquired pneumonia 33%, hospital-acquired pneumonia 37% and ventilator-associated pneumonia 24%, P = 0.15) with no inter-hospital differences (P = 0.08-0.91). Bronchoscopy was performed in 26%, its use predicted by admission hospital (one tertiary: OR 9.98, CI 95% 5.11-19.49, P < 0.001; one regional: OR 629, CI 95% 3.24-12.20, P < 0.001), clinical signs of consolidation (OR 3.72, CI 95% 2.09-662, P < 0.001) and diagnostic confidence (OR 2.19, CI 95% 1.29-3.72, P = 0.004). Bronchoscopy did not predict outcome (P = 0.11) or appropriate antibiotic selection (P = 0.69). Inappropriate antibiotic prescription was similar for all pneumonia types (11-13%, P = 0.12) and hospitals (0-16%, P = 0.25). Blood cultures were taken in 51% of cases. For community-acquired pneumonia, 70% received a third generation cephalosporin and 65% a macrolide. Third generation cephalosporins were less frequently used for mild infections (OR 0.38, CI 95% 0.16-0.90, P = 0.03), hospital-acquired pneumonia (OR 0.40, CI 95% 0.23-0.72, P < 0.01), ventilator-associated pneumonia (OR 0.04, CI 95% 0.02-0.13, P < 0.001), suspected aspiration (OR 0.20, CI 95% 0.04-0.92, P = 0.04), in one regional (OR 0.26, CI 95% 0.07-0.97, P = 0.05) and one tertiary hospital (OR 0.14, CI 95% 0.03-0.73, P = 0.02) but were more commonly used in older patients (OR 1.02, CI 95% 1.01-1.03, P = 0.01). There is practice variability in bronchoscopy and antibiotic use for pneumonia in Australian and New Zealand ICUs without significant impact on patient outcome, as the prevalence of inappropriate antibiotic prescription is low. There are opportunities for improving microbiological diagnostic work-up for isolation of aetiological pathogens.

Neighborhood environmental factors correlated with walking near home: Using SPACES

Purpose: The physical environment plays an important role in influencing participation in physical activity, although the specific factors that are correlated with different patterns of walking remain to be determined We examined correlations between physical environmental factors and self-reported walking for recreation and transport near home. Methods: The local neighborhood environments (defined as a 400-m radius from the respondent's home) of 1678 adults were assessed for their suitability for walking. The environmental data were collected during 2000 using the Systematic Pedestrian and Cycling Environmental Scan (SPACES) instrument together with information from other sources. We used logistic regression modeling to examine the relationship between the attributes of the physical environment and the self-reported walking behavior undertaken near home. Results: Functional features were correlated with both walking for recreation (odds ratio (OR) 1.62; 95% confidence interval (Cl): 1.20-2.19) and for transport (OR 1.30; 95% Cl: 0.97-1.73). A well-maintained walking surface was the main functional factor associated with walking for recreation (OR 2.04; 95% Cl: 1.43-2.91) and for transport (OR 2.13; 95% Cl: 1.53-2.96). Destination factors, such as shops and public transport, were significantly correlated with walking for transport (OR 1.80; 95% Cl: 1.33-2.44), but not recreation. Conclusion: The findings suggest that neighborhoods with pedestrian facilities that are attractive and comfortable and where there are local destinations (such as shops and public transport) are associated with walking near home.

Structure of the active site of sulfite dehydrogenase from Starkeya novella

In this paper, we report the results of molybdenum K-edge X-ray absorption studies performed on the oxidized and reduced active sites of the sulfite dehydrogenase from Starkeya novella. Our results provide the first direct structural information on the active site of the oxidized form of this enzyme and confirm the conclusions derived from protein crystallography that the molybdenum coordination is analogous to that of the sulfite oxidases. The molybdenum atom of the oxidized enzyme is bound by two Mo=O ligands at 1.73 angstrom and three thiolate Mo-S ligands at 2.42 angstrom, whereas the reduced enzyme has one oxo at 1.74 angstrom, one long oxygen at 2.19 angstrom (characteristic of Mo-OH2), and three Mo-S ligands at 2.40 angstrom.

Heritability and Stability of Resting Blood Pressure in Australian Twins

In Australian twins participating in three different studies (1979-1996), the contribution of genetic and environmental influences to variation in resting systolic (SBP) and diastolic blood pressure (DBP) was studied. The sample consisted of 368 monozygotic and 335 dizygotic twin pairs with measurements for both individuals. Blood pressure measurements in two studies were available for 115 complete twin pairs, and 49 twin pairs had measurements in three studies. This allowed assessment of blood pressure tracking over an average period of 12 years in the age range of 23 to 45 years. Multivariate analyses showed significant heritability (h(2)) of blood pressure in all studies (SBP h(2) = 19%-56%, DBP h(2) = 37%-52%). In addition, the analyses showed that the blood pressure tracking was explained by the same set of genetic factors. These results replicate an earlier finding in Dutch twins that also showed stability of the contribution of genetic factors to blood pressure tracking.

The prevalence and impact of overweight and obesity in an Australian obstetric population

Objective: To assess the prevalence and impact of overweight and obesity in an Australian obstetric population. Design, setting and participants: The Mater Mother's Hospital (MMH), South Brisbane, is an urban tertiary referral maternity hospital. We reviewed data for the 18401 women who were booked for antenatal care at the MMH, delivered between January 1998 and December 2002, and had a singleton pregnancy. Of those women, 14 230 had an estimated pre-pregnancy body mass index (BMI) noted in their record; 2978 women with BMI 40 kg/m(2)). Main outcome measures: Prevalence of overweight and obesity in an obstetric population; maternal, peripartum and neonatal outcomes associated with raised BMI. Results: Of the 14230 women, 6443 (45%) were of normal weight, and 4809 (34%) were overweight, obese or morbidly obese. Overweight, obese and morbidly obese women were at increased risk of adverse outcomes (figures represent adjusted odds ratio [AOR] [95% Cl]): hypertensive disorders of pregnancy (overweight 1.74 [1.45-2.15], obese 3.00 [2.40-3.74], morbidly obese 4.87 [3.27-7.24]); gestational diabetes (overweight 1.78 [1.25-2.52], obese 2.95 [2.05-4.25], morbidly obese 7.44 [4.42-12.54]); hospital admission longer than 5 days (overweight 1.36 [1.13-1.63], obese 1.49 [1.21-1.86], morbidly obese 3.18 [2.19-4.61]); and caesarean section (overweight 1.50 [1.36-1.66], obese 2.02 [1.79-2.29], morbidly obese 2.54 [1.94-3.321). Neonates born to obese and morbidly obese women had an increased risk of birth defects (obese 1.58 (1.02-2.46], morbidly obese 3.41 [1.67-6.94]); and hypoglycaemia (obese 2.57 [1.39-4.78], morbidly obese 7.14 [3.04-16.74]). Neonates born to morbidly obese women were at increased risk of admission to intensive care (2.77 [1.81-4.25]); premature delivery (< 34 weeks' gestation) (2.13 [1.13-4.01]); and jaundice (1.44 [1.09-1.89]). Conclusions: Overweight and obesity are common in pregnant women. Increasing BMI is associated with maternal and neonatal outcomes that may increase the costs of obstetric care. To assist in planning health service delivery, we believe that BMI should be routinely recorded on perinatal data collection sheets

Daily sunscreen application and betacarotene supplementation in prevention of basal-cell and squamous-cell carcinomas of the skin: a randomised controlled trial

Background The use of sunscreens on the skin can prevent sunburn but whether long-term use can prevent skin cancer is not known. Also, there is evidence that oral betacarotene supplementation lowers skin-cancer rates in animals, but there is limited evidence of its effect in human beings. Methods In a community-based randomised trial with a 2 by 2 factorial design, individuals were assigned to four treatment groups: daily application of a sun protection factor 15-plus sunscreen to the head, neck, arms, and hands, and betacarotene supplementation (30 mg per day); sunscreen plus placebo tablets; betacarotene only; or placebo only. Participants were 1621 residents of Nambour in southeast Queensland, Australia. The endpoints after 4.5 years of follow-up were the incidence of basal-cell and squamous-cell carcinomas both in terms of people treated for newly diagnosed disease and in terms of the numbers of tumours that occurred. Analysis of the effect of sunscreen was based only on skin cancers that developed on sites of daily application. All analyses were by intention to treat. Findings 1383 participants underwent full shin examination by a dermatologist in the follow-up period. 250 of them developed 758 new skin cancers during the follow-up period. There were no significant differences in the incidence of first new shin cancers between groups randomly assigned daily sunscreen and no daily sunscreen (basal-cell carcinoma 2588 vs 2509 per 100 000; rate ratio 1.03 [95% CI 0.73-1.46]; squamous-cell carcinoma 876 vs 996 per 100 000; rate ratio 0.88 [0.50-1.56]). Similarly, there was no significant difference between the betacarotene and placebo groups in incidence of either cancer (basal-cell carcinoma 3954 vs 3806 per 100 000; 1.04 [0.73-1.27]; squamous-cell carcinoma 1508 vs 1146 per 100 000; 1.35 [0.84-2.19]). In terms of the number of tumours, there was no effect on incidence of basal-cell carcinoma by sunscreen use or by betacarotene but the incidence of squamous-cell carcinoma was significantly lower in the sunscreen group than in the no daily sunscreen group (1115 vs 1832 per 100 000; 0.61 [0.46-0.81]). Interpretation There was no harmful effect of daily use of sunscreen in this medium-term study. Cutaneous squamous-cell carcinoma, but not basal-cell carcinoma seems to be amenable to prevention through the routine use of sunscreen by adults for 4.5 years. There was no beneficial or harmful effect on the rates of either type of skin cancer, as a result of betacarotene supplementation.