Release of prostaglandins from the rabbit renal medulla

Prostaglandin E₂-like material was released in large amounts from the rabbit renal papilla incubated in various media. Angiotensin I and II, bradykinin, noradrenaline and various other vasoactive agents did not influence significantly the spontaneous release of prostaglandin. Indomethacin produced a dose-dependent inhibition of prostaglandin release from our preparation. Our results indicate that the release of renal prostaglandins previously reported in response to angiotensin and noradrenaline is not due to a direct action of these agents upon the renal papillary tissue. Our data also confirm that the release of prostaglandin-like material from our preparation is the consequence of new synthesis.     

Optimal population designs for PK models with serial sampling

In various pharmaceutical applications, repeated measurements are taken from each subject, and model parameters are estimated from the collected data. Examples include dose response modeling and PK/PD studies with serial blood sampling, among others. The quality of the information in an experiment is reflected in the precision of estimates of model parameters, which is traditionally measured by their variance-covariance matrix. In this article, we concentrate on the example of a clinical PK study where multiple blood samples are taken for each enrolled patient, which leads to nonlinear mixed effects regression models with multiple responses. The sampling scheme for each patient is considered a multidimensional point in the space of admissible sampling sequences. We demonstrate how to optimize the precision of parameter estimates by finding the best number and allocation of sampling times. It is shown that a reduced number of samples may be taken without significant loss of precision of parameter estimates. Moreover, our approach allows for taking experimental costs into account, which leads to a more meaningful comparison of sampling schemes and to potential cost savings.     

Interseasonal variability in biomarkers of exposure in fish inhabiting a southwestern Australian estuary

The Swan-Canning Estuary, in southwestern Australia, undergoes distinct seasonal changes, with freshwater discharge predominant in the winter (wet) season and low flow with high salinity predominant in the dry summer season. To investigate seasonal variability in biomarkers of exposure in fish, black bream (Acanthopagrus butcheri) were collected from seven sites in the Swan-Canning Estuary in winter 2000 and in summer 2001. No interseasonal or intersite differences in serum sorbitol dehydrogenase concentration were found, indicating the measured mixed-function oxygenase (MFO) enzymes were not influenced by liver damage. The ethoxyresorufin-O-deethlyase (EROD) activity of the postspawning females was higher in summer than in winter but was significantly lower than that in males in both seasons, suggesting estradiol suppression in females. Sexual differences in ethoxycoumarin-O-deethylase (ECOD) activity were not evident in either season. Both EROD and ECOD activities and polycyclic aromatic hydrocarbons (PAH) biliary metabolites had significantly different patterns of induction between seasons. The ratio of naphthalene-type to benzo(a)pyrene-type biliary metabolites was significantly higher in summer, indicating the sources of petroleum hydrocarbons were petrogenic compared to in winter, when the source was a mixture of pyrogenic and petrogenic PAHs. There was no upstream or downstream gradient of response in any biomarker in either season, demonstrating that there were multiple sources of contaminant input into the estuary. Although winter biomarker levels were triggered by the discharge runoff from major roads and drains, summer biomarker levels appear to have been related to recreational boating use on the estuary.     

Alterations of Metabolic Enzymes in Australian Bass, Macquaria novemaculeata, After Exposure to Petroleum Hydrocarbons

Australian bass Macquaria novemaculeata were exposed to the water-accommodated fraction of Bass Strait crude oil, dispersed crude oil, or burnt crude oil to assess sublethal effects of oil spill remediation techniques on fish. Fish were exposed to these treatments for 16 days either through the water column or by way of a pre-exposed diet of amphipod Allorchestes compressa. Fish gills, liver, and white muscle were sampled and cytochrome C oxidase (CCO) and lactate dehydrogenase (LDH) activities quantified. In all treatments containing fish exposed by way of the water column, aerobic activity increased in the gills, whereas a decrease of this enzymic activity was observed in the liver and white muscle. Exposures by way of the food pathway indicated similar trends. Anaerobic (LDH) activity increased in the gills, liver, and white muscle after waterborne exposures. Stimulation in anaerobic activity also occurred in the liver and white muscle of fish after exposure to contaminated food. CCO activity in the gills was the most sensitive biomarker when monitoring waterborne exposures to petroleum hydrocarbons. In the gills, the dispersed oil treatment resulted in the most pronounced biological response, suggesting that in the short term the use of dispersants on an oil slick might cause the most perturbations to fish metabolism.     

Interannual variability in fish biomarkers in a contaminated temperate urban estuary

During the past decade the Swan-Canning estuary, Western Australia, has shown signs of stress which has been attributed to high nutrient inputs. There is little information on the effect of nonnutrient contaminants on biota inhabiting the estuary. A suite of biomarkers was measured on black bream (Acanthopagrus butcheri) to determine whether annual variations in fish biomarkers exist in the wet (winter) and dry (summer) seasons. Serum sorbitol dehydrogenase showed no significant differences between years, indicating that measured mixed-function oxygenase (MFO) enzyme activities were not affected by annual variations in hepatic tissue damage. Ethoxyresorufin-O-deethylase activity was lower in female black bream than in male fish while ethoxycoumarin-O-deethylase activity was not influenced by gender. Biomarker levels measured at various sites confirm that major roads and drains are significant contributors of MFO-inducing chemicals into the Swan-Canning estuary. No consistent upstream or downstream gradient in biomarker response was identified. The ratio of naphthalene-type to benzo(a)pyrene-type biliary metabolites was linked to runoff from urban areas into the estuary. There was high annual variability in all biomarkers in both seasons, suggesting that biannual monitoring is required to evaluate the effect of contaminants on the biota in the estuary.     

A prospective assessment of mortality in chronic spinal cord injury

STUDY DESIGN: Prospective mortality study. OBJECTIVE: To assess the relationship between comorbid medical conditions and other health-related factors to mortality in chronic spinal cord injury (SCI). SETTING: Boston, MA, USA. METHODS: Between 1994 and 2000, 361 males >/=1 year after injury completed a respiratory health questionnaire and underwent pulmonary function testing. Cause-specific mortality was assessed over a median of 55.6 months (range 0.33-74.4 months) through 12/31/2000 using the National Death Index. RESULTS: At entry, mean (+/-SD) age was 50.6+/-15.0 years (range 23-87) and years since injury was 17.5+/-12.8 years (range 1.0-56.5). Mortality was elevated (observed/expected deaths=37/25.1; SMR=1.47; 95% CI=1.04-2.03) compared to US rates. Risk factors for death were diabetes (RR=2.62; 95% CI=1.19-5.77), heart disease (RR=3.66; 95% CI=1.77-7.78), reduced pulmonary function, and smoking. The most common underlying and contributing causes of death were diseases of the circulatory system (ICD-9 390-459) in 40%, and of the respiratory system in 24% (ICD-9 460-519). CONCLUSIONS: These results suggest that much of the excess mortality in chronic SCI is related to potentially treatable factors. Recognition and treatment of cardiovascular disease, diabetes, and lung disease, together with smoking cessation may substantially reduce mortality in chronic SCI.     

Genome-wide identity-by-descent sharing among CEPH siblings

The concept of genetic identity-by-descent (IBD) has markedly advanced our understanding of the genetic similarity among relatives and triggered a number of developments in epidemiological genetics. However, no empirical measure of this relatedness throughout the whole human genome has yet been published. Analyzing highly polymorphic genetic variations from the Centre d'études du polymorphisme humain (CEPH) database, we report the first genome-wide estimation of the mean and variation in IBD sharing among siblings. From 1,522 microsatellite markers spaced at an average of 2.3 cM on 498 sibling pairs, we estimated a mean of 0.4994 and a standard deviation of 0.0395. In order to account for the impact of varying chromosomal lengths and recombination rates, the analysis was also performed at the chromosomal and marker levels and for paternal and maternal DNA separately. Based on the variation, we estimate an "effective number of segregating loci" of around 80 for sibling pairs over the whole genome (i.e., the number of loci that would yield the same standard deviation in IBD sharing if all loci were segregating independently). Finally, we briefly assess the impact of genotyping errors on IBD estimations, compare our results to published theoretical and simulated expectations, and discuss some implications of our findings.