Modulation of cytochrome P450 monooxygenase by cadmium chloride in the mouse liver: Involvement of transcription factor Nrf2.

Modulation of the cytochrome P450 (CYP) monooxygenase system and haem oxygenase by cadmium was investigated in male, adult DBA/2J mice treated with a single dose (16 Amol/kg body weight, i.p.) of cadmium chloride (CdCl2), at various time points. Total CYP content of liver microsomes decreased significantly (P < 0.05) at 12, 18, and 24 hours (22%, 47%, and 56%, respectively) after treatment. In contrast, progressive increases of hepatic coumarin 7-hydroxylase (COH) activity (indicative of CYP2A5 activity) were observed at 8 hrs (2-fold), 12 hrs (3-fold), and 7-fold at 18 and 24 hrs. Simultaneously, haem oxygenase activity increased significantly at 4 hours and continued to increase progressively to more than 50-fold compared to control. Liver CYP2A5 mRNA levels increased maximally 12 hours after treatment and decreased to almost half 6 hours later, while western blot analysis showed 2- and 3- fold increase in CYP2A5 apoprotein at 12 and 24 hours. The CYP2A5 mRNA levels in the liver increased after Cd treatment in Nrf2 +/+ but not in Nrf2 / mouse. This study demonstrates that hepatic haem oxygenase and CYP2A5 are upregulated by cadmium. The upregulation of haem oxygenase precedes that of CYP2A5. The strong upregulation of the CYP2A5 both at mRNA and enzyme activity levels, with a simultaneous decrease in the total CYP concentration suggest an unusual mode of regulation of CYP2A5 in response to cadmium exposure, amongst the CYP enzymes. The observed increase in the mRNA but not in protein levels after maximal induction may suggest involvement of post-transcriptional mechanisms in the regulation. Upregulation of CYP2A5 by cadmium in the Nrf2 +/+ mice but not in the Nrf2 / mice indicates a role for this transcription factor in the regulation.

Variable effects of larval size on post-metamorphic performance in the field

Larval quality may be capable of explaining much of the variation in the recruitment and subsequent population dynamics of benthic marine invertebrates. Whilst the effects of larval nutritional condition on adult performance have received the most attention, recent work has shown that larval size may also be an important and ubiquitous source of variation in larval quality. We examined the effects of variation in larval size on the post-metamorphic survival and growth of Watersipora subtorquata in 2 very different habitats - experimental substrata and pier pilings. We found strong effects of larval size on colony performance, although these varied among experiments. For colonies on experimental substrata, larval size positively affected adult survival and, initially, growth. However, after 3 wk in the field, there was no relationship between larval size and colony size, possibly because colonies were completely surrounded by newly settled organisms. Larval size also positively affected post-metamorphic growth of colonies on pier pilings, but, surprisingly, colonies that came from larger larvae had lower survival than colonies from smaller larvae. Overall, variation in larval size will strongly affect the recruitment and subsequent performance of adults in this species, although this may vary among different habitats. This study highlights the importance of examining the effects of larval quality on adult performance in as realistic conditions as possible, because of the strong interaction between larval size effects and the environment.

Post-familial families and the domestic division of labour

This paper takes as its starting point recent claims by Beck-Gernsheim (2002) that we are living in an era of post-familial families. Beck-Gernsheim (2002) argues that our lives are no longer structured as they once were by tradition, class, religion and kin. Instead the family has become a transitional phase as individuals strive for fulfillment of personal goals and personal life projects. The demographic evidence to support these claims is clearly evident in relation to changing patterns of family formation and dissolution, as well as the movement of married women into paid employment. But what is less evident is a decline in traditional patterns of gender stratification within families. This paper uses recent national data from Australia to examine the relationship between post-familial status, as indicated by marital status and employment, and time spent on housework. The results show that gender is still a clear predictor of time spent on housework, but that within gender there is evidence that gender inequality may be declining in non-traditional households.

Not so ancient: the extant crown group of Nothofagus represents a post-Gondwanan radiation

This study uses a molecular-dating approach to test hypotheses about the biogeography of Nothofagus. The molecular modelling suggests that the present-day subgenera and species date from a radiation that most likely commenced between 55 and 40 Myr ago. This rules out the possibility of a reconciled all-vicariance hypothesis for the biogeography of extant Nothofagus. However, the molecular dates for divergences between Australasian and South American taxa are consistent with the rifting of Australia and South America from Antarctica. The molecular dates further suggest a dispersal of subgenera Lophozonia and Fuscospora between Australia and New Zealand after the onset of the Antarctic Circumpolar Current and west wind drift. It appears likely that the New Caledonian lineage of subgenus Brassospora diverged from the New Guinean lineage elsewhere, prior to colonizing New Caledonia. The molecular approach strongly supports fossil-based estimates that Nothofagus diverged from the rest of Fagales more than 84 Myr ago. However, the mid-Cenozoic estimate for the diversification of the four extant subgenera conflicts with the palynological interpretation because pollen fossils, attributed to all four extant subgenera, were widespread across the Weddellian province of Gondwana about 71 Myr ago. The discrepancy between the pollen and molecular dates exists even when confidence intervals from several sources of error are taken into account. In contrast, the molecular age estimates are consistent with macrofossil dates. The incongruence between pollen fossils and molecular dates could be resolved if the early pollen types represent extinct lineages, with similar types later evolving independently in the extant lineages.

Psychosocial sequelae of the 1989 Newcastle earthquake .2. Exposure and morbidity profiles during the first 2 years post-disaster

Background. A sample of 1089 Australian adults was selected for the longitudinal component of the Quake Impact Study, a 2-year, four-phase investigation of the psychosocial effects of the 1989 Newcastle earthquake. Of these, 845 (78%) completed a survey 6 months post-disaster as well as one or more of the three follow-up surveys. Methods. The phase I survey was used to construct dimensional indices of self-reported exposure to threat the disruption and also to classify subjects by their membership of five 'at risk' groups (the injured; the displaced; owners of damaged small businesses; helpers in threat and non-threat situations). Psychological morbidity was assessed at each phase using the 12-item General Health Questionnaire (GHQ-12) and the Impact of Event Scale (IES). Results. Psychological morbidity declined over time but tended to stabilize at about 12 months post-disaster for general morbidity (GHQ-12) and at about 18 months for trauma-related (IES) morbidity. Initial exposure to threat and/or disruption were significant predictors of psychological morbidity throughout the study and had superior predictive power to membership of the targeted 'at risk' groups. The degree of ongoing disruption and other life events since the earthquake were also significant predictors of morbidity. The injured reported the highest levels of distress, but there was a relative absence of morbidity among the helpers. Conclusions. Future disaster research should carefully assess the threat and disruption experiences of the survivors at the time of the event and monitor ongoing disruptions in the aftermath in order to target interventions more effectively.

Risk factors for post-stroke depression

Objective. To examine possible risk factors in post-stroke depression (PSD) other than site of lesion in the brain Data sources. 191 first-ever stroke patients were examined physically shortly after their stroke and examined psychiatrically and physically 4 months post-stroke. Setting. A geographically defined segment of the metropolitan area of Perth, Western Australia, from which all strokes over a course of 18 months were examined (the Perth Community Stroke Study). Measures. Psychiatric Assessment Schedule, Mini Mental State Examination, Barthel Index, Frenchay Activities Index, physical illness and sociodemographic data were collected. Post-stroke depression (PSD) included both major depression and minor depression (dysthymia without the 2-year time stipulation) according to DSM-III (American Psychiatric Association) criteria. Patients depressed at the time of the stroke were excluded. Patients. 191 first-ever stroke patients, 111M, 80F, 28% had PSD, 17% major and 11% minor depression. Results. Significant associations with PSD at 4 months were major functional impairment, living in a nursing home, being divorced and having a high pre-stroke alcohol intake (M only). There was no significant association with age, sex, social class, cognitive impairment or pre-stroke physical illness. Conclusion. Results favoured the hypothesis that depression in an unselected group of stroke patients is no more common, and of no more specific aetiology, than it is among elderly patients with other physical illness.

Eye-movements and visual imagery: A working memory approach to the treatment of post-traumatic stress disorder

It has been claimed that the symptoms of post-traumatic stress disorder (PTSD) can be ameliorated by eye-movement desensitization-reprocessing therapy (EMD-R), a procedure that involves the individual making saccadic eye-movements while imagining the traumatic event. We hypothesized that these eye-movements reduce the vividness of distressing images by disrupting the function of the visuospatial sketchpad (VSSP) of working memory, and that by doing so they reduce the intensity of the emotion associated with the image. This hypothesis was tested by asking non-PTSD participants to form images of neutral and negative pictures under dual task conditions. Their images were less vivid with concurrent eye-movements and with a concurrent spatial tapping task that did not involve eye-movements. In the first three experiments, these secondary tasks did not consistently affect participants' emotional responses to the images. However, Expt 4 used personal recollections as stimuli for the imagery task, and demonstrated a significant reduction in emotional response under the same dual task conditions. These results suggest that, if EMD-R works, it does so by reducing the vividness and emotiveness of traumatic images via the VSSP of working memory. Other visuospatial tasks may also be of therapeutic value.

Ethanol feeding enhances inflammatory cytokine expression in lipopolysaccharide-induced hepatitis

Elevated concentrations of plasma tumour necrosis factor (TNF)-alpha, interleukin (IL)-1 and IL-6 have been detected in patients with alcoholic hepatitis and have been implicated in the pathogenesis of hepatocyte necrosis. The present study used a rat model to conduct a detailed histological and biochemical examination of the expression of various pro-inflammatory cytokines and associated liver pathology in ethanol-potentiated lipopolysaccharide (LPS)-induced liver injury. Male Wistar rats were pair-fed either the control or ethanol-containing (36% of caloric intake as ethanol) form of the Lieber-DeCarli liquid diet for 6 weeks. Liver injury was induced by the i.v. injection of LPS (1 mu g/g bodyweight), with animals being killed at O, 1, 3, 6, 12 and 24 h after injection. At the later time points, plasma transaminase and transpeptidase activities were significantly elevated in ethanol-fed LPS-treated rats compared with control-fed LPS-treated animals. At these times after LPS treatment, hepatocytes in ethanol-fed animals displayed fatty change and necrosis with an associated neutrophil polymorph infiltrate. Time course analysis revealed that plasma TNF-alpha (1-3 h post-LPS) and IL-6 (3 h post-LPS) bioactivity was significantly elevated in ethanol-fed compared with control-fed animals. No difference was seen in plasma IL-1 alpha concentration (maximal in both groups 6 h post-LPS). The expression of TNF-alpha, IL-1 alpha, IL-1 beta and IL-6 mRNA were elevated between 1 and 6 h post-LPS in the livers of both control and ethanol-fed rats. However, ethanol-fed LPS-treated animals exhibited significantly higher maximal expression of IL-1 and IL-6 mRNA. Comparison of the appearance of cytokine mRNA and plasma bioactivity indicated an effect of ethanol feeding on post-transcriptional processing and/or the kinetics of the circulating cytokines. Elevated levels of both hepatic cytokine mRNA expression and the preceding plasma cytokines are presumably a necessary prerequisite for hepatic injury seen in this model and, therefore, possibly for the damage seen in human alcoholics. Further studies using this model may lead to significant advances in our understanding of the pathogenic mechanisms of alcoholic liver disease in humans.

Mini-microabscess syndrome in liver transplant recipients

Cytomegalovirus (CMV) is a significant cause of morbidity in immunosuppressed patients. It is characterized in the liver by parenchymal microabscesses, usually containing CMV-infected cells. However, not all hepatic microabscesses are due to CMV infection. In 1992, we described ''mini'' microabscess (MMA) syndrome, a distinct clinical syndrome that occurs in transplanted livers. This report analyzes the clinical and laboratory features of 57 cases of MMA syndrome occurring in 52 patients and compares these with 19 biopsy-proven cases of CMV infection. The diagnosis of MMA syndrome can only be made histologically. The microabscesses are smaller and more numerous than in CMV infection, and there are no viral inclusions present. CMV DNA could not be detected in liver biopsy specimens with MMAs by using ''nested'' polymerase chain reaction (PCR), indicating that MMA syndrome is not caused by CMV infection. The pattern of liver enzyme and bilirubin elevation is predominantly hepatocellular, with transaminase levels elevated, on average, six to eight times the upper limit of normal. The clinical features of MMA syndrome are that it predominantly affects female (40 of 52 patients) orthotopic liver transplant (OLT) recipients of all ages (range, 11 months to 66.9 years). MMA syndrome is unrelated to the indication for initial OLT and tends to occur later after transplantation than CMV infection (median, 91 days post-OLT vs. 32 days for CMV hepatitis). Although the etiology of MMA syndrome is not clear, it does not appear to adversely affect graft or patient survival.

On the validity of the dispersion model of hepatic drug elimination when intravascular transit time densities are long-tailed

The dispersion model with mixed boundary conditions uses a single parameter, the dispersion number, to describe the hepatic elimination of xenobiotics and endogenous substances. An implicit a priori assumption of the model is that the transit time density of intravascular indicators is approximated by an inverse Gaussian distribution. This approximation is limited in that the model poorly describes the tail part of the hepatic outflow curves of vascular indicators. A sum of two inverse Gaussian functions is proposed as ail alternative, more flexible empirical model for transit time densities of vascular references. This model suggests that a more accurate description of the tail portion of vascular reference curves yields an elimination rate constant (or intrinsic clearance) which is 40% less than predicted by the dispersion model with mixed boundary conditions. The results emphasize the need to accurately describe outflow curves in using them as a basis for determining pharmacokinetic parameters using hepatic elimination models. (C) 1997 Society for Mathematical Biology.

Interconnected-tubes model of hepatic elimination

The distributed-tubes model of hepatic elimination is extended to include intermixing between sinusoids, resulting in the formulation of a new, interconnected-tubes model. The new model is analysed for the simple case of two interconnected tubes, where an exact solution is obtained. For the case of many strongly-interconnected tubes, it is shown that a zeroth-order approximation leads to the convection-dispersion model. As a consequence the dispersion number is expressed, for the first time, in terms of its main physiological determinants: heterogeneity of flow and density of interconnections between sinusoids. The analysis of multiple indicator dilution data from a perfused liver preparation using the simplest version of the model yields the estimate 10.3 for the average number of interconnections. The problem of boundary conditions for the dispersion model is considered from the viewpoint that the dispersion-convection equation is a zeroth-order approximation to the equations for the interconnected-tubes model. (C) 1997 Academic Press Limited.