Disposition kinetics of propranolol isomers in the perfused rat liver

The aim of this study was to define the determinants of the linear hepatic disposition kinetics of propranolol optical isomers using a perfused rat liver. Monensin was used to abolish the lysosomal proton gradient to allow an estimation of propranolol ion trapping by hepatic acidic vesicles. In vitro studies were used for independent estimates of microsomal binding and intrinsic clearance. Hepatic extraction and mean transit time were determined from outflow-concentration profiles using a nonparametric method. Kinetic parameters were derived from a physiologically based pharmacokinetic model. Modeling showed an approximate 34-fold decrease in ion trapping following monensin treatment. The observed model-derived ion trapping was similar to estimated theoretical values. No differences in ion-trapping values was found between R(+)- and S(-)- propranolol. Hepatic propranolol extraction was sensitive to changes in liver perfusate flow, permeability-surface area product, and intrinsic clearance. Ion trapping, microsomal and nonspecific binding, and distribution of unbound propranolol accounted for 47.4, 47.1, and 5.5% of the sequestration of propranolol in the liver, respectively. It is concluded that the physiologically more active S(-)- propranolol differs from the R(+)- isomer in higher permeability-surface area product, intrinsic clearance, and intracellular binding site values.

Increased duodenal expression of divalent metal transporter 1 and iron-regulated gene 1 in cirrhosis

Hepatic hemosiderosis and increased iron absorption are common findings in cirrhosis. It has been proposed that a positive relation exists between intestinal iron absorption and the development of hepatic hemosiderosis. The current study investigated the duodenal expression of the iron transport molecules divalent metal transporter 1 (DMT1 [IRE]), iron-regulated gene 1 (Ireg1 [ferroportin]), hephaestin, and duodenal cytochrome b (Dyctb) in 46 patients with cirrhosis and 20 control subjects. Total RNA samples were extracted from duodenal biopsy samples and the expression of the iron transport genes was assessed by ribonuclease protection assays. Expression of DMT1 and Ireg1 was increased 1.5 to 3-fold in subjects with cirrhosis compared with iron-replete control subjects. The presence of cirrhosis per se and serum ferritin (SF) concentration were independent factors that influenced the expression of DMT1. However, only SF concentration was independently associated with Iregl expression. In cirrhosis, the expression of DMT1 and Iregl was not related to the severity of liver disease or cirrhosis type. There was no correlation between the duodenal expression of DMT1 and Iregl and the degree of hepatic siderosis. In conclusion, the presence of cirrhosis is an independent factor associated with increased expression of DMT1 but not Iregl. The mechanism by which cirrhosis mediates this change in DMT1 expression has yet to be determined. Increased expression of DMT1 may play an important role in the pathogenesis of cirrhosis-associated hepatic iron overload.

The immediate and long term effects of singing on the mood states of people with traumatic brain injury

Mood changes in four male participants with traumatic brain injury (TBI) were observed following their participation in a 15-session song-singing programme. An analysis of the song material was undertaken to categorise the songs according to the predominant mood they portrayed. Results showed significant differences between participants for all moods (p

Participatory approach for the identification of dairy industry needs in the design of research, development and extension actions: Australian and Brazilian case studies

In both Australia and Brazil there are rapid changes occurring in the macroenvironment of the dairy industry. These changes are sometimes not noticed in the microenvironment of the farm, due to the labour-intensive nature of family farms, and the traditionally weak links between production and marketing. Trends in the external environment need to be discussed in a cooperative framework, to plan integrated actions for the dairy community as a whole and to demand actions from research, development and extension (R, D & E). This paper reviews the evolution of R, D & E in terms of paradigms and approaches, the present strategies used to identify dairy industry needs in Australia and Brazil, and presents a participatory strategy to design R, D & E actions for both countries. The strategy incorporates an integration of the opinions of key industry actors ( defined as members of the dairy and associated communities), especially farm suppliers ( input market), farmers, R, D & E people, milk processors and credit providers. The strategy also uses case studies with farm stays, purposive sampling, snowball interviewing techniques, semi-structured interviews, content analysis, focus group meetings, and feedback analysis, to refine the priorities for R, D & E actions in the region.

Association between chronic fatigue syndrome and the corticosteroid-binding globulin gene ALA SER224 polymorphism

Chronic fatigue syndrome (CFS) is characterized by idiopathic fatigue of greater than 6 months' duration with postexertional exacerbation and many other symptoms. A trend toward relative hypocortisolism is described in CFS. Twin and family studies indicate a substantial genetic etiologic component to CFS. Recently, severe corticosteroid-binding globulin (CBG) gene mutations have been associated with CFS in isolated kindreds. Human leukocyte elastase, an enzyme important in CBG catabolism at inflammatory sites, is reported to be elevated in CFS. We hypothesized that CBG gene polymorphisms may act as a genetic risk factor for CFS. A total of 248 patients with CFS defined by Centers for Disease Control criteria, and 248 controls were recruited. Sequencing and restriction enzyme testing of the CBG gene coding region allowed detection of severe CBG gene mutations and a common exon 3 polymorphism (c.825G --> T, Ala-Ser(224)). Plasma CBG levels were measured in 125 CFS patients and 198 controls by radioimmunoassay. Total and free (calculated and measured) cortisol levels were ascertained in single samples between 8-10 a.m. The age of onset (mid 30s) and gender ratio (2.2:1, female:male) of the patients were similar to those reported in U.S. epidemiologic studies. A trend toward a preponderance of serine(224) homozygosity among the CFS patients was noted, compared with controls (chi(2) = 5.31, P = 0.07). Immunoreactive-CBG (IR-CBG) levels were higher in Serine/Alanine (Ser/Ala) than Ala/Ala subjects and higher again in Ser/Ser subjects, this effect was strongest in controls; Ser/Ser: 46.1 +/- 1.8 (n = 31, P = 0.03) vs. Ser/Ala: 42.4 +/- 1.0 (n = 56, P = 0.05) vs. Ala/Ala: 40.8 +/- 1.7 mug/mL (n = 21). Despite higher CBG levels, there was a nonsignificant trend toward lower total and free plasma cortisol in serine allele positive patients, total cortisol: Ser/Ser: 13.3 +/- 1.4 (n = 34) vs. Ser/Ala: 14.0 +/- 0.7 (n = 66) vs. Ala/Ala: 15.4 +/- 1.0 (n = 23). Homozygosity for the serine allele of the CBG gene may predispose to CFS, perhaps due to an effect on hypothalamic-pituitary-adrenal axis function related to altered CBG-cortisol transport function or immune-cortisol interactions.

Do socioeconomic gradients in women's health widen over time and with age

A population-based study was conducted to investigate changes over time in women's well-being and health service use by socio-cconomic status and whether these varied by age. Data from 12,328 mid-age women (aged 45-50 years in 1996) and 10,430 older women (aged 70-75 years) from the Australian Longitudinal Study on Women's Health were analysed. The main outcome measures were changes in the eight dimensions of the Short Form General Health Survey (SF-36) adjusted for baseline scores, lifestyle and behavioural factors; health care utilisation at Survey 2; and rate of deaths (older cohort only). Cross-sectional analyses showed clear socioeconomic differentials in well-being for both cohorts. Differential changes in health across tertiles of socioeconomic status (SES) were more evident in the mid-age cohort than in the older cohort. For the mid-aged women in the low SES tertile, declines in physical functioning (adjusted mean change of -2.4, standard error (SE) 1.1) and general health perceptions (-1.5, SE 1.1) were larger than the high SES group (physical functioning -0.8 SE 1.1, general health perceptions -0.8 SE 1.2). In the older cohort, changes in SF-36 scores over time were similar for all SES groups but women in the high SES group had lower death rates than women in the low SES group (relative risk: 0.79, 95% confidence interval 0.64-0.98). Findings suggest that SES differentials in physical health seem to widen during women's mid-adult years but narrow in older age. Nevertheless, SES remains an important predictor of health, health service use and mortality in older Australian women. (C) 2003 Elsevier Ltd. All rights reserved.

Multiple imputation for body mass index: lessons from the Australian Longitudinal Study on Women's Health

In large epidemiological studies missing data can be a problem, especially if information is sought on a sensitive topic or when a composite measure is calculated from several variables each affected by missing values. Multiple imputation is the method of choice for 'filling in' missing data based on associations among variables. Using an example about body mass index from the Australian Longitudinal Study on Women's Health, we identify a subset of variables that are particularly useful for imputing values for the target variables. Then we illustrate two uses of multiple imputation. The first is to examine and correct for bias when data are not missing completely at random. The second is to impute missing values for an important covariate; in this case omission from the imputation process of variables to be used in the analysis may introduce bias. We conclude with several recommendations for handling issues of missing data. Copyright (C) 2004 John Wiley Sons, Ltd.