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.

The role of the complement system in ischemia-reperfusion injury

Ischemia-reperfusion (I/R) injury is a common clinical event with the potential to seriously affect, and sometimes kill, the patient. Interruption of blood supply causes ischemia, which rapidly damages metabolically active tissues. Paradoxically, restoration of blood flow to the ischemic tissues initiates a cascade of pathology that leads to additional cell or tissue injury. I/R is a potent inducer of complement activation that results in the production of a number of inflammatory mediators. The use of specific inhibitors to block complement activation has been shown to prevent local tissue injury after I/R. Clinical and experimental studies in gut, kidney, limb, and liver have shown that I/R results in local activation of the complement system and leads to the production of the complement factors C3a, C5a, and the membrane attack complex. The novel inhibitors of complement products may find wide clinical application because there are no effective drug therapies currently available to treat I/R injuries.

International evaluation of current and future requirements for environmental engineering education

The field of environmental engineering is developing as a result of changing environmental requirements. In response, environmental engineering education (E3) needs to ensure that it provides students with the necessary tools to address these challenges. In this paper the current status and future development of E3 is evaluated based on a questionnaire sent to universities and potential employers of E3 graduates. With increasing demands on environmental quality, the complexity of environmental engineering problems to be solved can be expected to increase. To find solutions environmental engineers will need to work in interdisciplinary teams. Based on the questionnaire there was a broad agreement that the best way to prepare students for these future challenges is to provide them with a fundamental education in basic sciences and related engineering fields. Many exciting developments in the environmental engineering profession will be located at the interface between engineering, science, and society. Aspects of all three areas need to be included in E3 and the student needs to be exposed to the tensions associated with linking the three.

Impact of social group processes and functional diversity on communication in networked organizations

This study examines the role of social group processes in perceptions of effective communication in Australian Cooperative Research Centres (CRCs). Communication professionals in 25 CRCs discussed the barriers and opportunities for communication in their diverse networked organizations. Thematic analysis of the transcripts highlighted the contribution of social group processes to both barriers and opportunities. Communication challenges implicated the social identity of organizational members, many of which were associated with distinct structural aspects of these organizations. Opportunities for communication frequently involved features that implicated social identity, including taking advantage of existing organizational or industry identities, preventing conflicting identities from becoming salient, and promoting a collective CRC identity.

The other side of the coin: safety of complementary and alternative medicine

Most consumers consider complementary and alternative medicine (CAM) products inherently safe. The growing simultaneous use of CAM products and pharmaceutical drugs by Australian consumers increases the risk of CAM-drug interactions. The Therapeutic Goods Administration (TGA) has a two-tier, risk-based regulatory system for therapeutic goods - CAM products are regulated as low risk products and are assessed for quality and safety; and sponsors of products must hold the evidence for any claim of efficacy made about them. Adverse reactions to CAM products can be classified as intrinsic (innate to the product), or extrinsic (where the risk is not related to the product itself, but results from the failure of good manufacturing practice). Adverse reactions to CAM practices can be classified as risks of commission (which includes removal of medical therapy) and risks of omission (which includes failure to refer when appropriate). While few systematic studies of adverse events with CAM exist, and under-reporting is likely, most CAM products and practices do not appear to present a high risk; their safety needs to be put into the perspective of wider safety issues. A priority for research is to rigorously define the risks associated with both CAM products and practices so that their potential impact on public health can be assessed.

Injury and risk-taking behavior - a systematic review

There is a substantial body of work in the scientific literature discussing the role of risk-taking behavior in the causation of injury. Despite the quantity of diverse writings on the subject most is in the form of theoretical commentaries. This review was conducted to critically assess the empirical evidence supporting the association between injury and risk-taking behavior. The review found six case-control studies and one retrospective cohort study, which met all the inclusion criteria. Meta-analysis was not possible due to the diversity of the independent and outcome variables in each of the studies reviewed. Overall the review found that risk-taking behavior, however it is measured, is associated with an increased chance of sustaining an injury except in the case of high skilled, risk-taking sports where the effect may be in the other direction. Drawing specific conclusions from the research presented in this review is difficult without an agreed conceptual framework for examining risk-taking behavior and injury. Considerable work needs to be done to provide a convincing evidence base on which to build public health interventions around risk behavior. However, sufficient evidence exists to suggest that effort in this area may be beneficial for the health of the community. (C) 2003 Elsevier Science Ltd. All rights reserved.

Academic journal publishing: Desiderata for the digital age

The consumption of academic journals has radically changed over the past decade, explains the author. While there has been an exponential rise in published scholarship, spiralling costs for commercial journals have caused cutbacks in subscriptions to academic journals by institutional libraries and raised calls for free online access to unpublished work that scholars have produced. The rise of the Internet has facilitated a concomitant growth in online scholarship. What, asks the author, are the promises on online scholarship?

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.

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.

Schistosome transcriptome analysis at the cutting edge

We live in the era of post-genomics, a term that was, until recently, inappropriate when considering the blood flukes of humans because of the relative lack of knowledge of the schistosome genome. The position has, however, changed dramatically following the recent publication of two landmark papers on transcriptome analysis of Schistosoma japonicum and Schistosoma mansoni. In a quantum leap, both studies report on the identification of many novel genes and genes not previously known from schistosomes. The datasets provide new insights into the biology of the schistosomes and offer an opportunity for identification of potential antischistosome vaccine candidates and drug targets. Remarkable recent progress has also been achieved in genomic sequencing, and completed genomes for both species can be expected shortly.

Functional expression and characterization of Eehinococcus granulosus thioredoxin peroxidase suggests a role in protection against oxidative damage

A full-length cDNA sequence coding for Echinococcus granulosus thioredoxin peroxidase (EgTPx) was isolated from a sheep strain protoscolex cDNA library by immunoscreening using a pool of sera from mice infected with oncospheres. EgTPx expressed as a fusion protein with glutathione S-transferase (GST) exhibited significant thiol-dependent peroxidase activity that protected plasmid DNA from damage by metal-catalyzed oxidation (MCO) in vitro. Furthermore, the suggested antioxidant role for EgTPx was reinforced in an in vivo assay, whereby its expression in BL21 bacterial cells markedly increased the tolerance and survival of the cells to high concentrations of H2O2 compared with controls. Immunolocalization studies revealed that EgTPx was specifically expressed in all tissues of the protoscolex and brood capsules. Higher intensity of labelling was detected in many, but not all, calcareous corpuscle cells in protoscoleces. The purified recombinant EgTPx protein was used to screen sera from heavily infected mice and patients with confirmed hydatid infection. Only a portion of the sera reacted positively with the EgTPx-GST fusion protein in Western blots, suggesting that EgTPx may form antibody-antigen complexes or that responses to the EgTPx antigen may be immunologically regulated. Recombinant EgTPx may prove useful for the screening of specific inhibitors that could serve as new drugs for treatment of hydatid disease. Moreover, given that TPx from different parasitic phyla were phylogenetically distant from host TPx molecules, the development of antiparasite TPx inhibitors that do not react with host TPx might be feasible. (C) 2003 Elsevier B.V. All rights reserved.

Scabies: more than just an irritation

Human scabies, caused by skin infestation with the arthropod mite, Sarcoptes scabiei, typically results in a papular, intensely pruritic eruption involving the interdigital spaces, and flexure creases. Recent research has led to a reassessment of the morbidity attributable to this parasite in endemic communities, particularly resulting from secondary skin sepsis and postinfective complications including glomerulonephritis. This has led to studies of the benefits of community based control programmes, and to concerns regarding the emergence of drug resistance when such strategies are employed. The renewed research interest into the biology of this infection has resulted in the application of molecular tools. This has established that canine and human scabies populations are genetically distinct, a finding with major implications for the formulation of public health control policies. Further research is needed to increase understanding of drug resistance, and to identify new drug targets and potential vaccine candidates.

Modeling the development of acquired clinical immunity to Plasmodium falciparum malaria

Individuals living in regions where malaria is endemic develop an acquired immunity to malaria which enables them to remain asymptomatic while still carrying parasites. Field studies indicate that cumulative exposure to a variety of diverse Plasmodium parasites is required for the transition from symptomatic to asymptomatic malaria. This study used a simulation model of the within-host dynamics of P. falciparum to investigate the development of acquired clinical immunity under different transmission conditions and levels of parasite diversity. Antibodies developed to P. falciparum erythrocyte membrane protein 1 (PfEMP1), a clonally variant molecule, were assumed to be a key human immunological response to P. falciparum infection, along with responses to clonally conserved but polymorphic antigens. The time to the development of clinical immunity was found to be proportional to parasite diversity and inversely proportional to transmission intensity. The effect of early termination of symptomatic infections by chemotherapy was investigated and found not to inhibit the host's ability to develop acquired immunity. However, the time required to achieve this state was approximately double that compared to when no treatment was administered. This study demonstrates that an immune response primarily targeted against PfEMP1 has the ability to reduce clinical symptoms of infections irrespective of whether treatment is administered, supporting its role in the development of acquired clinical immunity. The results also illustrate a novel use for simulation models of P. falciparum infections, investigation of the influence of intervention strategies on the development of naturally acquired clinical immunity.

Ultrasound organometry: the importance of body height adjusted normal ranges in assessing liver and spleen parameters among Chinese subjects with Schistosoma japonicum infection

Hepatosplenic measurements among 550 Chinese subjects, aged 3-59 years from Yueyang city-a nonendemic area for schistosomiasis in Hunan province, China-were performed to define normal ranges of ultrasound organometry for assessing hepatosplenic, morbidity in Schistosoma japonicum infection. Measurements included the size of the liver (left lobe and right lobe), the main portal vein stem, the peripheral periportal vein branches, and spleen length and thickness. The results document the significant relationship between body height and organometric parameters. The reference values stratified by body height improve the accuracy of assessment. Thus, height-based normal ranges established in this study can be applied in hospital routine and in field studies of patients infected with S. japonicum in Hunan province and in other endemic areas of China. (C) 2004 Elsevier B.V. All rights reserved.

Inhibition of 19-kDa C-terminal region of merozoite surface protein-1-specific antibody responses in neonatal pups by maternally derived 19-kDa C-terminal region of merozoite surface protein-1-specific antibodies but not whole parasite-specific antibodies

Immunizing pregnant women with a malaria vaccine is one approach to protecting the mother and her offspring from malaria infection. However, specific maternal Abs generated in response to vaccination and transferred to the fetus may interfere with the infant's ability to respond to the same vaccine. Using a murine model of malaria, we examined the effect of maternal 19-kDa C-terminal region of merozoite surface protein-1 (MSP1(19)) and Plasmodium yoelii Abs on the pups' ability to respond to immunization with MSP1(19). Maternal MSPI,g-specific Abs but not A yoelii-specific Abs inhibited Ab production following MSP1(19) immunization in 2-wk-old pups. This inhibition was correlated with the amount of maternal MSP1(19) Ab present in the pup at the time of immunization and was due to fewer specific B cells. Passively acquired Ab most likely inhibited the development of an Ab response by blocking access to critical B cell epitopes. If a neonate's ability to respond to MSP1(19) vaccination depends on the level of maternal Abs present at the time of vaccination, it may be necessary to delay immunization until Abs specific for the vaccinating Ag have decreased.