A novel plant toxin, persin, with in vivo activity in the mammary gland, induces Bim-dependent apoptosis in human breast cancer cells

Phytochemicals have provided an abundant and effective source of therapeutics for the treatment of cancer. Here we describe the characterization of a novel plant toxin, persin, with in vivo activity in the mammary gland and a p53-, estrogen receptor-, and Bcl-2-independent mode of action. Persin was previously identified from avocado leaves as the toxic principle responsible for mammary gland-specific necrosis and apoptosis in lactating livestock. Here we used a lactating mouse model to confirm that persin has a similar cytotoxicity for the lactating mammary epithelium. Further in vitro studies in a panel of human breast cancer cell lines show that persin selectively induces a G(2)-M cell cycle arrest and caspase-dependent apoptosis in sensitive cells. The latter is dependent on expression of the BH3-only protein Bim. Bim is a sensor of cytoskeletal integrity, and there is evidence that unique structure of the compound, persin could represent a novel class of microtubule-targeting agent with potential specificity for breast cancers.

Epidemiology of recreational exposure to freshwater cyanobacteria - an international prospective cohort study

Background: Case studies and anecdotal reports have documented a range of acute illnesses associated with exposure to cyanobacteria and their toxins in recreational waters. The epidemiological data to date are limited; we sought to improve on the design of some previously conducted studies in order to facilitate revision and refinement of guidelines for exposure to cyanobacteria in recreational waters. Methods: A prospective cohort study was conducted to investigate the incidence of acute symptoms in individuals exposed, through recreational activities, to low ( cell surface area < 2.4 mm(2)/mL), medium ( 2.4 - 12.0 mm(2)/mL) and high (> 12.0 mm(2)/mL) levels of cyanobacteria in lakes and rivers in southeast Queensland, the central coast area of New South Wales, and northeast and central Florida. Multivariable logistic regression analyses were employed; models adjusted for region, age, smoking, prior history of asthma, hay fever or skin disease ( eczema or dermatitis) and clustering by household. Results: Of individuals approached, 3,595 met the eligibility criteria, 3,193 (89%) agreed to participate and 1,331 (37%) completed both the questionnaire and follow-up interview. Respiratory symptoms were 2.1 (95% CI: 1.1 - 4.0) times more likely to be reported by subjects exposed to high levels of cyanobacteria than by those exposed to low levels. Similarly, when grouping all reported symptoms, individuals exposed to high levels of cyanobacteria were 1.7 ( 95% CI: 1.0 - 2.8) times more likely to report symptoms than their low-level cyanobacteria-exposed counterparts. Conclusion: A significant increase in reporting of minor self-limiting symptoms, particularly respiratory symptoms, was associated with exposure to higher levels of cyanobacteria of mixed genera. We suggest that exposure to cyanobacteria based on total cell surface area above 12 mm(2)/mL could result in increased incidence of symptoms. The potential for severe, life-threatening cyanobacteria-related illness is likely to be greater in recreational waters that have significant levels of cyanobacterial toxins, so future epidemiological investigations should be directed towards recreational exposure to cyanotoxins.

Biodegradation of the cyanobacterial toxin microcystin LR in natural water and biologically active slow sand filters

A bacterium (MJ-PV) previously demonstrated to degrade the cyanobacterial toxin microcystin LR, was investigated for bioremediation applications in natural water microcosms and biologically active slow sand filters. Enhanced degradation of microcystin LR was observed with inoculated (1 x 10(6) cell/mL) treatments of river water dosed with microcystin LR (> 80% degradation within 2 days) compared to uninoculated controls. Inoculation of MJ-PV at lower concentrations (1 x 10(2)-1 x 10(5)cells/mL) also demonstrated enhanced microcystin LR degradation over control treatments. Polymerase chain reactions (PCR) specifically targeting amplification of 16S rDNA of MJ-PV and the gene responsible for initial degradation of microcystin LR (mlrA) were successfully applied to monitor the presence of the bacterium in experimental trials. No amplified products indicative of an endemic MJ-PV population were observed in uninoculated treatments indicating other bacterial strains were active in degradation of microcystin LR, Pilot scale biologically active slow sand filters demonstrated degradation of microcystin LR irrespective of MJ-PV bacterial inoculation. PCR analysis detected the MJ-PV population at all locations within the sand filters where microcystin degradation was measured. Despite not observing enhanced degradation of microcystin LR in inoculated columns compared to uninoculated column, these studies demonstrate the effectiveness of a low-technology water treatment system like biologically active slow sand filters for removal of microcystins from reticulated water supplies. Crown Copyright (c) 2006 Published by Elsevier Ltd. All rights reserved.

Ethical issues in social research

There are numerous ethical issues that one must consider when developing a research project; however, much discussion about ethics in health research has focused on experimental studies such as clinical trials. As a result, there remains some ambiguity as to the ethical issues that need to be considered in health-related social research. This paper outlines a number of important ethical issues that CAM researchers should be aware of when developing, running and writing up social research. Maintaining high ethical standards is extremely important in social research as it protects participants and researchers, improves the quality of the data retrieved and ensures that future researchers will have access to participants within the community. (C) 2005 Elsevier Ltd. All rights reserved.

How can experience in clinical and community settings contribute to early medical education? A BEME systematic review

Review date: Review period January 1992-December 2001. Final analysis July 2004-January 2005. Background and review context: There has been no rigorous systematic review of the outcomes of early exposure to clinical and community settings in medical education. Objectives of review: (1) Identify published empirical evidence of the effects of early experience in medical education, analyse it, and synthesize conclusions from it. (2) Identify the strengths and limitations of the research effort to date, and identify objectives for future research. Search strategy: Ovid search of. BEI, ERIC, Medline, CIATAHL and EMBASE Additional electronic searches of: Psychinfo, Timelit, EBM reviews, SIGLE, and the Cochrane databases. Hand-searches of: Medical Education, Medical Teacher, Academic Medicine, Teaching and Learning in Medicine, Advances in Health Sciences Education, Journal of Educational Psychology. Criteria: Definitions: Experience: Authentic (real as opposed to simulated) human contact in a social or clinical context that enhances learning of health, illness and/or disease, and the role of the health professional. Early: What would traditionally have been regarded as the preclinical phase, usually the first 2 years. Inclusions: All empirical studies (verifiable, observational data) of early experience in the basic education of health professionals, whatever their design or methodology, including papers not in English. Evidence from other health care professions that could be applied to medicine was included. Exclusions: Not empirical; not early; post-basic; simulated rather than 'authentic' experience. Data collection: Careful validation of selection processes. Coding by two reviewers onto an extensively modified version of the standard BEME coding sheet. Accumulation into an Access database. Secondary coding and synthesis of an interpretation. Headline results: A total of 73 studies met the selection criteria and yielded 277 educational outcomes; 116 of those outcomes (from 38 studies) were rated strong and important enough to include in a narrative synthesis of results; 76% of those outcomes were from descriptive studies and 24% from comparative studies. Early experience motivated and satisfied students of the health professions and helped them acclimatize to clinical environments, develop professionally, interact with patients with more confidence and less stress, develop self-reflection and appraisal skill, and develop a professional identity. It strengthened their learning and made it more real and relevant to clinical practice. It helped students learn about the structure and function of the healthcare system, and about preventive care and the role of health professionals. It supported the learning of both biomedical and behavioural/social sciences and helped students acquire communication and basic clinical skills. There were outcomes for beneficiaries other than students, including teachers, patients, populations, organizations and specialties. Early experience increased recruitment to primary care/rural medical practice, though mainly in US studies which introduced it for that specific purpose as part of a complex intervention. Conclusions: Early experience helps medical students socialize to their chosen profession. It. helps them acquire a range of subject matter and makes their learning more real and relevant. It has potential benefits for other stakeholders, notably teachers and patients. It can influence career choices.

Kidney dysfunction and hypertension: Role for cadmium, P450 and heme oxygenases?

Cadmium (Cd) is a metal toxin of continuing worldwide concern. Daily intake of Cd, albeit in small quantities, is associated with a number of adverse health effects which are attributable to distinct pathological changes in a variety of tissues and organs. In the present review, we focus on its renal tubular effects in people who have been exposed environmentally to Cd at levels below the provisional tolerable intake level set for the toxin. We highlight the data linking such low-level Cd intake with tubular injury, altered abundance of cytochromes P450 (CYPs) in the kidney and an expression of a hypertensive phenotype. We provide updated knowledge on renal and vascular effects of the eicosanoids 20-hydroxyeicosatetraenoic acid (20-HETE) and eicosatrienoic acids (EETs), which are biologically active metabolites from arachidonate metabolism mediated by certain CYPs in the kidney. We note the ability of Cd to elicit oxidative stress and to alter metal homeostasis notably of zinc which may lead to augmentation of the defense mechanisms involving induction of the antioxidant enzyme heme oxygenase-1 (HO-1) and the metal binding protein metallothionein (MT) in the kidney. We hypothesize that renal Cd accumulation triggers the host responses mediated by HO-I and MT in an attempt to protect the kidney against injurious oxidative stress and to resist a rise in blood pressure levels. This hypothesis predicts that individuals with less active HO-1 (caused by the HO-1 genetic polymorphisms) are more likely to have renal injury and express a hypertensive phenotype following chronic ingestion of low-level Cd, compared with those having more active HO-1. Future analytical and molecular epidemiologic research should pave the way to the utility of induction of heme oxygenases together with dietary antioxidants in reducing the risk of kidney injury and hypertension in susceptible people.

Levels of 12 perfluorinated chemicals in pooled Australian serum, collected 2002-2003, in relation to age, gender, and region

Pooled serum samples from 3802 Australian residents were analyzed for four perfluoroalkylsulfonates, seven perfluoroalkylcarboxylates, and perfluorooctanesulfonamide (PFOSA). Serum was collected from men and women of five different age groups and from rural and urban regions in Australia. The highest mean concentration was obtained for perfluorooctane sulfonate (PFOS, 20.8 ng/mL) followed by perfluorooctanoic acid (PFOA, 7.6 ng/mL), perfluorohexane sulfonate (PFHxS, 6.2 ng/mL), perfluorononanoic acid (PFNA, 1.1 ng/mL), and PFOSA (0.71 ng/mL). Additional four PFCs were detected in 5-18 % of the samples at concentrations near the detection limits (0.1-0.5 ng/mL). An increase in PFOS concentration with increasing age in both regions and genders was observed. The male pool levels of some of the age groups compared to females were higher for PFOS, PFOA, and PFHxS. In contrast, PFNA concentrations were higher in the female pools. No substantial difference was found in levels of PFCs between the urban and rural regions. The levels are equal or higher than previously reported serum levels in Europe and Asia but lower compared to the U. S. A. These results suggest that emissions from production in the Northern Hemisphere are of less importance for human exposure.

Passive air sampling for persistent organic pollutants: Introductory remarks to the special issue

There have been a number of developments in the need, design and use of passive air samplers (PAS) for persistent organic pollutants (POPs). This article is the first in a Special Issue of the journal to review these developments and some of the data arising from them. We explain the need and benefit of developing PAS for POPs, the different approaches that can be used, and highlight future developments and needs. (c) 2006 Elsevier Ltd. All rights reserved.

Relevance of the deletion polymorphisms of the glutathione S-transferases GSTT1 and GSTM1 in pharmacology and toxicology

Although cytosolic glutathione S-transterase (GST) enzymes occupy a key position in biological detoxification processes, two of the most relevant human isoenzymes. GST1-1 and GSTM1-1, are genetically deleted (non-functional alleles GSTT1*0 and GsTM1*0) in a high percentage of the human population, with major ethnic differences. The structures of the GSTT and GSTM gene areas explain the underlying genetic processes. GSTT1-1 is highly conserved during evolution and plays a major role in phase-II biotransformation of a number of drugs and industrial chemicals. e.g. cytostatic drugs, hydrocarbons and halogenated hydrocarbons. GSTM1-1 is particularly relevant in the deactivation of carcinogenic intermediates of polycyclic aromatic hydrocarbons. Several lines of evidence Suggest that hGSTT1-1 and/or hGSTM1-1 play a role in the deactivation of reactive oxygen species that are likely to be involved in cellular processes of inflammation, ageing and degenerative diseases. There is cumulating evidence that combinations of the GSTM1*0 state with other genetic traits affecting the metabolism of carcinogens (CYP1A1, GSTP1) may predispose the aero-digestivc tract and lung, especially in smokers, to a higher risk of cancer. The GSTM1*0 status appears also associated with a modest increase in the risk of bladder cancer, consistent with a GSTM1 interaction with carcinogenic tobacco smoke constituents. Both human GST deletions, although largely counterbalanced by overlapping substrate affinities within the GST superfamily, have consequences when the organism comes into contact with distinct man-made chemicals. This appears relevant in industrial toxicology and in drug metabolism.

Validity of verbal autopsy procedures for determining cause of death in Tanzania

Objectives: To validate verbal autopsy (VA) procedures for use in sample vital registration. Verbal autopsy is an important method for deriving cause-specific mortality estimates where disease burdens are greatest and routine cause-specific mortality data do not exist. Methods: Verbal autopsies and medical records (MR) were collected for 3123 deaths in the perinatal/neonatal period, post-neonatal < 5 age group, and for ages of 5 years and over in Tanzania. Causes of death were assigned by physician panels using the International Classification of Disease, revision 10. Validity was measured by: cause-specific mortality fractions (CSMF); sensitivity; specificity and positive predictive value. Medical record diagnoses were scored for degree of uncertainty, and sensitivity and specificity adjusted. Criteria for evaluating VA performance in generating true proportional mortality were applied. Results: Verbal autopsy produced accurate CSMFs for nine causes in different age groups: birth asphyxia; intrauterine complications; pneumonia; HIV/AIDS; malaria (adults); tuberculosis; cerebrovascular diseases; injuries and direct maternal causes. Results for 20 other causes approached the threshold for good performance. Conclusions: Verbal autopsy reliably estimated CSMFs for diseases of public health importance in all age groups. Further validation is needed to assess reasons for lack of positive results for some conditions.

Participants who left a multiple-wave cohort study had similar baseline characteristics to participants who returned

PURPOSE: Research on determinants of an individual's pattern of response, considered as a profile across time, for cohort studies with multiple waves is limited. In this prospective population-based pregnancy cohort, we investigated baseline characteristics of participants after partitioning them according to their history of response to different interview waves. METHODS: Data are from the Mater-University of Queensland Study of Pregnancy 1981 to 1983 cohort, Brisbane, Australia. Complete baseline information was collected for 7223 of 7535 eligible individuals (95.9%). Follow-up occurred at 6 months, 5 years, and 14 years. Response rates were 93.0%, 72.5%, and 71.8%. Participants were allowed to leave and reenter the study. Participants were categorized as always, intermittent, or never responders. Intermittent responders were categorized further as leavers (responded at least once before leaving the study) or returners (left the study before reentering). RESULTS: Participants who always responded were older, more educated, married, Caucasian, and nonsmokers and had higher incomes. Intermittent responders shared similar baseline characteristics. Relative risk for being an intermittent responder was located between risks for always or never responding. CONCLUSIONS: Participants who left and reentered the study had baseline characteristics similar to participants who responded at least once and then left the study.

Is modern medicine at risk of losing the plot?

Contemporary medicine has much to its credit, but has created an insatiable demand for new technologies and more health services, fed by commercial promotion, professional advocacy and sociopolitical pressure. Total health expenditure at the national level is now almost 10% of gross domestic product and is expected to top 16% by 2020. After recent inquiries into the failings of its public health system, the Queensland Government has committed itself to a 25% increase in expenditure on health over the next 5 years. But will it lead to better population health, and is it sustainable? The return-on-investment curve for modern health care may be flattening out, in an environment of growing numbers of older patients with chronic illnesses, maldistribution of services and hospital overcrowding. A change in thinking is required if current medical practice is to avoid imploding when confronted with the next major economic downturn. Health policy, service funding and clinical training must focus on critical appraisal of the effectiveness of health care technologies and the structure and financing of health care systems. Practising clinicians will be obliged to provide leadership in determining value for money in the choice of health care for specific patient populations and how that care is delivered.