Regulation of redox and DNA repair genes by arsenic : low dose protection against oxidative stress?

We have evaluated the molecular responses of human epithelial cells to low dose arsenic to ascertain how target cells may respond to physiologically relevant concentrations of arsenic. Data gathered in numerous experiments in different cell types all point to the same conclusion: low dose arsenic induces what appears to be a protective response against subsequent exposure to oxidative stress or DNA damage, whereas higher doses often provoke synergistic toxicity. In particular, exposure to low, sub-toxic doses of arsenite, As(III), causes coordinate up-regulation of multiple redox and redox-related genes including thioredoxin (Trx) and glutathione reductase (GR). Glutathione peroxidase (GPx) is down-regulated in fibroblasts, but up-regulated in keratinocytes, as is glutathione S-transferase (GST). The maximum effect on these redox genes occurs after 24 h exposure to 5–10 mM As(III). This is 10-fold higher than the maximum As(III) concentrations required for induction of DNA repair genes, but within the dose region where DNA repair genes are co-ordinately down-regulated. These changes in gene regulation are brought about in part by changes in DNA binding activity of the transcription factors activating protein-1 (AP-1), nuclear factor kappa-B, and cAMP response element binding protein (CREB). Although sub-acute exposure to micromolar As(III) up-regulates transcription factor binding, chronic exposure to submicromolar As(III) causes persistent down-regulation of this response. Similar long-term exposure to micromolar concentrations of arsenate in drinking water results in a decrease in skin tumour formation in dimethylbenzanthracene (DMBA)/phorbol 12-tetradecanoate 13-acetate (TPA) treated mice. Altered response patterns after long exposure to As(III) may play a significant role in As(III) toxicology in ways that may not be predicted by experimental protocols using short-term exposures.

Corporate donations, the best interest of the company and the proper purpose doctrine

Corporate philanthropy is illegitimate spending by powerful corporate elite of someone else’s money; an attempt to bypass democratic allocation of taxes; philanthropy by individuals is laudable, but not by corporations.

Just as I wouldn’t want you to implement your personal judgments by writing checks on my bank account for charities of your choice, I feel it inappropriate to write checks on your corporate ‘bank account’ for the charities of my choice.

Arsenic, mode of action at biologically plausible low doses : what are the implications for low dose cancer risk?

Arsenic is an established human carcinogen. However, there has been much controversy about the shape of the arsenic response curve, particularly at low doses. This controversy has been exacerbated by the fact that the  mechanism(s) of arsenic carcinogenesis are still unclear and because there are few satisfactory animal models for arsenic-induced carcinogenesis. Recent epidemiological studies have shown that the relative risk for cancer among populations exposed to ≤60 ppb As in their drinking water is often lower than the risk for the unexposed control population. We have found that treatment of human keratinocyte and fibroblast cells with 0.1 to 1 μM arsenite (As^III) also produces a low dose protective effect against oxidative stress and DNA damage. This response includes increased transcription, protein levels and enzyme activity of several base excision repair genes, including DNA polymerase β and DNA ligase I. At higher concentrations (> 10 μM), As induces down-regulation of DNA repair, oxidative DNA damage and apoptosis. This low dose adaptive (protective) response by a toxic agent is known as hormesis and is characteristic of many agents that induce oxidative stress. A mechanistic model for arsenic carcinogenesis based on these data would predict that the low dose risk for carcinogenesis should be sub-linear. The threshold dose where toxicity outweighs protection is hard to predict based on in vitro dose response data, but might be estimated if one could determine the form (metabolite) and concentration of arsenic responsible for changes in gene regulation in the target tissues.

Identification of novel genes expressed during rhabdomyosarcoma differentiation using cDNA microarrays

Rhabdomyosarcomas (RMS) are highly aggressive tumors that are thought to arise as a consequence of the regulatory disruption of the growth and differentiation of skeletal muscle progenitor cells. Normal myogenesis is characterized by the expression of the myogenic regulatory factor gene family but, despite their expression in RMS, these tumor cells fail to complete the latter stages of myogenesis. The RMS cell line RD-A was treated with 12-O-tetradecanoylphorbol-13-acetate to induce differentiation and cultured for 10 days. RNA was extracted on days 1, 3, 6, 8 and 10. A human skeletal muscle cDNA microarray was developed and used to analyze the global gene expression of RMS tumors over the time-course of differentiation. As a comparison, the genes identified were subsequently examined during the differentiated primary human skeletal muscle cultures. Prothymosin alpha (PTMA), and translocase of inner mitochondrial membrane 10 (Tim10), two genes not previously implicated in RMS, showed reduced expression during differentiation. Marked differences in the expression of PTMA and Tim10 were observed during the differentiation of human primary skeletal muscle cells. These results identify several new genes with potential roles in the myogenic arrest present in rhabdomyosarcoma. PTMA expression in RMS biopsy samples might prove to be an effective diagnostic marker for this disease.

A conceptual framework of e-fraud control in an integrated supply chain

The integration of supply chains offers many benefits; yet, it may also render organisations more vulnerable to electronic fraud (e-fraud). E-fraud can drain on organisations’ financial resources, and can have a significant adverse effect on the ability to achieve their strategic objectives. Therefore, efraud control should be part of corporate board-level due diligence, and should be integrated into organisations’ practices and business plans.
Management is responsible for taking into consideration the relevant cultural, strategic and implementation elements that inter-relate with each other and to coordinating the human, technological and financial resources necessary to designing and implementing policies and procedures for controlling e-fraud. Due to the characteristics of integrated supply chains, a move from the traditional vertical approach to a systemic, horizontal-vertical approach is necessary. Although the e-fraud risk cannot be eliminated, risk mitigation policies and processes tailored to an organisation’s particular vulnerabilities can significantly reduce the risk and may even preclude certain classes of frauds.
In this paper, a conceptual framework of e-fraud control in an integrated supply chain is proposed. The proposed conceptual framework can help managers and practitioners better understand the issues and plan the activities involved in a systemic, horizontal-vertical approach to e-fraud control in an integrated supply chain, and can be a basis upon which empirical studies can be build.

Temporal processing and reading disability

The present investigation examined thehypothesis that early auditory temporalprocessing deficits cause later specificreading disability by impairing phonologicalprocessing (Farmer & Klein 1995; Tallal1980, 1984). Temporal processing ability atschool entry was examined using Tallal'sRepetition Test in a large unselected sample ofover 500 children followed over subsequentyears. Although our data confirmed the presenceof certain non-speech auditory processingdeficits in children later classified asspecific reading-disabled, many findings wereclearly at odds with a causal interpretation ofthis relationship. (1) Reading-disabled (RD)children were impaired at school entry on thesubtest with long interstimulus intervals(ISIs) but not the critical short-ISIsubtest. (2) RD children were not inferior toreading-age (RA) controls. (3) A subgroup of RDchildren with evidence of temporal deficitswere no less proficient on later phonologicalor reading measures than RD children with noevidence of early temporal impairment. (4)Although there was a reliable concurrentcorrelation between temporal deficits andphonological awareness at school entry(suggesting a possible common causeexplanation), early temporal deficits did notpredict later phonological impairment,pseudoword processing difficulties, or specificreading disability. On the other hand, earlytemporal deficits did predict later oralreceptive vocabulary and reading comprehensionweaknesses. These findings suggest thatauditory temporal deficits in dyslexics may beassociated with the same dysphasic-typesymptoms observed by Tallal and her colleaguesin specific language-impaired populations, butdo not cause the core phonological deficitsthat characterize dyslexic groups.

A controlled trial of internet-based cognitive-behavioural therapy for panic disorder with face-to-face support from a general practitioner or email support from a psychologist

Background: Panic disorder (PD) is one of the most common anxiety disorders seen in general practice, but provision of evidence-based cognitive-behavioural treatment (CBT) is rare. Many Australian GPs are now trained to deliver focused psychological strategies, but in practice this is time consuming and costly.

Objective: To evaluate the efficacy of an internet-based CBT intervention (Panic Online) for the treatment of PD supported by general practitioner (GP)-delivered therapeutic assistance.

Design: Panic Online supported by GP-delivered face-to-face therapy was compared to Panic Online supported by psychologist-delivered email therapy.

Methods: Sixty-five people with a primary diagnosis of PD (78% of whom also had agoraphobia) completed 12 weeks of therapy using Panic Online and therapeutic assistance with his/her GP (n = 34) or a clinical psychologist (n = 31). The mean duration of PD for participants allocated to these groups was 59 months and 58 months, respectively. Participants completed a clinical diagnostic interview delivered by a psychologist via telephone and questionnaires to assess panic-related symptoms, before and after treatment.

Results: The total attrition rate was 20%, with no group differences in attrition frequency. Both treatments led to significant improvements in panic attack frequency, depression, anxiety, stress, anxiety sensitivity and quality of life. There were no statistically significant differences in the two treatments on any of these measures, or in the frequency of participants with clinically significant PD at post assessment.

Conclusions: When provided with accessible online treatment protocols, GPs trained to deliver focused psychological strategies can achieve patient outcomes comparable to efficacious treatments delivered by clinical psychologists. The findings of this research provide a model for how GPs may be assisted to provide evidence-based mental healthcare successfully.

Therapist-assisted, internet-based treatment for panic disorder: can general practitioners achieve comparable patient outcomes to psychologists

Background: Mental illness is an escalating concern worldwide. The management of disorders such as anxiety and depression largely falls to family doctors or general practitioners (GPs). However, GPs are often too time constrained and may lack the necessary training to adequately manage the needs of such patients. Evidence-based Internet interventions represent a potentially valuable resource to reduce the burden of care and the cost of managing mental health disorders within primary care settings and, at the same time, improve patient outcomes.
Objective: The present study sought to extend the efficacy of a therapist-assisted Internet treatment program for panic disorder, Panic Online, by determining whether comparable outcomes could be achieved and maintained when Panic Online was supported by either GPs or psychologists.
Methods: Via a natural groups design, 96 people with a primary diagnosis of panic disorder (with or without agoraphobia) completed the Panic Online program over 12 weeks with the therapeutic assistance of their GP (n = 53), who had received specialist training in cognitive behavioral therapy, or a clinical psychologist (n = 43). Participants completed a clinical diagnostic telephone interview, conducted by a psychologist, and a set of online questionnaires to assess panic-related symptoms at three time periods (pretreatment, posttreatment, and 6 month follow-up).
Results: Both treatments led to clinically significant improvements on measures of panic and panic-related symptomatology from pretreatment to posttreatment. Both groups were shown to significantly improve over time. Improvements for both groups were maintained at follow-up; however, the groups did differ significantly on two quality of life domains: physical (F₁,₈₂ = 9.13, P = .00) and environmental (F₁,₈₂ = 4.41, P = .04). The attrition rate was significantly higher among those being treated by their GP (χ²₁ = 4.40, P = .02, N = 96).
Conclusions: This study provides evidence that Internet-based interventions are an effective adjunct to existing mental health care systems. Consequently, this may facilitate and enhance the delivery of evidence-based mental health treatments to increasingly large segments of the population via primary care systems and through suitably trained health professionals.

Is internet-based CBT for panic disorder and agoraphobia as effective as face-to-face CBT

This study compared Panic Online (PO), an internet-based CBT intervention, to best-practice face-to-face CBT for people with panic disorder with or without agoraphobia. Eighty-six people with a primary diagnosis of panic disorder were recruited from Victoria, Australia. Participants were randomly assigned to either PO (n = 46) or best practice face-to-face CBT (n = 40). Effects of the internet-based CBT program were found to be comparable to those of face-to-face CBT. Both interventions produced significant reductions in panic disorder and agoraphobia clinician severity ratings, self reported panic disorder severity and panic attack frequency, measures of depression, anxiety, stress and panic related cognitions, and displayed improvements in quality of life. Participants rated both treatment conditions as equally credible and satisfying. Participants in the face-to-face CBT treatment group cited higher enjoyment with communicating with their therapist. Consistent with this, therapists’ ratings for compliance to treatment and understanding of the CBT material was higher in the face-to-face CBT treatment group. PO required significantly less therapist time than the face-to-face CBT condition.

Investigation of educator adoption of knowledge media

Human development has occurred against a timeline that has seen the creation of and diffusion of one innovation after another. These innovations range from language to complex computing and information technologies. The latter are assisting with the distribution of information, and extend to the distribution of the human species beyond the planet Earth. From early times, information has been published and mostly for a fee to the publisher. The absorption and use of information has had a high priority in most societies from early times, and has become institutionalised in universities and institutes of technical learning. For most in Western societies, education is now a matter of ‘lifelong learning’. Today, we see higher education institutions, worldwide, adapting their organisational structures and operating procedures and forming strategic alliances with communications content providers and carriers as well as with information technology companies. Modern educational institutes seek productivity and efficiency. Many also seek to differentiate themselves from competitors. Technological convergence is often seen by management to be a saviour in many educational organisations. It is hoped that lower capital and recurrent costs can be achieved, and that competitors in an increasingly globalised industry can be held at bay by strategic use of knowledge media (Eisenstadt, 1995) commonly associated with distance education in the campus setting. Knowledge media set up costs, intellectual property costs and training costs for staff and students are often so high as to make their use not viable for Australian institutes of higher education. Against this backdrop, one might expect greater educator and student use of publisher produced textbooks and digital enhancements to the textbook, particularly those involved in distance education. A major issue is whether or not the timing of instructor adoption of converging information technology and communications technologies aligns with the wishes of both higher education management and government, and with those who seek commercial gain from the diffusion and adoption of such technologies. Also at issue is whether or not it is possible to explain variance in stated intentions to recommend adoption of new learning technologies in higher education and implementation. Will there occur educator recommendation for adoption of individual knowledge media such as World Wide Web access to study materials by students? And what will be the form of this tool and others used in higher education? This thesis reports on more recent changes in the technological environment and seeks to contribute to an understanding of the factors that lead to a willingness, or unwillingness, on the part of higher education instructors, as influencers and content providers, to utilise these technologies. As such, it is a diffusion study which seeks to fill a gap in the literature. Diffusion studies typically focus on predicting adoption based on characteristics of the potential adopter. Few studies examine the relationship between characteristics of the innovation and adoption. Nearly all diffusion studies involve what is termed discontinuous innovation (Robertson, 1971). That is, the innovation involves adoptees in a major departure from previous practice. This study seeks to examine the relationship between previous experience of related technologies and adoption or rejection of dynamically continuous innovation. Continuous and dynamically continuous innovations are the most numerous in the real world, yet they are numerically the least scrutinised by way of academic research. Moreover, the three-year longitudinal study of educators in Australian and New Zealand meets important criteria laid down by researchers Tornatzky and Klein (1982) and Rogers (1995), that are often not met by similar studies. In particular the study examines diffusion as it is unfolding, rather than selectively examining a single innovation and after the fact, thus avoiding a possible pro-innovation bias. The study examines the situation for both ‘all educators’ and ‘marketing / management educators’ alone in seeking to meet the following aim: Establish if intended adopters of specific knowledge media have had more experience of other computer-based technologies than have those not intending to adopt said knowledge media. The analytical phase entails use of factor analysis and discriminant analysis to conclude that it is possible to discriminate adopters of selected knowledge media based on previous use of related technologies. The study does not find any generalised factor that enables such discrimination among educators. Thus the study supports the literature in part, but fails to find generalised factors that enable unambiguous prediction of knowledge media adoption or otherwise among each grouping of educators examined. The implications are that even in the case of related products and services (continuous or dynamically continuous innovation), there is not statistical certainty that prior usage of related products or technologies is related to intentions to use knowledge media in the future. In this regard, the present study might be said to confirm the view that Rogers and Shoemaker's (1971) conceptualisation of perceived innovation characteristics may only apply to discontinuous innovations (Stratton, Lumpkin & Vitell, 1997). The implications for stakeholders such as higher education management is that when seeking to appoint new educators or existing staff to knowledge media project teams, there is some support for the notion that those who already use World Wide Web based technologies are likely to take these technologies into teaching situations. The same claim cannot be made for computer software use in general, nor Internet use in general.