Therapeutic approaches to disease modifying therapy for multiple sclerosis in adults: an Australian and New Zealand perspective: part 3 treatment practicalities and recommendations

In this third and final part of our review of multiple sclerosis (MS) treatment we look at the practical day-to-day management issues that are likely to influence individual treatment decisions. Whilst efficacy is clearly of considerable importance, tolerability and the potential for adverse effects often play a significant role in informing individual patient decisions. Here we review the issues surrounding switching between therapies, and the evidence to assist guiding the choice of therapy to change to and when to change. We review the current level of evidence with regards to the management of women in their child-bearing years with regards to recommendations about treatment during pregnancy and whilst breast feeding. We provide a summary of recommended pre- and post-treatment monitoring for the available therapies and review the evidence with regards to the value of testing for antibodies which are known to be neutralising for some therapies. We review the occurrence of adverse events, both the more common and troublesome effects and those that are less common but have potentially much more serious outcomes. Ways of mitigating these risks and managing the more troublesome adverse effects are also reviewed. Finally, we make specific recommendations with regards to the treatment of MS. It is an exciting time in the world of MS neurology and the prospects for further advances in coming years are high.

What are the implications of changing treatment delivery models for patients with inflammatory bowel disease : a discussion paper

An integrated model of care has been used effectively to manage chronic diseases; however, there is limited, yet encouraging evidence on its introduction in the management of inflammatory bowel disease (IBD), a chronic gastrointestinal condition. Here, the rationale for and implications of introducing an integrated model of care for patients with IBD are discussed, with a particular focus on psychology input, patient-centred care, efficiency as perceived by patients and doctors, financial implications and the possible means of model introduction. This is a discussion paper on the integrated model of care for IBD against a background of what has been learned from an integrated model of care established in other chronic conditions. Although limited, the emerging data on an integrated model of care in IBD are encouraging with respect to patient outcomes and savings in healthcare costs. In other conditions, the model has been well received by both patients and practitioners, although the loss of autonomy by doctors is listed among its drawbacks. The cost-effectiveness data are now sufficiently convincing to recommend the model's acceptance in principle. The model should be promoted at the policy level rather than by individual practitioners to facilitate equal access for patients with IBD on a larger scale than currently.

"I will start treatment when I think the time is right":HIV-positive gay men talk about their decision not to access antiretroviral therapy.

In a qualitative study, 20 HIV-infected Australian gay men were interviewed about their decision not to access antiretroviral drug therapy. The main reasons given for the decision were fear of side effects; fear of long-term damage to body organs; the inconvenience of the treatment regimens; belief that the regimen's demands would be a threat to morale; and belief that there was no reason to start therapy in the absence of AIDS-related symptoms. Actions taken by the men to monitor and maintain their health included seeing a doctor regularly; having regular T-cell and viral load tests; and trying to maintain a positive outlook by not letting HIV/AIDS 'take over' their lives. Almost half the men considered they had been subjected to unreasonable pressure to access therapy and there was considerable pride at having resisted this pressure. The findings suggest that the men disagreed with the biomedical model for managing HIV/AIDS only on the question of if and when to access therapy. They also suggest that underlying the men's dissent from the biomedical model was a different mode of thinking than is required by the model: while the model demands thinking that is abstract, the men focused strongly on factors close to the 'here and now' of immediate experience. The practical implications of the findings are explored.

Functional analysis of the sheep Wilson disease protein (sATP7B) in CHO cells

In this study we investigated the function of the sheep orthologue of ATP7B (sATP7B), the protein affected in the human copper toxicosis disorder Wilson disease. Two forms of sATP7B are found in the sheep, a ‘normal’ form and one with an alternate N terminus, both of which were expressed in CHO-K1 cells. Cells expressing either form of sATP7B were more resistant to copper than the parental CHO-K1 cells. Subcellular localisation studies showed that both forms of sATP7B were similarly located in the trans-Golgi network (TGN). When the extracellular copper concentration was increased, each form of sATP7B redistributed to a punctate, vesicular compartment that extended throughout the cytoplasm. Both forms of sATP7B recycled to the perinuclear location within one hour when the cells were subsequently incubated in basal medium. After treatment of cells with bafilomycin A1 sATP7B accumulated in cytoplasmic vesicles, implying that ATP7B continuously recycles via the endocytic pathway. These results suggest that both forms of sATP7B are functional copper-transport proteins and that the intracellular location and trafficking of the sheep protein within the cell also appears normal.

Creatine supplementation and riluzole treatment provide similar beneficial effects in copper, zinc superoxide dismutase (G93A) transgenic mice

This study investigated the effects of riluzole (Ril), creatine (Cr) and a combination of these treatments on the onset and progression of clinical signs and neuropathology in an animal model of familial amyotrophic lateral sclerosis, the G93A transgenic mouse (n=13–17 per group). The onset of clinical signs was delayed (P<0.05) by about 12 days in all treatment groups compared with control; however, no differences occurred between treatments. All animals were killed at 199 days of age. At the end of the experimental period the severity of clinical signs was less (P<0.05) with all treatments compared with control. Again no differences between treatments were observed. The treatments had no effect on the number of neurons in ventral horns of the lumbar region of the spinal cord. Transgenic mice ingesting Cr displayed elevated (P<0.05) total Cr levels in cerebral hemispheres (5%) and spinal cord (8%), but not skeletal muscles. These data demonstrate that treatment with Ril and Cr were both effective in delaying disease onset and clinical disability. To the age of killing, no additional benefit was conferred by co-administration of Ril and Cr.

Potential microbial and chemical hazards to waterbirds at the Western Treatment Plant

The Western Treatment Plant, a major sewage treatment plant west of Melbourne, Australia, is widely regarded as a significant conservation site for waterbirds. But experiences from various parts of the world suggest that sewage can also be hazardous to waterbirds, and has probably been responsible for mass-kill events. The intent of this contribution is to raise awareness about the potential for adverse impacts of sewage treatment plants on waterbirds, and to stimulate debate on the issue, with the ultimate objective of developing appropriate management strategies to mitigate the risk of mass kills.

Community-based study on knowledge, attitude and practice on the mode of transmission, prevention and treatment of the Buruli ulcer in Ga West District, Ghana

Buruli ulcer disease (BUD), a devastating tropical disease caused by Mycobacterium ulcerans, occurs in more than 80% of the administrative districts of Ghana. To elucidate community perceptions and
understanding of the aetiology of BUD, attitudes towards Buruli patients and treatment-seeking behaviours, we conducted a survey with 504 heads of households and seven focus group discussions in Ga West District, Ghana. Although 67% of participants regarded BUD as a health problem, 53% did not know its cause. Sixteen per cent attributed the cause to drinking non-potable water, 8.1% mentioned poor personal hygiene or dirty surroundings, and 5.5% identified swimming or wading in ponds as a risk factor. About 5.2% thought that witchcraft and curses cause BUD, and 71.8% indicated that BU sufferers first seek treatment from herbalists and only refer to the hospital as a last resort. The main
reasons were prospects of prolonged hospital stay, cost of transport, loss of earnings and opportunity associated with parents attending their children’s hospitalization over extended period, delays in being
attended by medical staff, and not knowing the cause of the disease or required treatment. The level of acceptance of BUD sufferers was high in adults but less so in children. The challenge facing health workers is to break the vicious cycle of poor medical outcomes leading to poor attitudes to hospital treatment in the community. Because herbalists are often the first people consulted by those who contract the disease, they need to be trained in early recognition of the pre-ulcerative stage of Buruli lesions.

Mortality rates, prevalence of malnutrition, and prevalence of lost pregnancies among the drought-ravaged population of Tete province Mozambique

Background: Tete Province, Mozambique has experienced chronic food insecurity and a dramatic fall in livestock numbers due to the cyclic problems characterized by the floods in 2000 and severe droughts in 2002 and 2003. The Province has been a beneficiary of emergency relief programs, which have assisted >22% of the population. However, these programs were not based on sound epidemiological data, and they have not established baseline data against which to assess the impact of the programs. Objective: The objective of this study was to document mortality rates, causes of death, the prevalence of malnutrition, and the prevalence of lost pregnancies after 2.5 years of humanitarian response to the crisis. Methods: A two-stage, 30-cluster household survey was conducted in the Cahora Bassa and Changara districts from 22 October to 08 November 2004. A total of 838 households were surveyed, with a population size of 4,688 people. Results: Anthropometric data were collected among children 6-59 months of age. In addition, crude mortality rates (CMRs), under five mortality rates (U5MRs), causes of deaths, and prevalence of lost pregnancies were determined among the sample population. The prevalence of malnutrition was 8.0% (95% confidence interval (CI)=6.2-9.8%) for acute malnutrition, 26.9% (95% CI=24.0-29.9%) for being underweight, and 37.0% (95% CI=33.8-40.2%) for chronic malnutrition. Boys were more likely to be underweight than were girls (odds ratio (OR)=1.34; 95% CI=1.00, 1.82; p<0.05) after controlling for age, household size, and food aid beneficiary status. Similarly, children 30-59 months of age were significantly less likely to suffer from acute malnutrition (OR=0.45; 95% CI=0.26, 0.79; p<0.01) and less likely to be underweight (OR=0.37; 95% CI=0.27, 0.51; p<0.01) than children 6-29 months of age, after adjusting for the other, aforementioned factors. The proportion of lost pregnancies was estimated at 7.7% (95% CI=4.5-11.0%). A total of 215 deaths were reported during the year preceding the survey. Thirty-nine (18.1%) children <5 years of age died. The CMR was 1.23/10 000/day (95% CI=1.08-1.38), and an U5MR was 1.03/10 000/day (95% CI=0.71-1.35). Diarrheal diseases, malaria, tuberculosis, and human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) accounted for more than two-thirds of all deaths. Conclusions: The observed CMR in Tete Province, Mozambique is three times higher than the baseline rate for sub-Saharan Africa and 1.4 times higher than the CMR cut-off point used to define excess mortality in emergencies. The current humanitarian response in Tete Province would benefit from an improved alignment of food aid programming in conjunction with diarrheal disease control, HIV/AIDS, and malaria prevention and treatment programs. The impact of the food programs would be improved if mutually acceptable food aid programme objectives, verifiable indicators relevant to each objective, and beneficiary targets and selection criteria are developed. Periodic re-assessments and evaluations of the impact of the program and evidenced-based decision-making urgently are needed to avert a chronic dependency on food aid.

Disentangling the stigma of HIV/AIDS from the stigmas of drugs use, commercial sex and commercial blood donation - a factorial survey of medical students in China

Background
HIV/AIDS related stigma interferes with the provision of appropriate care and support for people living with HIV/AIDS. Currently, programs to address the stigma approach it as if it occurs in isolation, separate from the co-stigmas related to the various modes of disease transmission including injection drug use (IDU) and commercial sex (CS). In order to develop better programs to address HIV/AIDS related stigma, the inter-relationship (or 'layering') between HIV/AIDS stigma and the co-stigmas needs to be better understood. This paper describes an experimental study for disentangling the layering of HIV/AIDS related stigmas.

Methods
The study used a factorial survey design. 352 medical students from Guangzhou were presented with four random vignettes each describing a hypothetical male. The vignettes were identical except for the presence of a disease diagnosis (AIDS, leukaemia, or no disease) and a co-characteristic (IDU, CS, commercial blood donation (CBD), blood transfusion or no co-characteristic). After reading each vignette, participants completed a measure of social distance that assessed the level of stigmatising attitudes.

Results
Bivariate and multivariable analyses revealed statistically significant levels of stigma associated with AIDS, IDU, CS and CBD. The layering of stigma was explored using a recently developed technique. Strong interactions between the stigmas of AIDS and the co-characteristics were also found. AIDS was significantly less stigmatising than IDU or CS. Critically, the stigma of AIDS in combination with either the stigmas of IDU or CS was significantly less than the stigma of IDU alone or CS alone.

Conclusion
The findings pose several surprising challenges to conventional beliefs about HIV/AIDS related stigma and stigma interventions that have focused exclusively on the disease stigma. Contrary to the belief that having a co-stigma would add to the intensity of stigma attached to people with HIV/AIDS, the findings indicate the presence of an illness might have a moderating effect on the stigma of certain co-characteristics like IDU. The strong interdependence between the stigmas of HIV/AIDS and the co-stigmas of IDU and CS suggest that reducing the co-stigmas should be an integral part of HIV/AIDS stigma intervention within this context.

The DALY, context and the determinants of the severity of disease: an exploratory comparison of paraplegia in Australia and Cameroon

This paper summarises the findings of an empirical investigation of some of the technical and social assumptions on which the disability adjusted life year (DALY) is based. The objectives of the study were to examine the notion that the burden of disease is broadly similar without regard to country, environment, gender or socio-economic status and to develop detailed descriptions of the experiences of the burden of disease as they related to these contextual factors. The study was a multi-factorial exploratory study employing qualitative and quantitative techniques to obtain data on the effects of country (development), environment (urban versus rural), gender and socio-economic status on people with paraplegia. The data provided an extensive and detailed compilation of context rich descriptions of living with paraplegia. Striking features of the data were the differences between countries with respect to the impact of the health conditions on functioning and highlight a context in which paraplegia of like clinical severity can be fatal in one environment and not in another. While there has been some focus on the control of social determinants of disease, there has been little work on the social determinants of the severity of disease. The underlying assumptions of the DALY, which ignore context in the assessment of the burden of disease, risk exacerbating inequalities by undervaluing the burden of disease in less-developed countries. There is a need to continue to subject the development of indicators to rigorous debate to determine a balance between the assumption of a global “average social milieu” and the treatment of each individual as belonging to their own context in the assessment of population health in order for indicators to be meaningful cross-culturally.

Liver cell transplantation leads to repopulation and functional correction in a mouse model of Wilson's disease

Background and Aim: The toxic milk (tx) mouse is a non-fatal animal model for the metabolic liver disorder, Wilson's disease. The tx mouse has a mutated gene for a copper-transporting protein, causing early copper accumulation in the liver and late accumulation in other tissues. The present study investigated the efficacy of liver cell transplantation (LCT) to correct the tx mouse phenotype.

Methods: Congenic hepatocytes were isolated and intrasplenically transplanted into 3–4-month-old tx mice, which were then placed on various copper-loaded diets to examine its influence on repopulation by transplanted cells. The control animals were age-matched untransplanted tx mice. Liver repopulation was determined by comparisons of restriction fragment length polymorphism ratios (DNA and mRNA), and copper levels were measured by atomic absorption spectroscopy.

Results: Repopulation in recipient tx mice was detected in 11 of 25 animals (44%) at 4 months after LCT. Dietary copper loading (whether given before or after LCT, or both) provided no growth advantage for donor cells, with similar repopulation incidences in all copper treatment groups. Overall, liver copper levels were significantly lower in repopulated animals (538 ± 68 µg/g, n = 11) compared to non-repopulated animals (866 ± 62 µg/g, n = 14) and untreated controls (910 ± 103 µg/g, n = 6; P < 0.05). This effect was also seen in the kidney and spleen. Brain copper levels remained unchanged.

Conclusion: Transplanted liver cells can proliferate and correct a non-fatal metabolic liver disease, with some restoration of hepatic copper homeostasis after 4 months leading to reduced copper levels in the liver and extrahepatic tissues, but not in the brain.

An Asia Pacific six-country study on HIV-related discrimination : introduction

This paper outlines a six-country study of institutionalised forms of HIV/AIDS-related discrimination in the Asia-Pacific region. Although recognised as a barrier to disease prevention and treatment, very limited data are available on the effects of institutionalised HIV-related stigma and discrimination. Understanding the forms of discrimination within the institutions where they occur is the first step to identifying effective ways of promoting compassionate, non-discriminatory treatment of PLWHA. Thus, the goal of this research project was to document institutional discrimination against PLWHA, as guided by the UNAIDS Protocol for the Identification of Discrimination Against People Living with HIV (2000), in six Asian countries: India, Thailand, Philippines, China, Vietnam and Indonesia. As a precursor to the six individual studies, this paper provides a brief overview of the literature on HIV discrimination, and then describes the UNAIDS Protocol and the shared methodological considerations relevant to all of the study sites. Commonalities in sampling, procedures and analysis are also discussed.

Guidelines for treatment of osteoporosis in men

BACKGROUND: Osteoporosis is associated with significant morbidity and mortality in men. Published randomised controlled trials assessing the benefits of therapy in men with osteoporosis are limited, but those available need to be used to develop management guidelines.

OBJECTIVE: To present evidence based guidelines for the treatment of osteoporosis in men.

DISCUSSION: It is estimated that 30-60% of men presenting with spinal fractures have another illness contributing to their bone disease. Therefore assessment and treatment of coexisting medical conditions is a vital part of management of osteoporosis. While primary prevention of fractures remains crucial, treatment to ensure further fractures do not occur is equally important. Alendronate is the treatment of choice for men with osteoporosis and fractures, with cyclical etidronate an appropriate alternative and testosterone replacement therapy is indicated in hypogonadal men presenting with osteoporosis.