Disruption of pro-oxidant and antioxidant systems with elevated expression of the ubiquitin proteosome system in the cachectic heart muscle of nude mice.

BACKGROUND: Current research into the mechanisms of organ atrophy associated with cancer cachexia have centred on the loss of skeletal muscle, as it is one of the most profound physical changes of the disease. However, many patients with cancer cachexia also experience significant atrophy of the heart. The mechanisms causing cardiac tissue wastage in cancer cachexia are largely unknown. However, it is believed to involve a number of molecular interactions between the tumour and host. Increased levels of oxidative stress have been found in cancer cachectic skeletal muscle and has been linked to the activation of the ubiquitin proteosome system (UPS). The aim of the current study was to examine the role of oxidative stress and the UPS in the hearts of mice with cancer cachexia. METHODS: Oxidative damage to DNA (8-OH-2dG), mRNA levels of the ROS-producing enzymes NADPH oxidase (NOX), and xanthine oxidase (XDH), the antioxidant enzyme superoxide dismutase (SOD) and key components of the UPS was measured in the heart of mice with cancer cachexia. Protein expression levels of NOX enzyme subunits and SOD enzyme activity was also measured in the same heart samples. RESULTS: 8-OH-2dG levels were 1.5-fold higher in the heart of mice with cancer cachexia, and this was associated with a 1.7-fold lower level of NOX2 mRNA and twofold higher XDH mRNA in the same hearts. Cancer cachexia was also associated with a 1.5-fold lower level of SOD activity in the heart. Accompanying these pro- and antioxidant differences was a significantly higher level of mRNA for the key UPS elements MURF-1 (4.3=fold) and MAFbx (3.8-fold) in the hearts of mice with cancer cachexia. CONCLUSIONS: The current study demonstrated that cardiac atrophy of cachectic mice is associated with oxidative damage to DNA in the myocardium. The higher levels of XDH mRNA in cachectic hearts suggest that xanthine oxidase may have an important role to play in producing oxidative stress. It appears that the combination of higher XDH expression and lower SOD enzyme activity are key contributors to oxidative stress and cardiac tissue damage in cancer-induced cardiac atrophy. Oxidative stress in the myocardium as with skeletal muscle may also induce increased expression of the E3 ligases MURF-1 and MAFbx as seen in this study.

A comparison of mental health legislation from diverse Commonwealth jurisdictions.

INTRODUCTION: In the regulation of involuntary treatment, a balance must be found between duties of care and protection and the right to self-determination. Despite its shared common roots, the mental health legislation of Commonwealth countries approaches this balance in different ways. When reform is planned, lessons can be learned from the experiences of other countries. METHOD: Criteria for involuntary treatment used in a sample of 32 Commonwealth Mental Health Acts were compared using a framework developed from standards derived from the Universal Declaration of Human Rights. Reasons for non-compliance were considered and examples of good practice were noted. Changes in the criteria used over time and across areas with differing levels of economic development were analysed. RESULTS: 1. Widespread deviation from standards was demonstrated, suggesting that some current legislation may be inadequate for the protection of the human rights of people with mental disorders. 2. Current trends in Commonwealth mental health law reform include a move towards broad diagnostic criteria, use of capacity and treatability tests, treatment in the interests of health rather than safety, and regular reviews of treatment orders. Nevertheless, there are some striking exceptions. DISCUSSION: Explanations for deviation from the standards include differing value perspectives underpinning approaches to balancing conflicting principles, failure to keep pace with changing attitudes to mental disorder, and variations in the resources available for providing treatment and undertaking law reform. Current good practice provides examples of ways of dealing with some of these difficulties.

Capacity to make health care decisions: its importance in clinical practice.

BACKGROUND: Assessment of capacity plays a pivotal role in determining when decisions need to be made on behalf of an individual. It therefore has major clinical management implications for health care professionals and civil liberties implications for the person concerned. In many countries, there is a presumption that adults have the capacity to make health care decisions. However, in persons with a mental disability, capacity may be temporarily or permanently impaired. METHODS: A selective review is presented which considers: (i) the broad approaches taken to determining capacity; (ii) the abilities commonly assessed in determining capacity; and (iii) the principles underlying health care decision-making for adults who are without capacity. RESULTS: Capacity is a functional concept, determined by the person's ability to understand, retain, and weigh up information relevant to the decision in order to arrive at a choice, and then to communicate that choice. We have reviewed the studies that examined decision-making abilities in people with dementia, chronic mental illness or intellectual disabilities. Approaches to decision-making in adults who lack capacity include: anticipatory decisions made through advance health care statements or decisions by proxy based on 'best interests' or 'substituted judgement'. CONCLUSIONS: The understanding of clinical and legal aspects of capacity is still developing. This paper examines current concepts of capacity and decision-making on behalf of those without capacity. We propose a framework, in line with current ethical and legal guidelines, as an aid to clinicians when they are seeking consent for a health care intervention.