Copper in disorders with neurological symptoms: Alzheimer`s, Menkes, and Wilson Diseases

Copper is an essential element for the activity of a number of physiologically important enzymes. Enzyme-related malfunctions may contribute to severe neurological symptoms and neurological diseases: copper is a component of cytochrome c oxidase, which catalyzes the reduction of oxygen to water, the essential step in cellular respiration. Copper is a cofactor of Cu/Zn-superoxide-dismutase which plays a key role in the cellular response to oxidative stress by scavenging reactive oxygen species. Furthermore, copper is a constituent of dopamine-β-hydroxylase, a critical enzyme in the catecholamine biosynthetic pathway. A detailed exploration of the biological importance and functional properties of proteins associated with neurological symptoms will have an important impact on understanding disease mechanisms and may accelerate development and testing of new therapeutic approaches. Copper binding proteins play important roles in the establishment and maintenance of metal-ion homeostasis, in deficiency disorders with neurological symptoms (Menkes disease, Wilson disease) and in neurodegenerative diseases (Alzheimer’s disease). The Menkes and Wilson proteins have been characterized as copper transporters and the amyloid precursor protein (APP) of Alzheimer’s disease has been proposed to work as a Cu(II) and/or Zn(II) transporter. Experimental, clinical and epidemiological observations in neurodegenerative disorders like Alzheimer’s disease and in the genetically inherited copper-dependent disorders Menkes and Wilson disease are summarized. This could provide a rationale for a link between severely dysregulated metal-ion homeostasis and the selective neuronal pathology.

The molecular basis of copper homeostasis and copper-related disorders

Copper is an essential trace element that can be extremely toxic in excess due to the pro-oxidant activity of copper ions. Inherited disorders of copper transport, Menkes disease (copper deficiency), and Wilson disease (copper toxicosis) are caused by mutations of two closely related Cu transporting-ATPases, and demonstrate the essentiality and potential toxicity of copper. Other copper toxicosis conditions in humans and animals have been described, but are not well understood at a molecular level. Copper homeostatic mechanisms are being discovered. One such mechanism is copper-induced trafficking of the Cu-ATPases, which allows cells to provide copper to secreted cupro-proteins but also to efflux excess copper. Oxidative damage induced by copper may be involved in the pathogenesis of neurodegenerative conditions such as Alzheimer's disease, familial amyotrophic lateral sclerosis, and prion diseases.

Zinc deficiency and its inherited disorders - A review

Zinc is an essential trace element required by all living organisms because of its critical roles both as a structural component of proteins and as a cofactor in enzyme catalysis. The importance of zinc in human metabolism is illustrated by the effects of zinc deficiency, which include a diminished immune response, reduced healing and neurological disorders. Furthermore, nutritional zinc deficiency can be fatal in newborn or growing animals. While zinc deficiency is commonly caused by dietary factors, several inherited defects of zinc deficiency have been identified. Acrodermatitis enteropathica is the most commonly described inherited condition found in humans. In several of the few cases that have been reported, this disorder is associated with mutations in the hZIP4 gene, a member of the SLC39 family, whose members encode membranebound putative zinc transporters. Mutations in other members of this family or in different genes may account for other cases of acrodermatitis in which defects in hZIP4 have not been detected. Another inherited form of zinc deficiency occurs in the lethal milk mouse, where a mutation in ZnT4 gene, a member of the SLC30 family of transmembrane proteins results in impaired secretion of zinc into milk from the mammary gland. A similar disorder to the lethal milk mouse occurs in humans. In the few cases studied, no changes in ZnT4 orthologue, hZnT4, were detected. This, and the presence of several minor phenotypic differences between the zinc deficiency in humans and mice, suggests that the human condition is caused by defects in genes that are yet to be identified. Taking into account the fact that there are no definitive tests for zinc deficiency and that this disorder can go undiagnosed, plus the recent identification of multiple members of the SCL30 and SLC39, it is likely that mutations in other genes may underlie additional inherited disorders of zinc deficiency.

Australian gp's preferences for education about depression and related disorders

OBJECTIVE: To Investigate Australian general practitioners' experiences of accessing education about depression and their preferences for future education on depression and related disorders.
METHOD: Six hundred and eight anonymous surveys were distributed to GPs through 52 rural and urban divisions of general practice; 420 were retumed.
RESULTS: Educational formats involving direct contact with people having mental health expertise were highly valued. Distance education and web based technologies were least used. In the previous year, women and older GPs had spent more time on education about depression. Most intended to undertake more such education in the future and said that education in psychosocial strategies would be very useful. General practitioners' attitudes to further education about depression were influenced by their gender, practice location, and their previous mental health training.
DISCUSSION: More face-to-face training may be desirable to take advantage of GPs' willingness to spend more time on education about depression and related disorders.

Developmental language disorders and adolescent risk: a public-health advocacy role for speech pathologists?

Within the multi-disciplinary team concerned with child and adolescent development, speech pathologists are uniquely positioned to understand the nature and overall developmental significance of language acquisition in childhood and adolescence. Other disciplines contribute valuable insights about psychosocial development during the childhood and adolescent years. The field of developmental psychology, for example provides a large and convincing body of evidence about the role of academic success as a protective factor against a range of psychosocial harms, in particular substance misuse, truancy, early school leaving, and juvenile offending. In this paper, we argue that juvenile offending embodies the notion of "adolescent risk", but in Australia in particular, has been under-investigated with respect to possible associations with developmental language disorders and subsequent academic failure. We present findings pertaining to a sample of 30 male juvenile offenders completing community based orders. Performance on a range of oral language processing and production skills was poorer than that of a demographically similar comparison group. Our results confirm the need to conceptualize language within a broader risk and protective framework. We therefore emphasize the public health importance of early language competence, by virtue of the psychosocial protection it confers on young people with respect to the development of prosocial skills, transition to literacy and overall academic achievement. We argue that speech pathologists are best positioned to advocate at a policy level about the broader public health importance of oral language competence.

Preventing the onset of depressive disorders : a meta-analytic review of psychological interventions

OBJECTIVE: A growing number of studies have tested the efficacy of preventive interventions in reducing the incidence of depressive disorders. Until now, no meta-analysis has integrated the results of these studies. METHOD: The authors conducted a meta-analysis. After a comprehensive literature search, 19 studies were identified that met inclusion criteria. The studies had to be randomized controlled studies in which the incidence of depressive disorders (based on diagnostic criteria) in an experimental group could be compared with that of a control group. RESULTS: The mean incidence rate ratio was 0.78, indicating a reduction of the incidence of depressive disorders by 22% in experimental compared with control groups. Heterogeneity was low to moderate (I²=33%). The number needed to treat to prevent one case of depressive disorder was 22. Moderator analyses revealed no systematic differences between target populations or types of prevention (universal, selective, or indicated). The data included indications that prevention based on interpersonal psychotherapy may be more effective than prevention based on cognitive-behavioral therapy. CONCLUSIONS: Prevention of new cases of depressive disorders does seem to be possible. Prevention may become an important way, in addition to treatment, to reduce the enormous public health burden of depression in the coming years.

The role of omega-3 fatty acids in mood disorders

Research has established that docosahexaenoic acid (DHA), a long-chain omega-3 polyunsaturated fatty acid (PUFA), plays a fundamental role in brain structure and function. Epidemiological and cross-sectional studies have also identified a role for long-chain omega-3 PUFA, which includes DHA, eicosapentaenoic acid, and docosapentaenoic acid, in the etiology of depression. In the past ten years, there have been 12 intervention studies conducted using various preparations of longchain omega-3 PUFA in unipolar and bipolar depression. The majority of these studies administered long-chain omega-3 PUFA as an adjunct therapy. The studies have been conducted over 4 to 16 weeks of intervention and have often included small cohorts. In four out of the seven studies conducted in depressed individuals and in two out of the five studies in bipolar patients, individuals have reported a positive outcome following supplementation with ethyl-eicosapentaenoic acid or fish oil containing long-chain omega-3 PUFA. In the three trials that researched the influence of DHA-rich preparations, no significant effects were reported. The mechanisms that have been invoked to account for the benefits of long-chain omega-3 PUFA in depression include reductions in prostaglandins derived from arachidonic acid, which lead to decreased brain-derived neurotrophic factor levels and/or alterations in blood flow to the brain.

Protein kinase C isozymes as potential therapeutic targets in immune disorders

Background: Members of the protein kinase C (PKC) family are key signalling mediators in immune responses, and pharmacological inhibition of PKCs may be useful for treating immune-mediated diseases. Objective: To review and discuss the insights gained so far into various PKC isozymes and the therapeutic potential and challenges of developing PKC inhibitors for immune disorder therapy. Methods: A literature review of the role of PKCs in immune cell signalling and recent studies describing immune functions associated with PKC isozyme deficiency in relevant mouse disease models, followed by specific case studies of current and potential therapeutic strategies targeting PKCs. Results/conclusion: There is vast amount of data supporting PKC isozymes as attractive drug targets for certain immune disorders. Although the development of specific PKC isozyme inhibitors has been challenging, some progress has been made. It remains to be seen if broad-scale or isozyme-selective inhibition of PKC will have clinical efficacy.

Towards co-design with users who have autism spectrum disorders

People with cognitive disorders, such as autism or Asperger’s syndrome, face many barriers when being involved in the co-design of information and communications technologies (ICT). Cognitive disorders may require that co-design techniques be modified to fit with individual abilities. Up until recently, with technology design, purpose and use being in the hands of ‘experts’ there was little opportunity for customisation. However, ICT bring together various threads that make open many new possibilities. Not only are technologies cheaper, more powerful and more available than ever, but now parents, support agencies and people with autism spectrum disorders expect information technologies to be part of their worlds, and they have the capacity to participate in co-design for customisation. However, co-design techniques have not evolved to the extent that they capture this potential democratisation of the ICT. This paper reports on an investigation of the potential to develop a set of guidelines for co-design techniques to enable people with autism spectrum disorders to participate in ICT design.

Prevalence and cost of musculoskeletal disorders: a population-based, public hospital system healthcare consumption approach.

Objective: To use a population-level, public-hospital approach to compare the prevalence and cost of musculoskeletal diseases (MSD) with other clinical specialties.

Methods: A healthcare utilization survey of 4 million individual records over 4 years, from all major public hospitals in the state of Victoria (estimated population 4.8 million residents in 2000/01) from 1997/98 to 2000/01. Main outcome measures were inpatient episodes of care, bed-days, and outpatient clinic encounters. MSD was defined as the combination of orthopedics and rheumatology.

Results: After obstetrics, MSD was the most frequent outpatient service, with orthopedics accounting for 9.9% of all visits in 2000/01. The proportion of MSD outpatient encounters (on average 11.6% of the total) was constant over the study period. Among 26 medical specialties, MSD had the sixth highest number of inpatient episodes (6.2% in 2000/01), following renal dialysis (14.6%), general surgery (8.2%), obstetrics (7.6%), gastroenterology (7.1%), and general medicine (6.7%). MSD was the fifth highest consumer of bed-days, occupying on average 7.7% of all beds per annum in the period 1997/98 to 2000/01, behind psychiatry (10.1%), respiratory medicine (8.5%), rehabilitation (8.3%), and general medicine (7.8%). MSD was the third most-costly discipline in 2000/01, with total costs of over A dollars 169 million (9.7% of total inpatient costs that year), behind respiratory medicine (11.6%) and general surgery (11.5%).

Conclusion: Compared to other diseases, MSD consumes a substantial proportion of healthcare resources in Victorian public hospitals. These data have important implications for allocation of healthcare resources, clinical care pathways, and prevention strategies.

Readiness for treatment in high risk offenders with personality disorders

Low engagement and non-completion of therapeutic interventions are important issues in the treatment and rehabilitation of offenders and mentally disordered offenders. Such factors influence a range of outcomes, including the reduction of clinical and criminogenic needs. In this paper it is proposed that low engagement and non-completion are usefully viewed as a consequence of low readiness for treatment. The dimensions of readiness are summarized (from the Multifactor Offender Readiness Model) and applied to high risk offenders with severe personality disorders. A readiness analysis has implications for the assessment and treatment of this patient/offender population and is useful in identifying future research and clinical priorities.