Mutations in the DLG3 gene cause nonsyndromic X-linked mental retardation

We have identified truncating mutations in the human DLG3 ( neuroendocrine dlg) gene in 4 of 329 families with moderate to severe X-linked mental retardation. DLG3 encodes synapse-associated protein 102 (SAP102), a member of the membrane-associated guanylate kinase protein family. Neuronal SAP102 is expressed during early brain development and is localized to the postsynaptic density of excitatory synapses. It is composed of three amino-terminal PDZ domains, an src homology domain, and a carboxyl-terminal guanylate kinase domain. The PDZ domains interact directly with the NR2 subunits of the NMDA glutamate receptor and with other proteins responsible for NMDA receptor localization, immobilization, and signaling. The mutations identified in this study all introduce premature stop codons within or before the third PDZ domain, and it is likely that this impairs the ability of SAP102 to interact with the NMDA receptor and/or other proteins involved in downstream NMDA receptor signaling pathways. NMDA receptors have been implicated in the induction of certain forms of synaptic plasticity, such as long-term potentiation and long-term depression, and these changes in synaptic efficacy have been proposed as neural mechanisms underlying memory and learning. The disruption of NMDA receptor targeting or signaling, as a result of the loss of SAP102, may lead to altered synaptic plasticity and may explain the intellectual impairment observed in individuals with DLG3 mutations.

Assessing cost-effectiveness in mental health: family interventions for schizophrenia and related conditions

Objective: Existing evidence suggests that family interventions can be effective in reducing relapse rates in schizophrenia and related conditions. Despite this, such interventions are not routinely delivered in Australian mental health services. The objective of the current study is to investigate the incremental cost-effectiveness ratios (ICERs) of introducing three types of family interventions, namely: behavioural family management (BFM); behavioural intervention for families (BIF); and multiple family groups (MFG) into current mental health services in Australia. Method: The ICER of each of the family interventions is assessed from a health sector perspective, including the government, persons with schizophrenia and their families/carers using a standardized methodology. A two-stage approach is taken to the assessment of benefit. The first stage involves a quantitative analysis based on disability-adjusted life years (DALYs) averted. The second stage involves application of 'second filter' criteria (including equity, strength of evidence, feasibility and acceptability to stakeholders) to results. The robustness of results is tested using multivariate probabilistic sensitivity analysis. Results: The most cost-effective intervention, in order of magnitude, is BIF (A$8000 per DALY averted), followed by MFG (A$21 000 per DALY averted) and lastly BFM (A$28 000 per DALY averted). The inclusion of time costs makes BFM more cost-effective than MFG. Variation of discount rate has no effect on conclusions. Conclusions: All three interventions are considered 'value-for-money' within an Australian context. This conclusion needs to be tempered against the methodological challenge of converting clinical outcomes into a generic economic outcome measure (DALY). Issues surrounding the feasibility of routinely implementing such interventions need to be addressed.

Assessing cost-effectiveness - Mental health: introduction to the study and methods

Objective: The Assessing Cost-Effectiveness - Mental Health (ACE-MH) study aims to assess from a health sector perspective, whether there are options for change that could improve the effectiveness and efficiency of Australia's current mental health services by directing available resources toward 'best practice' cost-effective services. Method: The use of standardized evaluation methods addresses the reservations expressed by many economists about the simplistic use of League Tables based on economic studies confounded by differences in methods, context and setting. The cost-effectiveness ratio for each intervention is calculated using economic and epidemiological data. This includes systematic reviews and randomised controlled trials for efficacy, the Australian Surveys of Mental Health and Wellbeing for current practice and a combination of trials and longitudinal studies for adherence. The cost-effectiveness ratios are presented as cost (A$) per disability-adjusted life year (DALY) saved with a 95% uncertainty interval based on Monte Carlo simulation modelling. An assessment of interventions on 'second filter' criteria ('equity', 'strength of evidence', 'feasibility' and 'acceptability to stakeholders') allows broader concepts of 'benefit' to be taken into account, as well as factors that might influence policy judgements in addition to cost-effectiveness ratios. Conclusions: The main limitation of the study is in the translation of the effect size from trials into a change in the DALY disability weight, which required the use of newly developed methods. While comparisons within disorders are valid, comparisons across disorders should be made with caution. A series of articles is planned to present the results.

Falls prevention in rural general practice: what stands the test of time and where to from here?

Objective: General practitioner recall of the 1992-96 'Stay on Your Feet'(SOYF) program and its influence on practice were surveyed five years post-intervention to gauge sustainability of the SOYF General Practice (GP) component. Methods: A survey assessed which SOYF components were still in existence, current practice related to falls prevention, and interest in professional development. All general practitioners (GPs) situated within the boundaries of a rural Area Health Service were mailed a survey in late 2001. Results: Response rate was 66.5% (139/ 209). Of 117 GPs in practice at the time of SOYF, 80.2% reported having heard of SOYF and 74.4% of those felt it had influenced practice. Half (50.9%) still had a copy of the SOYF GP resource and of those, 58.6% used it at least 'occasionally'. Three-quarters of GPs surveyed (75.2%) checked medications 'most/almost all' of the time with patients over 60 years; 46.7% assessed falls risk factors; 41.3% gave advice; and 22.6% referred to allied health practitioners. GPs indicated a strong interest in falls prevention- related professional development. There was no significant association between use of the SOYF resource package and any of the current falls prevention practices (all chi(2)>0.05). Conclusions and implications: There was high recall of SOYF and a general belief that it influenced practice. There was little indication that use of the resource had any lasting influence on GPs' practices. In future, careful thought needs to go into designing a program that has potential to affect long-term change in GPs' falls prevention practice.

Material influence on the stress corrosion cracking of rock bolts

Rock bolt stress corrosion cracking (SCC) has been investigated using the linearly increasing stress test (LIST). One series of experiments determined the threshold stress of various bolt metallurgies (900 MPa for 1355AXRC, and 800 MPa for MAC and MA840B steels). The high values of threshold stress suggest that SCC begins in rock bolts when they are sheared by moving rock strata. SCC only occurred for environmental conditions which produce hydrogen on the sample surface, leading to hydrogen embrittlement and SCC. Different threshold potentials were determined for a range of metallurgies. Cold work was shown to increase the resistance of the steel to SCC. Rock bolt rib geometry does not have a direct impact on the SCC resistance properties of the bolt, although the process by which the ribs are produced can introduce tensile stresses into the bolt which lower its resistance to SCC. (C) 2004 Elsevier Ltd. All rights reserved.

Improving access to evidence-based mental health care: general practitioners and allied health professionals collaborate

This study evaluated whether projects conducted through the Access to Allied Health Services component of the Australian Better Outcomes in Mental Health Care initiative are improving access to evidence-based, non-pharmacological therapies for people with depression and anxiety. Synthesising data from the first 29 projects funded through the initiative, the study found that the models utilised in the projects have evolved over time. The projects have achieved a high level uptake; at a conservative estimate, 710 GPs and 160 allied health professionals (AHPs) have provided care to 3,476 consumers. The majority of these consumers have depression (77%) and/or anxiety disorders (55%); many are low income earners (57%); and a number have not previously accessed mental health care (40%). The projects have delivered 8,678 sessions of high quality care to these consumers, most commonly providing CBT-based cognitive and behavioural interventions (55% and 41%, respectively). In general, GPs, AHPs and consumers are sanguine about the projects, and have reported positive consumer outcomes. However, as with any new initiative, there are some practical and professional issues that need to be addressed. The projects are improving access to evidence-based, non-pharmacological therapies. The continuation and expansion of the initiative should be a priority.

Offspring size effects in the marine environment: A field test for a colonial invertebrate

A central tenet of life-history theory is the presence of a trade-off between the size and number of offspring that a female can produce for a given clutch. A crucial assumption of this trade-off is that larger offspring perform better than smaller offspring. Despite the importance of this assumption empirical, field-based tests are rare, especially for marine organisms. We tested this assumption for the marine invertebrate, Diplosoma listerianum, a colonial ascidian that commonly occurs in temperate marine communities. Colonies that came from larger larvae had larger feeding structures than colonies that came from smaller larvae. Colonies that came from larger larvae also had higher survival and growth after 2 weeks in the field than colonies that came from smaller larvae. However, after 3 weeks in the field the colonies began to fragment and we could not detect an effect of larval size. We suggest that offspring size can have strong effects on the initial recruitment of D. listerianum but because of the tendency of this species to fragment, offspring size effects are less persistent in this species than in others.

Mental health and socio-economic variations in Australian suicide

This paper investigates the relationship between suicide rates and prevalence of mental disorder and suicide attempts, across socio-economic status (SES) groups based on area of residence. Australian suicide data (1996-1998) were analysed in conjunction with area-based prevalences of mental disorder derived from the National Survey of Mental Health and Well-Being (1997). Poisson regression models of suicide risk included age, quintile of area-based SES, urban-rural residence, and country of birth (COB), with males and females analysed separately. Analysis focussed on the association between suicide and prevalences of (ICD-10) affective disorders, anxiety disorders, substance use disorders and suicide attempts by SES group. Prevalences of other psychiatric symptomatology, substance use problems, health service utilisation, stressful life-events and personality were also investigated. Significant increasing gradients were evident from high to low SES groups for prevalences of affective disorders, anxiety disorders (females only), and substance use disorders (males only); sub-threshold drug and alcohol problems and depression; and suicide attempts and suicide (males only). Prevalences of mental disorder, other sub-threshold mental health items and suicide attempts were significantly associated with suicide, but in most cases associations were reduced in magnitude and became statistically non-significant after adjustment for COB, urban-rural residence, and SES. For male suicide the relative risk (RR) in the lowest SES group compared to the highest was 1.40 (95% CI 1.29-1.52, p < 0.001) for all ages, and 1.46 (95% CI 1.27-1.67, p < 0.001) for male youth (20-34 years). This relationship was not substantially modified in males when regression models included prevalences of affective disorders, and other selected mental health variables and demographic factors. From a population perspective, SES remained significantly associated with suicide after controlling for the prevalence of mental disorders and other psychiatric symptomatology. Mental conditions and previous suicidal behaviour may play an intermediary role between SES and suicide, but this study suggests that an independent relationship between suicide and SES also exists. (c) 2005 Elsevier Ltd. All rights reserved.

Macroscopic test of quantum mechanics versus stochastic electrodynamics

We identify a test of quantum mechanics versus macroscopic local realism in the form of stochastic electrodynamics. The test uses the steady-state triple quadrature correlations of a parametric oscillator below threshold.

Conformational dynamics of thyroid hormones by variable temperature nuclear magnetic resonance: The role of side chain rotations and cisoid/transoid interconversions

H-1 NMR spectra of the thyroid hormone thyroxine recorded at low temperature and high field show splitting into two peaks of the resonance due to the H2,6 protons of the inner (tyrosyl) ring. A single resonance is observed in 600 MHz spectra at temperatures above 185 K. An analysis of the line shape as a function of temperature shows that the coalescence phenomenon is due to an exchange process with a barrier of 37 kJ mol(-1). This is identical to the barrier for coalescence of the H2',6' protons of the outer (phenolic) ring reported previously for the thyroid hormones and their analogues. It is proposed that the separate peaks at low temperature are due to resonances for H2,6 in cisoid and transoid conformers which are populated in approximately equal populations. These two peaks are averaged resonances for the individual H2 and H6 protons. Conversion of cisoid to transoid forms can occur via rotation of either the alanyl side chain or the outer ring, from one face of the inner ring to the other. It is proposed that the latter process is the one responsible for the observed coalescence phenomenon. The barrier to rotation of the alanyl side chain is greater than or equal to 37 kJ mol(-1), which is significantly larger than has previously been reported for Csp(2)-Csp(3) bonds in other Ph-CH2-X systems. The recent crystal structure of a hormone agonist bound to the ligand-binding domain of the rat thyroid hormone receptor (Wagner et al. Nature 1995, 378, 690-697) shows the transoid form to be the bound conformation. The significant energy barrier to cisoid/transoid interconversion determined in the current study combined with the tight fit of the hormone to its receptor suggests that interconversion between the forms cannot occur at the receptor site but that selection for the preferred bound form occurs from the 50% population of the transoid form in solution.