Brain-derived neurotrophic factor (BDNF) gene : no major impact on antidepressant treatment response

The brain-derived neurotrophic factor (BDNF) has been suggested to play a pivotal role in the aetiology of affective disorders. In order to further clarify the impact of BDNF gene variation on major depression as well as antidepressant treatment response, association of three BDNF polymorphisms [rs7103411, Val66Met (rs6265) and rs7124442] with major depression and antidepressant treatment response was investigated in an overall sample of 268 German patients with major depression and 424 healthy controls. False discovery rate (FDR) was applied to control for multiple testing. Additionally, ten markers in BDNF were tested for association with citalopram outcome in the STAR*D sample. While BDNF was not associated with major depression as a categorical diagnosis, the BDNF rs7124442 TT genotype was significantly related to worse treatment outcome over 6 wk in major depression (p=0.01) particularly in anxious depression (p=0.003) in the German sample. However, BDNF rs7103411 and rs6265 similarly predicted worse treatment response over 6 wk in clinical subtypes of depression such as melancholic depression only (rs7103411: TTtreatment response in ANOVA models when the remaining SNPs were considered as covariates. The STAR*D analyses did not yield significant results at any of the ten BDNF markers. Our results do not support an association between genetic variation in BDNF and antidepressant treatment response or remission. Post-hoc analyses provide some preliminary support for a potential minor role of genetic variation in BDNF and antidepressant treatment outcome in the context of melancholic depression.

The cost effectiveness of Naltrexone added to cognitive-behavioral therapy in the treatment of alcohol dependence

he purpose of this study was to evaluate the comparative cost of treating alcohol dependence with either cognitive behavioral therapy (CBT) alone or CBT combined with naltrexone (CBT+naltrexone). Two hundred ninety-eight outpatients dependent on alcohol who were consecutively treated for alcohol dependence participated in this study. One hundred seven (36%) patients received adjunctive pharmacotherapy (CBT+naltrexone). The Drug Abuse Treatment Cost Analysis Program was used to estimate treatment costs. Adjunctive pharmacotherapy (CBT+naltrexone) introduced an additional treatment cost and was 54% more expensive than CBT alone. When treatment abstinence rates (36.1% CBT; 62.6% CBT+naltrexone) were applied to cost effectiveness ratios, CBT+naltrexone demonstrated an advantage over CBT alone. There were no differences between groups on a preference-based health measure (SF-6D). In this treatment center, to achieve 100 abstainers over a 12-week program, 280 patients require CBT compared with 160 CBT+naltrexone. The dominant choice was CBT+naltrexone based on modest economic advantages and significant efficiencies in the numbers needed to treat.

Mechanisms of change in negative thinking and urinary monoamines in depressed patients during acute treatment with group cognitive behavior therapy and antidepressant medication

This naturalistic study investigated the mechanisms of change in measures of negative thinking and in 24-h urinary metabolites of noradrenaline (norepinephrine), dopamine and serotonin in a sample of 43 depressed hospital patients attending an eight-session group cognitive behavior therapy program. Most participants (91%) were taking antidepressant medication throughout the therapy period according to their treating Psychiatrists' prescriptions. The sample was divided into outcome categories (19 Responders and 24 Non-responders) on the basis of a clinically reliable change index [Jacobson, N.S., & Truax, P., 1991. Clinical significance: a statistical approach to defining meaningful change in psychotherapy research. Journal of Consulting and Clinical Psychology, 59, 12–19.] applied to the Beck Depression Inventory scores at the end of the therapy. Results of repeated measures analysis of variance [ANOVA] analyses of variance indicated that all measures of negative thinking improved significantly during therapy, and significantly more so in the Responders as expected. The treatment had a significant impact on urinary adrenaline and metadrenaline excretion however, these changes occurred in both Responders and Non-responders. Acute treatment did not significantly influence the six other monoamine metabolites. In summary, changes in urinary monoamine levels during combined treatment for depression were not associated with self-reported changes in mood symptoms.

The mechanical response of the ovine lumbar anulus fibrosus to uniaxial, biaxial and shear loads

Analytical and computational models of the intervertebral disc (IVD) are commonly employed to enhance understanding of the biomechanics of the human spine and spinal motion segments. The accuracy of these models in predicting physiological behaviour of the spine is intrinsically reliant on the accuracy of the material constitutive representations employed to represent the spinal tissues. There is a paucity of detailed mechanical data describing the material response of the reinforced­ground matrix in the anulus fibrosus of the IVD. In the present study, the ‘reinforced­ground matrix’ was defined as the matrix with the collagen fibres embedded but not actively bearing axial load, thus incorporating the contribution of the fibre-fibre and fibre-matrix interactions. To determine mechanical parameters for the anulus ground matrix, mechanical tests were carried out on specimens of ovine anulus, under unconfined uniaxial compression, simple shear and biaxial compression. Test specimens of ovine anulus fibrosus were obtained with an adjacent layer of vertebral bone/cartilage on the superior and inferior specimen surface. Specimen geometry was such that there were no continuous collagen fibres coupling the two endplates. Samples were subdivided according to disc region - anterior, lateral and posterior - to determine the regional inhomogeneity in the anulus mechanical response. Specimens were loaded at a strain rate sufficient to avoid fluid outflow from the tissue and typical stress-strain responses under the initial load application and under repeated loading were determined for each of the three loading types. The response of the anulus tissue to the initial and repeated load cycles was significantly different for all load types, except biaxial compression in the anterior anulus. Since the maximum applied strain exceeded the damage strain for the tissue, experimental results for repeated loading reflected the mechanical ability of the tissue to carry load, subsequent to the initiation of damage. To our knowledge, this is the first study to provide experimental data describing the response of the ‘reinforced­ground matrix’ to biaxial compression. Additionally, it is novel in defining a study objective to determine the regionally inhomogeneous response of the ‘reinforced­ground matrix’ under an extensive range of loading conditions suitable for mechanical characterisation of the tissue. The results presented facilitate the development of more detailed and comprehensive constitutive descriptions for the large strain nonlinear elastic or hyperelastic response of the anulus ground matrix.

Advance Directives Refusing Treatment as an Expression of Autonomy: Do the Courts Practise What They Preach?

The principle of autonomy is at the heart of the right of a competent individual to make an advance directive that refuses life-sustaining medical treatment, and to have that directive complied with by medical professionals. That right is protected by both the common law and, to an extent, by legislation that has been enacted in the United Kingdom and many jurisdictions in Australia. The courts have a critical role in protecting that autonomy, both in those jurisdictions in which the common law continues to operate, and in those jurisdictions which are now governed by statute, and in which judicial determinations will need to be made about legislative provisions. The problem explored in this article is that while the judiciary espouses the importance of autonomy in its judgments, that rhetoric is frequently not reflected in the decisions that are reached. In the United Kingdom and Australia, there is a relatively small number of decisions that consider the validity and applicability of advance directives that refuse life-sustaining medical treatment. This article critically evaluates all of the publicly available decisions and concludes that there is cause for concern. In some cases, there has been an unprincipled evolution of common law principles, while in others there has been inappropriate adjudication through operational irregularities or failure to apply correct legal principles. Further, some decisions appear to be based on a strained interpretation of the facts of the case. The apparent reluctance of some members of the judiciary to give effect to advance directives that refuse treatment is also evidenced by the language used in the judgments. While the focus of this article is on common law decisions, reference will also be made to legislation and the extent to which it has addressed some of the problems identified in this article.

Withholding or withdrawing life-sustaining treatment from children

Difficult questions regarding the withholding or withdrawing of life-sustaining medical treatment can arise in relation to children (being those under 18 years old). This editorial considers some of the legal principles that are relevant in such cases in Australia, particularly Queensland.

The Treatment of Neonatal Seizures: A Critical Review of the Evidence

In a critical review of the literature to assess the efficacy of monotherapy and subsequent combinant anticonvulsant therapy in the treatment of neonatal seizures, four studies were examined; three randomised control trials and one retrospective cohort study. Each study used phenobarbital for monotherapy with doses reaching a maximum of 40mg/kg. Anticonvulsant drugs used in conjunction with phenobarbitone for combinant therapy included midazolam, clonazepam, lorazepam, phenytoin and lignocaine. Each study used an electroencephalograph for seizure diagnosis and neonatal monitoring when determining therapy efficacy and final outcome assessments. Collectively the studies suggest neither monotherapy nor combinant therapy are entirely effective in seizure control. Monotherapy demonstrated a 29% - 50% success rate for complete seizure control whereas combinant therapy administered after the failure of monotherapy demonstrated a success rate of 43% - 100%. When these trials were combined the overall success for monotherapy was 44% (n = 34/78) and for combinant therapy 72% ( n = 56/78). Though the evidence was inconclusive, it would appear that combinant therapy is of greater benefit to infants unresponsive to monotherapy. Further research such as multi-site randomised controlled trials using standardised criteria and data collection are required within this specialised area.

Withholding and withdrawing life-sustaining medical treatment

• At common law, a competent adult can refuse life-sustaining medical treatment, either contemporaneously or through an advance directive which will operate at a later time when the adult’s capacity is lost. • Legislation in most Australian jurisdictions also provides for a competent adult to complete an advance directive that refuses life-sustaining medical treatment. • At common law, a court exercising its parens patriae jurisdiction can consent to, or authorise, the withdrawal or withholding of life-sustaining medical treatment from an adult or child who lacks capacity if that is in the best interests of the person. A court may also declare that the withholding or withdrawal of treatment is lawful. • Guardianship legislation in most jurisdictions allows a substitute decision-maker, in an appropriate case, to refuse life-sustaining medical treatment for an adult who lacks capacity. • In terms of children, a parent may refuse life-sustaining medical treatment for his or her child if it is in the child’s best interests. • While a refusal of life-sustaining medical treatment by a competent child may be valid, this decision can be overturned by a court. • At common law and generally under guardianship statutes, demand for futile treatment need not be complied with by doctors.

Children, Obesity and Exercise: Prevention, Treatment and Management of Childhood and Adolescent Obesity

Throughout the developed world there is an increasing prevalence of childhood obesity. Because of this increase, and awareness of the risks to long term health that childhood obesity presents, the phenomena is now described by many as a global epidemic. Children, Obesity and Exercise provides sport, exercise and medicine students and professionals with an accessible and practical guide to understanding and managing childhood and adolescent obesity. It covers: overweight, obesity and body composition; physical activity, growth and development; psycho-social aspects of childhood obesity; physical activity behaviours; eating behaviours; measuring childrens behaviour; interventions for prevention and management of childhood obesity. Children, Obesity and Exercise addresses the need for authoritative advice and innovative approaches to the prevention and management of this chronic problem.

Interactions between energy intake and expenditure in the development and treatment of obesity.

Summary There are four interactions to consider between energy intake (EI) and energy expenditure (EE) in the development and treatment of obesity. (1) Does sedentariness alter levels of EI or subsequent EE? and (2) Do high levels of EI alter physical activity or exercise? (3) Do exercise-induced increases in EE drive EI upwards and undermine dietary approaches to weight management and (4) Do low levels of EI elevate or decrease EE? There is little evidence that sedentariness alters levels of EI. This lack of cross-talk between altered EE and EI appears to promote a positive EB. Lifestyle studies also suggest that a sedentary routine actually offers the opportunity for over-consumption. Substantive changes in non exercise activity thermogenesis are feasible, but not clearly demonstrated. Cross talk between elevated EE and EI is initially too weak and takes too long to activate, to seriously threaten dietary approaches to weight management. It appears that substantial fat loss is possible before intake begins to track a sustained elevation of EE. There is more evidence that low levels of EI does lower physical activity levels, in relatively lean men under conditions of acute or prolonged semi-starvation and in dieting obese subjects. During altered EB there are a number of small but significant changes in the components of EE, including (i) sleeping and basal metabolic rate, (ii) energy cost of weight change alters as weight is gained or lost, (iii) exercise efficiency, (iv) energy cost of weight bearing activities, (v) during substantive overfeeding diet composition (fat versus carbohydrate) will influence the energy cost of nutrient storage by ~ 15%. The responses (i-v) above are all “obligatory” responses. Altered EB can also stimulate facultative behavioural responses, as a consequence of cross-talk between EI and EE. Altered EB will lead to changes in the mode duration and intensity of physical activities. Feeding behaviour can also change. The degree of inter-individual variability in these responses will define the scope within which various mechanisms of EB compensation can operate. The relative importance of “obligatory” versus facultative, behavioural responses -as components of EB control- need to be defined.

Mechanical properties of thin sol-gel films

This thesis presents a study of the mechanical properties of thin films. The main aim was to determine the properties of sol-gel derived coatings. These films are used in a range of different applications and are known to be quite porous. Very little work has been carried out in this area and in order to study the mechanical properties of sol-gel films, some of the work was carried out on magnetron sputtered metal coatings in order to validate the techniques developed in this work. The main part of the work has concentrated on the development of various bending techniques to study the elastic modulus of the thin films, including both a small scale three-point bending, as well as a novel bi-axial bending technique based on a disk resting on three supporting balls. The bending techniques involve a load being applied to the sample being tested and the bending response to this force being recorded. These experiments were carried out using an ultra micro indentation system with very sensitive force and depth recording capabilities. By analysing the result of these forces and deflections using existing theories of elasticity, the elastic modulus may be determined. In addition to the bi-axial bending study, a finite element analysis of the stress distribution in a disk during bending was carried out. The results from the bi-axial bending tests of the magnetron sputtered films was confirmed by ultra micro indentation tests, giving information of the hardness and elastic modulus of the films. It was found that while the three point bending method gave acceptable results for uncoated steel substrates, it was very susceptible to slight deformations of the substrate. Improvements were made by more careful preparation of the substrates in order to avoid deformation. However the technique still failed to give reasonable results for coated specimens. In contrast, biaxial bending gave very reliable results even for very thin films and this technique was also found to be useful for determination of the properties of sol-gel coatings. In addition, an ultra micro indentation study of the hardness and elastic modulus of sol-gel films was conducted. This study included conventionally fired films as well as films ion implanted in a range of doses. The indentation tests showed that for implantation of H⁺ ions at doses exceeding 3x10¹⁶ ions/cm², the mechanical properties closely resembled those of films that were conventionally fired to 450°C.