Platelet glutamate receptor supersensitivity in major depressive disorder.

Dysregulation of glutamate has been described in depression, and supersensitivity of platelet glutamate receptors has been found in both psychotic major depression and schizophrenia. The aim of this study was to examine the platelet glutamate receptor sensitivity in patients with nonpsychotic, unipolar major depression to assess whether this is a marker of depression or of psychosis. Glutamate receptor sensitivity was assessed using the platelet intracellular calcium response to glutamate (0-100 micromol) measured by spectrofluorometry. The depression group showed a significantly greater platelet intracellular calcium response to glutamate stimulation than the control group, both in terms of absolute values (p = 0.007) and percentage of response from baseline (p = 0.030). These data suggest that platelet glutamate receptors may be supersensitive in depression and that the platelet may be a possible peripheral marker of glutamate function in depression.

Sex- and age-specific associations between income and incident major osteoporotic fractures in Canadian men and women: a population-based analysis

We investigated sex- and age-specific associations between income and fractures at the hip, humerus, spine, and forearm in adults aged ≥50 years. Compared to men with the highest income, men with the lowest income had an increased fracture risk at all skeletal sites. These associations were attenuated in women.

Cellular localization and associations of the major lipolytic proteins in human skeletal muscle at rest and during exercise

Lipolysis involves the sequential breakdown of fatty acids from triacylglycerol and is increased during energy stress such as exercise. Adipose triglyceride lipase (ATGL) is a key regulator of skeletal muscle lipolysis and perilipin (PLIN) 5 is postulated to be an important regulator of ATGL action of muscle lipolysis. Hence, we hypothesized that non-genomic regulation such as cellular localization and the interaction of these key proteins modulate muscle lipolysis during exercise. PLIN5, ATGL and CGI-58 were highly (>60%) colocated with Oil Red O (ORO) stained lipid droplets. PLIN5 was significantly colocated with ATGL, mitochondria and CGI-58, indicating a close association between the key lipolytic effectors in resting skeletal muscle. The colocation of the lipolytic proteins, their independent association with ORO and the PLIN5/ORO colocation were not altered after 60 min of moderate intensity exercise. Further experiments in cultured human myocytes showed that PLIN5 colocation with ORO or mitochondria is unaffected by pharmacological activation of lipolytic pathways. Together, these data suggest that the major lipolytic proteins are highly expressed at the lipid droplet and colocate in resting skeletal muscle, that their localization and interactions appear to remain unchanged during prolonged exercise, and, accordingly, that other post-translational mechanisms are likely regulators of skeletal muscle lipolysis.

Opportunity lost? The major in mental health nursing in Australia

The ongoing difficulty in educating and sustaining an adequate nursing workforce in mental health settings has been identified throughout the world. Different strategies have been implemented internationally to deal with this situation. In Australia major streams in mental health nursing were introduced in some Australian universities to promote mental health nursing as a viable career choice for nursing students. Fourteen universities had implemented or planned to implement a major stream in mental health nursing. From a survey of these programs a lack of consistency in the structure and content of programs was evident. For most programs the intakes had been relatively small, although retention rates appeared promising.

Exposure to As(III) and As(V) changes the Ca²⁺-activation properties of the two major fibre types from the chelae of the freshwater crustacean Cherax destructor

Arsenic is a known carcinogen found in the soil in gold mining regions at concentrations thousands of times greater than gold. Mining releases arsenic into the environment and surrounding water bodies. The main chemical forms of arsenic found in the environment are inorganic arsenite (As(III)) and arsenate (As(V)). Yabbies (Cherax destructor) accumulate arsenic at levels comparable to those in the sediment of their environment but the effect on their physiological function is not known. The effects of arsenic exposure (10 ppm sodium arsenite, AsNaO2 - 5.7 ppm As(III)) and 10 ppm arsenic acid, Na2HAsO4·7H2O - 2.6 ppm As(V)) for 40 days on the contractile function of the two major fibre types from the chelae were determined. After exposure, individual fibres were isolated from the chela, "skinned" (membrane removed) and attached to the force recording apparatus. Contraction was induced in solutions containing increasing [Ca(2+)] until a maximum Ca(2+)-activation was obtained. Submaximal force responses were plotted as a percentage of the maximum Ca(2+)-activated force. As(V) exposure resulted in lower levels of calcium required for activation than As(III) indicating an increased sensitivity to Ca(2+) after long term exposure to arsenate compared to arsenite. Myosin heavy chain and tropomyosin content in individual fibres was also decreased as a result of arsenic exposure. Single fibres exposed to As(V) produced significantly more force than muscle fibres from control animals. Long-term exposure of yabbies to arsenic alters the contractile function of the two major fibre types in the chelae.

Validation of patient health questionnaire (PHQ) for major depression in Chinese outpatients with multiple somatic symptoms: A multicenter cross-sectional study

Background: Despite the high co-morbidity of depressive symptoms in patients with multiple somatic symptoms, the validity of the 9-item Patient Health Questionnaire (PHQ-9) has not yet been investigated in Chinese patients with multiple somatic symptoms. Methods: The multicenter cross-sectional study was conducted in ten outpatient departments located in four cities in China. The psychometric properties of the PHQ-9 were examined by confirmative factor analysis (CFA). Criterion validation was undertaken by comparing results with depression diagnoses obtained from the Mini International Neuropsychiatric Interview (MINI) as the gold standard. Results: Overall, 491 patients were recruited of whom 237 had multiple somatic symptoms (SOM+ group, PHQ-15 ≥ 10). Cronbach's α of the PHQ-9 was 0.87, 0.87, and 0.90 for SOM+ patients, SOM- patients, and total sample respectively. All items and the total score were moderately correlated. The factor models of PHQ-9 tested by CFA yielded similar diagnostic performance when compared to sum score estimation. Multi-group confirmatory factor analysis based on unidimensional model showed similar psychometric properties over the groups with low and high somatic symptom burden. The optimal cut-off point to detect depression in Chinese outpatients was 10 for PHQ-9 (sensitivity=0.77, specificity=0.76) and 3 for PHQ-2 (sensitivity=0.77, specificity=0.74). Limitations: Potential selection bias and nonresponse bias with applied sampling method. Conclusions: PHQ-9 (cut-off point=10) and PHQ-2 (cut-off point=3) were reliable and valid to detect major depression in Chinese patients with multiple somatic symptoms.

An adjunctive antidepressant nutraceutical combination in treating major depression: study protocol and clinical considerations

Current treatment for major depressive disorder (MDD), a prevalent and disabling mental illness, is inadequate, with two-thirds of people treated with first-line antidepressants not achieving remission. MDD is for many a chronic condition, often requiring multiple treatment attempts, thus development of additional interventions is urgently required. An emerging approach to improve non-response to antidepressants is the use of adjunctive nutraceuticals. The pathophysiology of MDD is considered to involve a range of abnormalities (monoamine impairment, neuro-endocrinological changes, reduced brain-derived neurotrophic factor, and cytokine alterations). By targeting an array of these key neurobiological pathways via specific nutraceuticals (S-adenosyl methionine; [SAMe], 5-HTP [active tryptophan], folinic acid [active folic acid], omega-3 fatty acids, and zinc), there is the potential to provide a more comprehensive therapeutic biological approach to treat depression. We are currently conducting a National Health and Medical Research Council funded study in Australia (APP1048222). The clinical trial is phase II/III, multi-site, 3-arm, 8-week, randomised, double-blind, placebo-controlled study using SAMe + folinic acid versus a combination nutraceutical (SAMe, 5-HTP, folinic acid, omega-3, and zinc) or matching placebo in 300 currently depressed participants with diagnosed MDD who are non-responsive to current antidepressants (ANZCTR, protocol number: 12613001300763). The results may provide evidence for a novel adjunctive neurobiological approach for treating depression.

The association between major depressive disorder, use of antidepressants and bone mineral density (BMD) in men.

OBJECTIVE: Both depression and use of antidepressants have been negatively associated with bone mineral density (BMD) but mainly in studies among postmenopausal women. Therefore, the aim of this study was to investigate these relationships in men. METHODS: Between 2006 and 2011, 928 men (aged 24-98 years) from the Geelong Osteoporosis Study completed a comprehensive questionnaire, clinical measurements and had BMD assessments at the forearm, spine, total hip and total body. Major depressive disorder (MDD) was identified using a structured clinical interview (SCID-I/NP). The cross-sectional associations between BMD and both MDD and antidepressant use were analyzed using multivariable linear regression. RESULTS: Of the study population, 84 (9.1%) men had a single MDD episode, 50 (5.4%) had recurrent episodes and 65 (7.0%) were using antidepressants at the time of assessment. Following adjustments, recurrent MDD was associated with lower BMD at the forearm and total body (-6.5%, P=0.033 and -2.5%, P=0.033, respectively compared to men with no history of MDD), while single MDD episodes were associated with higher BMD at the total hip (+3.4%, P=0.030). Antidepressant use was associated with lower BMD only in lower-weight men (<75-110 kg depending on bone site). CONCLUSIONS: Both depression and use of antidepressants should be taken into account as possible risk factors for osteoporosis in men.

Effects of persisting emotional impact from child abuse and norepinephrine transporter genetic variation on antidepressant efficacy in major depression: a pilot study

OBJECTIVE: Previous studies suggest child abuse and serotonergic polymorphism influence depression susceptibility and antidepressant efficacy. Polymorphisms of the norepinephrine transporter (NET) may also be involved. Research in the area is possibly clouded by under reporting of abuse in researcher trials. METHODS: Adults (n=51) with major depressive disorder has 8 weeks treatment with escitalopram or venlafaxine. Abuse history was obtained, the ongoing emotional impact of which was measured with the 15-item impact of event scale (IES-15). The 17-item Hamilton Depression Rating Scale (HDRS) was applied serially. Two NET polymorphisms (rs2242446 and rs5569) were assayed, blinded to HDRS ratings and abuse history. RESULTS: No subjects reporting abuse with high impact in adulthood (IES-15 ≥26, n=12) remitted; whereas 77% reporting low impact (IES-15 <26; n=26) remitted (p<0.001). Subjects reporting high impact abuse (n=12) had a 50-fold (95% confidence interval=4.85-514.6) greater odds of carrying rs2242446-TT genotype, but the small sample size leaves this finding vulnerable to type I error. CONCLUSIONS: The level of persisting impact of child abuse appears relevant to antidepressant efficacy, with susceptibility to such possibly being influence by NET rs2242446 polymorphism. Larger studies may be merited to expand on this pilot level finding given potential for biomarker utility.

Effects of asenapine in bipolar I patients meeting proxy criteria for moderate-to-severe mixed major depressive episodes: a post hoc analysis

OBJECTIVE: Depression is the predominant psychosocial and suicide burden in bipolar disorder, yet there is a paucity of evidence-based treatments for bipolar depression. METHODS: This post hoc subgroup analysis of data pooled from two 3-week, randomized, placebo- and olanzapine-controlled trials (December 2004-April 2006, N = 489 and November 2004-April 2006, N = 488) examined a subgroup of patients meeting criteria for moderate-to-severe mixed major depressive episodes, defined using DSM-IV-TR criteria for mixed episodes (mania and major depression simultaneously) with a baseline Montgomery-Asberg Depression Rating Scale (MADRS) total score ≥ 20. RESULTS: Decreases in MADRS scores (least squares mean [SE]), the a priori primary outcome, were significantly greater in the asenapine group than in the placebo group from baseline to day 7 (-11.02 [1.82] vs -4.78 [1.89]; P = .0195), day 21 (-14.03 [2.01] vs -7.43 [2.09]; P = .0264), and endpoint (-10.71 [1.76] vs -5.19 [1.98]; P = .039). Decreases in MADRS scores with asenapine were significantly greater than with olanzapine from baseline to day 7 (-6.26 [1.47]; P = .0436). Decreases in Young Mania Rating Scale mean total score were greater with asenapine than with placebo or olanzapine at all time points assessed. A significantly greater reduction from baseline to day 21 in the Short Form-36 mental component summary score was observed with asenapine, but not olanzapine, compared with placebo (16.57 vs 5.97; P = .0093). Asenapine was generally well tolerated. CONCLUSIONS: These data provide support for the potential efficacy of asenapine in mixed major depressive episodes; however, these data cannot be linearly extrapolated to nonmixed major depression.

Mechanisms underlying neurocognitive dysfunctions in recurrent major depression

Recent work shows that depression is intimately associated with changes in cognitive functioning, including memory, attention, verbal fluency, and other aspects of higher-order cognitive processing. Changes in cognitive functioning are more likely to occur when depressive episodes are recurrent and to abate to some degree during periods of remission. However, with accumulating frequency and duration of depressive episodes, cognitive deficits can become enduring, being evident even when mood improves. Such changes in cognitive functioning give depression links to mild cognitive impairment and thereby with neurodegenerative conditions, including Alzheimer's disease, Parkinson's disease, schizophrenia, and multiple sclerosis. Depression may then be conceptualized on a dimension of depression - mild cognitive impairment - dementia. The biological underpinnings of depression have substantial overlaps with those of neurodegenerative conditions, including reduced neurogenesis, increased apoptosis, reactive oxygen species, tryptophan catabolites, autoimmunity, and immune-inflammatory processes, as well as decreased antioxidant defenses. These evolving changes over the course of depressive episodes drive the association of depression with neurodegenerative conditions. As such, the changes in cognitive functioning in depression have important consequences for the treatment of depression and in reconceptualizing the role of depression in wider neuroprogressive conditions. Here we review the data on changes in cognitive functioning in recurrent major depression and their association with other central conditions.

Nocebo effects in the treatment of major depression: results from an individual study participant-level meta-analysis of the placebo arm of duloxetine clinical trials

BACKGROUND: The nocebo effect, when a harmless substance creates harmful effects in a person who takes it, is a clinically salient yet seldom studied phenomenon that may be associated with poorer treatment outcomes, perceived adverse events, and treatment discontinuation. The covert presence of nocebo responders in clinical trials may contribute to outcome variance in both placebo and active treatment arms for important primary and secondary endpoints. Nocebo effects are thought to be driven by expectancy and conditioning. METHOD: This study analyzed pooled clinical trial data in the placebo arms of controlled trials of antidepressant medications to investigate variables associated with the emergence of adverse outcomes in placebo-treated participants (N = 2,457). Specifically, we examined treatment-emergent adverse events (TEAEs) and discontinuation in placebo-treated individuals. Trials were commenced between 1993 and 2010 as studies of duloxetine versus active comparator and/or placebo. RESULTS: TEAEs were reported by 1,569 placebo-treated participants (63.9%), with 115 (4.7%) discontinuing from the studies due to TEAEs and 274 (11.2%) showing worsening of Hamilton Depression Rating Scale total score during placebo treatment. There was specifically no evidence to support the expectancy hypothesis, that reported TEAEs were influenced by adverse effects described in the clinical trials participant information and consent forms, or the conditioning hypothesis, that reported TEAEs would be influenced by adverse effect profiles of previous antidepressant medications used by these study participants. There was some evidence to suggest that people who had previously used complementary medications were more likely to report TEAEs. Variables specific to individual studies were the strongest predictors of TEAEs. DISCUSSION: In this study, TEAEs were very common among placebo-treated clinical trial participants. Unexpectedly, there was no evidence to associate TEAEs with adverse clinical outcomes, nor were the conditioning or expectancy hypotheses supported by these data. CONCLUSIONS: The nocebo effect is a common, covert, and poorly understood driver of clinical outcomes that requires further investigation.

Are Chinese stock markets increasing integration with other markets in the greater China region and other major markets?

This paper investigates the cointegrating and long-term causal relationships between the Shanghai A and B-share market, and between these two markets and the Hong Kong, the Taiwanese, the Japanese and the US market of two sub periods between July 1993 and March 2007. On the basis of a new Granger non-causality test procedure developed by Toda-Yamamoto (1995) and Johansen’s (1988) cointegration test, my results suggest that a long-term equilibrium relationship measured by cointegration has been merged between
the Chinese A-share market and the other markets in greater China region as well as the US market during the post-crisis period which covers the period since Chinese A-share market was opened to the Qualified Foreign Institutional Investors (QFII) in 2002. I also found that the Shanghai A-share market uni-directionally Granger-causes the other regional markets after the Asian financial crisis, while the A-share market and Hong Kong H-share market have had a significant feedback relationship since then. However, I found no evidence there has been cointegrating relationship between Shanghai B-share market and any other market ever since the B-share market was opened to the local retail investors in 2001.

Colorectal preOperative surgical score (CrOSS) for mortality in major colorectal surgery

BACKGROUND: Colorectal surgery carries a significant mortality risk, with reported rates of 1-6% for elective surgery and up to 22% in the emergency setting. Both clinicians and patients will benefit from being able to predict the likelihood of death before surgery. Recently, we have described and validated two risk stratification models for colorectal surgery, the Barwon Health 2012 and Association Française de Chirurgie models. However, these models are not suitable for assessment at patient's bedside. The purpose of this study is to develop a simplified preoperative model capable of predicting mortality following colorectal surgery. METHODS: The new model is termed Colorectal preOperative Surgical Score (CrOSS). The development and internal validation of CrOSS was performed using a prospectively maintained colorectal database. External validation was performed using retrospective data. Univariate and multivariate analyses were performed in model development. Calibration and discrimination were used for model validation. RESULTS: There were 474 and 389 consecutive colorectal surgeries at Geelong Hospital and Western Hospital. Overall mortality rates were 5.16% and 1.03%, respectively. Significant predictors for mortality were as follows: age ≥70, urgent operation, albumin ≤30 g/L and congestive heart failure (receiver operating characteristic (ROC) = 0.870, calibration P-value = 0.937). The predicted risk of mortality was stratified according to the risk profile of 0.39-66.51%. When validated externally, CrOSS predicted mortality accurately (ROC = 0.847, calibration P-value = 0.199). CONCLUSIONS: A robust and simple preoperative model has been created to risk-stratify patients for colorectal surgery. This was successfully validated at another tertiary hospital.