Aims To report nationally representative data on the prevalence and correlates (including psychiatric comorbidity and treatment) of DSM-IV alcohol abuse and dependence in Australian adults. Design The 2007 National Survey of Mental Health and Wellbeing (NSMHWB). Setting Australian nationally representative household survey. Participants 8841 Australian adults (16-85 years). Measurements Interview schedule that assessed symptoms of the most prevalent DSM-IV mental disorders in the life-time and the past 12 months. Findings Prevalence of life-time and 12-month disorders was 18.3% and 2.9% for alcohol abuse and 3.9% and 1.4% for alcohol dependence. Current alcohol abuse and dependence was significantly more common in males and younger adults. There were significant associations between current alcohol use and other drug use disorders (OR 18.2) and between anxiety disorders and alcohol use disorders (OR 2.6). Only 22.4% of those with alcohol use disorders were treated for their alcohol disorder. Conclusions Alcohol use disorders are highly prevalent, especially among young adult males. Comorbidity between anxiety and other drug use disorders is common and remains a significant challenge for the delivery of effective health-care services and treatment. The low rate of effective interventions for alcohol problems is a significant public health concern.

Objective: To determine whether or not the use of an arginine-containing nutritional supplement could result in signifi cantly shorter pressure ulcer (PU) healing times in people with spinal cord injuries living in the community, compared with a comparative historical control group. Method: Eighteen spinal-cord-injured patients (all part of a hospital spinal outreach service) received 9g of a commercial powdered arginine supplement per day until full PU healing occurred. Healing rates were compared against 17 historical control patients (as assessed by medical history audit). Results: Baseline characteristics (age, gender, injury level and time) were similar between groups. Mean ulcer healing times were 10.5 +/- 1.3 weeks versus 21 +/- 3.7 weeks (p<0.05) in the intervention and control groups respectively. Comparison of healing rates in the intervention group against expected healing rates derived from the medical literature showed that intervention patients had a signifi cantly shorter mean healing time (category 2 PU: 5.5+/-1.3 weeks versus 13.4 weeks; category 3 PU: 12.5 +/- 1.9 weeks versus 18.2 weeks; category 4 PU: 14.4 +/- 4.8 weeks versus 22.1 weeks). A diagnosis of diabetes did not significantly alter healing rates in either group. Conclusion: Results from this observational study show a promising benefit of arginine supplementation on PU healing for individuals with spinal cord injury living in the community.

INTRODUCTION AND AIMS: Benzodiazepine use is associated with elevated levels of harm. The current study aimed to ascertain the long-term nature of the relationship between benzodiazepine use and clinical profile among heroin users. DESIGN AND METHODS: Longitudinal cohort, with follow-up at 3, 12, 24 and 36 months. Participants were 615 heroin users recruited for the Australian Treatment Outcome Study. RESULTS: At baseline, current benzodiazepine users were more likely to be committing crime, had poorer psychological health and poorer physical health. Baseline benzodiazepine use was not associated with the likelihood across follow-up of heroin use (P = 0.44), committing crime (P = 0.17), poorer psychological health (P = 0.31) or poorer physical health (P = 0.48). Current benzodiazepine use was, however, associated with a greater likelihood of concurrent heroin use (OR 2.77), crime (OR 2.04), poorer psychological health (beta = -4.47) and poorer physical health (beta = -2.33). DISCUSSION AND CONCLUSIONS: Clinicians should be aware that reductions in benzodiazepine use are associated with reductions in harm, and that baseline benzodiazepine status does not equate to poor long-term outcome.

Lympho-epithelial Kazal-type-related inhibitor (LEKTI) is recognized as a serine protease inhibitor and is thought to play a key role in skin barrier function through the inhibition of kallikrein (KLK) activities and regulation of skin desquamation. LEKTI has a total of 15 potential inhibitory domains, and we hypothesize that it has other potential targets in the skin. To identify candidate protease targets of LEKTI, a label-free quantitative proteomic approach was employed. This work describes a novel, rapid, and noninvasive method for the identification and quantitation of the major proteins present in the uppermost layers of the skin. By using cells scraped from the elbow, we were able to rapidly identify and quantitate 79 proteins. Caspase 14 and bleomycin hydrolase were identified as the proteases of highest abundance. Despite the fact that caspase 14 is a cysteine protease and LEKTI is described as a serine protease inhibitor, we demonstrate that caspase 14 is inhibited by full-length LEKTI and 5 recombinant fragments of LEKTI to varied extents. Details of the development of the methods used for the creation of the skin proteome and the inhibition of caspase 14 by LEKTI and implications for LEKTI as a multifunctional protease inhibitor are discussed.

Modern manufacturing facilities for bioproducts are highly automated with advanced process monitoring and data archiving systems. The time dynamics of hundreds of process parameters and outcome variables over a large number of production runs are archived in the data warehouse. This vast amount of data is a vital resource to comprehend the complex characteristics of bioprocesses and enhance production robustness. Cell culture process data from 108 'trains' comprising production as well as inoculum bioreactors from Genentech's manufacturing facility were investigated. Each run constitutes over one-hundred on-line and off-line temporal parameters. A kernel-based approach combined with a maximum margin-based support vector regression algorithm was used to integrate all the process parameters and develop predictive models for a key cell culture performance parameter. The model was also used to identify and rank process parameters according to their relevance in predicting process outcome. Evaluation of cell culture stage-specific models indicates that production performance can be reliably predicted days prior to harvest. Strong associations between several temporal parameters at various manufacturing stages and final process outcome were uncovered. This model-based data mining represents an important step forward in establishing a process data-driven knowledge discovery in bioprocesses. Implementation of this methodology on the manufacturing floor can facilitate a real-time decision making process and thereby improve the robustness of large scale bioprocesses.

The tripartite model of posttraumatic stress disorder (PTSD) articulated in DSM-IV has received limited empirical support. Over the past decade, a burgeoning literature on PTSD symptom structure has accumulated suggesting several alternative models. Elucidating the latent structure of PTSD has important clinical and theoretical implications. This paper presents the first confirmatory factor analytic investigation of PTSD symptoms in an epidemiologically based trauma-exposed sample from Australia. Data from a subsample of respondents from the 2007 National Survey of Mental Health and Wellbeing (NSMHWB; n=2677) were submitted to confirmatory factor analysis and several alternative conceptual models were tested. Empirical support was found for an intercorrelated four-factor model reflecting re-experiencing, avoidance, dysphoria, and hyperarousal symptoms. Given that the DSM is currently under revision, research addressing structural validity concerns is especially timely. The present findings renew calls in the structural literature suggesting that the structure of PTSD should be revised in DSM-V.

Protein phosphatase (PP) 2A is a heterotrimeric enzyme regulated by specific subunits. The B56 (or B(dash) / PR61 / PPP2R5) class of B subunits direct PP2A or its substrates to different cellular locations, and the B56alpha, beta and epsilon isoforms are known to localize primarily in the cytoplasm. Here we studied the pathways that regulate B56alpha subcellular localization. We detected B56alpha in the cytoplasm and nucleus, and at the nuclear envelope and centrosomes, and show that cytoplasmic localization is dependent on CRM1 mediated nuclear export. The inactivation of CRM1 by leptomycin B or by siRNA knockdown caused nuclear accumulation of ectopic and endogenous B56alpha. Conversely, CRM1 overexpression shifted B56alpha to the cytoplasm. We identified a functional nuclear export signal at the carboxy terminus (NES; aa451 to 469), and site directed mutagenesis of the NES (L461A) caused nuclear retention of full length B56alpha. Active NESs were identified at similar positions in the cytoplasmic B56beta and epsilon isoforms, but not in the nuclear localized B56delta or gamma isoforms. The transient expression of B56alpha induced nuclear export of the PP2A catalytic (C) subunit and this was blocked by the L461A NES mutation. In addition, B56alpha colocated with the PP2A active (A) subunit at centrosomes, and its centrosome targeting involved sequences that bind to the A subunit. Fluorescence Recovery After Photobleaching (FRAP) assays revealed dynamic and immobile pools of B56alphaGFP, which was rapidly exported from the nucleus and subject to retention at centrosomes. We propose that B56alpha can act as a PP2A C subunit chaperone and regulates PP2A activity at diverse subcellular locations.

PURPOSE:: Measures of comfort are important in the prescription and development of footwear. The purpose of our study was to examine 3 commonly used scales (visual analogue scale (VAS), Likert and ranking scale) to determine the most reliable, calculate a minimal clinically important change in rating scales and explore dimensions of comfort important to the patient. METHODS:: 20 subjects were consecutively allocated to 2 experiments consisting of 5 sessions of repeated measures. Using comfort measures from each subject's usual jogging shoe, experiment 1examined the reliability of the VAS and Likert scales over 6 dimensions of the foot, including overall comfort. The second experiment examined the reliability of ranking scale by assessing the ranked position of the shoe. Comfort measures were taken in both walking and jogging. RESULTS:: The ranking scale was the most stable scale. Mixed linear modelling found VAS was more stable than the Likert scale. The VAS required 2 sessions to become reliable for all measures but those taken from the heel, which required more. Using data-derived approach, a clinically important change in comfort was 9.59 mm on the 100 mm VAS, an anchor-based approach was 10.2 mm. Subjects identified arch comfort as the most important consideration in footwear comfort. CONCLUSIONS:: Ranking scale and VAS are reliable measures of footwear comfort. Using the VAS, a change 9.59 mm and10.2 mm indicate a clinically relevant change in comfort. The most important dimensions to the patient are overall comfort and the arch.

Although the potential role of Pim2 as a cooperative oncogene has been well described in lymphoma, its role in leukemia has remained largely unexplored. Here we show that high expression of Pim2 is observed in patients with acute promyelocytic leukemia (APL). To further characterize the cooperative role of Pim2 with PML-RARalpha, we used a well-established PML-RARalpha (PRalpha) mouse model. Pim2 coexpression in PRalpha-positive hematopoietic progenitor cells (HPC) induces leukemia in recipient mice after a short latency. Pim2/PRalpha cells were able to repopulate mice in serial transplantations and to induce disease in all of these recipients. Neither Pim2 nor PRalpha alone were sufficient to induce leukemia upon transplantation in this model. The disease induced by Pim2 over-expression in PRalpha cells contained a slightly higher fraction of immature myeloid cells, when compared to the previously described APL disease induced by PRalpha. However, it also clearly resembled an APL-like phenotype and showed signs of differentiation upon ATRA treatment in vitro. These results support the hypothesis that Pim2, which is also a known target of Flt3-ITD (another gene that cooperates with PML-RARalpha), cooperates with PRalpha to induce APL-like disease.

Periodontal disease is perhaps the most common infectious disease in humans. Gingival crevicular fluid (GCF) is a local inflammatory exudate of the periodontal tissues. Its composition greatly varies between health and periodontal disease. GCF collection is rapid and noninvasive, but previous approaches aiming to analyze its composition have mainly involved single protein biomarkers. The aim of this study was to perform analysis of the GCF exudatome from healthy and periodontally diseased sites by LC/MS(E), a label-free mass spectrometry method that enables simultaneous protein identification and absolute quantification in biological fluids. In total, 154 proteins of human, bacterial, and viral origin were identified in the 40 GCF samples obtained from the 10 subjects (five healthy and five generalized aggressive periodontitis). The proportion of bacterial, viral, and yeast protein was increased in disease, compared to health. The presence of host defense-related proteins, such as Cystatin-B and defensins, was confirmed to be present only in health. Among the newly identified GCF proteins were L-plastin detected only in disease (15.6 +/- 12.1 fmol) and Annexin-1 detected in 5-fold higher levels in health. Nevertheless, pro-inflammatory cytokines or periodontal pathogen proteins were rarely detected. Conclusively, the LC/MS(E) technology may facilitate characterization of GCF proteome in periodontal health and disease, thus conferring prognostic and diagnostic value. Larger cohort studies are required to characterize the complete GCF proteome in health and disease.

The skeletal muscle ryanodine receptor plays a crucial role in excitation-contraction (EC) coupling and is implicated in various congenital myopathies. The periodic paralyses are a heterogeneous, dominantly inherited group of conditions mainly associated with mutations in the SCN4A and the CACNA1S genes. The interaction between RyR1 and DHPR proteins underlies depolarization-induced Ca(2+) release during EC coupling in skeletal muscle. We report a 35-year-old woman presenting with signs and symptoms of a congenital myopathy at birth and repeated episodes of generalized, atypical normokalaemic paralysis in her late teens. Genetic studies of this patient revealed three heterozygous RYR1 substitutions (p.Arg2241X, p.Asp708Asn and p.Arg2939Lys) associated with marked reduction of the RyR1 protein and abnormal DHPR distribution. We conclude that RYR1 mutations may give rise to both myopathies and atypical periodic paralysis, and RYR1 mutations may underlie other unresolved cases of periodic paralysis with unusual features.

This article systematically reviews the available literature to improve our understanding of the physiological basis for orthoses under the kinematic, shock attenuation and neuromotor control paradigms. The propositions made under these three paradigms have not been systematically reviewed collectively, and as such, there is no single-point synthesis of this clinically relevant body of evidence and somewhat disparate findings. Our comprehensive search strategy yielded 22 papers. Under each paradigm, the role of orthoses with different design features including combinations of posting, moulding and density was analysed. Where possible, data have been pooled to provide an increased level of confidence in findings. The main findings in the kinematic paradigm were that posted non-moulded orthoses systematically reduced peak rearfoot eversion (2.12 degrees (95% CI 0.72 to 3.53)) and tibial internal rotation (1.33 degrees (0.12 to 2.53)) in non-injured cohorts. In the shock attenuation paradigm, it was found that non-posted moulded and posted moulded orthoses produced large reductions in loading rate and vertical impact force when compared with a control and to a posted non-moulded orthosis. The neuromotor control paradigm seems to be the least conclusive in its outcome. Based on our review, this paper concludes with rudimentary guidelines for the prescription of orthosis, that sports medicine practitioners may use in their clinical decision-making process. The need for further research focusing on the role of injury, particularly in neuromotor control modification and long-term adaptation to orthoses, was highlighted.

Most developmentally programmed cell death in metazoans is mediated by caspases. During Drosophila metamorphosis, obsolete tissues, including the midgut and salivary glands, are removed by programmed cell death [1]. The initiator caspase Dronc and its activator Ark are required for the death of salivary glands, but not for midgut removal [2, 3]. In addition to caspases, complete removal of salivary glands requires autophagy [4]. However, the contribution of autophagy to midgut cell death has not been explored. Examination of combined mutants of the main initiator and effector caspases revealed that the canonical apoptotic pathway is not required for midgut cell death. Further analyses revealed that the caspase Decay is responsible for most of the caspase activity in dying midguts, yet inhibition of this activity has no effect on midgut removal. By contrast, midgut degradation was severely delayed by inhibition of autophagy, and this occurred without a decrease in caspase activity. Surprisingly, the combined inhibition of caspases and autophagy did not result in an additional delay in midgut removal. Together, our results indicate that autophagy, not caspases, is essential for midgut programmed cell death, providing the first in vivo evidence of caspase-independent programmed cell death that requires autophagy despite the presence of high caspase activity.

Charcot-Marie-Tooth (CMT) disease is genetically heterogeneous and subdivided into demyelinating (CMT 1) and axonal (CMT 2) types based on neurophysiology findings. CMT1A, the commonest form associated with duplication of the PMP22 segment on chromosome 17p, often arises in childhood but is generally a slowly progressive disease. We report 2 children presenting with clinical features of an acute inflammatory demyelinating polyneuropathy (AIDP) who were subsequently diagnosed with underlying CMT1A. Both children had neurophysiology and histopathology features consistent with CMT1. Immunoglobulin treatment was initiated considering the evidence of superimposed inflammation and appeared to modify disease progression. Our findings indicate that CMT1A predisposes to a superimposed inflammatory neuropathy. Recognition of this association is difficult, particularly in children without clear family history, but of great importance as immunomodulatory treatment may improve outcome. In addition, we postulate that an underlying genetic polyneuropathy should be suspected if the recovery from AIDP is slower than expected, or incomplete.

BACKGROUND: Cardiosphere-derived cells (CDCs) isolated from human endomyocardial biopsies reduce infarct size and improve cardiac function in mice. Safety and efficacy testing in large animals is necessary for clinical translation. METHODS AND RESULTS: Mesenchymal stem cells, which resemble CDCs in size and thrombogenicity, have been associated with infarction after intracoronary infusion. To maximize CDC engraftment while avoiding infarction, we optimized the infusion protocol in 19 healthy pigs. A modified cocktail of CDCs in calcium-free PBS, 100 U/mL of heparin, and 250 microg/mL of nitroglycerin eliminated infusion-related infarction. Subsequent infusion experiments in 17 pigs with postinfarct left ventricular dysfunction showed CDC doses > or =10(7) but <2.5 x 10(7) result in new myocardial tissue formation without infarction. In a pivotal randomized study, 7 infarcted pigs received 300,000 CDCs/kg (approximately 10(7) total) and 7 received placebo (vehicle alone). Cardiac magnetic resonance imaging 8 weeks later showed CDC treatment decreased relative infarct size (19.2% to 14.2% of left ventricle infarcted, P=0.01), whereas placebo did not (17.7% to 15.3%, P=0.22). End-diastolic volume increased in placebo, but not in CDC-treated animals. Hemodynamically, the rate of pressure change (dP/dt) maximum and dP/dt minimum were significantly better with CDC infusion. There was no difference between groups in the ability to induce ventricular tachycardia, nor was there any tumor or ectopic tissue formation. CONCLUSIONS: Intracoronary delivery of CDCs in a preclinical model of postinfarct left ventricular dysfunction results in formation of new cardiac tissue, reduces relative infarct size, attenuates adverse remodeling, and improves hemodynamics. The evidence of efficacy without obvious safety concerns at 8 weeks of follow-up motivates human studies in patients after myocardial infarction and in chronic ischemic cardiomyopathy.

1 The internal anal sphincter (IAS) has a spontaneous tone and is the main contributor to the maintenance of faecal continence. The spontaneous resting tone exhibited by the sphincter can be modified by neurotransmitters from the autonomic and enteric nervous systems. 2 In this review, the influence of the sympathetic and parasympathetic nervous systems on IAS tone are discussed and the putative roles of nitric oxide, carbon monoxide, vasoactive intestinal peptide and adenosine triphosphate in non-adrenergic non-cholinergic transmission are considered. 3 Faecal incontinence is a common condition that places a heavy financial burden on the health service and severely affects patients' quality of life. Resting anal pressure is reduced in patients with faecal incontinence and agents that increase sphincter tone tend to relieve symptoms. The results of clinical studies of the use of phenylephrine to treat faecal incontinence are reviewed. 4 It is concluded that the IAS is a potential target for drug development for the treatment of faecal incontinence.