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This study echoes the rising demand for bio-based material in concrete composite structures in the race to accelerate carbon neutrality in construction. Noticing that most previous studies are focused on straight timber or engineered bamboo-to-concrete composite beams, this study focuses on: 1) developing unique and practical curved laminated bamboo-concrete (LBC) composite beams; 2) experimentally investigating and comparing the structural performances of the curved and straight LBC composite beams; 3) developing a novel and proper in-member interface shear slip calibration method that captures the longitudinal after-slip strain redistribution, validated by stain gauge measurements. This study also highlights the interlayer shear bonding strength of laminated bamboo as the thresholding parameter that determines the composite beams' overall flexural strength, evidenced by detailed failure mode analysis. The proposed interface shear slip calibration method can be extended to the other types of shear connectors such as screws, shear plates, etc.

The shear modulus of timber and timber-based composite materials is a fundamental mechanical property, which is used in the design of timber and engineered wood products. The problem of experimentally determining appropriate values of shear modulus for timber-based composite is not as simple and straightforward as in isotropic materials. Although the torsion test is a recommended standard approach to determine the shear modulus of structural-size timber and glulam beams, it is difficult to measure the rotational deformations of the timber beams. Therefore, in this paper, a stereo camera system combined with a photogrammetric approach is proposed to evaluate the values and variations of the shear modulus of glulam beams under the torsion test. The photogrammetric approach is a non-contact method, which provides an efficient and alternative approach for measuring the deformations of the torsion specimens in three dimensions. A series of experiments was conducted on glulam timber beams under the torsion test to investigate the applicability of the optical approach to evaluate the values and variations of shear modulus as well as to investigate the effect of applying torques in a clockwise or anticlockwise direction on the shear modulus of the beams. This optical system not only allows the performance and reliability of the traditional sensors to be assessed, but also allows the rotational deformation of the torsion samples to be monitored at various locations. This enables the values of shear modulus at different cross-sections of the torsion specimens to be evaluated without the need to use more devices. The test results showed that applying torques to the glulam timber specimens during loading and unloading in either a clockwise or anticlockwise direction does not influence or cause a significant change in the shear modulus of the beams. By comparing shear modulus values of glulam beams measured based on different shear spans, it was found that the larger the shear span the smaller the shear modulus value. This might indicate that the variations of shear modulus values at these different gauge lengths need to be considered.

Background There is urgent need for new medications for psychiatric disorders. Mental illness is expected to become the leading cause of disability worldwide by 2030. Yet, the last two decades have seen the pharmaceutical industry withdraw from psychiatric drug discovery after costly late-stage trial failures in which clinical efficacy predicted pre-clinically has not materialised, leading to a crisis in confidence in preclinical psychopharmacology. Methods Based on a review of the relevant literature, we formulated some principles for improving investment in translational neuroscience aimed at psychiatric drug discovery. Results We propose the following 8 principles that could be used, in various combinations, to enhance CNS drug discovery: (1) consider incorporating the NIMH Research Domain Criteria (RDoC) approach; (2) engage the power of translational and systems neuroscience approaches; (3) use disease-relevant experimental perturbations; (4) identify molecular targets via genomic analysis and patient-derived pluripotent stem cells; (5) embrace holistic neuroscience: a partnership with psychoneuroimmunology; (6) use translational measures of neuronal activation; (7) validate the reproducibility of findings by independent collaboration; and (8) learn and reflect. We provide recent examples of promising animal-to-human translation of drug discovery projects and highlight some that present re-purposing opportunities. Conclusions We hope that this review will re-awaken the pharma industry and mental health advocates to the opportunities for improving psychiatric pharmacotherapy and so restore confidence and justify re-investment in the field.

Cancer is the second leading cause of death globally in 2018 with an estimated 9.6 million deaths. The costs of managing malignant ureteric obstruction (MUO) is a significant burden to any healthcare system. However, the management of MUO has long been a challenge for urologists. The standard options of percutaneous nephrostomy or polymer double J stents are fraught with problems. We report a large patient series with long-term follow-up in the use of Resonance metallic ureteric stents to relieve MUO, and identification of risk factors associated with stent failure.All patients with MUO who were arranged to have Resonance metallic ureteric stent insertion at two university hospitals were included in this cohort study, starting from June 2011 to July 2016. Data were retrieved retrospectively. The primary outcome was the total duration of stent patency before stent failure due to malignant disease progression. Stent failure was defined as ureteric obstruction identified on imaging (functional radioisotope scan or antegrade pyelogram), acute renal failure resolved by subsequent percutaneous nephrostomy, or any other cause requiring stent removal prematurely. Secondary outcomes were identification of factors associated with stent failure, grade III or above complication, and development of a risk-adopted model to predict metallic ureteric stent patency rates in MUO patients. Median duration of functioning metallic ureteric stent was determined with Kaplan-Meier survival curve.A total of 124 renal units in 95 patients with MUO were eligible for the study, with a median follow-up period of 22.9 months. About 106 (85.5%) renal units had successful metallic stent insertion, of whom 41 (33.1%) renal units ultimately progressed to ureteric obstruction despite the metallic stents, and required subsequent insertion of nephrostomies. Median duration of functioning metallic ureteric stents was 25 months. Female gender (HR 3.0, 95% CI: 1.3-7.2,Resonance metallic ureteral stents are able provide a median of 25 months of ureteric drainage in patients with MUO. Determining whether a patient has one or both risks factors (female gender and bladder lesion) will allow one to estimate the duration of metallic stent patency, which in turn may aid in determining cost-effectiveness in individual patients.

Funder: Health Technology Assessment Programme; Grant(s): Award ID: 15/153/02, INTRODUCTION: In one-third of all abdominal aortic aneurysms (AAAs), the aneurysm neck is short (juxtarenal) or shows other adverse anatomical features rendering operations more complex, hazardous and expensive. Surgical options include open surgical repair and endovascular aneurysm repair (EVAR) techniques including fenestrated EVAR, EVAR with adjuncts (chimneys/endoanchors) and off-label standard EVAR. The aim of the UK COMPlex AneurySm Study (UK-COMPASS) is to answer the research question identified by the National Institute for Health Research Health Technology Assessment (NIHR HTA) Programme: 'What is the clinical and cost-effectiveness of strategies for the management of juxtarenal AAA, including fenestrated endovascular repair?' METHODS AND ANALYSIS: UK-COMPASS is a cohort study comparing clinical and cost-effectiveness of different strategies used to manage complex AAAs with stratification of physiological fitness and anatomical complexity, with statistical correction for baseline risk and indication biases. There are two data streams. First, a stream of routinely collected data from Hospital Episode Statistics and National Vascular Registry (NVR). Preoperative CT scans of all patients who underwent elective AAA repair in England between 1 November 2017 and 31 October 2019 are subjected to Corelab analysis to accurately identify and include every complex aneurysm treated. Second, a site-reported data stream regarding quality of life and treatment costs from prospectively recruited patients across England. Site recruitment also includes patients with complex aneurysms larger than 55 mm diameter in whom an operation is deferred (medical management). The primary outcome measure is perioperative all-cause mortality. Follow-up will be to a median of 5 years. ETHICS AND DISSEMINATION: The study has received full regulatory approvals from a Research Ethics Committee, the Confidentiality Advisory Group and the Health Research Authority. Data sharing agreements are in place with National Health Service Digital and the NVR. Dissemination will be via NIHR HTA reporting, peer-reviewed journals and conferences. TRIAL REGISTRATION NUMBER: ISRCTN85731188.

There is urgent need for new medications for psychiatric disorders. Mental illness is expected to become the leading cause of disability worldwide by 2030. Yet, the last two decades have seen the pharmaceutical industry withdraw from psychiatric drug discovery after costly late-stage trial failures in which clinical efficacy predicted pre-clinically has not materialised, leading to a crisis in confidence in preclinical psychopharmacology.Based on a review of the relevant literature, we formulated some principles for improving investment in translational neuroscience aimed at psychiatric drug discovery.We propose the following 8 principles that could be used, in various combinations, to enhance CNS drug discovery: (1) consider incorporating the NIMH Research Domain Criteria (RDoC) approach; (2) engage the power of translational and systems neuroscience approaches; (3) use disease-relevant experimental perturbations; (4) identify molecular targets via genomic analysis and patient-derived pluripotent stem cells; (5) embrace holistic neuroscience: a partnership with psychoneuroimmunology; (6) use translational measures of neuronal activation; (7) validate the reproducibility of findings by independent collaboration; and (8) learn and reflect. We provide recent examples of promising animal-to-human translation of drug discovery projects and highlight some that present re-purposing opportunities.We hope that this review will re-awaken the pharma industry and mental health advocates to the opportunities for improving psychiatric pharmacotherapy and so restore confidence and justify re-investment in the field.

Both no-slip and free-slip effects are enforced to the lid-driven cavity walls with Robin boundary condition. Viscous heating and cooling process happen when the shear force applied at the top lid is removed and the cavity is exposed to natural convection. This numerical study is performed for a two-dimensional laminar incompressible fluid flow with unsteadiness. The governing equations of time-dependent vorticity-stream function and thermal energy equation are solved using a finite difference method. Dissipation of viscous-heating of the cavity flow to the ambient is observed. The in-house Matlab® code is firstly verified with Ansys Fluent® finite element method at steady state. With no-slip boundary condition, temperature profile shows a reduction with acumination style at the beginning of the cooling process whereas a blunted profile is shown in free-slip boundary condition with temperature profile reduces dawdlingly. This is due to the movement of fluid is still able to create viscous heating at the outset of cooling process and this effect is even more pronounced at high Reynolds number when subject to free-slip boundary condition.

Background Many health authorities recommend influenza vaccination of older adults to reduce disease burden. We hypothesized that in tropical and subtropical areas with more prolonged influenza seasons, twice-annual influenza vaccination might provide older adults with improved immunity against influenza. Methods In 2014-2015, Hong Kong experienced a substantial A(H3N2) winter epidemic with a mismatched vaccine. Local authorities procured and administered to older adults the 2015 southern hemisphere influenza vaccine, which included an updated and matching A/Switzerland/9715293/2013(H3N2) strain. We compared immune parameters in pre- and postvaccination sera from older adults ≥75 years of age who received 1 vs 2 influenza vaccines per year. Results We enrolled 978 older adults with 470 vaccinations for summer 2015 and 827 vaccinations for winter 2015-2016. Recipients of southern hemisphere vaccination had higher geometric mean titers (GMTs) by the hemagglutination inhibition assay against all 3 vaccine strains. When receiving influenza vaccination for the subsequent winter, the southern hemisphere vaccine recipients had higher prevaccination GMTs but lower postvaccination GMTs, compared to those who had not received the southern hemisphere vaccine. Furthermore, cellular immunity was impacted by biannual vaccination, with reduced influenza-specific CD4 T-cell responses in the second season of vaccination. Conclusions We observed some reductions in immune responses in the twice-annual vaccination group compared with the once-annual vaccination group, in the context of unchanging vaccine strains, while protection was likely to have been improved during the summer and autumn for the twice-annual vaccination group due to the continued circulation of the A/Switzerland/9715293/2013(H3N2) virus.

Background Enhanced influenza vaccines may improve protection for older adults, but comparative immunogenicity data are limited. Our objective was to examine immune responses to enhanced influenza vaccines, compared to standard-dose vaccines, in community-dwelling older adults. Methods Community-dwelling older adults aged 65–82 years in Hong Kong were randomly allocated (October 2017–January 2018) to receive 2017–2018 Northern hemisphere formulations of a standard-dose quadrivalent vaccine, MF59-adjuvanted trivalent vaccine, high-dose trivalent vaccine, or recombinant-hemagglutinin (rHA) quadrivalent vaccine. Sera collected from 200 recipients of each vaccine before and at 30-days postvaccination were assessed for antibodies to egg-propagated vaccine strains by hemagglutination inhibition (HAI) and to cell-propagated A/Hong Kong/4801/2014(H3N2) virus by microneutralization (MN). Influenza-specific CD4+ and CD8+ T cell responses were assessed in 20 participants per group. Results Mean fold rises (MFR) in HAI titers to egg-propagated A(H1N1) and A(H3N2) and the MFR in MN to cell-propagated A(H3N2) were statistically significantly higher in the enhanced vaccine groups, compared to the standard-dose vaccine. The MFR in MN to cell-propagated A(H3N2) was highest among rHA recipients (4.7), followed by high-dose (3.4) and MF59-adjuvanted (2.9) recipients, compared to standard-dose recipients (2.3). Similarly, the ratio of postvaccination MN titers among rHA recipients to cell-propagated A(H3N2) recipients was 2.57-fold higher than the standard-dose vaccine, which was statistically higher than the high-dose (1.33-fold) and MF59-adjuvanted (1.43-fold) recipient ratios. Enhanced vaccines also resulted in the boosting of T-cell responses. Conclusions In this head-to-head comparison, older adults receiving enhanced vaccines showed improved humoral and cell-mediated immune responses, compared to standard-dose vaccine recipients. Clinical Trials Registration NCT03330132.

Less than half of patients suffering from major depressive disorder, a leading cause of disability worldwide, achieve remission with current antidepressants, making it imperative to develop more effective treatment. A new therapeutic direction is emerging from the increased understanding of natural resilience as an active stress-coping process. It is known that potassium (K+) channels in the ventral tegmental area (VTA) are an active mediator of resilience. However, no druggable targets have been identified to potentiate active resilience mechanisms. In the chronic social defeat stress model of depression, we report that KCNQ-type K+ channel openers, including FDA-approved drug retigabine (ezogabine), show antidepressant efficacy. We demonstrate that overexpression of KCNQ channels in the VTA dopaminergic neurons and either local infusion or systemic administration of retigabine normalized neuronal hyperactivity and depressive behaviours. These findings identify KCNQ as a target for conceptually novel antidepressants that function through the potentiation of active resilience mechanisms., National Institutes of Health (U.S.). Ruth L. Kirschstein National Research Service Award (F31 MH095425), National Institutes of Health (U.S.). Ruth L. Kirschstein National Research Service Award (T32 MH 087004), National Institutes of Health (U.S.). Ruth L. Kirschstein National Research Service Award (F32 MH096464), National Institute of Mental Health (U.S.) (NIMH R01 MH092306)

The structural, magnetic and transport properties of LaMnO 3 /LaAlO 3 (2 unit cells) (LMO/LAO) multilayers with different thicknesses of LMO layer grown on SrTiO 3 substrates were studied. Structural investigations confirmed that all the samples were fully epitaxial and the out-of-plane lattice constant increased with rising LMO layer thickness t from 1 to 4 unit cells. Ferromagnetic behavior could be observed only when t was above 2 unit cells, while the coercive field reduced with increasing t . Transport measurements indicated that all the multilayers were insulating and the activation energy of the multilayers were much larger than single-layered LMO films. These results provide a promising route for tuning the structure, electronic and magnetic properties in other strong-correlated materials.

Rationale This review attempts to summarize the current status in relation to the use of positron emission tomography (PET) imaging in the assessment of synaptic concentrations of endogenous mediators in the living brain. Objectives Although PET radioligands are now available for more than 40 CNS targets, at the initiation of the Innovative Medicines Initiative (IMI) “Novel Methods leading to New Medications in Depression and Schizophrenia” (NEWMEDS) in 2009, PET radioligands sensitive to an endogenous neurotransmitter were only validated for dopamine. NEWMEDS work-package 5, “Cross-species and neurochemical imaging (PET) methods for drug discovery”, commenced with a focus on developing methods enabling assessment of changes in extracellular concentrations of serotonin and noradrenaline in the brain. Results Sharing the workload across institutions, we utilized in vitro techniques with cells and tissues, in vivo receptor binding and microdialysis techniques in rodents, and in vivo PET imaging in non-human primates and humans. Here, we discuss these efforts and review other recently published reports on the use of radioligands to assess changes in endogenous levels of dopamine, serotonin, noradrenaline, γ-aminobutyric acid, glutamate, acetylcholine, and opioid peptides. The emphasis is on assessment of the availability of appropriate translational tools (PET radioligands, pharmacological challenge agents) and on studies in non-human primates and human subjects, as well as current challenges and future directions. Conclusions PET imaging directed at investigating changes in endogenous neurochemicals, including the work done in NEWMEDS, have highlighted an opportunity to further extend the capability and application of this technology in drug development.

A theoretical model is presented for analysing the shear behaviour and predicting the shear strength of reinforced concrete (RC) interior beam-column joints. The model presented is referred to as the modified rotating-angle softened-truss model (MRA-STM), which is modified from the rotating-angle softened-truss model and the modified compression field theory. In the proposed methodology, the RC interior joint is treated as an RC shear panel that is subjected to vertical and horizontal shear stresses transferred from adjacent columns and beams. Employing the deep beam analogy, the characteristic strut and truss actions typical in beam-column joints are represented by the effective transverse compression stresses and the softened concrete truss in the model. Sixteen RC interior beam-column joints were subsequently analysed with the proposed model. Shear strengths of the RC interior beam-column joints predicted by the proposed model show very good agreement with the experimental results.

Depression is a polygenic and highly complex psychiatric disorder that is currently a major burden on society. Depression is highly heterogeneous in presentation and frequently exhibits high co-morbidity with other psychiatric and somatic deficits. Commonly used treatments, such as selective serotonin reuptake inhibitors (SSRIs), are not ideal since only a subset of patients achieve remission. In addition, the reason why some individuals respond to SSRIs while others don’t are unknown. Here we begin to ask what the basis of treatment-resistance is, and propose new strategies to model this phenomenon in animals. We focus specifically on animal models that offer the appropriate framework to study treatment resistance with face, construct and predictive validity.

Background Delayed consultation for potential cancer symptoms influences treatment outcomes and remains problematic. Delay components (Appraisal versus Utilization) and respective associations are poorly understood. Methods Eligible participants were Cantonese-speaking Chinese women, ≥21 years old, with self-discovered breast symptoms, recruited in surgical clinics before their first consultation, and naive to their diagnosis. Overall 425/433 (98%) women completed a questionnaire on psychosocial, demographic and medical factors, how and when women discovered their breast symptom(s), and their subsequent decision making; 135/425 women (32%) were later diagnosed with breast cancer. Results Twenty-two per cent of women delayed >3 months before consultation. Women with breast cancer (28%) more often had prolonged delay than women with benign disease (19%). Attributing symptom to a non-cancerous condition, low fear on symptom discovery, not disclosing symptoms to others, and no prior breast symptom history predicted prolonged (>60 days) Appraisal Delay. Low fear on symptom discovery, seldom thinking about the symptom, and consultation for other reasons predicted prolonged (>14 days) Utilization Delay. Factors predicting Appraisal and Utilization Delays differentiated cancer from non-cancer groups. Conclusions Indecision over symptom meaning comprised the main component of Appraisal and Total Delay, suggesting that educational strategies targeting atypical symptoms should reduce avoidable delays following self-discovered breast symptoms. Copyright © 2011 John Wiley & Sons, Ltd.

Innovation is essential for the identification of novel pharmacological therapies to meet the treatment needs of patients with psychiatric disorders. However, over the last 20 yr, in spite of major investments targets falling outside the classical aminergic mechanisms have shown diminished returns. The disappointments are traced to failures in the target identification and target validation effort, as reflected by the poor ability of current bioassays and animal models to predict efficacy and side-effects. Mismatch between disease biology and how psychiatric diseases are categorized has resulted in clinical trials of highly specific agents in heterogeneous patients, leading to variable treatment effects and failed studies. As drug hunters, one sees the opportunity to overhaul the pharmaceutical research and development (R&D) process. Improvements in both preclinical and clinical translational research need to be considered. Linking pharmacodynamic markers with disease biology should provide more predictive and innovative early clinical trials which in turn will increase the success rate of discovering new medicines. However, to exploit these exciting scientific discoveries, pharmaceutical companies need to question the conventional drug research and development model which is silo-driven, non-integrative across the confines of a company, non-disclosing across the pharmaceutical industry, and often independent from academia. This leads to huge redundancy in effort and lack of contextual learning in real time. Nevertheless, there are signs that drug discovery in the 21st century will see more intentional government, academic and industrial collaborations to overcome the above challenges that could eventually link mechanistic disease biology to segments of patients, affording them the benefits of rational and targeted therapy.

Cerebral arteriovenous malformation (AVM) typically shows signal void on conventional MR images, making differentiation of each component difficult. We analyzed the MR signal intensity of AVM components on T1-weighted gradient recalled echo pulse sequence images. We retrospectively studied 29 patients with AVM between 2006 and 2008. Patients were excluded if they had 1) intracranial hemorrhage, 2) previous intervention for AVM. All patients underwent MR study on a 3T system (Magentom TIM Trio, Siemens). Pulse sequences included T1-weighted gradient recalled echo (T1GRE), T2-weighted (T2), time-of-flight (TOF), and contrast-enhanced T1-weighted (cT1) images. Digital subtracted angiography (DSA) was performed in all patients as a diagnostic standard. Signal intensity of each AVM component was recorded and compared between pulse sequences. Nine patients were studied (five men; mean age 39.1 years) and nine AVM were identified (mean size, 3.9 cm). Three different signal intensities (hypo-, iso-, and hyper-intensity) were observed in all nine patients on T1GRE. Only one signal intensity was seen on T2 (flow void) and cT1 images (hyperintensity) in nine patients. Two different signal intensities were observed in all seven patients with TOF images. The T1GRE image showed the largest number of different signal intensities of AVM when compared with other pulse sequences, thus providing clearer structural delineation. Routine use of the T1GRE pulse sequence can help pre-therapeutic planning or follow-up of AVM.

Asenapine is a novel psychopharmacologic agent under development for the treatment of schizophrenia and bipolar disorder. We determined and compared the human receptor binding affinities and functional characteristics of asenapine and several antipsychotic drugs. Compounds were tested under comparable assay conditions using cloned human receptors. In comparison with the antipsychotics, asenapine showed high affinity and a different rank order of binding affinities (pKi) for serotonin receptors (5-HT1A [8.6], 5-HT1B [8.4], 5-HT2A [10.2], 5-HT2B [9.8], 5-HT2C [10.5], 5-HT5 [8.8], 5-HT6 [9.6] and 5-HT7 [9.9]), adrenoceptors (alpha1 [8.9], alpha2A [8.9], alpha2B [9.5] and alpha2C [8.9]), dopamine receptors (D1 [8.9], D2 [8.9], D3 [9.4] and D4 [9.0]) and histamine receptors (H1 [9.0] and H2 [8.2]). It had much lower affinity (pKi

The novel psychopharmacologic agent, asenapine, has high affinity for a range of receptors including the dopaminergic receptors.We examined the long-term effects of multiple doses of asenapine on dopamine receptor subtypes: D(1)-like (D(1) and D(5)), D(2), D(3), and D(4).Rats were given asenapine 0.03, 0.1, or 0.3 mg/kg (subcutaneously, twice daily) or vehicle for 4 weeks. Receptor binding was determined by autoradiography from brain sections collected from the medial prefrontal cortex (mPFC), dorsolateral frontal cortex, caudate putamen (CPu), nucleus accumbens (NAc), and hippocampus (HIP).Four weeks of asenapine at 0.3 mg/kg significantly (P0.05) increased D(1)-like binding in the mPFC (by 26%), NAc (59%), and CPu (55%). Asenapine (0.1 and 0.3 mg/kg) also increased D(2) binding in mPFC (43% and 55%, respectively). All doses of asenapine dose-dependently increased D(2) binding in HIP (by 32%, 45%, and 63%, respectively). In contrast, only 0.3 mg/kg of asenapine significantly (P0.05) increased D(2) binding in the NAc (32%) and CPu (41%). Repeated treatment with 0.1 and 0.3 mg/kg of asenapine increased D(4) binding in the NAc (36% and 71%), CPu (27% and 70%), and HIP (48% and 77%). However, asenapine, at the doses tested, did not significantly alter D(3) binding in the brain regions examined in this study.These results indicate that asenapine has region-specific and dose-dependent effects on dopamine receptor subtypes in rat forebrain, which may contribute to asenapine's unique psychopharmacological properties.

Background Illness perceptions are linked to individual help-seeking and preventive behaviors. Previous illness perception studies have identified five dimensions of illness-related experience and behaviour. The Revised Illness Perception Questionnaire (IPQ-R) for genetic predisposition (IPQ-R-GP) was developed to measure illness perceptions in those genetically-predisposed to blood disease. We adapted the IPQ-R-GP to measure perceptions of generalized cancer predisposition. This paper describes the development and validation of the Cancer Predisposition Perception Scale (CPPS). Methods The draft CPPS scale was first administered to 167 well Hepatitis B carriers and 123 other healthy individuals and the factor structure was examined using Exploratory Factor Analysis. Then the factor structure was confirmed in a second sample comprising 148 healthy controls, 150 smokers and 152 passive smokers using Confirmatory Factor Analysis (CFA). Results Six-factors comprising 26 items provided optimal fit by eigen and scree-plot methods, accounting for 58.9% of the total variance. CFA indicated good fit of the six-factor model after further excluding three items. The six factors, Emotional representation (5 items), Illness coherence (4 items), Treatment control (3 items), Consequences (5 items), Internal locus of control (2 items) and External locus of control (4 items) demonstrated adequate-to-good subscale internal consistency (Cronbach’s α = 0.63–0.90). Divergent validity was suggested by low correlations with optimism, self-efficacy, and scales for measuring physical and psychological health symptoms. Conclusion The CPPS appears to be a valid measure of perceived predisposition to generic cancer risks and can be used to examine cancer-risk-related cognitions in individuals at higher and lower cancer risk.

The positive findings of norbolethone in 2002 and tetrahydrogestrinone in 2003 in human athlete samples confirmed that designer steroids were indeed being abused in human sports. In 2005, an addition to the family of designer steroids called 'Madol' [also known as desoxy-methyltestosterone (DMT)] was seized by government officials at the US-Canadian border. Two years later, a positive finding of DMT was reported in a mixed martial arts athlete's sample. It is not uncommon that doping agents used in human sports would likewise be abused in equine sports. Designer steroids would, therefore, pose a similar threat to the horseracing and equestrian communities. This paper describes the in vitro metabolism studies of DMT and five of its structural analogues with different substituents at the 17α position (RH, ethyl, vinyl, ethynyl and

A novel set of azabicyclic aryl amides have been identified as potent and selective agonists of the alpha7 nAChR. A two-pronged approach was taken to improve the potential hERG liability of previously disclosed alpha7 nAChR agonist, PNU-282,987, while maintaining the compound's other desirable pharmacological properties. The first approach involved further exploration of the aryl carboxylic acid fragment of PNU-282,987, while the second approach focused on modification of the azabicyclic amine portion of PNU-282,987. The best compounds from each series are characterized by rapid brain penetration, good oral bioavailability in rat, and demonstrate in vivo efficacy in a rat P50 auditory sensory gating assay. At least one analog from each series (1h, 1o, 2a, 9a, and 18a) shows an improved hERG safety profile over PNU-282,987.

N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide (14, PHA-543,613), a novel agonist of the alpha7 neuronal nicotinic acetylcholine receptor (alpha7 nAChR), has been identified as a potential treatment of cognitive deficits in schizophrenia. Compound 14 is a potent and selective alpha7 nAChR agonist with an excellent in vitro profile. The compound is characterized by rapid brain penetration and high oral bioavailability in rat and demonstrates in vivo efficacy in auditory sensory gating and, in an in vivo model to assess cognitive performance, novel object recognition.

A library of benzamides was tested for alpha7 nicotinic acetylcholine receptor (nAChR) agonist activity using a chimeric receptor in a functional, cell-based, high-throughput assay. From this library, quinuclidine benzamides were found to have alpha7 nAChR agonist activity. The SAR diverged from the activity of this compound class verses the 5-HT(3) receptor, a structural homologue of the alpha7 nAChR. PNU-282987, the most potent compound from this series, was also shown to open native alpha7 nAChRs in cultured rat neurons and to reverse an amphetamine-induced gating deficit in rats.

Extraskeletal Ewing's sarcoma (EES) is rarely found in the head and neck region. We report here a case of EES of the parapharyngeal space in a 53-year-old man who presented with blurred vision, dysphagia, hoarseness and right facial numbness. CT examination showed a large, seemingly well-defined soft tissue mass in the right parapharyngeal space with skull base destruction and intracranial extension. The patient showed poor response to chemotherapy and radiotherapy and died 6 months after initial presentation. A review of the literature revealed no previous reports of EES occurring in the parapharyngeal space.

Cooperation in the action of agonists suggests that there are multiple binding sites on 5-hydroxytryptamine3 (5-HT3) receptors. The purpose of this study was to characterize these binding sites and their interactions on both native and cloned 5-HT3 receptors. The affinities of competitive 5-HT3 receptor antagonists were similar regardless of whether the receptors were labeled with [3H]RS-42358, [3H]granisetron, or 1-(m-[3H]chlorophenyl)biguanide ([3H]mCPG). By contrast, the affinities of the agonists 5-HT, mCPG, and phenylbiguanide were approximately 10-fold higher when the receptors were labeled with [3H]mCPG. The dissociation of [3H]mCPG, [3H]RS-42358, and [3H]RS-25259, but not [3H]granisetron, from both cloned and native 5-HT3 receptors was markedly slower in the presence of 5-HT or 2-methyl-5-HT than in the presence of antagonists such as RS-42358. This suggests that the binding of these agonists to unoccupied sites on the receptor can increase the receptor's affinity for prebound ligands and thereby slow their dissociation. These data support previous indications of positive cooperation among multiple binding sites on both native and cloned 5-HT3 receptors, and they extend this idea by demonstrating that agonists can modify the interaction of some, but not all, antagonists with the receptor.

(2002). Biomimetric Processing Of Bioactive Apatite - Ceramic Composites. Materials Technology: Vol. 17, No. 4, pp. 228-231.

Depression and anxiety disorders are associated with increased release of peripheral cytokines; however, their functional relevance remains unknown. Using a social stress model in mice, we find preexisting individual differences in the sensitivity of the peripheral immune system that predict and promote vulnerability to social stress. Cytokine profiles were obtained 20 min after the first social stress exposure. Of the cytokines regulated by stress, IL-6 was most highly up-regulated only in mice that ultimately developed a susceptible behavioral phenotype following a subsequent chronic stress, and levels remained elevated for at least 1 mo. We confirmed a similar elevation of serum IL-6 in two separate cohorts of patients with treatment-resistant major depressive disorder. Before any physical contact in mice, we observed individual differences in IL-6 levels from ex vivo stimulated leukocytes that predict susceptibility versus resilience to a subsequent stressor. To shift the sensitivity of the peripheral immune system to a pro- or antidepressant state, bone marrow (BM) chimeras were generated by transplanting hematopoietic progenitor cells from stress-susceptible mice releasing high IL-6 or from IL-6 knockout (IL-6(-/-)) mice. Stress-susceptible BM chimeras exhibited increased social avoidance behavior after exposure to either subthreshold repeated social defeat stress (RSDS) or a purely emotional stressor termed witness defeat. IL-6(-/-) BM chimeric and IL-6(-/-) mice, as well as those treated with a systemic IL-6 monoclonal antibody, were resilient to social stress. These data establish that preexisting differences in stress-responsive IL-6 release from BM-derived leukocytes functionally contribute to social stress-induced behavioral abnormalities.

Dopamine D3 receptors have been implicated in the aetiology of schizophrenia and the actions of antipsychotic drugs. The initial studies reported here assessed the involvement of such receptors in the in vivo actions of the atypical antipsychotic clozapine and the putative D3-preferring antagonist PNU-99194A in drug discrimination assays. Rats trained to discriminate clozapine consistently generalized to PNU-99194A in two separate studies. However, four other putative D3-preferring antagonists (PD 152255, (+)-S14297, nafadotride and (+)-AJ 76) did not induce generalization to clozapine. In rats trained to discriminate PNU-99194A, which has been suggested to induce a stimulus mediated specifically by D3 antagonism, the D3-preferring antagonist (+)-UH 232 and clozapine both induced full generalization. However, the PNU-99194A-trained animals also generalized fully to the muscarinic antagonists scopolamine and trihexyphenidyl. A possible explanation for the symmetrical generalization observed between clozapine and PNU-99194A is that these drugs have common muscarinic antagonist actions, since muscarinic antagonists have been reported to substitute for clozapine in numerous prior studies. However, in vitro receptor binding studies with M1-M5 receptors indicated that (with the possible exception of the M4 receptor), no muscarinic receptor subtype had high affinity for both clozapine, PNU-99194A and scopolamine. In addition, other binding studies indicated that whereas clozapine and PNU-99194A had high affinity for the D3 receptor, scopolamine did not. It is therefore concluded that: (1) The generalization seen between clozapine, PNU-99194A and muscarinic antagonists may be mediated by common effects 'downstream' from either muscarinic or D3 receptors; (2) D3 antagonism does not play a critical role in the clozapine stimulus (since D3-preferring antagonists did not consistently induce generalization to clozapine); (3) although D3 antagonism plays a role in the PNU-91994A stimulus (since the D3-preferring antagonist (+)-UH 232 induced full generalization, in accord with results from prior studies with other D3-preferring antagonists, the PNU-99194A stimulus also has commonalities with that induced by muscarinic antagonists and clozapine. The in vivo differences observed between PNU-99194A and other D3-preferring antagonists should be borne in mind when this agent is used as a tool to study D3 receptor functioning in vivo. The similarities between the PNU-99194A and clozapine stimuli suggest tentatively that compounds with a profile like PNU-99194A may have antipsychotic actions similar to clozapine. Some preclinical data are suggestive of such effects of PNU-99194A.

Nicergoline is a semisynthetic ergoline derivative indicated for the treatment of cognitive impairment in various forms of dementia. It is currently available for use in Italy and some other European countries, in Latin America and the Near and Far East. In animal studies nicergoline exhibits a broad spectrum of actions on cellular and molecular mechanisms involved in the pathophysiology of dementia. Nicergoline appears to enhance cholinergic and catecholaminergic neurotransmitter function and improve related cognitive deficits; stimulate phosphoinositide turnover; modulate protein kinase C (PKC) translocation and PKC-mediated α-secretase processing of amyloid precursor protein; increase regional cerebral blood flow, and glucose uptake and utilisation; activate protein synthesis; protect neurons from death induced by oxidative stress or apoptosis; and interact with endogenous nerve growth factor-mediated processes providing trophic support to cholinergic neurons. Whether these actions are interrelated or represent multiple, unrelated effects is still unknown, but all may be relevant to the therapeutical use of the drug. Recent double-blind, placebo-controlled, randomised clinical studies of up to 12 months’ duration indicated a measurable effect of nicergoline on cognitive performance in patients with dementing illnesses. Medium and long term treatment resulted in significantly greater cognitive improvement or less decline than placebo as measured by Mini-Mental State Examination (MMSE) or Alzheimer’s Disease Assessment Scale — Cognitive Subscale (ADAS-cog) scores. While deterioration represents the natural course of the disease, nicergoline-treated patients improved or maintained their previous clinical status. The objective improvement of the cognitive symptoms was paralleled by a stabilised or improved clinical global condition as evaluated by clinicians, caregivers and patients. Nicergoline was well tolerated in all clinical studies. The type, frequency and severity of adverse events were generally comparable with those observed in the placebo control groups. No clinically or statistically significant changes in vital signs and laboratory evaluations were reported, except for an asymptomatic increase of serum uric acid levels. Overall, data strongly support the hypothesis that nicergoline might interfere with fundamental molecular mechanisms underlying cognitive processes in vivo. The clinical results also indicate that nicergoline is a well tolerated and effective treatment that improves cognitive and global functions in patients with mild to moderate dementia.

Background: Reboxetine is a potent antidepressant, with efficacy comparable to that of imipramine, desipramine, and fluoxetine, and has improved side-effect profile. The basis of its efficacy and improved tolerability is sought through studies of reboxetine in a number of pharmacological models of depression. Methods: Pharmacological selectivity for uptake systems was defined by uptake and binding assays for the three monoamine uptake sites. Specificity was determined in 39 different receptor and 6 enzyme assays. In vivo selectivity was defined by measurement of neuronal firing rates in the locus coeruleus, dorsal raphe, and substantia nigra. Reserpine-induced blepharospasm and hypothermia, clonidine-induced hypothermia, defined reboxetine's in vivo pharmacology. Reboxetine's antidepressant potential was evaluated behaviorally by the tail-suspension test, forced swimming, and the DRL 72 operant responding test. Results: Reboxetine is a potent, selective, and specific norepinephrine reuptake inhibitor (selective NRI) as determined by both in vitro and in vivo measurements. Unlike desipramine or imipramine, reboxetine has weak affinity (Ki > 1000 nmol/L) for muscarinic, histaminergic H1, adrenergic α 1 , and dopaminergic D 2 receptors. In vivo action of reboxetine is entirely consistent with the pharmacological action of an antidepressant with preferential action at the norepinephrine reuptake site. Reboxetine showed an antidepressant profile in all tests of antidepressant activity used. Significant decreases in immobility were observed in the tail suspension test and behavioral despair test. Increased efficiency in responding was observed in the DRL 72 test. Conclusions: Reboxetine is a potent, selective, and specific noradrenergic reuptake inhibitor. It has a superior pharmacological selectivity to existing tricyclic antidepressants and selective serotonin reuptake inhibitors when tested in a large number of in vitro and in vivo systems. Given the pharmacological profile, reboxetine is expected to be a selective and potent tool for psychopharmacological research. The use of reboxetine in the clinic will also help clarify the role norepinephrine plays in depression.

Constructed ponds and wetlands are widely used in urban design to serve a number of functions including stormwater management. The design of constructed wetlands for stormwater management involves a number of multi-disciplinary inputs. Fundamental to their sustainable operation are the proper control of the hydrologic regime of the wetland and optimal flow hydrodynamics within the wetland. Many ofthe problems encountered in constructed wetlands can be minimised or avoided by good engineering design principles. Poor wetland hydrodynamics are often identified as a major contributor to wetland management problems. Ponds and wetlands with a high hydraulic efficiency are expected to promote full utilisation ofthe available detention storage and near plug flow conditions. The shape and layout of urban ponds and wetlands are often varied to suit the landscape and to satisfy aesthetic requirements as an urban water feature. These can be achieved while maintaining an effective stormwater treatment outcome if steps are taken to ensure that the hydrodynamic behaviour of the system is not severely compromised. A consistent measure is required to allow the effects of design features to be evaluated against this criterion. This paper introduces a new measure for hydraulic efficiency that combines existing measures of flow uniformity and effective volume. Case studies are presented on the use of this measure to assess the effects of different pond and wetland shapes, locations of inlet and outlet, botanical layouts and basin morphology on the flow hydrodynamics.

Aluminum (Al) has been said to associate with the Alzheimer's-like neurodegeneration in humans. One of the proposed mechanisms for the action of Al is that excess Al might interfere with trace metal metabolism. In this study, the levels of Ca, Mg, Cu, and Zn in blood, liver, and different regions of the brain (separated into the cortex, hippocampus, cerebellum, and brainstem) were measured in mice after daily oral administration of AICI3 (100 mg/kg body weight) for 2 mo. It was found that upon prolonged oral administration of AI, serum Al level was elevated significantly. There was no marked change in serum Ca, Mg, Zn, or Cu content. In the liver, Al content was not increased but there was a significant elevation in Cu and Zn content compared to control animals, probably due to the prolonged administration of the acidic salt solution. In brain, there was a significant twofold increase in Al in the hippocampus and a significant decrease in Al in the cortex. In addition to regional changes in AI content, Zn content in the hippocampus and increased Cu content in the hippocampus, cortex, and brainstem were significantly reduced. Data demonstrated that Al could alter Zn and Cu homeostasis in selected brain regions. The possible relation between Al and neuronal cell injury was discussed.

In view of the important role of PKC in synaptic plasticity we have investigated the ability of Nicergoline to affect translocation of PKC isoforms in synaptosomes obtained from distinct brain areas. In isolated synaptosomes obtained from rat hippocampus and striatum, nicergoline was able to induce in a concentration dependent fashion the translocation of the Ca++-dependent PKC isozymes α and β, but not of the Ca++independent ϵ. The effect is confined to hippocampus and striatum. MDL, the major nicergoline metabolite, is more potent in modulating PKC activity in all the brain areas evaluated. These data suggest that PKC may represent an pharmacological target at presynaptic level for nicergoline and its derivates.

A sequence stratigraphic study of the Upper Miocene Stage IVe has been carried out in the Labuan-Paisley Syncline, Northwest Sabah Basin with the aim of identifying new hydrocarbon plays in the study area. The Stage IVe contains up to 4,000 m thick, clastic sediments deposited in coastal plain to bathyal environments probably between 8.2 Ma and 10.5 Ma indicating an immense sedimentation rate of approximately 1,700 metreslMa. The top and base of the Stage IVe are marked by the Shallow Regional and Upper Intermediate Unconformities respectively which are pronounced tectonic boundaries in the NW Sabah Basin. The overall regressive Stage IVe sediments are characterised by oblique to shingled progradation towards the westerly-northwesterly directions as suggested by the mapping of the pronounced shelf­ edges. A generalised third-order sequence witlUn the Stage IVe includes very thin transgressive systems tract and very thick highstand and lowstand systems tracts. A Type-I, third order sequence boundary separates the Stage IVe into two third-order sequences. This sequence boundary is evidenced by the occurrence of a major erosional slump scar at the western part of the syncline. The depositional model derived from this study includes thick shelf sands and basin floor/submarine fans interspersed by thinner sands of the levee-channel complexes at the shelf slopes. "The Intra Stage IVe sequence boundary is thought likely to be caused by the fall in sea-level probably between 8.5 Ma and 9.0 Ma. This fall in.sea-Ievel is not represented in the global sea-level chart of Haq et al. (1987), suggesting that this fall in sea-level could be small and localised but it is evident in a basin with large sediment supply. This sequence stratigraphic study has resulted in the identification of various hydrocarbon plays. They comprise basin floor/submarine fans, slope fan/levee channel complex and shelf-edge/slump scar plays. The 'basin floor /submarine fan play is considered the highest ranked but requires additional seismic coverage for detailed mapping.

Central to the hydrological and botanical design of constructed wetlands for stormwater quality management is the proper control of their hydrologic regime. The hydrologic regime, defined as the probabilistic distribution of inundation depth in the wetland, reflects the inherent variability of storm inflows to the wetland and is directly influenced by the discharge characteristics of the outlet structure of the wetland. The influence of three typical outlet structures on the hydrologic regime of a hypothetical wetland was investigated using a continuous simulation approach. The three outlet types investigated were that of a culvert, a riser and a siphon. Simulations found that all three devices provides equally effective control of the ability of the wetland to capture and detain storm runoff but can have different influence on the hydrologic regime of the wetland. The siphon-controlled wetland was found to exhibit a more even distribution of inundation depth compared to the other two outlet types.

SUMMARY Cortical dysplasia is a neuronal migration disorder occasionally associated with anomalous draining veins. However, to our knowledge, no intracranial haemorrhage in conjunction with this association has been reported in the literature. We herein report a 7-month-old baby girl with cortical dysplasia associated with an ipsilateral cortical draining vein and complicated with subdural haemorrhage, with the diagnosis made by computed tomography and magnetic resonance imaging. This case demonstrated that patients with this condition could have an excellent prognosis even when the anomalous veins coexist with intracranial haemorrhage. We postulate that venous rupture may be the cause of this condition and further discuss the possible pathophysiology.

Background Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine are the most common form of medication treatment for major depression. However, approximately 50% of depressed patients fail to achieve an effective treatment response. Understanding how gene expression systems respond to treatments may be critical for understanding antidepressant resistance. Methods We take a novel approach to this problem by demonstrating that the gene expression system of the dentate gyrus responds to fluoxetine (FLX), a commonly used antidepressant medication, in a stereotyped-manner involving changes in the expression levels of thousands of genes. The aggregate behavior of this large-scale systemic response was quantified with principal components analysis (PCA) yielding a single quantitative measure of the global gene expression system state. Results Quantitative measures of system state were highly correlated with variability in levels of antidepressant-sensitive behaviors in a mouse model of depression treated with fluoxetine. Analysis of dorsal and ventral dentate samples in the same mice indicated that system state co-varied across these regions despite their reported functional differences. Aggregate measures of gene expression system state were very robust and remained unchanged when different microarray data processing algorithms were used and even when completely different sets of gene expression levels were used for their calculation. Conclusions System state measures provide a robust method to quantify and relate global gene expression system state variability to behavior and treatment. State variability also suggests that the diversity of reported changes in gene expression levels in response to treatments such as fluoxetine may represent different perspectives on unified but noisy global gene expression system state level responses. Studying regulation of gene expression systems at the state level may be useful in guiding new approaches to augmentation of traditional antidepressant treatments.

BACKGROUND AND PURPOSE: The roles of DTI and dynamic susceptibility contrast-enhanced–PWI in predicting the angiographic vascularity of meningiomas have not been studied. We aimed to investigate if these 2 techniques could reflect the angiographic vascularity of meningiomas. MATERIALS AND METHODS: Thirty-two consecutive patients with meningiomas who had preoperative dynamic susceptibility contrast-enhanced–PWI, DTI, and conventional angiography were retrospectively included. The correlations between angiographic vascularity of meningiomas, classified with a 4-point grading scale, and the clinical or imaging variables—age and sex of patient, as well as size, CBV, fractional anisotropy, and ADC of meningiomas—were analyzed. The meningiomas were dichotomized into high-vascularity and low-vascularity groups. The differences in clinical and imaging variables between the 2 groups were compared. Receiver operating characteristic curve analysis was used to determine the diagnostic performance of these variables. RESULTS: In meningiomas, angiographic vascularity correlated positively with CBV but negatively with fractional anisotropy. High-vascularity meningiomas demonstrated significantly higher CBV but lower fractional anisotropy as compared with low-vascularity meningiomas. In differentiating between the 2 groups, the area under the curve values were 0.991 for CBV and 0.934 for fractional anisotropy on receiver operating characteristic curve analysis. CONCLUSIONS: CBV and fractional anisotropy correlate well with angiographic vascularity of meningiomas. They may differentiate between low-vascularity and high-vascularity meningiomas.

[3H]GR 113808 binding studies in guinea-pig brain tissue revealed a temperature dependency and pharmacological specificity consistent with labelling of a 5-HT4 receptor. Detailed comparison of competition data between brain regions from human and guinea-pig suggest minor differences in the rank order of affinity. Studies in brain tissue from patients with Alzheimer's, Huntington's and Parkinson's disease have revealed specific deficits in 5-HT4 receptor densities.

The enantiomers of the indolyl-2-oxoacetamide 5 were found to have 5-HT3 receptor partial agonist activity with (R)-5 having higher potency than (S)-5.

Central to wetland design for stormwater pollution management is the proper control of the hydrologic regime of these wetlands and wet detention basins. The paper proposes a stochastic approach in determining the appropriate wetland size for stormwater treatment in recognition of the inherent variability of stormwater runoff and pollutant load generation within a storm event and between storm event. The determination of wetland size would include the use of stochastic generation of stormwater runoff and continuous wetland behaviour simulation. A typical design chart summarising the interaction between wetland size, prescribed retention period of stormwater and wetland hydrologic effectiveness for Melbourne is presented. The chart enables the selection of the appropriate storage volume and outlet characteristics on the basis of long-term average effectiveness of the wetland to retain stormwater over a desired minimum period rather than a prescribed level of performance for an individual probablistic event.