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Abstract Background National data on dementia prevalence are not always available, yet it may be possible to obtain estimates from large surveys that include dementia screening instruments. In Australia, many of the dementia prevalence estimates are based on European data collected between 15 and 50 years ago. We derived population-based estimates of probable dementia and possible cognitive impairment in Australian studies using the Mini-Mental State Examination (MMSE), and compared these to estimates of dementia prevalence from meta-analyses of European studies. Methods Data sources included a pooled dataset of Australian longitudinal studies (DYNOPTA), and two Australian Bureau of Statistics National Surveys of Mental Health and Wellbeing. National rates of probable dementia (MMSE < 24) and possible cognitive impairment (24-26) were estimated using combined sample weights. Results Estimates of probable dementia were higher in surveys than in meta-analyses for ages 65-84, but were similar at ages 85 and older. Surveys used weights to account for sample bias, but no adjustments were made in meta-analyses. Results from DYNOPTA and meta-analyses had a very similar pattern of increase with age. Contrary to trends from some meta-analyses, rates of probable dementia were not higher among women in the Australian surveys. Lower education was associated with higher prevalence of probable dementia. Data from investigator-led longitudinal studies designed to assess cognitive decline appeared more reliable than government health surveys. Conclusions This study shows that estimates of probable dementia based on MMSE in studies where cognitive decline and dementia are a focus, are a useful adjunct to clinical studies of dementia prevalence. Such information and may be used to inform projections of dementia prevalence and the concomitant burden of disease.

A global survey of coral reefs reveals that overfishing is driving resident shark species toward extinction, causing diversity deficits in reef elasmobranch (shark and ray) assemblages. Our species-level analysis revealed global declines of 60 to 73% for five common resident reef shark species and that individual shark species were not detected at 34 to 47% of surveyed reefs. As reefs become more shark-depleted, rays begin to dominate assemblages. Shark-dominated assemblages persist in wealthy nations with strong governance and in highly protected areas, whereas poverty, weak governance, and a lack of shark management are associated with depauperate assemblages mainly composed of rays. Without action to address these diversity deficits, loss of ecological function and ecosystem services will increasingly affect human communities.

Epstein-Barr virus-induced gene 2 (EBI2) is an important chemotactic receptor that is involved in proper B-cell T-cell interactions. Epstein-Barr virus (EBV) has been shown to upregulate this gene upon infection of cell lines, but the timing and mechanism of this upregulation, as well as its importance to EBV infection, remain unknown. This work investigated EBV's manipulation of EBI2 expression of primary naive B cells. EBV infection induces EBI2 expression resulting in elevated levels of EBI2 after 24 h until 7 days post-infection, followed by a dramatic decline (P=0.027). Increased EBI2 expression was not found in non-specifically stimulated B cells or when irradiated virus was used. The EBV lytic gene BRRF1 exhibited a similar expression pattern to EBI2 (R2=0.4622). BRRF1-deficient EBV could not induce EBI2. However, B cells transduced with BRRF1 showed elevated expression of EBI2 (P=0.042), a result that was not seen with transduction of a different EBV lytic transfection factor, BRLF1. Based on these results, we conclude that EBI2 expression is directly influenced by EBV infection and that BRRF1 is necessary and sufficient for EBI2 upregulation during infection.

Sharks are considered the apex predator of coral reefs, but the consequences of their global depletion are uncertain. Here we explore the ecological roles of sharks on coral reefs and, conversely, the importance of reefs for sharks. We find that most reef-associated shark species do not act as apex predators but instead function as mesopredators along with a diverse group of reef fish. While sharks perform important direct and indirect ecological roles, the evidence to support hypothesised shark-driven trophic cascades that benefit corals is weak and equivocal. Coral reefs provide some functional benefits to sharks, but sharks do not appear to favour healthier reef environments. Restoring populations of sharks is important and can yet deliver ecological surprise., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Introduction: The anti-IgE therapy omalizumab is currently licensed for the treatment of moderate to severe allergic asthma and chronic idiopathic urticaria. Owing to limitations in the use of omalizumab, a need exists for optimized anti-IgE therapies to broaden clinical indications and patient populations, and to improve dosing schedules. The objective of this phase I, randomized, placebo/omalizumab-controlled, first-in-human, dose-escalation study was to evaluate the pharmacokinetics, pharmacodynamics, and safety of the high-affinity, anti-IgE therapy MEDI4212 in non-Japanese and Japanese subjects with atopy and/or diagnostic IgE ≥ 30 IU/mL., Methods: Subjects with atopy and/or baseline IgE ≥ 30 IU/mL were randomized to a single dose of subcutaneous (5, 15, 60, 150, or 300 mg) or intravenous (300 mg) MEDI4212, subcutaneous omalizumab, or placebo. Following administration, pharmacokinetic, pharmacodynamic [IgE (free and total), and cellular FcεRI expression], and safety assessments were made., Results: MEDI4212 rapidly suppressed free serum IgE to a greater extent than omalizumab; however, recovery of free IgE to baseline in MEDI4212-dosed subjects was rapid when compared with the slow and gradual recovery seen in omalizumab-dosed individuals. The loss of IgE suppression corresponded with a rapid decrease of serum MEDI4212. FcεRI expression on dendritic cells and basophils was reduced following MEDI4212 dosing. MEDI4212 was well tolerated by subjects; adverse events were generally of low severity and no subjects discontinued due to adverse events., Conclusions: The increased potency of MEDI4212 may be of clinical interest for individuals with high-diagnostic IgE levels where more extensive IgE suppression is required for clinical response. However, the modest duration of free IgE suppression below the target concentration noted with MEDI4212 in this study suggests limited potential for dosing schedule advantages over omalizumab., Funding: MedImmune., Trial Registration: ClinicalTrials.gov identifier, NCT01544348.

This paper discusses the first phase of a longitudinal study underway in Australia to ascertain the broad health benefits of specific types of biophilic design for workers in a building site office. A bespoke site design was formulated to include open plan workspace, natural lighting, ventilation, significant plants, prospect and views, recycled materials and use of non-synthetic materials. Initial data in the first three months was gathered from a series of demographic questions and from interviews and observations of site workers. Preliminary data indicates a strong positive effect from incorporating aspects of biophilic design to boost productivity, ameliorate stress, enhance well-being, foster a collaborative work environment and promote workplace satisfaction, thus contributing towards a high performance workspace. The longitudinal study spanning over two years will track human-plant interactions in a biophilic influenced space, whilst also assessing the concomitant cognitive, social, psychological and physical health benefits for workers.

Background: Chronic obstructive pulmonary disease (COPD) is associated with eosinophilic airway inflammation in 10-20% of patients. Benralizumab, an anti-interleukin-5 receptor α monoclonal antibody, depletes blood and sputum eosinophils. We aimed to establish whether benralizumab reduces acute exacerbations of COPD in patients with eosinophilia and COPD., Methods: We did this randomised, double-blind, placebo-controlled, phase 2a study between Nov 18, 2010, and July 13, 2013, at 26 sites in the UK, Poland, Germany, Canada, the USA, Denmark, and Spain. Adults aged 40-85 years, with moderate-to-severe COPD, at least one acute exacerbation of COPD, and a sputum eosinophil count of 3·0% or more within the previous year, were randomly assigned (1:1) via computer-generated permuted block randomisation (block size of four), with an interactive voice or web-response system, to receive placebo or 100 mg benralizumab subcutaneously, every 4 weeks (three doses), then every 8 weeks (five doses) over 48 weeks. Study site personnel included in study assessments, participants, and data analysts, were masked to treatment allocation. The primary endpoint was the annualised rate of acute exacerbations of COPD at week 56, defined as the number of acute exacerbations divided by total duration of person-year follow-up. Secondary and exploratory endpoints included COPD-specific Saint George's Respiratory Questionnaire (SGRQ-C), Chronic Respiratory Questionnaire self-administered standardised format (CRQ-SAS), pre-bronchodilator forced expiratory volume in 1 second (FEV1), and safety. We did a prespecified subgroup analysis by baseline blood eosinophil count. Analyses were by intention to treat and per-protocol. This trial is registered with ClinicalTrials.gov, number NCT01227278., Findings: We randomly assigned 101 patients to receive placebo (n=50) or benralizumab (n=51), of whom 88 (87%) patients completed the study. Six patients who completed the study were excluded from the per-protocol population because of major protocol violations; the per-protocol population thus included 82 patients. Benralizumab did not reduce the annualised rate of acute exacerbations of COPD compared with placebo in the per-protocol population, with rates of 0·95 (0·68-1·29; n=40) versus 0·92 (0·67-1·25; n=42). Mean pre-bronchodilator FEV1 change from baseline to week 56 was -0·06 L (SD 0·24) with placebo, and 0·13 L (0·41) with benralizumab (p=0·014). Numerical, albeit non-significant, improvement in acute exacerbations of COPD, SGRQ-C, CRQ-SAS, and FEV1 were greater in benralizumab-treated patients with baseline blood eosinophil concentrations of 200 cells per μL or more or 300 cells per μL or more. Incidence of treatment-emergent adverse events was similar between the two groups, with the most common events being respiratory disorders (31 [62%] of 50 patients given placebo vs 32 [63%] of 51 given benralizumab) and infections (28 [56%] vs 27 [53%]). A higher incidence of serious treatment-emergent adverse events were recorded in patients in the benralizumab group than in those in the placebo group (14 vs nine patients), although none of these events were considered by the investigator to be benralizumab related., Interpretation: Compared with placebo, benralizumab did not reduce the rate of acute exacerbations of COPD. However, the results of prespecified subgroup analysis support further investigation of benralizumab in patients with COPD and eosinophilia., Funding: MedImmune., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Aim: To assess the bioavailability and pharmacokinetics of CAT-354, an anti-IL-13 human monoclonal IgG4 antibody, following subcutaneous (s.c.) and intravenous (i.v.) administration., Methods: This was a single-dose, randomized, open-label, parallel-group bioavailability study. Healthy male subjects aged 20-54 years were randomly assigned to one of three dose groups (n= 10/group) to receive CAT-354: 150 mg i.v.; 150 mg s.c. or 300 mg s.c. (two 150 mg injections). Serum pharmacokinetics, adverse events (AEs), vital signs, electrocardiograms and laboratory parameters were assessed., Results: CAT-354 showed bioavailability of 62% and 60% after 150 mg and 300 mg s.c. doses, respectively, and linear pharmacokinetics over the dose range tested. Peak serum concentrations in the s.c. groups occurred after 3-9 (median 5) days, with a mean elimination half-life of 19.2 +/- 3.1 days (150 mg) and 19.4 +/- 3.59 days (300 mg) after s.c. and 21.4 +/- 2.46 days after i.v. administration. Volume of distribution at steady state (V(ss)) was 4960 +/- 1440 ml kg(-1) after i.v. (slightly greater than plasma volume). Average apparent clearances (CL/F) were 292 +/- 82.3 and 307 +/- 109 ml day(-1) after 150 and 300 mg s.c., respectively; systemic CL of 188 +/- 84.0 ml day(-1) after i.v. dosing was consistent with endogenous IgG and reticuloendothelial elimination. No severe or serious AEs occurred. Among 40 reported AEs, 25 were headache, sinus disorders/respiratory symptoms and changes in body temperature perception., Conclusions: CAT-354 exhibited bioavailability of approximately 60% when given s.c. to healthy male subjects.

Considerable controversy exists concerning the positive and negative syndrome scale (PANSS), one of the most widely used instruments in schizophrenia research. In this article we revisited the factor structure and external validity of the PANSS in a sample of 500 participants with DSM IV diagnoses of schizophrenia. We found that a model with six latent factors provided a relatively good fit, considered adequate by two rules of thumb. Five factors corresponded closely to those typically derived in other studies: Negative, Positive, Excited/Activation, Anxious-Depressed/Dysphoric, and Disorganized/Autistic preoccupation. The sixth factor seemed to have face validity and was labeled Withdrawn. With the exception of Anxious-Depressed/Dysphoric, Cronbach's Alpha ranged from 0.70 to 0.85 suggesting an acceptable internal consistency. External validity was studied through correlations with socio-demographic variables, DSM IV (subtype) diagnoses, clinical characteristics, and drug use. The many significant correlations suggested that the six PANSS scales measure meaningful aspects of schizophrenia. Furthermore, the pattern of correlations varied, providing evidence that the scales assessed partly different aspects of the disease. Our analyses also suggested that some of the controversy about the PANSS can possibly be attributed to methodological factors where the substantial cross-loadings of some PANSS items may play an important role.

Dry powder inhalers (DPIs) are increasingly being used to deliver drugs for the treatment of asthma. Both the aerosolization and delivery of the drug from a DPI to the lung are dependent on an adequate inspiratory effort from the patient, and it is well-known that the air flow achieved early in the inspiratory profile is important in determining particle size distribution from the inhaler. The present study assessed the peak inspiratory flow (PIF) generated through the Clickhaler DPI, and the early inspiratory flow at 150 mL of inspired volume (IF(150)), in asthmatic children. These measurements were made in a well-controlled setting, and two attempts were recorded to establish maximum achievement. Results were obtained from 57 children aged 6-17 years, showing a (mean +/- SD) best PIF of 60.5 +/- 18.7 L/min (range, 26.8-97.0). The mean PIF overall was 54.2 +/- 20.8 L/min (7.9-97.0). For children aged 6-8 years, the mean best PIF was 46.5 +/- 14.6 L/min (26.8-71.1); for those aged 9 years or more, it was >65 L/min (30.3-97.0). PIF values were unrelated to % predicted FEV(1) measurements. Best IF(150) (mean +/- SD) was 42.9 +/- 13.6 L/min (23.1-66.6) in children aged 6-8 years, and >55 L/min (28.0-86.4) for the older children, showing that high flow rates were achieved early in the inspiratory profile. These data indicate that children with stable asthma can generate adequate inspiratory flow rates to operate the Clickhaler effectively., (Copyright 2003 Wiley-Liss, Inc.)

Study Objective: To determine the absolute bioavailability of cilomilast, and assess the effects of food, dosing time, and coadministration of antacid agents on its bioavailability and pharmacokinetics in healthy volunteers., Setting: Clinical pharmacology unit., Design: Five prospective pharmacokinetic studies: one single-blind, dose-escalating, placebo-controlled trial; four open-label, randomized studies., Subjects: Ninety-six healthy adult volunteers who were nonsmokers., Intervention: In the first study, four subjects received intravenous cilomilast 1, 2, and 4 mg. In the second study, 16 subjects received oral cilomilast 15 mg or intravenous cilomilast 4 mg. In the other three studies, a total of 76 subjects were given single oral 15-mg doses; one study compared its effects in fed versus fasted subjects, one looked for differences of morning versus evening dosing, and one examined coadministration with aluminum hydroxide-magnesium hydroxide., Measurements and Main Results: After intravenous administration of cilomilast, plasma concentrations increased in an approximately dose-proportional manner; the half-life, approximately 6.5 hours, was dose independent. Cilomilast clearance and volume of distribution were small. After oral dosing, the absolute bioavailability was consistently close to 100%. Absorption was slower in fed subjects than in fasted (median 2-hr delay in time to reach maximum plasma concentration, average 39% reduction in maximum plasma concentration), but the area under the concentration-time curve from time zero to infinity (systemic availability) was unaffected. Pharmacokinetic parameters were not influenced by time of dosing or coadministration of antacid., Conclusion: The absolute bioavailability of oral cilomilast was 100%; it was not adversely affected by time of dosing or coadministration with food or antacid.

Partial depolarisation of smooth muscle in endothelium-denuded rat aortic ring preparations, by increasing physiological buffer KC1 concentrations from 4.7 to 14.7 mM, produced a leftward shift of concentration response curves (CRCs) to the alpha 1-adrenoceptor agonist noradrenaline (NA), phenylephrine and methoxamine, without changing maximal responses, whereas maximal responses to clonidine (CLON), also an alpha 1-agonist in this tissue were considerably increased. Partial depolarisation did not alter responses to 10 nM NA or 100 nM CLON in Ca2+(-free) buffer, but significantly increased the contractions obtained on adding Ca2+ back in the presence of the agonists. The potentiation of NA (2.5 and 5 nm) contractions by partial depolarisation was prevented by the voltage-operated Ca2+ channel (VOCC) antagonist nifedipine (NIF, 1 microM). NIF did not significantly affect NA CRCs in 4.7 mM KCl, whereas responses in 14.7 mM KCl were significantly decreased, indicating VOCC recruitment by NA only in the latter condition. Initial depletion of intracellular Ca2+ stores with 1 microM thapsigargin (THAP) in Ca2+(-free) buffer did not alter NA CRCs subsequently obtained in normal Ca2+. However, after THAP-pretreatment, these NA responses (in both 4.7 and 14.7 mM KC1) were attenuated by NIF, indicating that VOCCs were activated by NA in THAP-treated tissues. SKF 96365 (SKF, 30 microM), which can block VOCC and non-VOCC routes of extracellular Ca2+ influx, inhibited NA responses in 4.7 mM and 14.7 mM KCl, possibly implying a role for both types of Ca2+ entry in contractions. However, the greater inhibitory effects of SKF in THAP-pretreated tissues, probably reflected the mobilisation of VOCCs by NA following THAP exposure, because SKF was shown separately to block VOCC-mediated contractions in tissues depolarised with 100 mM KCl alone. 10 microM niflumic acid, an inhibitor of Ca2+(-activated) Cl- channels, did not affect responses to NA in 4.7 mM or 14.7 mM KC1, suggesting that VOCC opening induced by NA in 14.7 mM KCl was not due to depolarisation produced by alpha 1-adrenoceptor induced Cl- efflux. CRCs for NA were unaffected by pretreatment of rings with 100 ng ml-1 pertussis toxin (PT), suggesting a lack of involvement of PT-sensitive G proteins in the contractions obtained either in 4.7 or 14.7 mM KCl. BMY 7378 (100 microM), a selective antagonist for alpha 1D-adrenoceptors, competitively inhibited NA contractions with apparent pKB values of 8.7 +/- 0.2 and 8.4 +/- 0.1 in 4.7 mM and 14.7 mM KCl, respectively. Pretreatment of rings with chloroethylclonidine (100 microM), an irreversible antagonist of alpha 1B-and alpha 1D-adrenoceptors, produced similar rightward shifts in CRCs to NA by 3.2 +/- 0.2 and 3.7 +/- 0.3 log concentration units in 4.7 mM and 14.7 mM KCl, respectively, without changing maximal responses. Inositol phosphate (IP) turnover produced by NA in aortic rings was not significantly different in 4.7 mM compared with 14.7 mM KCl. As a whole, these results suggest that partial depolarisation of the rat aorta with KCl enhances alpha 1-adrenoceptor mediated contractions predominantly via the alpha 1D-subtype, and by a mechanism to be identified which allows greater recruitment of VOCCs by NA. In addition, the ability of THAP-pretreatment also to enhance VOCC activation by NA suggests that Ca2+ release from, or prevention of its reuptake into, intracellular stores may contribute to those processes leading to VOCC opening.

1. The effects of constant nicotine infusions (0.25, 1.0 and 4.0 mg kg-1 day-1) on extracellular dopamine levels in the nucleus accumbens (NAc) and on locomotor activity have been compared with the changes evoked by repeated daily injections (0.4 mg kg-1 day-1 for 5 days) of the drug. 2. The extracellular dopamine concentration in the NAc was significantly increased (P < 0.05) following a challenge dose of nicotine (0.4 mg kg-1, s.c.) in animals which had been pretreated with daily injections of the drug. This effect was accompanied by an enhanced locomotor response to nicotine. 3. The stimulant effects of nicotine on mesolimbic dopamine secretion and on locomotor activity were significantly inhibited (P < 0.01) by the prior administration of mecamylamine (2.0 mg kg-1, s.c.) but not by hexamethonium (2.0 mg kg-1, s.c.). 4. The constant infusion of nicotine at a rate of 1 and 4 but not 0.25 mg kg-1 day-1 abolished the sensitized dopamine response in the NAc to an injection of nicotine in animals pretreated with the drug. The locomotor responses to nicotine in the nicotine-pretreated rats were significantly attenuated by the infusion of nicotine at all 3 doses, although the nicotine induced locomotor activity, in the rats infused with 0.25 mg kg-1 day-1 was also significantly (P < 0.05) higher than that observed in the rats treated acutely with nicotine. 5. Significantly (P<0.01) enhanced mesolimbic dopamine responses, to a challenge injection of nicotine(0.4 mg kg-1, s.c.), were observed 2 and 7 days after termination of the infusion of nicotine (4 mg kg-1 day-1 for 14 days); locomotor responses were enhanced (P<0.01) 1, 2 and 7 days after termination of the infusion.6. The results suggest that sensitized mesolimbic dopamine responses to nicotine occur as a result of stimulation of centrally located nicotinic receptors but that these receptors may be desensitized during periods of chronic exposure to nicotine at doses which may be relevant to smoking.

A study was made of the acute and chronic (15 days) functional and morphologic effects on the rat kidney of warm ischemia and contralateral nephrectomy, in order to define a suitable animal model for testing renal transplant preservation techniques when warm ischemia is a contributing factor. Spontaneous recovery from 30-min warm ischemia was complete, and the model was consequently unsuitable; the high mortality from 90 min was unacceptable. Warm ischemia of 60 minutes produced severe renal tubular necrosis, an acceptable mortality, residual morphologic damage, and impairment of isolated kidney perfusion parameters at 15 days. Renal function in vivo was normal in many of these animals, despite appreciable residual morphologic changes, and it is evident that functional data alone are not sufficient for assessment of preservation regimens.