Transformation of the cryobehavior of rye protoplasts by modification of the plasma membrane lipid composition.
The freezing tolerance of protoplasts isolated from nonacclimated rye leaves (Secale cereale L. cv Puma) was significantly altered by using a pH-induced protoplastliposome fusion technique to modify the lipid composition of the plasma membrane. The increase in freezing tolerance was elicited by fusion with liposomes composed of either the total phospholipid fraction isolated from the plasma membrane of cold-acclimated leaves or single mono- or diunsaturated species of phosphatidylcholine (PtdCho). Of the PtdCho species tested, dilinoleoylphosphatidylcholine ([Lin(2)]PtdCho) and dilinolenoylphosphatidylcholine ([Lnn(2)]PtdCho) liposomes were the most effective; 1-palmitoyl-2-oleoylphosphatidylcholine, 1-palmitoyl-2-linoleoylphosphatidylcholine, or dioleoylphosphatidylcholine liposomes were somewhat less effective; dimyristoylphosphatidylcholine or dipalmitoylphosphatidylcholine liposomes had no effect. The increased freezing tolerance was the result of a transformation in the cryobehavior of the plasma membrane during freeze-induced osmotic contraction. In control nonacclimated protoplasts, osmotic contraction resulted in endocytotic vesiculation of the plasma membrane which was irreversible and resulted in lysis during osmotic expansion after melting of the suspending medium. In nonacclimated protoplasts fused with mono- or diunsaturated species of PtdCho, osmotic contraction resulted in the reversible formation of exocytotic extrusions of the plasma membrane-as normally occurs in protoplasts isolated from cold-acclimated leaves (acclimated protoplasts). In scanning electron micrographs, the morphology of the extrusions of nonacclimated protoplasts fused with [Lin(2)]PtdCho was virtually indistinguishable from that of the extrusions formed in acclimated protoplasts. These studies provide direct evidence that changes in the lipid composition of the plasma membrane are causally related to one facet of the cold-acclimation process.


The competitive dynamics of toxic Alexandrium fundyense and non-toxic Alexandrium tamarense: The role of temperature.
The dinoflagellate Alexandrium produces paralytic shellfish poisoning toxins. The genus is globally distributed, with Scottish waters being of particular interest due to the co-occurrence of different species and strains. In Scottish waters, Alexandrium was historically thought to be dominated by the highly toxic (Group I) Alexandrium fundyense. However, the morphologically indistinguishable (Group III) Alexandrium tamarense has recently also been found to co-occur, raising important questions in relation to Alexandrium biogeography. To begin to address these, we investigated Alexandrium growth, yield and toxin production in a range of temperature conditions characteristics of present and potential future conditions, using a recently developed flow cytometry method that allowed, for the first time, simultaneous enumeration of the cryptic species in co-culture. Experiments were undertaken in a range of temperatures (12, 15, 18 and 21°C) in the phosphate (P) limiting conditions that promotes A. fundyense toxicity. Cell/biomass yield was greater for A. tamarense at all temperatures, with observed growth rates varying with temperature. Growth rather and yield were different in mono- and co-culture with the outcome of these interactions also being temperature dependent. For toxic A. fundyense, GTX-3, STX and NEO were the dominant analogues, but total toxicity, toxicity per cell and the number of, and relative proportion of, toxin analogues changed in relation to the onset of P limitation and also as a function of temperature, with the highest toxin concentrations per cell being observed at 12°C. Toxin concentrations were approximately double in P limited stationary phase compared to exponential growth. Toxin concentrations were lower in the co-cultures, indicating inhibition of production in the presence of non-toxic A. tamarense. The strong performance of A. tamarense is in co-culture at odds with the historical understanding that Scottish waters were dominated by A. fundyense and indicates that changes in water temperatures, and also potentially alleopathic interactions, will influence Alexandrium populations and hence the PSP toxicity threat to humans from shellfish.


Genetic variants in T helper cell type 1, 2 and 3 pathways and gastric cancer risk in a Polish population.
Host immune responses are known determinants of gastric cancer susceptibility. We previously reported an increased gastric cancer risk associated with common variants of several T helper type 1 (Th1) cytokine genes in a population-based case-control study in Warsaw, Poland. In the present study, we augmented our investigation to include additional Th1 genes as well as key genes in the Th2 and Th3 pathways. Analysis of 378 cases and 435 age- and sex-matched controls revealed associations for polymorphisms in the Th1 IL7R gene and one polymorphism in the Th2 IL5 gene. The odd ratios (ORs) for IL7R rs1494555 were 1.4 [95% confidence interval (CI), 1.0-1.9] for A/G and 1.5 (95% CI, 1.0-2.4) for G/G carriers relative to A/A carriers (P = 0.04). The ORs for IL5 rs2069812 were 0.9 (95% CI, 0.7-1.3) for C/T and 0.6 (95% CI, 0.3-1.0) T/T carriers compared with C/C carriers (P = 0.03). These results suggest that IL5 rs2069812 and IL7R rs1389832, rs1494556 and rs1494555 polymorphisms may contribute to gastric cancer etiology.


Functional characterization of naturally occurring variants of human hepatitis B virus containing the core internal deletion mutation.
Naturally occurring variants of human hepatitis B virus (HBV) containing the core internal deletion (CID) mutation have been found frequently in HBV carriers worldwide. Despite numerous sequence analysis reports of CID variants in patients, in the past decade, CID variants have not been characterized functionally, and thus their biological significance to HBV infection remains unclear. We report here two different CID variants identified from two patients that are replication defective, most likely due to the absence of detectable core protein. In addition, we were unable to detect the presence of the precore protein and e antigen from CID variants. However, the production of polymerase appeared to be normal. The replication defect of the CID variants can be rescued in trans by complementation with wild-type core protein. The rescued CID variant particles, which utilize the wild-type core protein, presumably are enveloped properly since they can be secreted into the medium and band at a position similar to that of mature wild-type Dane particles, as determined by gradient centrifugation analysis. Our results also provide an explanation for the association of CID variants with helper or wild-type HBV in nature. The significance of CID variants in HBV infection and pathogenesis is discussed.


Laboratory evaluation of a physiologic sampling pump (PSP).
Recently, physiologic sampling pumps (PSPs), which can adjust their sampling rates in proportion to wearers' minute ventilation (V[combining dot above](E)), have been proposed to better estimate exposure to airborne contaminants in the workplace. A laboratory evaluation was conducted to compare the performance of a new PSP with a traditional sampling pump (TSP) in an exposure chamber. Fifteen subjects (aged 19-36 years) performed two replicate sessions of step-tests for correlated and uncorrelated exposure scenarios on four separate days. When exposed to a scenario in which subject V[combining dot above](E) is highly correlated with m-xylene concentration over the sampling period (r = 0.93), the PSP-measured time-weighted average (TWA) concentrations are higher than TSP-measured concentrations (average ratio of PSP to TSP = 1.18). The ratio of PSP- and TSP-measured TWA concentrations for the uncorrelated scenario (r = 0.02) is closer to one, as expected, with an average value of 0.94. The test results of the linear mixed model further indicate that the performance of the PSP is unaffected by the anthropometric and physiological characteristics of the wearer. Potential differences in exposure estimates resulting from the use of the two instruments were examined in light of various schemes which can potentially occur in the field. With the capability of estimating the total volume of air inhaled over the sampling period with improved accuracy, PSPs show promise in reducing the inherent uncertainty in current risk assessment approaches that entail constant-flow (TSP) sampling approaches.


Discovery of a selective NaV1.7 inhibitor from centipede venom with analgesic efficacy exceeding morphine in rodent pain models.
Loss-of-function mutations in the human voltage-gated sodium channel NaV1.7 result in a congenital indifference to pain. Selective inhibitors of NaV1.7 are therefore likely to be powerful analgesics for treating a broad range of pain conditions. Herein we describe the identification of µ-SLPTX-Ssm6a, a unique 46-residue peptide from centipede venom that potently inhibits NaV1.7 with an IC50 of ∼25 nM. µ-SLPTX-Ssm6a has more than 150-fold selectivity for NaV1.7 over all other human NaV subtypes, with the exception of NaV1.2, for which the selectivity is 32-fold. µ-SLPTX-Ssm6a contains three disulfide bonds with a unique connectivity pattern, and it has no significant sequence homology with any previously characterized peptide or protein. µ-SLPTX-Ssm6a proved to be a more potent analgesic than morphine in a rodent model of chemical-induced pain, and it was equipotent with morphine in rodent models of thermal and acid-induced pain. This study establishes µ-SPTX-Ssm6a as a promising lead molecule for the development of novel analgesics targeting NaV1.7, which might be suitable for treating a wide range of human pain pathologies.


Applications of Artificial Intelligence to Electronic Health Record Data in Ophthalmology.
Widespread adoption of electronic health records (EHRs) has resulted in the collection of massive amounts of clinical data. In ophthalmology in particular, the volume range of data captured in EHR systems has been growing rapidly. Yet making effective secondary use of this EHR data for improving patient care and facilitating clinical decision-making has remained challenging due to the complexity and heterogeneity of these data. Artificial intelligence (AI) techniques present a promising way to analyze these multimodal data sets. While AI techniques have been extensively applied to imaging data, there are a limited number of studies employing AI techniques with clinical data from the EHR. The objective of this review is to provide an overview of different AI methods applied to EHR data in the field of ophthalmology. This literature review highlights that the secondary use of EHR data has focused on glaucoma, diabetic retinopathy, age-related macular degeneration, and cataracts with the use of AI techniques. These techniques have been used to improve ocular disease diagnosis, risk assessment, and progression prediction. Techniques such as supervised machine learning, deep learning, and natural language processing were most commonly used in the articles reviewed.


Prevalence of anaemia in pregnancy in a regional health facility in South Africa.
Anaemia is a major global health problem affecting an estimated 42% of pregnant women worldwide. There is a paucity of South African (SA) data on anaemia in pregnancy, despite the fact that parasitic infections are endemic and the nutritional status of sections of the population is poor. To determine the prevalence of anaemia among antenatal attendees in a regional hospital in Durban, SA. This was a cross-sectional prospective study in a regional health facility in an urban setting serving a population of low socioeconomic status. Venous blood samples to perform a full blood count were obtained from antenatal attendees at their first clinic visit. Two thousand pregnant women were studied; the mean (standard deviation) age and gestational age at booking was 27.6 (7.6) years and 21.7 (7.1) weeks, respectively. Eight hundred and fifty-four (42.7%) were anaemic (haemoglobin (Hb) levels<11 g/dL). The majority (81.4%) were mildly anaemic. There were five (0.6%) cases of severe anaemia (Hb<7 g/dL). The prevalence of anaemia was significantly higher in HIV-positive compared with HIV-negative pregnant women (71.3% v. 28.7%; p<0.0001). The common morphology was normochromic normocytic (n=588, 68.9%). The prevalence of anaemia was 42.7%. In the majority (81.4%) the anaemia was mild and normocytic and normochromic (68.9%). Anaemia is a common problem among antenatal attendees in an SA urban population.


What structural length scales can be detected by the spectral variance of a microscope image?
A spectroscopic microscope, configured to detect interference spectra of backscattered light in the far zone, quantifies the statistics of refractive-index (RI) distribution via the spectral variance (Σ˜2) of the acquired bright-field image. Its sensitivity to subtle structural changes within weakly scattering, label-free media at subdiffraction scales shows great promise in fields from material science to medical diagnostics. We further investigate the length-scale sensitivity of Σ˜ and reveal that, in theory, it can detect RI fluctuations at any spatial frequency whatsoever. Based on a 5% noise floor, Σ˜ detects scales from ∼22 to 200-700 nm (exact values depend on sample structure and thickness). In an example involving mass-density distribution characteristic of biological cell nuclei, we suggest the level of chromatin organization, which can be quantified via Σ˜.


Selective trapping of CO2 gas and cage occupancy in CO2-N2 and CO2-CO mixed gas hydrates.
Hydrate-based CO2 trapping from CO2-N2 and CO2-CO gas mixtures is shown by Raman spectroscopy - the results are of interest for new separation and capture technology. A better trapping efficiency is measured for low CO2 concentrations and N2-based gas mixtures. Moreover, it is observed that CO molecules would impede hydrate formation from ice when a CO-enriched gas mixture is considered.


Expression and prognostic significance of the polymeric immunoglobulin receptor in esophageal and gastric adenocarcinoma.
The polymeric immunoglobulin receptor (PIGR) has been proposed to be a candidate prognostic biomarker in a few cancer forms, and one previous study reported that reduced PIGR expression signifies more aggressive tumours of the distal esophagus and gastroesophageal junction (GEJ). In the present study, we examined the expression, clinicopathological correlates and prognostic significance of PIGR expression in an extended cohort of adenocarcinoma of the upper gastrointestinal tract. Immunohistochemical PIGR expression was examined in a consecutive cohort of patients with surgically resected, radio-chemonaive adenocarcinoma of the esophagus, GE-junction and stomach (n = 173), including paired samples of benign-appearing squamous epithelium (n = 51), gastric mucosa (n = 114), Barrett's esophagus (BE) or intestinal metaplasia (IM) (n = 57) and lymph node metastases (n = 75). Non-parametric tests were applied to explore associations between PIGR expression in primary tumours and clinicopathological characteristics. Classification and regression tree analysis was applied for selection of prognostic cut-off. The impact of PIGR expression on overall survival (OS) and recurrence-free survival (RFS) was assessed by Kaplan-Meier analysis and hazard ratios (HR) calculated by adjusted and unadjusted Cox proportional hazards modelling. PIGR expression was significantly higher in intestinal metaplasia (BE or gastric IM) compared to normal tissues and cancer (p < 0.001). Reduced PIGR expression in primary tumours was significantly associated with more advanced tumour stage (p = 0.002) and inversely associated with involved margins (p = 0.034). PIGR expression did not differ between primary tumours and lymph node metastases. There was no significant difference in PIGR expression between tumours with and without a background of intestinal metaplasia. High PIGR expression was an independent predictor of a prolonged OS (HR = 0.60, 95% CI 0.36-0.99) and RFS (HR = 0.49, 95% CI 0.27-0.90) in patients with radically resected (R0) primary tumours and of an improved RFS (HR = 0.32, 95% CI 0.15-0.69) in curatively treated patients with R0 resection/distant metastasis-free disease. High PIGR expression independently predicts a decreased risk of recurrence and an improved survival in patients with adenocarcinoma of the upper gastrointestinal tract. These findings are of potential clinical relevance and merit further validation.


Final results of a phase IIa, randomised, open-label trial to evaluate the percutaneous intramyocardial transplantation of autologous skeletal myoblasts in congestive heart failure patients: the SEISMIC trial.
The SEISMIC study was an open-label, prospective, randomised study to assess the safety and feasibility of percutaneous myoblast implantation in heart failure patients with implanted cardioverter-defibrillators (ICD). Patients were randomised 2:1 to autologous skeletal myoblast therapy vs. optimal medical treatment. The primary safety end-point was defined as the incidence of procedural and device related serious adverse events, whereas the efficacy endpoints were defined as the change in global LVEF by MUGA scan, change in NYHA classification of heart failure and in the distance achieved during a six-minute walk test (6MW) at 6-month follow-up. Forty subjects were randomised to the treatment arm (n=26), or to the control arm (n=14). There were 12 sustained arrhythmic events and one death after episodes of ventricular tachycardia (VT) in the treatment group and 14 events in the control group (P=ns). At 6-month follow-up, 6MW distance improved by 60.3±54.1?meters in the treated group as compared to no improvement in the control group (0.4±185.7?meters; P=ns). In the control group, 28.6% experienced worsening of heart failure status (4/14), while 14.3% experienced an improvement in NYHA classification (2/14). In the myoblast-treatment arm, one patient experienced a deterioration in NYHA classification (8.0%), whereas five patients improved one or two classes (20.0%; P=0.06). However, therapy did not improve global LVEF measured by MUGA at 6-month follow-up. These data indicate that implantation of myoblasts in patients with HF is feasible, appears to be safe and may provide symptomatic relief, though no significant effect was detected on global LVEF.


[Bisap-O: obesity included in score BISAP to improve prediction of severity in acute pancreatitis].
Most patients with acute pancreatitis exhibits a self-limiting clinical course and relatively free of major complications. Several scores have been created with the intention of achieving adequate and early predict the severity of pancreatitis in order to reduce this mortality. BISAP score was validated in 2008 as a predictor of mortality for acute pancreatitis, obesity is an independent risk factor that increases the risk of severity in patients with acute pancreatitis.The aim of this study is to determine whether obesity BISAP added a score improves prediction of severity in patients with acute pancreatitis. This study was conducted in Daniel Alcides Carrión Hospital, Lima, Peru. The patient data were collected in the Emergency Service, it was a cross-sectional retrospective study, between January 2009 and June 2010. We evaluated a total of 99 patients with acute pancreatitis. Etiology of the 99 were biliary pancreatitis. Only 2 ended in death (2%). Most cases occurred in female patients 77/22 (77.8%). Sixteen of the 99 patients (16%) were considered severe acute pancreatitis. 90% (89/99) had a BISAP <3, 10% a BISAP ≥ 3, fifteen of the 99 patients had a BISAP-O> 3, of them 12 were actually considered a severe pancreatitis. Of 16 patients with severe pancreatitis, 14 patients had a BMI>25. (P = 0.03, OR = 4.39). BISAP-O has a sensitivity, specificity, PPV and NPV of 75%, 96.4%, 80% and 95.2% respectively, with an accuracy of 92.3%. The area under the curve for BISAP-O was 0.94 (95% CI 0.89 to 0.99). There was no difference when compared with the other studied scores (p = 0.45). BISAP The score is a simple method that can be used to predict the severity of acute pancreatitis. Obesity associated BISAP (BISAP-O) provides higher sensitivity and diagnostic accuracy to score BISAP and can serve as a parameter to help predict severity in patients with acute pancreatitis. It was not possible to assess the BISAP-O score as a predictor of mortality for patients with acute pancreatitis, due to the low mortality rate in the present study. Further studies are required to validate the score BISAP associated with obesity in predicting severity.


Validation of a decision rule for selective TSH screening in atrial fibrillation.
Atrial fibrillation (AF) is the most common cardiac dysrhythmia. Current guidelines recommend obtaining thyroid-stimulating hormone (TSH) levels in all patients presenting with AF. Our aim was to investigate the utility of TSH levels for emergency department (ED) patients with a final diagnosis of AF while externally validating and potentially refining a clinical decision rule that recommends obtaining TSH levels only in patients with previous stroke, hypertension, or thyroid disease. We conducted a retrospective, cross-sectional study of consecutive patients who presented to an ED from January 2011 to March 2014 with a final ED diagnosis of AF. Charts were reviewed for historical features and TSH level. We assessed the sensitivity and specificity of the previously derived clinical decision rule. Of the 1,964 patients who were eligible, 1,458 (74%) had a TSH level available for analysis. The overall prevalence of a low TSH (<0.3μIU/mL) was 2% (n=36). Elevated TSH levels (>5μIU/mL) were identified in 11% (n=159). The clinical decision rule had a sensitivity of 88.9% (95% CI [73.0-96.4]) and a specificity of 27.5% (95% CI [25.2-29.9]) for identifying a low TSH. When analyzed for its ability to identify any abnormal TSH values (high or low TSH), the sensitivity and specificity were 74.4% (95% CI [67.5-80.2]) and 27.3% (95% CI [24.9-29.9]), respectively. Low TSH in patients presenting to the ED with a final diagnosis of AF is rare (2%). The sensitivity of a clinical decision rule including a history of thyroid disease, hypertension, or stroke for identifying low TSH levels in patients presenting to the ED with a final diagnosis of atrial fibrillation was lower than originally reported (88.9% vs. 93%). When elevated TSH levels were included as an outcome, the sensitivity was reduced to 74.4%. We recommend that emergency medicine providers not routinely order TSH levels for all patients with a primary diagnosis of AF. Instead, these investigations can be limited to patients with new onset AF or those with a history of thyroid disease with no known TSH level within three months.


Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member.
The transforming growth factor-beta (TGF-beta) superfamily encompasses a large group of growth and differentiation factors playing important roles in regulating embryonic development and in maintaining tissue homeostasis in adult animals. Using degenerate polymerase chain reaction, we have identified a new murine TGF-beta family member, growth/differentiation factor-8 (GDF-8), which is expressed specifically in developing and adult skeletal muscle. During early stages of embryogenesis, GDF-8 expression is restricted to the myotome compartment of developing somites. At later stages and in adult animals, GDF-8 is expressed in many different muscles throughout the body. To determine the biological function of GDF-8, we disrupted the GDF-8 gene by gene targeting in mice. GDF-8 null animals are significantly larger than wild-type animals and show a large and widespread increase in skeletal muscle mass. Individual muscles of mutant animals weigh 2-3 times more than those of wild-type animals, and the increase in mass appears to result from a combination of muscle cell hyperplasia and hypertrophy. These results suggest that GDF-8 functions specifically as a negative regulator of skeletal muscle growth.


Role of the active site guanine in the glmS ribozyme self-cleavage mechanism: quantum mechanical/molecular mechanical free energy simulations.
The glmS ribozyme catalyzes a self-cleavage reaction at the phosphodiester bond between residues A-1 and G1. This reaction is thought to occur by an acid-base mechanism involving the glucosamine-6-phosphate cofactor and G40 residue. Herein quantum mechanical/molecular mechanical free energy simulations and pKa calculations, as well as experimental measurements of the rate constant for self-cleavage, are utilized to elucidate the mechanism, particularly the role of G40. Our calculations suggest that an external base deprotonates either G40(N1) or possibly A-1(O2'), which would be followed by proton transfer from G40(N1) to A-1(O2'). After this initial deprotonation, A-1(O2') starts attacking the phosphate as a hydroxyl group, which is hydrogen-bonded to deprotonated G40, concurrent with G40(N1) moving closer to the hydroxyl group and directing the in-line attack. Proton transfer from A-1(O2') to G40 is concomitant with attack of the scissile phosphate, followed by the remainder of the cleavage reaction. A mechanism in which an external base does not participate, but rather the proton transfers from A-1(O2') to a nonbridging oxygen during nucleophilic attack, was also considered but deemed to be less likely due to its higher effective free energy barrier. The calculated rate constant for the favored mechanism is in agreement with the experimental rate constant measured at biological Mg(2+) ion concentration. According to these calculations, catalysis is optimal when G40 has an elevated pKa rather than a pKa shifted toward neutrality, although a balance among the pKa's of A-1, G40, and the nonbridging oxygen is essential. These results have general implications, as the hammerhead, hairpin, and twister ribozymes have guanines at a similar position as G40.


Vitamin A deficiency: An oxidative stress marker in sodium fluoride (NaF) induced oxidative damage in developing rat brain.
Fluoride induced oxidative stress through depletion in levels of various anti-oxidants such as glutathione, superoxide dismutase (SOD), fat soluble vitamins (D and E) with increased levels of lipid peroxidation (LPO) and fluoride aggravate the damage in rodents as well as in humans. Vitamins A, a fat soluble vitamin possess antioxidant property which plays a significant role in scavenging the free radicals species similar to vitamin D and E. Vitamin A is involved in neural tissue development and plasticity. The growing evidence about vitamin A being antioxidant in different biological reactions formed the basis to determine the effect of fluoride on its levels. The present study was conducted in Wistar rat pups. The pregnant wistar rats were dosed with 20 ppm sodium fluoride (NaF) from day one of pregnancy till the pups were aged day 30. The serum was collected from developing rat pups on regular intervals (14th, 21st, 30th day) and vitamin A levels were analyzed by High performance liquid chromatography (HPLC). Body weights, Behavioural studies and spectrophotometric estimation of SOD, LPO in brain lysates were also performed. The results showed significant decrease (p<0.001) in vitamin A in fluoride induced samples in comparison to the control samples suggesting that decreased levels of vitamin A can be used as another marker in fluoride induced toxicity studies.


Efficacy of tiapride in the treatment of psychiatric disorders: A systematic review.
Tiapride is an atypical antipsychotic used to treat alcohol withdrawal, aggressiveness and agitation, headache, dyskinesias, tic and Tourette's disorder. More recently, it has been proposed for the treatment of delirium and agitation in hospitalised patients with COVID-19. Although its safety profile makes it suitable for use in vulnerable populations, the use of tiapride for psychiatric disorders is limited. This work aims to systematically review the available evidence on the efficacy and tolerability of tiapride in individuals with a psychiatric disorder. We searched PubMed, Embase, PsycINFO, GreyLit, OpenGrey, and ProQuest up to March 2020 for randomised controlled trials focussing on the use of tiapride in the treatment of individuals with a psychiatric disorder (e.g., mood disorder, schizophrenia spectrum, substance use disorder). The Risk of Bias 2 was performed for the quality assessment of the included studies. We identified 579 records. Of them, six studies (published between 1982 and 2010) were included in the review. Four studies referred to alcohol withdrawal, and two to the management of agitation in elderly patients with dementia. None of the studies reported significant differences between tiapride and other active comparators in terms of efficacy and tolerability. The overall risk of bias was moderate to high. Tiapride may be considered as a relatively safe treatment option for selected patients with alcohol withdrawal or agitation in dementia. However, solid evidence of its efficacy in the scientific literature is lacking. High-quality trials remain necessary to fully sustain its use in clinical practice.


Health and mental health needs of children in US military families.
The wars in Afghanistan and Iraq have been challenging for US uniformed service families and their children. Almost 60% of US service members have family responsibilities. Approximately 2.3 million active duty, National Guard, and Reserve service members have been deployed since the beginning of the wars in Afghanistan and Iraq (2001 and 2003, respectively), and almost half have deployed more than once, some for up to 18 months' duration. Up to 2 million US children have been exposed to a wartime deployment of a loved one in the past 10 years. Many service members have returned from combat deployments with symptoms of posttraumatic stress disorder, depression, anxiety, substance abuse, and traumatic brain injury. The mental health and well-being of spouses, significant others, children (and their friends), and extended family members of deployed service members continues to be significantly challenged by the experiences of wartime deployment as well as by combat mortality and morbidity. The medical system of the Department of Defense provides health and mental health services for active duty service members and their families as well as activated National Guard and Reserve service members and their families. In addition to military pediatricians and civilian pediatricians employed by military treatment facilities, nonmilitary general pediatricians care for >50% of children and family members before, during, and after wartime deployments. This clinical report is for all pediatricians, both active duty and civilian, to aid in caring for children whose loved ones have been, are, or will be deployed.


Copper-dependent activation of hypoxia-inducible factor (HIF)-1: implications for ceruloplasmin regulation.
Cellular oxygen partial pressure is sensed by a family of prolyl-4-hydroxylase domain (PHD) enzymes that modify hypoxia-inducible factor (HIF)alpha subunits. Upon hydroxylation under normoxic conditions, HIFalpha is bound by the von Hippel-Lindau tumor suppressor protein and targeted for proteasomal destruction. Since PHD activity is dependent on oxygen and ferrous iron, HIF-1 mediates not only oxygen- but also iron-regulated transcriptional gene expression. Here we show that copper (CuCl(2)) stabilizes nuclear HIF-1alpha under normoxic conditions, resulting in hypoxia-response element (HRE)-dependent reporter gene expression. In in vitro hydroxylation assays CuCl(2) inhibited prolyl-4-hydroxylation independently of the iron concentration. Ceruloplasmin, the main copper transport protein in the plasma and a known HIF-1 target in vitro, was also induced in vivo in the liver of hypoxic mice. Both hypoxia and CuCl(2) increased ceruloplasmin (as well as vascular endothelial growth factor [VEGF] and glucose transporter 1 [Glut-1]) mRNA levels in hepatoma cells, which was due to transcriptional induction of the ceruloplasmin gene (CP) promoter. In conclusion, our data suggest that PHD/HIF/HRE-dependent gene regulation can serve as a sensory system not only for oxygen and iron but also for copper metabolism, regulating the oxygen-, iron- and copper-binding transport proteins hemoglobin, transferrin, and ceruloplasmin, respectively.


Using qualitative probability in reverse-engineering gene regulatory networks.
This paper demonstrates the use of qualitative probabilistic networks (QPNs) to aid Dynamic Bayesian Networks (DBNs) in the process of learning the structure of gene regulatory networks from microarray gene expression data. We present a study which shows that QPNs define monotonic relations that are capable of identifying regulatory interactions in a manner that is less susceptible to the many sources of uncertainty that surround gene expression data. Moreover, we construct a model that maps the regulatory interactions of genetic networks to QPN constructs and show its capability in providing a set of candidate regulators for target genes, which is subsequently used to establish a prior structure that the DBN learning algorithm can use and which 1) distinguishes spurious correlations from true regulations, 2) enables the discovery of sets of coregulators of target genes, and 3) results in a more efficient construction of gene regulatory networks. The model is compared to the existing literature using the known gene regulatory interactions of Drosophila Melanogaster.


Inhibition of Hsp90 augments docetaxel therapy in castrate resistant prostate cancer.
First line treatment of patients with castrate resistant prostate cancer (CRPC) primarily involves administration of docetaxel chemotherapy. Unfortunately, resistance to docetaxel therapy is an ultimate occurrence. Alterations in androgen receptor (AR) expression and signaling are associated mechanisms underlying resistance to docetaxel treatment in CRPC. Heat shock protein 90 (Hsp90) is a molecular chaperone, which regulates the activation, maturation and stability of critical signaling proteins involved in prostate cancer, including the AR. This knowledge and recent advances in compound design and development have highlighted Hsp90 as an attractive therapeutic target for the treatment of CRPC. We recently reported the development of a MYC-CaP castrate resistant (MYC-CaP/CR) transplant tumor model, which expresses amplified wild type AR. Within, we report that a second generation Hsp90 inhibitor, NVP-AUY922, inhibits cell growth and significantly induces cell death in MYC-CaP/CR and Pten-CaP/cE2 cell lines. NVP-AUY922 induced proteasome degradation of AR, though interestingly does not require loss of AR protein to inhibit AR transcriptional activity. Further, NVP-AUY922 increased docetaxel toxicity in MYC-CaP/CR and Pten-CaP/cE2 cell lines in vitro. Finally, NVP-AUY922/docetaxel combination therapy in mice bearing MYC-CaP/CR tumors resulted in greater anti-tumor activity compared to single treatment. This study demonstrates that NVP-AUY922 elicits potent activity towards AR signaling and augments chemotherapy response in a mouse model of CRPC, providing rationale for the continued clinical development of Hsp90 inhibitors in clinical trials for treatment of CRPC patients.


Acute Post-Prandial Cognitive Effects of Brown Seaweed Extract in Humans.
(Poly)phenols and, specifically, phlorotannins present in brown seaweeds have previously been shown to inhibit α-amylase and α-glucosidase, key enzymes involved in the breakdown and intestinal absorption of carbohydrates. Related to this are observations of modulation of post-prandial glycemic response in mice and increased insulin sensitivity in humans when supplemented with seaweed extract. However, no studies to date have explored the effect of seaweed extract on cognition. The current randomized, placebo-controlled, double-blind, parallel groups study examined the impact of a brown seaweed extract on cognitive function post-prandially in 60 healthy adults (N = 30 per group). Computerized measures of episodic memory, attention and subjective state were completed at baseline and 5 times at 40 min intervals over a 3 h period following lunch, with either seaweed or placebo consumed 30 min prior to lunch. Analysis was conducted with linear mixed models controlling for baseline. Seaweed led to significant improvements to accuracy on digit vigilance (p = 0.035) and choice reaction time (p = 0.043) tasks. These findings provide the first evidence for modulation of cognition with seaweed extract. In order to explore the mechanism underlying these effects, future research should examine effects on cognition in parallel with blood glucose and insulin responses.


Multichannel electroencephalographic assessment of auditory evoked response suppression in schizophrenia.
Reduced auditory evoked response (AER) suppression in a paired-stimulus paradigm (where suppression equals the difference between S1 and S2 amplitudes divided by S1 amplitude) may index genetic liability for schizophrenia. The present report is a multiple-channel electroencephalographic (EEG) study of AER suppression among 20 normal and 20 schizophrenia subjects. The typical paired-stimulus paradigm was used to evoke time-locked AERs. AER responses were scored at P50 and N100 in the time domain using both single (Cz) and multichannel data (after reduction using principal components analysis, PCA), and were scored for information in the gamma (20-50 Hz) and low-frequency (1-20 Hz) ranges using multichannel information (also after PCA). The time domain analyses demonstrated that schizophrenia patients differ from normal in amplitude of response to the first, but not to the second, stimulus for both P50 and N100. The frequency domain data demonstrated that schizophrenia patients differed from normal on amplitude of the low-frequency response (LFR) to the first, but not to the second, stimulus. The groups did not differ significantly on amplitudes of the gamma-band responses. Group separations were largest for the multichannel N100 and LFR data, with the LFR demonstrating a modestly better risk ratio for differentiating schizophrenia from normal subjects. The present results suggest two novel differences from previous AER suppression studies: (1) S1 amplitudes largely determine differences between normal and schizophrenia groups on AER suppression, and (2) frequency domain analyses may provide important complimentary information when studying AERs in schizophrenia.


Characterization and assessment of an avian repetitive DNA sequence as an icterid phylogenetic marker.
The first tandemly repeated sequence examined in a passerine bird, a 431-bp PstI fragment named pMAT1, has been cloned from the genome of the brown-headed cowbird (Molothrus ater). The sequence represents about 5-10% of the genome (about 4 x 10(5) copies) and yields prominent ethidium bromide stained bands when genomic DNA cut with a variety of restriction enzymes is electrophoresed in agarose gels. A particularly striking ladder of fragments is apparent when the DNA is cut with HinfI, indicative of a tandem arrangement of the monomer. The cloned PstI monomer has been sequenced, revealing no internal repeated structure. There are sequences that hybridize with pMAT1 found in related nine-primaried oscines but not in more distantly related oscines, suboscines, or nonpasserine species. Little sequence similarity to tandemly repeated PstI cut sequences from the merlin (Falco columbarius), saurus crane (Grus antigone), or Puerto Rican parrot (Amazona vittata) or to HinfI digested sequence from the Toulouse goose (Anser anser) was detected. The isolated sequence was used as a probe to examine DNA samples of eight members of the tribe Icterini. This examination revealed phylogenetically informative characters. The repeat contains cutting sites from a number of restriction enzymes, which, if sufficiently polymorphic, would provide new phylogenetic characters. Sequences like these, conserved within a species, but variable between closely related species, may be very useful for phylogenetic studies of closely related taxa.


Carnivore carcasses are avoided by carnivores.
Ecologists have traditionally focused on herbivore carcasses as study models in scavenging research. However, some observations of scavengers avoiding feeding on carnivore carrion suggest that different types of carrion may lead to differential pressures. Untested assumptions about carrion produced at different trophic levels could therefore lead ecologists to overlook important evolutionary processes and their ecological consequences. Our general goal was to investigate the use of mammalian carnivore carrion by vertebrate scavengers. In particular, we aimed to test the hypothesis that carnivore carcasses are avoided by other carnivores, especially at the intraspecific level, most likely to reduce exposure to parasitism. We take a three-pronged approach to study this principle by: (i) providing data from field experiments, (ii) carrying out evolutionary simulations of carnivore scavenging strategies under risks of parasitic infection, and (iii) conducting a literature-review to test two predictions regarding parasite life-history strategies. First, our field experiments showed that the mean number of species observed feeding at carcasses and the percentage of consumed carrion biomass were substantially higher at herbivore carcasses than at carnivore carcasses. This occurred even though the number of scavenger species visiting carcasses and the time needed by scavengers to detect carcasses were similar between both types of carcasses. In addition, we did not observe cannibalism. Second, our evolutionary simulations demonstrated that a risk of parasite transmission leads to the evolution of scavengers with generally low cannibalistic tendencies, and that the emergence of cannibalism-avoidance behaviour depends strongly on assumptions about parasite-based mortality rates. Third, our literature review indicated that parasite species potentially able to follow a carnivore-carnivore indirect cycle, as well as those transmitted via meat consumption, are rare in our study system. Our findings support the existence of a novel coevolutionary relation between carnivores and their parasites, and suggest that carnivore and herbivore carcasses play very different roles in food webs and ecosystems.


Fine-scale substrate heterogeneity in green roof plant communities: The constraint of size.
Heterogeneity-diversity relationship (HDR) is commonly shown to be positive in accordance with classic niche processes. However, recent soil-based studies have often found neutral and even negative HDRs. Some of the suggested reasons for this discrepancy include the lack of resemblance between manipulated substrate and natural settings, the treated areas not being large enough to contain species' root span, and finally limited-sized plots may not sustain focal species' populations over time. Vegetated green roofs are a growing phenomenon in many cities that could be an ideal testing ground for this problem. Recent studies have focused on the ability of these roofs to sustain stable and diverse plant communities and substrate heterogeneity that would increase niches on the roof has been proposed as a method to attain this goal. We constructed an experimental design using green roof experimental modules (4 m2) where we manipulated mineral and organic substrate component heterogeneity in different subplots (0.25 m2) within the experimental module while maintaining the total sum of mineral and organic components. A local annual plant community was seeded in the modules and monitored over three growing seasons. We found that plant diversity and biomass were not affected by experimentally created substrate heterogeneity. In addition, we found that different treatments, as well as specific subplot substrates, had an effect on plant community assemblages during the first year but not during the second and third years. Substrate heterogeneity levels were mostly unchanged over time. The inability to retain plant community composition over the years despite the maintenance of substrate differences supports the hypothesis that maintenance of diversity is constrained at these spatial scales by unfavorable dispersal and increased stochastic events as opposed to predictions of classic niche processes.


Lynch syndrome screening in colorectal cancer: results of a prospective 2-year regional programme validating the NICE diagnostics guidance pathway throughout a 5.2-million population.
Screening all patients newly diagnosed with colorectal cancer (CRC) for possible Lynch syndrome (LS) has been recommended in the United Kingdom since the National Institute for Health and Care Excellence (NICE) released new diagnostics guidance in February 2017. We sought to validate the NICE screening pathway through a prospective regional programme throughout a 5.2-million population during a 2-year period. Pathology departments at 14 hospital trusts in the Yorkshire and Humber region of the United Kingdom were invited to refer material from patients with newly diagnosed CRC aged 50 years or over between 1 April 2017 and 31 March 2019 for LS screening. Testing consisted of immunohistochemistry for MLH1, PMS2, MSH2 and MSH6 followed by BRAF mutation analysis ± MLH1 promoter methylation testing in cases showing MLH1 loss. A total of 3141 individual specimens were submitted for testing from 12 departments consisting of 3061 unique tumours and 2791 prospectively acquired patients with CRC. Defective mismatch repair (dMMR) was observed in 15% of cases. In cases showing MLH1 loss, 76% contained a detectable BRAF mutation and, of the remainder, 77% showed MLH1 promoter hypermethylation. Of the patients included in the final analysis, 81 (2.9%) had an indication for germline testing. LS screening using the NICE diagnostics guidance pathway is deliverable at scale identifying significant numbers of patients with dMMR. This information is used to refer patients to regional clinical genetics services in addition to informing treatment pathways including the use of adjuvant/neoadjuvant chemotherapy and immunotherapy.


Mutational analysis of the hepatitis B virus P gene product: domain structure and RNase H activity.
To correlate the hepatitis B virus P gene with the enzymatic activities predicted to participate in hepadnavirus reverse transcription, a series of P gene mutants containing missense mutations, in-phase insertions, and in-phase deletions was constructed by site-directed mutagenesis. These mutants were tested in the context of otherwise intact hepatitis B virus genomes for the ability to produce core particles containing the virus-associated polymerase activity. The results obtained suggest that the P protein consists of three functional domains and a nonessential spacer arranged in the following order: terminal protein, spacer, reverse transcriptase/DNA polymerase, and RNase H. The first two domains are separated by a spacer region which could be deleted to a large extent without significant loss of endogenous polymerase activity. In cotransfection experiments, all P gene mutants could be complemented in trans by constructs expressing the wild-type gene product but not by a second P gene mutant. This indicates that the multifunctional P gene is expressed as a single translational unit and independent of the core gene and furthermore that the gene product is freely diffusible and not processed before core assembly.


Virgin birth in a hammerhead shark.
Parthenogenesis has been documented in all major jawed vertebrate lineages except mammals and cartilaginous fishes (class Chondrichthyes: sharks, batoids and chimeras). Reports of captive female sharks giving birth despite being held in the extended absence of males have generally been ascribed to prior matings coupled with long-term sperm storage by the females. Here, we provide the first genetic evidence for chondrichthyan parthenogenesis, involving a hammerhead shark (Sphyrna tiburo). This finding also broadens the known occurrence of a specific type of asexual development (automictic parthenogenesis) among vertebrates, extending recently raised concerns about the potential negative effect of this type of facultative parthenogenesis on the genetic diversity of threatened vertebrate species.


In Vitro Enzyme Measurement to Test Pharmacological Chaperone Responsiveness in Fabry and Pompe Disease.
The use of personalized medicine to treat rare monogenic diseases like lysosomal storage disorders (LSDs) is challenged by complex clinical trial designs, high costs, and low patient numbers. Hundreds of mutant alleles are implicated in most of the LSDs. The diseases are typically classified into 2 to 3 different clinical types according to severity. Moreover, molecular characterization of the genotype can help predict clinical outcomes and inform patient care. Therefore, we developed a simple cell culture assay based on HEK293H cells heterologously over-expressing the mutations identified in Fabry and Pompe disease. A similar assay has recently been introduced as a preclinical test to identify amenable mutations for Pharmacological Chaperone Therapy (PCT) in Fabry disease. This manuscript describes an amended cell culture assay which enables rapid phenotypic assessment of allelic variants in Fabry and Pompe disease to identify eligible patients for PCT and may aid in the development of novel pharmacochaperones.


Anxiety modulates the degree of attentive resources required to process emotional faces.
The present study contributes to the ongoing debate over the extent to which attentive resources are required for emotion perception. Although fearful facial expressions are strong competitors for attention, we predict that the magnitude of this effect may be modulated by anxiety. To test this hypothesis, healthy volunteers who varied in their self-reported levels of trait and state anxiety underwent an attentional blink task. Both fearful and happy facial expressions were subject to a strong attentional blink effect for low-anxious individuals. For those reporting high anxiety, a blink occurred for both fearful and happy facial expressions, but the magnitude of the attentional blink was significantly reduced for the fearful expressions. This supports the proposals that emotion perception is not fully automatic and that anxiety is related to a reduced ability to inhibit the processing of threat-related stimuli. Thus, individual differences in self-reported anxiety are an important determinant of the attentional control of emotional processing.


Power limits for microbial life.
To better understand the origin, evolution, and extent of life, we seek to determine the minimum flux of energy needed for organisms to remain viable. Despite the difficulties associated with direct measurement of the power limits for life, it is possible to use existing data and models to constrain the minimum flux of energy required to sustain microorganisms. Here, a we apply a bioenergetic model to a well characterized marine sedimentary environment in order to quantify the amount of power organisms use in an ultralow-energy setting. In particular, we show a direct link between power consumption in this environment and the amount of biomass (cells cm(-3)) found in it. The power supply resulting from the aerobic degradation of particular organic carbon (POC) at IODP Site U1370 in the South Pacific Gyre is between ∼10(-12) and 10(-16) W cm(-3). The rates of POC degradation are calculated using a continuum model while Gibbs energies have been computed using geochemical data describing the sediment as a function of depth. Although laboratory-determined values of maintenance power do a poor job of representing the amount of biomass in U1370 sediments, the number of cells per cm(-3) can be well-captured using a maintenance power, 190 zW cell(-1), two orders of magnitude lower than the lowest value reported in the literature. In addition, we have combined cell counts and calculated power supplies to determine that, on average, the microorganisms at Site U1370 require 50-3500 zW cell(-1), with most values under ∼300 zW cell(-1). Furthermore, we carried out an analysis of the absolute minimum power requirement for a single cell to remain viable to be on the order of 1 zW cell(-1).


The expression of protein kinase B in gastric cancer cell apoptosis induced by 12-O-tetradecanoylphorbol-1, 3-acetate.
Protein kinase B (PKB/Akt) is a serine-threonine kinase functioning downstream of phosphatidylinositol 3-kinase (PI-3 kinase) in response to mitogen or growth factor stimulation. In several cell types, it plays an important anti-apoptotic role. TPA is a potent regulator of the growth of many different cell types. Here, we detected that TPA could induce cell apoptosis in the gastric cancer cell line, BGC-823. We also found that TPA inhibited the expression of PKB/Akt in a TPA concentration- and time-dependent manner. Furthermore, TPA inhibited the phosphorylation of PKB at Ser473, but did not affect the phosphorylation of Thr308. It only attenuated the expression of PKB/Akt and the phosphorylation of Ser473 in the cell nucleus, whereas it did not change the PKB/Akt distribution in BGC-823 cells. These results suggest that PKB/Akt inhibition by TPA may be the important factor in the mechanism of effect of TPA on gastric cell lines.


Assessment of trace metal concentrations in muscle tissue of certain commercially available fish species from Kayseri, Turkey.
Regular consumption of fish has been widely recommended by health authorities. However, it is known that some species accumulate high levels of contaminants including heavy metals (e.g., Hg, Cd, Pb, and As). In this study, Cu, Pb, Co, Ni, Cr, Mn, Cd, and Fe were determined in the muscle tissue of 11 commercially available fish species (Sparus auratus, Dicentrarchus labrax, Mullus barbatus, Belone belone, Psetta maxima, Epinephelus aeneus, Salmothymus, Soleidae, Pomatomus saltatrix, Engraulis encrasicolus, and Sarda sarda) supplied from retailers in Kayseri, Turkey. Determinations were carried out by flame atomic absorption spectrometry after the wet digestion method. The average metal concentrations of the 11 species were determined in the range of 0.54-1.79, 0.82-1.40, 2.38-4.54, 1.23-3.67, 5.01-5.97, 0.77-3.59, 0.48-1.06, and 5.05-122.8 μg/g wet weight for Cu, Pb, Co, Ni, Cr, Mn, Cd, and Fe, respectively. The permissible tolerable daily intake (PTDI) and calculated daily intake (CDI) values were compared, and the calculated daily intake values of the samples were found to be below the established values. Correlations between the metal contents in samples were investigated by performing correlation tests with SPSS 13.0 for windows.


Diagnostic ultrasound in patients with shoulder pain: An inter-examiner agreement and reliability study among Dutch physical therapists.
A cross-sectional inter-examiner agreement and reliability study among physical therapists in primary care. musculoskeletal ultrasound (MSU) is frequently used by physical therapists to improve specific diagnosis in patients with shoulder pain, especially for the diagnosis rotator cuff tendinopathy (RCT) including tears. To estimate the inter-examiner agreement and reliability in physical therapists using MSU for patients with shoulder pain. Physical therapists performed diagnostic MSU in 62 patients with shoulder pain. Both physical therapists were blinded to each other's results and patients were not informed about the test results. We calculated the overall inter-examiner agreement, specific positive and negative inter-examiner agreement, and inter-examiner reliability (Cohen's Kappa's). Overall agreement for detecting RC ruptures ranged from 61.7% to 85.5% and from 43.9% to 91.4% for specific positive agreement. The specific negative agreement was lower with values ranging from 44.4% to 79.1% for RC ruptures. Overall agreement for other pathology than ruptures related to SAPS, ranged from 72.6% to 93.6% and from 77.3% to 96% for specific positive agreement. The specific negative agreement was lower with values ranging from 44.4% to 79.1% for RC ruptures and 52.5%-83.3% for other pathology than ruptures related to SAPS. Reliability values varied from substantial for any thickness ruptures to moderate for partial thickness ruptures and fair for full thickness tears. Moreover, reliability was fair for cuff tendinopathy. The reliability for AC arthritis and no pathology found was fair and moderate. There was substantial agreement for the calcifying tendinopathy. Physical therapists using MSU agree on the diagnosis of cuff tendinopathy and on the presence of RCT in primary care, but agree less on the absence of pathology.


Antenatal depression and antidepressants during pregnancy: unraveling the complex interactions for the offspring.
During pregnancy the risk for a woman to develop a depressive episode is as high as 20%. Antenatal depression is not harmless for the developing child as several changes, including neurodevelopmental alterations, have been reported. Sometimes it is unavoidable to treat a pregnant mother with antidepressants, especially when she is suicidal. Currently, selective serotonin reuptake inhibitors (SSRIs) are the pharmacological choice of antidepressant treatment. SSRIs do not cause gross teratogenic alterations and are generally considered safe for use in pregnancy. However, although SSRIs may relieve the maternal symptoms, they definitively cross the placenta partially influencing the neurodevelopment of the fetus. In this review an overview is given of the effects on the offspring of maternal antenatal depression and the putative neurodevelopmental effects of SSRI treatment during pregnancy. Although we primarily focus on human data, some animal data are discussed to describe possible mechanisms on how SSRIs are affecting underlying biological mechanisms associated with depression. In summary, maternal depression may have long-lasting effects on the offspring, whereas prenatal SSRI exposure also increases the risk for long-lasting effects. It remains to be determined whether the effects found after SSRI treatment in pregnant women are only due to the SSRI exposure or if the underlying depression is also contributing to these effects. The possibility of epigenetic alterations as one of the underlying mechanisms that is altered by SSRI exposure is discussed. However much more research in this area is needed to explain the exact role of epigenetic mechanisms in SSRI exposure during pregnancy.


Air pollution and cardiovascular disease: a statement for healthcare professionals from the Expert Panel on Population and Prevention Science of the American Heart Association.
Air pollution is a heterogeneous, complex mixture of gases, liquids, and particulate matter. Epidemiological studies have demonstrated a consistent increased risk for cardiovascular events in relation to both short- and long-term exposure to present-day concentrations of ambient particulate matter. Several plausible mechanistic pathways have been described, including enhanced coagulation/thrombosis, a propensity for arrhythmias, acute arterial vasoconstriction, systemic inflammatory responses, and the chronic promotion of atherosclerosis. The purpose of this statement is to provide healthcare professionals and regulatory agencies with a comprehensive review of the literature on air pollution and cardiovascular disease. In addition, the implications of these findings in relation to public health and regulatory policies are addressed. Practical recommendations for healthcare providers and their patients are outlined. In the final section, suggestions for future research are made to address a number of remaining scientific questions.


Computational immunology meets bioinformatics: the use of prediction tools for molecular binding in the simulation of the immune system.
We present a new approach to the study of the immune system that combines techniques of systems biology with information provided by data-driven prediction methods. To this end, we have extended an agent-based simulator of the immune response, C-ImmSim, such that it represents pathogens, as well as lymphocytes receptors, by means of their amino acid sequences and makes use of bioinformatics methods for T and B cell epitope prediction. This is a key step for the simulation of the immune response, because it determines immunogenicity. The binding of the epitope, which is the immunogenic part of an invading pathogen, together with activation and cooperation from T helper cells, is required to trigger an immune response in the affected host. To determine a pathogen's epitopes, we use existing prediction methods. In addition, we propose a novel method, which uses Miyazawa and Jernigan protein-protein potential measurements, for assessing molecular binding in the context of immune complexes. We benchmark the resulting model by simulating a classical immunization experiment that reproduces the development of immune memory. We also investigate the role of major histocompatibility complex (MHC) haplotype heterozygosity and homozygosity with respect to the influenza virus and show that there is an advantage to heterozygosity. Finally, we investigate the emergence of one or more dominating clones of lymphocytes in the situation of chronic exposure to the same immunogenic molecule and show that high affinity clones proliferate more than any other. These results show that the simulator produces dynamics that are stable and consistent with basic immunological knowledge. We believe that the combination of genomic information and simulation of the dynamics of the immune system, in one single tool, can offer new perspectives for a better understanding of the immune system.


Maturational characteristics of HIV-specific antibodies in viremic individuals.
Despite the rare appearance of potent HIV-neutralizing mAbs in infected individuals requiring prolonged affinity maturation, little is known regarding this process in the majority of viremic individuals. HIV-infected individuals with chronic HIV viremia have elevated numbers of nonconventional tissue-like memory (TLM) B cells that predominate in blood over conventional resting memory (RM) B cells. Accordingly, we investigated affinity maturation in these 2 memory B cell populations. Analysis of IgG-expressing TLM B cells revealed a higher number of cell divisions compared with RM B cells; however, TLM B cells paradoxically displayed significantly lower frequencies of somatic hypermutation (SHM). To assess Ab reactivity in TLM and RM B cells, single-cell cloning was performed on HIV envelope CD4-binding site-sorted (CD4bs-sorted) B cells from 3 individuals with chronic HIV viremia. Several clonal families were present among the 127 cloned recombinant mAbs, with evidence of crosstalk between TLM and RM B cell populations that was largely restricted to non-VH4 families. Despite evidence of common origins, SHM frequencies were significantly decreased in TLM-derived mAbs compared with SHM frequencies in RM-derived mAbs. However, both cell populations had lower frequencies of SHMs than did broadly neutralizing CD4bs-specific mAbs. There was a significant correlation between SHM frequencies and the HIV-neutralizing capacities of the mAbs. Furthermore, HIV neutralization was significantly higher in the RM-derived mAbs compared with that seen in the TLM-derived mAbs, and both SHM frequencies and neutralizing capacity were lowest in TLM-derived mAbs with high polyreactivity. Thus, deficiencies in memory B cells that arise during chronic HIV viremia provide insight into the inadequacy of the Ab response in viremic individuals.


Timing and intensity of exposure to interferon-γ critically determines the function of monocyte-derived dendritic cells.
A growing body of evidence suggests that inflammatory cytokines have a dualistic role in immunity. In this study, we sought to determine the direct effects of interferon-γ (IFN-γ) on the differentiation and maturation of human peripheral blood monocyte-derived dendritic cells (moDC). Here, we report that following differentiation of monocytes into moDC with granulocyte-macrophage colony-stimulating factor and interleukin-4, IFN-γ induces moDC maturation and up-regulates the co-stimulatory markers CD80/CD86/CD95 and MHC Class I, enabling moDC to effectively generate antigen-specific CD4(+) and CD8(+) T-cell responses for multiple viral and tumour antigens. Early exposure of monocytes to high concentrations of IFN-γ during differentiation promotes the formation of macrophages. However, under low concentrations of IFN-γ, monocytes continue to differentiate into dendritic cells possessing a unique gene-expression profile, resulting in impairments in subsequent maturation by IFN-γ or lipopolysaccharide and an inability to generate effective antigen-specific CD4(+) and CD8(+) T-cell responses. These findings demonstrate that IFN-γ imparts differential programmes on moDC that shape the antigen-specific T-cell responses they induce. Timing and intensity of exposure to IFN-γ can therefore determine the functional capacity of moDC.


Medicare's flagship test of pay-for-performance did not spur more rapid quality improvement among low-performing hospitals.
Medicare's flagship hospital pay-for-performance program, the Premier Hospital Quality Incentive Demonstration, began in 2003 but changed its incentive design in late 2006. The goals were to encourage greater quality improvement, particularly among lower-performing hospitals. However, we found no evidence that the change achieved these goals. Although the program changes were intended to provide strong incentives for improvement to the lowest-performing hospitals, we found that in practice the new incentive design resulted in the strongest incentives for hospitals that had already achieved quality performance ratings just above the median for the entire group of participating hospitals. Yet during the course of the program, these hospitals improved no more than others. Our findings raise questions about whether pay-for-performance strategies that reward improvement can generate greater improvement among lower performing providers. They also cast some doubt on the extent to which hospitals respond to the specific structure of economic incentives in pay-for-performance programs.


A critical role for IRF5 in regulating allergic airway inflammation.
Interferon regulatory factor 5 (IRF5) is a key transcription factor involved in the control of the expression of proinflammatory cytokine and responses to infection, but its role in regulating pulmonary immune responses to allergen is unknown. We used genetic ablation, adenoviral vector-driven overexpression, and adoptive transfer approaches to interrogate the role of IRF5 in pulmonary immunity and during challenge with the aeroallergen, house dust mite. Global IRF5 deficiency resulted in impaired lung function and extracellular matrix (ECM) deposition. IRF5 was also essential for effective responses to inhaled allergen, controlling airway hyperresponsiveness, mucus secretion, and eosinophilic inflammation. Adoptive transfer of IRF5-deficient alveolar macrophages into the wild-type pulmonary milieu was sufficient to drive airway hyperreactivity, at baseline or following antigen challenge. These data identify IRF5-expressing macrophages as a key component of the immune defense of the airways. Manipulation of IRF5 activity in the lung could therefore be a viable strategy for the redirection of pulmonary immune responses and, thus, the treatment of lung disorders.


Sialorrhea: a management challenge.
Sialorrhea (drooling or excessive salivation) is a common problem in neurologically impaired children (i.e., those with mental retardation or cerebral palsy) and in adults who have Parkinson's disease or have had a stroke. It is most commonly caused by poor oral and facial muscle control. Contributing factors may include hypersecretion of saliva, dental malocclusion, postural problems, and an inability to recognize salivary spill. Sialorrhea causes a range of physical and psychosocial complications, including perioral chapping, dehydration, odor, and social stigmatization, that can be devastating for patients and their families. Treatment of sialorrhea is best managed by a clinical team that includes primary health care providers, speech pathologists, occupational therapists, dentists, orthodontists, neurologists, and otolaryngologists. Treatment options range from conservative (i.e., observation, postural changes, biofeedback) to more aggressive measures such as medication, radiation, and surgical therapy. Anticholinergic medications, such as glycopyrrolate and scopolamine, are effective in reducing drooling, but their use may be limited by side effects. The injection of botulinum toxin type A into the parotid and submandibular glands is safe and effective in controlling drooling, but the effects fade in several months, and repeat injections are necessary. Surgical intervention, including salivary gland excision, salivary duct ligation, and duct rerouting, provides the most effective and permanent treatment of significant sialorrhea and can greatly improve the quality of life of patients and their families or caregivers.


Non-Alcoholic Fatty Liver Disease, Liver Fibrosis, and Regional Amyloid-β and Tau Pathology in Middle-Aged Adults: The Framingham Study.
Liver steatosis and fibrosis are emerging as risk factors for multiple extrahepatic health conditions; however, their relationship with Alzheimer's disease pathology is unclear. To examine whether non-alcoholic fatty liver disease (NAFLD) and FIB-4, a non-invasive index of advanced fibrosis, are associated with brain amyloid-β (Aβ) and tau pathology. The study sample included Framingham Study participants from the Offspring and Third generation cohorts who attended exams 9 (2011-2014) and 2 (2008-2011), respectively. Participants underwent 11C-Pittsburgh Compound-B amyloid and 18F-Flortaucipir tau positron emission tomography (PET) imaging and abdomen computed tomography, or had information on all components of the FIB-4 index. Linear regression models were used to assess the relationship of NAFLD and FIB-4 with regional tau and Aβ, adjusting for potential confounders and multiple comparisons. Of the subsample with NAFLD information (N = 169; mean age 52±9 y; 57% males), 57 (34%) had NAFLD. Of the subsample with information on liver fibrosis (N = 177; mean age 50±10 y; 51% males), 34 (19%) had advanced fibrosis (FIB-4 > 1.3). Prevalent NAFLD was not associated with Aβ or tau PET. However, FIB-4 index was significantly associated with increased rhinal tau (β= 1.03±0.33, p = 0.002). Among individuals with prevalent NAFLD, FIB-4 was related to inferior temporal, parahippocampal gyrus, entorhinal and rhinal tau (β= 2.01±0.47, p < 0.001; β= 1.60±0.53, p = 0.007, and β= 1.59±0.47, p = 0.003 and β= 1.60±0.42, p = 0.001, respectively) and to Aβ deposition overall and in the inferior temporal and parahippocampal regions (β= 1.93±0.47, p < 0.001; β= 1.59±0.38, p < 0.001, and β= 1.52±0.54, p = 0.008, respectively). This study suggests a possible association between liver fibrosis and early Alzheimer's disease pathology, independently of cardio-metabolic risk factors.


Qualitative study of principles pertaining to lifestyle and pressure ulcer risk in adults with spinal cord injury.
The aim of this article is to identify overarching principles that explain how daily lifestyle considerations affect pressure ulcer development as perceived by adults with spinal cord injury (SCI). Qualitative in-depth interviews over an 18-month period with 20 adults with spinal injury and a history of pressure ulcers were conducted using narrative and thematic analyses. Eight complexly interrelated daily lifestyle principles that explain pressure ulcer development were identified: perpetual danger; change/disruption of routine; decay of prevention behaviors; lifestyle risk ratio; individualization; simultaneous presence of prevention awareness and motivation; lifestyle trade-off; and access to needed care, services and supports. Principles pertaining to the relationship between in-context lifestyle and pressure ulcer risk underscore previous quantitative findings, but also lead to new understandings of how risk unfolds in everyday life situations. Pressure ulcer prevention for community-dwelling adults with SCI can potentially be enhanced by incorporating principles, such as the decay of prevention behaviors or lifestyle trade-off, that highlight special patterns indicative of elevated risk. The identified principles can be used to theoretically drive future research or to guide innovative lifestyle-focused intervention approaches. Public policies that promote short-term preventive interventions at critical junctures throughout a person's life should be considered.


Covid-19 Response From Global Makers: The Careables Cases of Global Design and Local Production.
Makerspaces-informal shared spaces that offer access to technologies, resources and a community of peer learners for making-across the globe initiated a rapid response to the lack of medical hardware supplies during the global pandemic outbreak in early 2020 caused by the Corona virus (COVID-19). As our health systems faced unexperienced pressure, being close to collapsing in some countries, and global supply chains failing to react immediately, makers started to prototype, locally produce and globally share designs of Open Source healthcare products, such as face shields and other medical supplies. Local collaboration with hospitals and healthcare professionals were established. These bottom-up initiatives from maker networks across the globe are showing us how responsible innovation is happening outside the constraints of profit-driven large industries. In this qualitative study we present five cases from a global network of makers that contributed to the production of personal protective equipment (PPE) and healthcare-related products. We draw our cases from the experiences made in Careables, a mixed community of people and organizations committed to the co-design and making of open, personalized healthcare for everyone. With the presented cases we reflect on the potential implications for post-pandemic local production of healthcare products and analyze them from a social innovation perspective. These global experiences are valuable indications of transformative innovations that can reduce dependencies from international supply chains and mainstream mass production.


Nursing Students' Attitudes Towards People Diagnosed with Mental Illness and Mental Health Nursing: An International Project from Europe and Australia.
The stigma associated with a diagnosis of mental illness is well known yet has not reduced significantly in recent years. Health professionals, including nurses, have been found to share similar negative attitudes towards people with labelled with mental illness as the general public. The low uptake of mental health nursing as a career option reflects these stigmatised views and is generally regarded as one of the least popular areas of in which to establish a nursing career. The aim of the current project was to examine nursing students' attitudes towards the concept of mental illness and mental health nursing across four European countries (Ireland, Finland, Norway and the Netherlands), and Australia, using the Opening Minds Scale and the Mental Health Nurse Education survey. The surveys were distributed to students prior to the commencement of the mental health theory component. Attitudes towards mental health nursing were generally favourable. Differences in opinion were evident in attitudes towards mental illness as a construct; with students from Australia and Ireland tending to have more positive attitudes than students from Finland, Norway and the Netherlands. The future quality of mental health services is dependent on attracting sufficient nurses with the desire, knowledge and attitudes to work in mental health settings. Understanding attitudes towards mental illness and mental health nursing is essential to achieving this aim.


Carbon nanotubes stimulate synovial inflammation by inducing systemic pro-inflammatory cytokines.
Carbon nanotubes (CNTs) have promising applications in a wide range of biomedical fields, including imaging, drug/gene delivery and other therapeutics; however, the biosafety concerns of CNTs should be addressed. To date, many reports have documented the toxicological effects on the cells, tissue or organs that are in direct contact with the tubes; however, there is limited evidence to unravel the secondary toxicity upon CNT treatment. Moreover, more effort is needed to gain a definitive understanding of the adverse outcome pathway (AOP) for CNTs, and a pragmatic framework for risk assessment has not been established yet. In the current study, we aimed to decipher the secondary toxicity to joints under CNT exposure. We demonstrated that carboxylated multi-wall CNTs (MWCNTs-COOH) significantly provoked systemic pro-inflammatory responses, leading to synovial inflammation within knee joints, as evidenced by the infiltration of pro-inflammatory cells in the synovium and meniscus. Mechanistic studies showed that MWCNTs-COOH stimulated pro-inflammatory effects by activating macrophages, and the secreted pro-inflammatory cytokines primed the synoviocytes and chondrocytes, resulting in enhanced production of a large array of enzymes involved in articular cartilage degeneration, including matrix metalloproteinase (MMP) members and cyclooxygenase (COX) members, and increased enzymatic activity of MMPs was demonstrated. Blockade of the cytokines by antibodies significantly attenuated the production of these enzymes. Our current study thus suggests that there is a novel secondary toxicity of CNTs, namely a new AOP to understand the indirect effects of carbon nanotubes: synovial inflammation due to the alteration of the priming state of synoviocytes and chondrocytes under CNT-induced systemic inflammatory conditions.


Long-term outcomes of surgical therapies for Parkinson's disease.
The surgical lesion of different brain structures has been used as a treatment for Parkinson's disease (PD) for several decades. More recently, the favored therapeutic approach has involved the administration of levodopa and the use of DBS. These two major therapeutic advances have greatly modified both the clinical condition of patients and the history of the disease. With the introduction of L-dopa in 1967, patients could regain mobility, because their akinesia, tremor, and rigidity were greatly improved, with consequent significant improvement in quality of life and increased life expectancy. However, after the so-called "honeymoon" period in which the disease seemed to be controlled, motor fluctuations and L-dopa-induced dyskinesias mitigated the initial enthusiasm. In the 1990s, unilateral pallidotomy and DBS of the globus palllidus internus and STN reduced these motor fluctuations and dyskinesias remarkably, thereby inaugurating a new era in the surgical treatment of PD. Short- and medium-term follow-up studies of patients who underwent surgery have documented sustained, significant motor benefits. However, given the progressive nature of PD and the purely symptomatic effects of pallidotomy and DBS, the long-term clinical evolution of these surgical patients currently seems to be associated with a new PD phenotype, mainly characterized by axial motor problems and cognitive impairment. Here, we analyze the long-term clinical outcomes of surgical PD patients with at least 5-year follow-up, focusing on the long-term motor symptoms that were initially responsive to surgery.


'I mean I expect that it's pretty safe': Perceptions of food trust in pregnancy - implications for primary health care practice.
Pregnancy is a time in which food choice is of particular importance. Trust in the food supply and those who regulate it is receiving greater acknowledgement because of the influence of trust on food choice. No prior investigation into pregnant women and food trust has been conducted. This paper identifies factors that determine the nature and extent of pregnant women's trust in food; sources of information which influence pregnant women's food choices; and how trust impacts on pregnant women's food choices. In-depth interviews were conducted with 13 pregnant women; nine were pregnant with their first child and four were in their second or subsequent pregnancy. Food choices of pregnant women were predominantly influenced by nutrition and perceived quality of food. Risktaking behaviour, such as the consumption of foods considered high risk during pregnancy, was common amongst participants. The sample was characterised by a dependence on expert information, limited reflexivity in relation to food safety, and contradictory practice such as risk-taking behaviours in regard to high risk foods were observed. Further research is needed to confirm findings in this study. Research into consumption of high-risk foods and the information received from healthcare providers would be useful in creating a clearer understanding of whether provision of information is sufficient in communicating risks and promoting a healthy pregnancy.


A common structural component for β-subunit mediated modulation of slow inactivation in different KV channels.
Potassium channels are tetrameric proteins providing potassium selective passage through lipid embedded proteinaceous pores with highest fidelity. The selectivity results from binding to discrete potassium binding sites and stabilization of a hydrated potassium ion in a central internal cavity. The four potassium binding sites, generated by the conserved TTxGYGD signature sequence are formed by the backbone carbonyls of the amino acids TXGYG. Residues KV1.5-Val481, KV4.3-Leu368 and KV7.1- Ile 313 represent the amino acids in the X position of the respective channels. Here, we study the impact of these residues on ion selectivity, permeation and inactivation kinetics as well as the modulation by β-subunits using site-specific mutagenesis, electrophysiological analyses and molecular dynamics simulations. We identify this position as key in modulation of slow inactivation by structurally dissimilar β-subunits in different KV channels. We propose a model in which structural changes accompanying activation and β-subunit modulation allosterically constrain the backbone carbonyl oxygen atoms via the side chain of the respective X-residue in the signature sequence to reduce conductance during slow inactivation.


Nonimaging speckle interferometry for high-speed nanometer-scale position detection.
We experimentally demonstrate a nonimaging approach to displacement measurement for complex scattering materials. By spatially controlling the wavefront of the light that incidents on the material, we concentrate the scattered light in a focus on a designated position. This wavefront acts as a unique optical fingerprint that enables precise position detection of the illuminated material by simply measuring the intensity in the focus. By combining two fingerprints we demonstrate position detection along one in-plane dimension with a displacement resolution of 2.1 nm. As our approach does not require an image of the scattered field, it is possible to employ fast nonimaging detectors to enable high-speed position detection of scattering materials.


The genetic consequences of different dispersal behaviours in lycaenid butterfly species.
Many studies in population ecology have shown that related species have different dispersal behaviours. Species with sedentary and migratory behaviour exist in butterflies. While the genetic responses to population isolation are well studied, the effects of different dispersal behaviours of species are widely unknown. Therefore, we analysed 19 allozyme loci of two lycaenid butterflies, Cupido minimus as a sedentary butterfly and Aricia agestis as a mobile and expansive species. We collected 594 individuals (280 of C. minimus and 314 of A. agestis) in a western German study region with adjacent areas in Luxembourg and northeastern France. The genetic differentiation among populations of A. agestis (FST=3.9%) was lower than in C. minimus (FST=5.6%). Both species built up an isolation-by-distance system, which is more pronounced in A. agestis than in C. minimus. The genetic diversity in C. minumus populations (e.g. Ptot=73.5%) is higher for all analysed parameters than in A. agestis (e.g. Ptot=52.1%). Both species show specific genetic characteristics fitting with their different dispersal behaviours and respective ecological strategies. In the light of conservation genetics, we deduce that highly fragmented populations do not necessarily have a high extinction probability, but this risk depending much more on specific population genetic structures. In the studied species, C. minimus preserves a complex genetic constitution by high population densities. The patchily distributed A. agestis represents less rare alleles, present only in some populations, and holds up genetic diversity by high mobility.


[A case of Hodgkin's disease with endotracheal tumor presenting with severe airflow obstruction].
A 22-year-old woman was admitted to our hospital complaining of productive cough and dyspnea even at rest, and marked cervical lymphadenopathy. Marked stridor and orthopnea were observed, and auscultation of the chest revealed widespread expiratory wheeze which was not relieved by bronchodilators administered intravenously. Chest X-ray and CT scan revealed hilar lymphadenopathy and invasive tumor of the mediastinum. Bronchoscopy demonstrated narrowing of the trachea anteriorly and posteriorly and a submucosal nodular tumor protruding from the right anterior wall, causing approximately 90% occlusion of the lumen of the lower third of the trachea, but distal bronchi were intact. Microscopic findings of inguinal lymph node biopsy specimen revealed mixed cellular lymphoma compatible with Hodgkin's disease. Systemic chemotherapy resulted in relief of symptoms, and two months later, the endotracheal tumor had disappeared bronchoscopically, with slight residual stenosis of the trachea. Before treatment, pulmonary function tests indicated markedly impaired forced volume in 1 second in both expiratory and inspiratory cycles, especially in the latter phase. After remission, however, obstructive ventilatory dysfunction was observed. The cause of prolonged air flow obstruction was thought to be marked infiltration and almost total involvement of the tracheal wall by tumor with a nodular appearance of the lumen. Endotracheal tumor in Hodgkin's disease is rare, and there are few reports on pulmonary function associated with intrathoracic involvement of malignant lymphoma.


Neighborhood walkability, physical activity, and walking behavior: the Swedish Neighborhood and Physical Activity (SNAP) study.
More knowledge concerning the association between physical activity and objectively measured attributes of the built environment is needed. Previous studies on the association between objectively measured neighborhood walkability, physical activity, and walking have been conducted in the U.S. or Australia and research findings are available from only one country in Europe - Belgium. The first aim of this Swedish study of 2269 adults was to examine the associations between neighborhood walkability and walking for active transportation or leisure, and moderate-to-vigorous physical activity (MVPA) and whether these hypothesized associations are moderated by age, gender, income, marital status and neighborhood-level socioeconomic status. The second aim was to determine how much of the total variance of the walking and physical activity outcomes can be attributed to neighborhood-level differences. Neighborhood walkability was objectively measured by GIS methods. An index consisting of residential density, street connectivity, and land use mix was constructed to define 32 highly and less walkable neighborhoods in Stockholm City. MVPA was measured objectively during 7 days with an accelerometer and walking was assessed using the validated International Physical Activity Questionnaire (IPAQ). Multilevel linear as well as logistic models (mixed-effects, mixed-distribution models) were used in the analysis. The statistically significant and "adjusted" results for individuals living in highly walkable neighborhoods, as compared to those living in less walkable neighborhoods, were: (1) 77% and 28% higher odds for walking for active transportation and walking for leisure, respectively, (2) 50 min more walking for active transportation/week, and (3) 3.1 min more MVPA/day. The proportion of the total variance at the neighborhood level was low and ranged between 0.0% and 2.1% in the adjusted models. The findings of the present study stress that future policies concerning the built environment must be based on context-specific evidence, particularly in the light of the fact that neighborhood redevelopments are time-consuming and expensive.


Traffic-Related Air Pollution as a Risk Factor for Dementia: No Clear Modifying Effects of APOEɛ4 in the Betula Cohort.
It is widely known that the apolipoprotein E (APOE) ɛ4 allele imposes a higher risk for Alzheimer's disease (AD). Recent evidence suggests that exposure to air pollution is also a risk factor for AD, and results from a few studies indicate that the effect of air pollution on cognitive function and dementia is stronger in APOEɛ4 carriers than in non-carriers. Air pollution and interaction with APOEɛ4 on AD risk thus merits further attention. We studied dementia incidence over a 15-year period from the longitudinal Betula study in Northern Sweden. As a marker for long-term exposure to traffic-related air pollution, we used modelled annual mean nitrogen oxide levels at the residential address of the participants at start of follow-up. Nitrogen oxide correlate well with fine particulate air pollution levels in the study area. We had full data on air pollution, incidence of AD and vascular dementia (VaD), APOEɛ4 carrier status, and relevant confounding factors for 1,567 participants. As expected, air pollution was rather clearly associated with dementia incidence. However, there was no evidence for a modifying effect by APOEɛ4 on the association (p-value for interaction > 0.30 for both total dementia (AD+VaD) and AD). The results from this study do not imply that adverse effects of air pollution on dementia incidence is limited to, or stronger in, APOEɛ4 carriers than in the total population.


Effect of dietary raw and fermented sour cherry kernel (Prunus cerasus L.) on growth performance, carcass traits, and meat quality in broiler chickens.
Sour cherry kernels are waste products of the fruit juice industry. Solid-state fermentation has great potential for recycling the agro-industrial residues. In the present study, the effect of raw sour cherry kernel (RC) and fermented sour cherry kernel (FC) by Aspergillus niger on growth performance, carcass traits and meat quality in broiler chickens was investigated. A total of 343 one-day-old male broilers (Ross 308) were randomly allocated to 7 treatments with 7 replicates for each treatment and 7 birds in each replicate. The chicks were fed on a basal diet (control) and basal diet supplemented with RC or FC at the 1, 2, and 4% level. Dietary RC improved (P < 0.001) the feed conversion ratio (FCR) at the 1% inclusion level although chicks fed 2 and 4% RC had lower (P < 0.01) body weight (BW), body weight gain (BWG), and feed intake (FI) from day 1 to 42, compared with that of the birds in the control group. Dietary FC with 1% inclusion level increased (P ≤ 0.05) BWG from day 22 to 42 and also enhanced (P < 0.001) the FCR from day 1 to 42. However, 4% dietary FC had an adverse effect (P < 0.01) on BW, BWG, FI, and the FCR, compared with the control group. The bursa of Fabricius weight was raised (P < 0.01) as the supplemental FC level increased. Dietary RC and FC elevated gut weight (P < 0.01) and length (P ≤ 0.05). Broilers fed on 2% FC had a higher (P ≤ 0.05) ash level and a lower (P ≤ 0.05) b* value in thigh meat, compared with the 2% RC group. The results indicate that FC can be used in broiler nutrition up to 2% level although RC can be added to broiler diets up to 1% level without a detrimental effect on growth performance. Dietary inclusion of 1% RC or FC can be recommended due to the positive effects on broiler chickens.


Neutrophils activated by BJcuL, a C-type lectin isolated from Bothrops jararacussu venom, decrease the invasion potential of neuroblastoma SK-N-SH cells in vitro.
Neuroblastoma is a pediatric tumor with a mortality rate of 40% in the most aggressive cases. Tumor microenvironment components as immune cells contribute to the tumor progression; thereby, the modulation of immune cells to a pro-inflammatory and antitumoral profile could potentialize the immunotherapy, a suggested approach for high-risk patients. Preview studies showed the antitumoral potential of BJcuL, a C- type lectin isolated from Bothrops jararacussu venom. It was able to induce immunomodulatory responses, promoting the rolling and adhesion of leukocytes and the activation of neutrophils. SK-N-SH cells were incubated with conditioned media (CM) obtained during the treatment of neutrophils with BJcuL and fMLP, a bacteria-derived peptide highly effective for activating neutrophil functions. Then we evaluated the effect of the same stimulation on the co-cultivation of neutrophils and SK-N-SH cells. Tumor cells were tested for viability, migration, and invasion potential. In the viability assay, only neutrophils treated with BJcuL (24 h) and cultivated with SK-N-SH were cytotoxic. Migration of tumor cells decreased when incubated directly (p < 0.001) or indirectly (p < 0.005) with untreated neutrophils. When invasion potential was evaluated, neutrophils incubated with BJcuL reduced the total number of colonies of SK-N-SH cells following co-cultivation for 24 h (p < 0.005). Treatment with CM resulted in decreased anchorage-free survival following 24 h of treatment (p < 0.001). Data demonstrated that SK-N-SH cells maintain their migratory potential in the face of neutrophil modulation by BJcuL, but their invasive capacity was significantly reduced.


Predicting changes in the distribution and abundance of species under environmental change.
Environmental changes are expected to alter both the distribution and the abundance of organisms. A disproportionate amount of past work has focused on distribution only, either documenting historical range shifts or predicting future occurrence patterns. However, simultaneous predictions of abundance and distribution across landscapes would be far more useful. To critically assess which approaches represent advances towards the goal of joint predictions of abundance and distribution, we review recent work on changing distributions and on effects of environmental drivers on single populations. Several methods have been used to predict changing distributions. Some of these can be easily modified to also predict abundance, but others cannot. In parallel, demographers have developed a much better understanding of how changing abiotic and biotic drivers will influence growth rate and abundance in single populations. However, this demographic work has rarely taken a landscape perspective and has largely ignored the effects of intraspecific density. We advocate a synthetic approach in which population models accounting for both density dependence and effects of environmental drivers are used to make integrated predictions of equilibrium abundance and distribution across entire landscapes. Such predictions would constitute an important step forward in assessing the ecological consequences of environmental changes.


Potential risk of medication discrepancies and reconciliation errors at admission and discharge from an inpatient medical service.
Medication discrepancies, defined as unexplained variations among drug regimens at care transitions, are common. Some are unintended and cause reconciliation errors that are potentially detrimental for patients. To determine the prevalence of medication discrepancies and reconciliation errors at admission and discharge in hospitalized patients and explore risk factors for reconciliation errors and their potential clinical impact. An observational prospective study was conducted at a general teaching hospital. Patients who were admitted to the internal medicine service and were receiving chronic preadmission treatment were included in the study. Preadmission treatment was compared with the treatment prescribed on admission (first 48 hours) and at hospital discharge, and discrepancies and reconciliation errors were identified. The primary endpoint was the presence of reconciliation errors at admission and/or discharge. Potential risk factors (patient-, medication-, and system-related) for reconciliation errors were analyzed using a multivariate logistic regression model. Of the 120 patients enrolled in the study between April and August 2009, 109 (90.8%) showed 513 discrepancies. The prevalence of patients with reconciliation errors was 20.8% (95% CI 13.6 to 28.1). Intended medication discrepancies were more frequent at admission (96.6%) than at discharge (75.5%), while reconciliation errors were more frequent at discharge (24.5%) than at admission (3.4%). The prevalence ratio (admission vs discharge) was 2.4 (95% CI 1.9 to 3.0) for discrepancies and 0.65 (95% CI 0.32 to 1.32) for reconciliation errors. The logistic regression analysis revealed an association between the number of discrepancies at admission (OR 1.21; 95% CI 1.01 to 1.44) and age (OR 1.05; 95% CI 0.99 to 1.10) and an increased risk of reconciliation errors. Medication reconciliation strategies should focus primarily on avoiding errors at discharge. Since medication discrepancies at admission may predispose patients to reconciliation errors, early detection of such discrepancies would logically reduce the risk of reconciliation errors. Medication reconciliation programs must implement a process for gathering accurate preadmission drug histories and must submit this information to a critical assessment of patients' needs.