IgG Immune Complexes Break Immune Tolerance of Human Microglia.
Microglia are phagocytic cells involved in homeostasis of the brain and are key players in the pathogenesis of multiple sclerosis (MS). A hallmark of MS diagnosis is the presence of IgG Abs, which appear as oligoclonal bands in the cerebrospinal fluid. In this study, we demonstrate that myelin obtained post mortem from 8 out of 11 MS brain donors is bound by IgG Abs. Importantly, we show that IgG immune complexes strongly potentiate activation of primary human microglia by breaking their tolerance for microbial stimuli, such as LPS and Poly I:C, resulting in increased production of key proinflammatory cytokines, such as TNF and IL-1β. We identified FcγRI and FcγRIIa as the two main responsible IgG receptors for the breaking of immune tolerance of microglia. Combined, these data indicate that IgG immune complexes potentiate inflammation by human microglia, which may play an important role in MS-associated inflammation and the formation of demyelinating lesions.


Environmental arsenic exposure: From genetic susceptibility to pathogenesis.
More than 200 million people in 70 countries are exposed to arsenic through drinking water. Chronic exposure to this metalloid has been associated with the onset of many diseases, including cancer. Epidemiological evidence supports its carcinogenic potential, however, detailed molecular mechanisms remain to be elucidated. Despite the global magnitude of this problem, not all individuals face the same risk. Susceptibility to the toxic effects of arsenic is influenced by alterations in genes involved in arsenic metabolism, as well as biological factors, such as age, gender and nutrition. Moreover, chronic arsenic exposure results in several genotoxic and epigenetic alterations tightly associated with the arsenic biotransformation process, resulting in an increased cancer risk. In this review, we: 1) review the roles of inter-individual DNA-level variations influencing the susceptibility to arsenic-induced carcinogenesis; 2) discuss the contribution of arsenic biotransformation to cancer initiation; 3) provide insights into emerging research areas and the challenges in the field; and 4) compile a resource of publicly available arsenic-related DNA-level variations, transcriptome and methylation data. Understanding the molecular mechanisms of arsenic exposure and its subsequent health effects will support efforts to reduce the worldwide health burden and encourage the development of strategies for managing arsenic-related diseases in the era of personalized medicine.


Immunoreactive atrial natriuretic hormone levels increase in deoxycorticosterone acetate-treated pigs.
Extensive evidence reported here and elsewhere indicates a hormonal role for atrial natriuretic factor. In the light of this evidence, it appears that atrial natriuretic hormone is a more appropriate term for these peptides than atrial natriuretic factor. Plasma levels of immunoreactive atrial natriuretic hormone were measured daily in seven pigs before and 1 week after subcutaneous implantation of deoxycorticosterone acetate (DOCA). Nine other animals underwent daily measurements of mean arterial pressure and central venous pressure during similar treatments. Plasma immunoreactive atrial natriuretic hormone levels rose progressively during the first 3 days after implantation, from a basal level of 60 +/- 9 pmol/L to a peak level of 159 +/- 21 pmol/L (p less than 0.05), and they remained significantly elevated throughout the rest of the 7-day observation period. In two animals that were restudied 6 weeks after DOCA implantation, plasma immunoreactive atrial natriuretic hormone had returned to preimplantation levels. The rise in plasma hormone levels after DOCA implantation closely paralleled the previously reported time course of mineralocorticoid escape. Whether atrial natriuretic hormone plays an important part in the escape phenomenon remains to be determined.


C-Reactive Protein and The Risk of Atrial Fibrillation: A Systematic Review and Meta-Analysis.
There is increasing evidence linking C-reactive protein (CRP) and atrial fibrillation (AF). Despite the abundance of literature, confusion exists regarding this association because of inconsistent results. MEDLINE and Cochrane Controlled Trials Register databases were carefully searched through July, 2009 combining the following terms "C-reactive protein" and "atrial fibrillation". Reference lists of selected articles and reviews were also screened to identify additional relevant studies. Of the 129 studies initially identified, 8 studies with 7507 subjects (719 with AF) were included in the meta-analysis. Analysis yielded a relative risk of 1.63 (1.43, 1.86) for occurrence of AF when CRP level was above a cut off of 3-3.5 mg/l. When 3 studies with data on a higher cut off of 4.5-5.0 mg/l were analyzed separately, the relative risk was 4.03 (3.1, 5.25). Our study suggests that elevated CRP is associated with increased risk for AF. The risk appears incremental with higher CRP levels conferring proportionately increased risk. There is an urgent need for further large scale, well designed prospective studies to assess the relationship between CRP and AF.


Antiviral suppression vs restoration of RIG-I signaling by hepatitis C protease and polymerase inhibitors.
Expression of the nonstructural protein (NS)3/4A protease in cells infected with hepatitis C virus (HCV) results in cleavage of the mitochondrial antiviral-signaling protein (MAVS) and disruption of signaling pathways that lead to viral activation of interferon regulatory factor 3 (IRF-3) and synthesis of type 1 interferons (IFN-alpha/beta). High concentrations of inhibitors of NS3/4A reverse this signaling defect, but quantitative analyses of this potential therapeutic effect are lacking. This study quantitatively assessed the rescue of IRF-3 signaling by NS3/4A inhibitors, compared with in vitro antiviral activity. Antiviral activities of 2 NS3/4A protease inhibitors (TMC435350 and an analog, TMC380765) and a nonnucleoside polymerase inhibitor (Tib-3) were determined in HCV replicon cells and in cells infected with genotype 1a and 2a viruses. The capacity to rescue IRF-3 activation in these cells was assessed by monitoring IFN-beta promoter activity following challenge with Sendai virus. Inhibitor-induced changes in NS3 and MAVS expression were assessed in immunoblots. Both protease inhibitors were capable of rescuing IFN-beta promoter activation but only at concentrations approximately 100-fold the antiviral 50% effective concentration (EC(50)) for genotype 1 virus. No rescue was observed with the polymerase inhibitor, even at a concentration 600-fold greater than the EC(50). IRF-3 activation did not correlate with reductions in NS3/4A levels or detection of full-length MAVS. Overexpression of the product of NS3/4A cleavage of MAVS did not result in a dominant-negative effect on signaling. NS3/4A protease inhibitors can restore IRF-3 signaling in HCV-infected cells but only at concentrations far in excess of the antiviral EC(50).


Spontaneous transmitter release is critical for the induction of long-term and intermediate-term facilitation in Aplysia.
Long-term plasticity can differ from short-term in recruiting the growth of new synaptic connections, a process that requires the participation of both the presynaptic and postsynaptic components of the synapse. How does information about synaptic plasticity spread from its site of origin to recruit the other component? The answer to this question is not known in most systems. We have investigated the possible role of spontaneous transmitter release as such a transsynaptic signal. Until recently, relatively little has been known about the functions of spontaneous release. In this paper, we report that spontaneous release is critical for the induction of a learning-related form of synaptic plasticity, long-term facilitation in Aplysia. In addition, we have found that this signaling is engaged quite early, during an intermediate-term stage that is the first stage to involve postsynaptic as well as presynaptic molecular mechanisms. In a companion paper, we show that spontaneous release from the presynaptic neuron acts as an orthograde signal to recruit the postsynaptic mechanisms of intermediate-term facilitation and initiates a cascade that can culminate in synaptic growth with additional stimulation during long-term facilitation. Spontaneous release could make a similar contribution to learning-related synaptic plasticity in mammals.


Immigrant Naturalisation, Employment and Occupational Status in Western Europe.
Does citizenship facilitate access to employment and higher status jobs? Existing studies have produced mixed results across mostly single case studies in Europe and North America. To investigate whether this heterogeneity depends on varying institutional and socio-economic conditions, in this paper we analyse the labour market outcomes of immigrants who have naturalised in 13 West European countries. Our empirical analysis draws on data from the 2014 European Labour Force Survey Ad Hoc Module on immigrants. In order to cope with the selective nature of the naturalisation process, we employ a bivariate probit model that accounts for unobserved characteristics of naturalising immigrants. Our main results show a positive relationship across these destination countries between citizenship and the probability of employment, as well as between citizenship and occupational status, but only for immigrant men from developing countries. For women and for migrants from developed countries, we observe no significant differences between citizens and non-citizens. Liberalising the access to citizenship does not diminish the positive returns on employment from naturalisation. For immigrant men from developing countries there is evidence of a trade-off between easier access to citizenship and the returns on occupational status.


Efficacy of pneumococcal vaccination in adults: a meta-analysis.
Clinical trials and meta-analyses have produced conflicting results of the efficacy of unconjugated pneumococcal polysaccharide vaccine in adults. We sought to evaluate the vaccine's efficacy on clinical outcomes as well as the methodologic quality of the trials. We searched several databases and all bibliographies of reviews and meta-analyses for clinical trials that compared pneumococcal polysaccharide vaccine with a control. We examined rates of pneumonia and death, taking the methodologic quality of the trials into consideration. We included 22 trials involving 101 507 participants: 11 trials reported on presumptive pneumococcal pneumonia, 19 on all-cause pneumonia and 12 on all-cause mortality. The current 23-valent vaccine was used in 8 trials. The relative risk (RR) was 0.64 (95% confidence interval [CI] 0.43-0.96) for presumptive pneumococcal pneumonia and 0.73 (95% CI 0.56-0.94) for all-cause pneumonia. There was significant heterogeneity between the trials reporting on presumptive pneumonia (I(2) = 74%, p < 0.001) and between those reporting on all-cause pneumonia (I(2) = 90%, p < 0.001). The RR for all-cause mortality was 0.97 (95% CI 0.87-1.09), with moderate heterogeneity between trials (I(2) = 44%, p = 0.053). Trial quality, especially regarding double blinding, explained a substantial proportion of the heterogeneity in the trials reporting on presumptive pneumonia and all-cause pneumonia. There was little evidence of vaccine protection in trials of higher methodologic quality (RR 1.20, 95% CI 0.75-1.92, for presumptive pneumonia; and 1.19, 95% CI 0.95-1.49, for all-cause pneumonia in double-blind trials; p for heterogeneity > 0.05). The results for all-cause mortality in double-blind trials were similar to those in all trials combined. There was little evidence of vaccine protection among elderly patients or adults with chronic illness in analyses of all trials (RR 1.04, 95% CI 0.78-1.38, for presumptive pneumococcal pneumonia; 0.89, 95% CI 0.69-1.14, for all-cause pneumonia; and 1.00, 95% CI 0.87-1.14, for all-cause mortality). Pneumococcal vaccination does not appear to be effective in preventing pneumonia, even in populations for whom the vaccine is currently recommended.


Alcohol and drug use outcomes among vulnerable women living with HIV: results from the Western Cape Women's Health CoOp.
Alcohol and other drug use can negatively affect adherence to and retention in antiretroviral therapy (ART) among people living with HIV/AIDS. Yet, there are few brief interventions that reduce these behaviors among this population. This article presents the findings from a randomized field experiment that assessed the effects of a woman-focused intervention (the Women's Health CoOp [WHC]) on reducing alcohol and other drug use among vulnerable women in Cape Town, South Africa. The analyses were limited to 84 women living with HIV who reported drinking alcohol at baseline. Because of the small sample size, analyses were performed using an exact logistic regression procedure. At 12-month follow-up, women in the WHC arm were more likely to be abstinent from alcohol (odds ratio [OR] = 3.61; 95% confidence intervals [CI] = 1.23, 11.70; p = 0.016) and somewhat more likely to test negative for other drugs (OR = 3.07; 95% CI = 0.83, 12.31; p = 0.105), compared with women in the comparison arms. This study provides preliminary evidence of the efficacy of a brief, woman-focused intervention in reducing alcohol and other drug use among vulnerable women living with HIV and it has implications for HIV treatment.


IL-1R signaling within the central nervous system regulates CXCL12 expression at the blood-brain barrier and disease severity during experimental autoimmune encephalomyelitis.
Multiple sclerosis (MS) is an autoimmune disease of the CNS characterized by disruption of the blood-brain barrier (BBB). This breach in CNS immune privilege allows undeterred trafficking of myelin-specific lymphocytes into the CNS where they induce demyelination. Although the mechanism of BBB compromise is not known, the chemokine CXCL12 has been implicated as a molecular component of the BBB whose pattern of expression is specifically altered during MS and which correlates with disease severity. The inflammatory cytokine IL-1beta has recently been shown to contribute not only to BBB permeability but also to the development of IL-17-driven autoimmune responses. Using experimental autoimmune encephalomyelitis, the rodent model of MS, we demonstrate that IL-1beta mediates pathologic relocation of CXCL12 during the induction phase of the disease, before the development of BBB disruption. We also show that CD4, CD8, and, surprisingly gammadelta T cells are all sources of IL-1beta. In addition, gammadelta T cells are also targets of this cytokine, contributing to IL-1beta-mediated production of IL-17. Finally, we show that the level of CNS IL-1R determines the clinical severity of experimental autoimmune encephalomyelitis. These data suggest that T cell-derived IL-1beta contributes to loss of immune privilege during CNS autoimmunity via pathologic alteration in the expression of CXCL12 at the BBB.


Taurine concentrations in animal feed ingredients; cooking influences taurine content.
The aim of this study was to determine the taurine content in a variety of animal feeds. There is very little information on the taurine content of ingredients used in home-prepared diets for dogs and cats, and foods fed to wild animals in captivity. This study reports the taurine content of both common and alternative feed ingredients, and compares taurine loss as a result of different methods of food preparation. Foods were selected based on their use in commercial and home-prepared diets. Animal muscle tissue, particularly marine, contained high taurine concentrations. Plant products contained either low or undetectable amounts of taurine. The amount of taurine that remained in a feed ingredient after cooking depended upon the method of food preparation. When an ingredient was constantly surrounded by water during the cooking process, such as in boiling or basting, more taurine was lost. Food preparation methods that minimized water loss, such as baking or frying, had higher rates of taurine retention.


Multiple density-dependence mechanisms regulate a migratory bird population during the breeding season.
The mechanisms regulating bird populations are poorly understood and controversial. We provide evidence that a migratory songbird, the black-throated blue warbler (Dendroica caerulescens), is regulated by multiple density-dependence mechanisms in its breeding quarters. Evidence of regulation includes: stability in population density during 1969-2002, strong density dependence in time-series analyses of this period, an inverse relationship between warbler density and annual fecundity, and a positive relationship between annual fecundity and recruitment of yearlings in the subsequent breeding season. Tests of the mechanisms causing regulation were carried out within the Hubbard Brook Experimental Forest, New Hampshire, during 1997-1999. When individuals from abutting territories were experimentally removed in a homogeneous patch of high-quality habitat, the fecundity of focal pairs nearly doubled, revealing a locally operating crowding mechanism. A site-dependence mechanism was indicated by an inverse relationship between population size and mean territory quality, as well as by greater annual fecundity on the sites that were most frequently occupied and of highest quality. These site-dependence relationships were revealed by intensive monitoring of territory quality and demography at the landscape spatial scale. Crowding and site-dependence mechanisms, therefore, acted simultaneously but at different spatial scales to regulate local abundance of this migratory bird population.


Can Exposure to Online Conversations About Death and Dying Influence Death Competence? An Exploratory Study Within an Australian Massive Open Online Course.
A Massive Open Online Course, Dying2Learn, was designed to foster community death conversations and strengthen community awareness of palliative care and death as a normal process. This exploratory study used a pre-post prospective design to determine if participation in Dying2Learn and exposure to online conversations about death and dying resulted in any significant influence on death competence in 134 participants who completed the Coping-with-Death-Scale both at the beginning and end of the course in 2016. Death competence refers to a range of attitudes and capabilities people have for dealing with death. Results at the end of the course indicated that engagement in Dying2Learn led to significant improvements in death competence scores over time (medium-to-large effect size). The positive impact was greater for those who completed more of the course, and effectiveness did not depend on sociodemographic characteristics. In conclusion, this study found that an online learning platform in the form of a Massive Open Online Course could engage community members in meaningful social discussion about death and dying, and that exposure to these conversations was beneficial for all participants regardless of previous exposure to death. Further exploration is required to determine whether this change in death competence will have an impact on participant's behavior in the community regarding death conversations and preparedness.


The Effects of Ketamine on Cognitive Function in Elderly Patients Undergoing Ophthalmic Surgery: A Pilot Study.
Acute postoperative cognitive dysfunction is characterized by neurocognitive dysfunction and confusion. In this study, we compared the cognitive status of a geriatric population undergoing ophthalmic surgery, as assessed by the Short Portable Mental Status Questionnaire (SPMSQ) before and after ketamine administration. Eighty patients were enrolled and randomly assigned in a double-blind study to receive either ketamine (0.3 mg/kg dose) or physiologic solution (control group). Sixty-five (control, n = 32; ketamine, n = 33) patients completed the trial. Cognitive performance was assessed with an abbreviated version of the SPMSQ. Measurements of analgesia, sedation, intraocular pressure, and hemodynamic variables were recorded. With respect to cognitive performance, the baseline evaluation was similar for the control and ketamine groups. Postoperative evaluation showed an improvement only in the ketamine group. No increase in intraocular pressure or a secondary nystagmus was observed. The average dose of midazolam was higher in the control group, but the difference was not clinically significant. After surgery, analgesic behavior was better in the ketamine group than in the control group. There were no differences between groups in the sedation scale or in hemodynamic variables. The administration of 0.3 mg/kg ketamine during ophthalmic surgery in geriatric patients changed their cognitive status as assessed by the SPMSQ, decreased the required dose of anesthetics, and produced no increase in intraocular pressure or in hemodynamic variables. However, because the evaluation only analyzed the immediate effects of the administered drug, further research will be required to examine the impact of ketamine on the postoperative cognitive performance of geriatric patients before the drug can be formally recommended for this purpose.


Spontaneous Coronary Artery Dissection: Insights From Histology and Optical Coherence Tomography.
Spontaneous coronary artery dissection (SCAD) is a well-known but infrequent cause of acute coronary syndrome (ACS), and often goes unrecognized. Although management of SCAD is, at times, controversial, when a patient presents with ACS, percutaneous coronary intervention (PCI) is frequently necessary. We present a patient with ST-segment elevation myocardial infarction (STEMI) with SCAD that illustrates two important points: use of intracoronary optical coherence tomography to guide PCI, and histologic assessment to provide a unique insight into the etiology of SCAD. Following the case, we briefly review the important aspects of the pathophysiology, epidemiology, diagnosis, and interventional management of SCAD.


Particulate matter 2.5 induced arrhythmogenesis mediated by TRPC3 in human induced pluripotent stem cell-derived cardiomyocytes.
Particulate matter (PM) is one of the most important environmental issues worldwide, which is associated with not only pulmonary but also cardiovascular diseases. However, the underlying biological mechanisms of PM related cardiovascular dysfunction remained poorly defined, especially mediated by the pathway of direct impact on vascular and heart. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) provide an ideal platform for studying PM-exposed cellular diseases model in vitro. Here, we investigated the direct effects of particulate matter 2.5 (PM2.5) on hiPSC-CMs and the potential mechanism at non-cytotoxic concentrations. Cell viability, contraction amplitude and spontaneous beating rate of iPSC-CMs after direct exposure to PM2.5 showed that the concentration of lower than 100 µg/ml would not lead to cytotoxic effects. Calcium-mediated optical mapping illustrated that there was a concentration-dependent reduction in quantification of calcium transient amplitude and an increase in the incidence of early after depolarizations due to PM2.5 treatment. Furthermore, there were dramatic dosage-dependent shortening in action potential duration and decrease in L-type calcium peak current density. The Ingenuity Pathway Analysis of our transcriptive study indicated that PM2.5 exposure preferentially influenced the expression of genes involved in calcium signaling. Among them the up-regulation of TRPC3 potentially played an important role in the electrophysiological alteration of PM2.5 on hiPSC-CMs, which could be ameliorated by pretreatment with pyr3, the inhibitor of TRPC3. In conclusion, our results demonstrated that exposure to PM2.5 was capable of increasing propensity to cardiac arrhythmias which could be attenuated with TRPC3 inhibition.


In vivo fluorescence of the ocular fundus exhibits retinal pigment epithelium lipofuscin characteristics.
To characterize the intrinsic fluorescence (autofluorescence) of the human ocular fundus with regard to its excitation and emission spectra, age relationship, retinal location, and topography, and to identify the dominant fluorophore among the fundus layers. Using a novel fundus spectrophotometer, fluorescence measurements were made at 7 degrees temporal to the fovea and at the fovea in 30 normal subjects and in 3 selected patients. Topographic measurements were made in 3 subjects. Ex vivo measurements of fluorescence of human retinal pigment epithelium (RPE) were obtained and compared to in vivo data. Fundus fluorescence reveals a broad band of emission between 500 and 750 nm, a maximum of approximately 630 nm, and optimal excitation of approximately 510 nm. Exhibiting a significant increase with age, this fluorescence is highest at 7 degrees to 15 degrees from the fovea, shows a well-defined foveal minimum, and decreases toward the periphery. In vivo fluorescence spectra are consistent with those obtained ex vivo on human RPE. Measurements with short wavelength excitation are strongly influenced by ocular media absorption and reveal an additional minor fluorophore in the fovea. Spectral characteristics, correlation with age, topographic distribution, and retinal location between the choriocapillaris and the photoreceptors suggest that the dominant fundus fluorophore is RPE lipofuscin. The minor fluorophore is probably in the neurosensory retina but has not been identified.


Toenail selenium levels and the subsequent risk of prostate cancer: a prospective cohort study.
Results of a randomized controlled trial have suggested a protective effect of selenium against prostate cancer. Few other prospective studies have been conducted to confirm or refute this. The association between prostate cancer and baseline toenail selenium level was evaluated in the Netherlands Cohort Study, conducted among 58,279 men, aged 55-69 years at entry. In September 1986, the cohort members completed a questionnaire on risk factors for cancer and provided toenail clippings for determination of baseline selenium status. After 6.3 years of follow-up, 540 incident prostate carcinoma cases and 1,211 subcohort members with complete toenail selenium data were available for case-cohort analyses. In multivariate survival analysis, an inverse association between toenail selenium level and prostate cancer risk was observed. Incidence rate ratios in increasing selenium quintiles were 1.00 (ref), 1.05, 0.69, 0.75, and 0.69 (95% confidence interval, 0.48-0.99), respectively (P-trend=0.008). This association persisted after exclusion of cases diagnosed during early follow-up. The inverse association was more pronounced in ex-smokers than current smokers, and unclear in never-smokers. Analysis of effect modification by intake of antioxidant vitamins C, E, and the carotenoids alpha-carotene, beta-carotene, beta-cryptoxanthin, lycopene, and lutein/zeaxanthin showed a strong, significant interaction with beta-cryptoxanthin, and to a lesser extent with vitamin C. These results confirm the hypothesis that higher selenium intake may reduce prostate cancer risk. Future research on optimum dose level is needed.


Comparison of tendon tensions estimated from two biomechanical models of the thumb.
Despite the paramount function of the thumb in daily life, thumb biomechanical models have been little developed and studied. Moreover, only two studies provided quantitative anthropometric data of tendon moment arms. To investigate thumb tendon tensions, biomechanicians and clinicians have to know the performances and the limits of these two data sets. The aim of this study was thus to compare the results of these two models and evaluate their performances in regard to prior electromyographic measurements (EMG). Thumb posture was recorded during the classical key pinch and pulp pinch grips. Various fingertip forces applied at the distal segment were simulated in a range including extension, adduction, flexion, abduction. Input data of thumb postures and fingertip forces were used to compute tendon tensions with both models. Tendon tensions obtained using these two models were then compared and correlated to EMG measurements provided in the literature. The results showed that both models predicted relevant muscle coordination for five of the nine muscles modelled. Opponent and abductor longus muscle coordinations were badly estimated by both models. Each model was sensible to kinematic errors but not in the same proportion. This study pointed out the advantages/limits of the two models to use them more appropriately for clinical and/or research purposes.


Follow up of patients presenting with fatigue to an infectious diseases clinic.
To determine the symptomatic and functional status during follow up of patients referred to hospital with unexplained fatigue and to identify patient variables associated with persistent functional impairment. Follow up by postal questionnaire six weeks to four years (median 1 year) after initial clinical assessment of patients referred to hospital during 1984-8. Infectious diseases outpatient clinic in a teaching hospital. 200 consecutive patients with fatigue of uncertain cause for at least six weeks; 177 fulfilled the inclusion criteria. Findings at initial assessment; current symptoms, beliefs about the cause of illness, coping behaviours emotional disorder, social variables including membership of self help organizations, and degrees of recovery and functional impairment from questionnaire responses. 144 (81%) patients returned completed questionnaires. Initial assessment did not indicate the cause of fatigue, other than preceding infection. The proportion of patients with functional impairment was significantly smaller with longer follow up (33% (11/33) at two to four years, 73% (29/40) at six weeks to six months; chi 2 for trend = 12.5, df = 1; p less than 0.05). Functional impairment was significantly associated with belief in a viral cause of the illness (odds ratio = 3.9; 95% confidence interval 1.5 to 9.9), limiting exercise (3.2; 1.5 to 6.6), avoiding alcohol (4.5; 1.8 to 11.3), changing or leaving employment (3.1; 1.4 to 6.9), belonging to a self help organization (7.8; 2.5 to 23.9), and current emotional disorder (4.4; 2.0 to 9.3). Short term prognosis for recovery of function was poor but improved with time. Most patients had made a functional recovery by two years after initial clinic attendance. Impaired functioning was more likely with certain patient characteristics. Prospective studies are required to clarify whether these associations are the consequences of a more disabling illness or indicate factors contributing to impaired function.


22-nm immersion interference lithography.
Immersion interference lithography was used to pattern gratings with 22-nm half pitch. This ultrahigh resolution was made possible by using 157-nm light, a sapphire coupling prism with index 2.09, and a 30-nm-thick immersion fluid with index 1.82. The thickness was controlled precisely by spin-casting the fluid rather than through mechanical means. The photoresist was a diluted version of a 193-nm material, which had a 157-nm index of 1.74. An analysis of the trade-off between fluid index, absorption coefficient, gap size and throughput indicated that, among the currently available materials, employing a high-index but absorbing fluid is preferable to using a highly transparent but low-index immersion media.


A recessive C-terminal Jervell and Lange-Nielsen mutation of the KCNQ1 channel impairs subunit assembly.
The LQT1 locus (KCNQ1) has been correlated with the most common form of inherited long QT (LQT) syndrome. LQT patients suffer from syncopal episodes and high risk of sudden death. The KCNQ1 gene encodes KvLQT1 alpha-subunits, which together with auxiliary IsK (KCNE1, minK) subunits form IK(s) K(+) channels. Mutant KvLQT1 subunits may be associated either with an autosomal dominant form of inherited LQT, Romano-Ward syndrome, or an autosomal recessive form, Jervell and Lange-Nielsen syndrome (JLNS). We have identified a small domain between residues 589 and 620 in the KvLQT1 C-terminus, which may function as an assembly domain for KvLQT1 subunits. KvLQT1 C-termini do not assemble and KvLQT1 subunits do not express functional K(+) channels without this domain. We showed that a JLN deletion-insertion mutation at KvLQT1 residue 544 eliminates important parts of the C-terminal assembly domain. Therefore, JLN mutants may be defective in KvLQT1 subunit assembly. The results provide a molecular basis for the clinical observation that heterozygous JLN carriers show slight cardiac dysfunctions and that the severe JLNS phenotype is characterized by the absence of KvLQT1 channel.


Apc1638T: a mouse model delineating critical domains of the adenomatous polyposis coli protein involved in tumorigenesis and development.
The adenomatous polyposis coli (APC) gene is considered as the true gatekeeper of colonic epithelial proliferation: It is mutated in the majority of colorectal tumors, and mutations occur at early stages of tumor development in mouse and man. These mutant proteins lack most of the seven 20-amino-acid repeats and all SAMP motifs that have been associated with down-regulation of intracellular beta-catenin levels. In addition, they lack the carboxy-terminal domains that bind to DLG, EB1, and microtubulin. APC also appears to be essential in development because homozygosity for mouse Apc mutations invariably results in early embryonic lethality. Here, we describe the generation of a mouse model carrying a targeted mutation at codon 1638 of the mouse Apc gene, Apc1638T, resulting in a truncated Apc protein encompassing three of the seven 20 amino acid repeats and one SAMP motif, but missing all of the carboxy-terminal domains thought to be associated with tumorigenesis. Surprisingly, homozygosity for the Apc1638T mutation is compatible with postnatal life. However, homozygous mutant animals are characterized by growth retardation, a reduced postnatal viability on the B6 genetic background, the absence of preputial glands, and the formation of nipple-associated cysts. Most importantly, Apc1638T/1638T animals that survive to adulthood are tumor free. Although the full complement of Apc1638T is sufficient for proper beta-catenin signaling, dosage reductions of the truncated protein result in increasingly severe defects in beta-catenin regulation. The SAMP motif retained in Apc1638T also appears to be important for this function as shown by analysis of the Apc1572T protein in which its targeted deletion results in a further reduction in the ability of properly controlling beta-catenin/Tcf signaling. These results indicate that the association with DLG, EB1, and microtubulin is less critical for the maintenance of homeostasis by APC than has been suggested previously, and that proper beta-catenin regulation by APC appears to be required for normal embryonic development and tumor suppression.


Hormone-induced chromosomal instability in p53-null mammary epithelium.
The absence of p53 function increases risk for spontaneous tumorigenesis in the mammary gland. Hormonal stimulation enhances tumor risk in p53-null mammary epithelial cells as well as the incidence of aneuploidy. Aneuploidy appears in normal p53-null mammary epithelial cells within 5 weeks of hormone stimulation. Experiments reported herein assessed a possible mechanism of hormone-induced aneuploidy. Hormones increased DNA synthesis equally between wild-type (WT) and p53-null mammary epithelial cells. There were two distinct responses in p53-null cells to hormone exposure. First, Western blot analysis demonstrated that the levels of two proteins involved in regulating sister chromatid separation and the spindle checkpoint, Mad2 and separase (ESPL1) were increased in null compared with WT cells. In contrast, the levels of securin and Rad21 proteins were not increased in hormone-stimulated p53-null compared with WT cells. ESPL1 RNA was also increased in p53-null mouse mammary cells in vivo by 18 h of hormone stimulation and in human breast MCF7 cells in monolayer culture by 8 h of hormone stimulation. Furthermore, both promoters contained p53 and steroid hormone response elements. Mad2 protein was increased as a consequence of the absence of p53 function. The increase in Mad2 protein was observed also at the cellular level by immunohistochemistry. Second, hormones increased gene amplication in the distal arm of chromosome 2, as shown by comparative genomic hybridization. These results support the hypothesis that hormone stimulation acts to increase aneuploidy by several mechanisms. First, by increasing mitogenesis in the absence of the p53 checkpoint in G2, hormones allow the accumulation of cells that have experienced chromosome missegregation. Second, the absolute rate of chromosome missegregation may be increased by alterations in the levels of two proteins, separase and Mad2, which are important for maintaining chromosomal segregation and the normal spindle checkpoint during mitosis.


Serodiagnosis of cysticercosis by ELISA-inhibition test using monoclonal antibodies.
Monoclonal antibodies (Mabs) were produced against crude scolex extract of T. solium metacestodes, and applied to ELISA-inhibition test for improving the specificity of serodiagnosis of human cysticercosis. Four hybridomas secreting species-specific anticysticercal Mabs (Cya-1, Cya-7, Cya-28 and Cya-31) were selected. Each Mab reacted on antigenic components of 25.5 kDa (Cya-1), 28 kDa (Cya-7), 87.5 kDa (Cya-28), and 12.5 kDa (Cya-31). IFA showed that Cya-1 was located at the calcium corpuscles, and Cya-7 at the loose connective tissue of T. solium metacestode scolex. Cya-28 and Cya-31 reacted on the tegument of the scolex. By conventional ELISA, 23 out of 28 (82.1%) cysticercosis patients were found serologically positive, but 1 out of 9 (11.1%) sparganosis cases and 6 out of 31 (19.4%) paragonimiasis cases showed false positives. By ELISA-inhibition test using species-specific anti-cysticercal Mab Cya-7, 19 out of 28 (67.9%) cysticercosis cases were found serologically positive, but there were no false positives in other parasitic infections.


Strong links promote the emergence of cooperative elites.
The maintenance of cooperative behavior is fundamental for the prosperity of human societies. Empirical studies show that high cooperation is frequently associated with the presence of strong social ties, but they are silent on whether a causal mechanism exists, how it operates, and what features of the social environment are conducive to its emergence. Here we show experimentally that strong ties increase cooperation and welfare by enabling the emergence of a close-knit and strongly bound cooperative elite. Crucially, this cooperative elite is more prevalent in social environments characterized by a large payoff difference between weak and strong ties, and no gradation in the process of strengthening a tie. These features allow cooperative individuals to adopt an all or nothing strategy to tie strengthening based on the well-known mechanism of direct reciprocity: participants become very selective by forming strong ties only with other cooperative individuals and severing ties with everyone else. Once formed, these strong ties are persistent and enhance cooperation. A dichotomous society emerges with cooperators prospering in a close-knit, strongly bound elite, and defectors earning low payoffs in a weakly connected periphery. Methodologically, our set-up provides a framework to investigate the role of the strength of ties in an experimental setting.


Marine litter plastics and microplastics and their toxic chemicals components: the need for urgent preventive measures.
Persistent plastics, with an estimated lifetime for degradation of hundreds of years in marine conditions, can break up into micro- and nanoplastics over shorter timescales, thus facilitating their uptake by marine biota throughout the food chain. These polymers may contain chemical additives and contaminants, including some known endocrine disruptors that may be harmful at extremely low concentrations for marine biota, thus posing potential risks to marine ecosystems, biodiversity and food availability. Although there is still need to carry out focused scientific research to fill the knowledge gaps about the impacts of plastic litter in the marine environment (Wagner et al. in Environ Sci Eur 26:9, 2014), the food chain and human health, existing scientific evidence and concerns are already sufficient to support actions by the scientific, industry, policy and civil society communities to curb the ongoing flow of plastics and the toxic chemicals they contain into the marine environment. Without immediate strong preventive measures, the environmental impacts and the economic costs are set only to become worse, even in the short term. Continued increases in plastic production and consumption, combined with wasteful uses, inefficient waste collection infrastructures and insufficient waste management facilities, especially in developing countries, mean that even achieving already established objectives for reductions in marine litter remains a huge challenge, and one unlikely to be met without a fundamental rethink of the ways in which we consume plastics. This document was prepared by a working group of Regional Centres of the Stockholm and Basel Conventions and related colleagues intended to be a background document for discussion in the 2017 Conference of the Parties (COP) of the Basel Convention on hazardous wastes and the Stockholm Convention on persistent organic pollutants (POPs). The COP finally approved that the issue of plastic waste could be dealt by its Regional Centres and consistently report their activities on the matter to next COP's meetings.


Human in-vivo brain magnetic resonance current density imaging (MRCDI).
Magnetic resonance current density imaging (MRCDI) and MR electrical impedance tomography (MREIT) are two emerging modalities, which combine weak time-varying currents injected via surface electrodes with magnetic resonance imaging (MRI) to acquire information about the current flow and ohmic conductivity distribution at high spatial resolution. The injected current flow creates a magnetic field in the head, and the component of the induced magnetic field ΔBz,c parallel to the main scanner field causes small shifts in the precession frequency of the magnetization. The measured MRI signal is modulated by these shifts, allowing to determine ΔBz,c for the reconstruction of the current flow and ohmic conductivity. Here, we demonstrate reliable ΔBz,c measurements in-vivo in the human brain based on multi-echo spin echo (MESE) and steady-state free precession free induction decay (SSFP-FID) sequences. In a series of experiments, we optimize their robustness for in-vivo measurements while maintaining a good sensitivity to the current-induced fields. We validate both methods by assessing the linearity of the measured ΔBz,c with respect to the current strength. For the more efficient SSFP-FID measurements, we demonstrate a strong influence of magnetic stray fields on the ΔBz,c images, caused by non-ideal paths of the electrode cables, and validate a correction method. Finally, we perform measurements with two different current injection profiles in five subjects. We demonstrate reliable recordings of ΔBz,c fields as weak as 1 nT, caused by currents of 1 mA strength. Comparison of the ΔBz,c measurements with simulated ΔBz,c images based on FEM calculations and individualized head models reveals significant linear correlations in all subjects, but only for the stray field-corrected data. As final step, we reconstruct current density distributions from the measured and simulated ΔBz,c data. Reconstructions from non-corrected ΔBz,c measurements systematically overestimate the current densities. Comparing the current densities reconstructed from corrected ΔBz,c measurements and from simulated ΔBz,c images reveals an average coefficient of determination R2 of 71%. In addition, it shows that the simulations underestimated the current strength on average by 24%. Our results open up the possibility of using MRI to systematically validate and optimize numerical field simulations that play an important role in several neuroscience applications, such as transcranial brain stimulation, and electro- and magnetoencephalography.


A high performance, cost-effective, open-source microscope for scanning two-photon microscopy that is modular and readily adaptable.
Two-photon laser scanning microscopy has revolutionized the ability to delineate cellular and physiological function in acutely isolated tissue and in vivo. However, there exist barriers for many laboratories to acquire two-photon microscopes. Additionally, if owned, typical systems are difficult to modify to rapidly evolving methodologies. A potential solution to these problems is to enable scientists to build their own high-performance and adaptable system by overcoming a resource insufficiency. Here we present a detailed hardware resource and protocol for building an upright, highly modular and adaptable two-photon laser scanning fluorescence microscope that can be used for in vitro or in vivo applications. The microscope is comprised of high-end componentry on a skeleton of off-the-shelf compatible opto-mechanical parts. The dedicated design enabled imaging depths close to 1 mm into mouse brain tissue and a signal-to-noise ratio that exceeded all commercial two-photon systems tested. In addition to a detailed parts list, instructions for assembly, testing and troubleshooting, our plan includes complete three dimensional computer models that greatly reduce the knowledge base required for the non-expert user. This open-source resource lowers barriers in order to equip more laboratories with high-performance two-photon imaging and to help progress our understanding of the cellular and physiological function of living systems.


Nitrate leaching in important crops of the Valencian Community region (Spain).
In the Valencian Community there are many areas in which the nitrate content of groundwater is higher than the limit of 50 mg l(-1) established by the European Union. A recent survey of drinking water quality showed that around 8% of the Valencian Community population had water supplies with nitrate content above that limit. The Valencian Community has an intensive agricultural base that includes citrus trees, fruit trees, and vegetables. A summary of the available nitrate leaching results in vegetable fields and citrus orchards is presented. It is demonstrated in the main vegetables grown, that N inputs were much higher than the values recommended by some researchers, and that nitrate leaching values were in most cases within the range of 150-300 kg N ha(-1). Artichoke, early potato, and onion were the three crops with higher leaching rates than other crops, based on simulation studies made for several of the main vegetable growing areas of the Valencian Community. The mineral N content in the 0-60 cm layer at planting time in the vegetable fields is, in many cases, greater than 200 kg ha(-1); fertilizer application could be greatly reduced if some recommendation system similar to the N(min) system used in other European countries was adopted. A simplified N balance in onion and early potato crops showed that the lower limit for mineralization in the 0-60 cm soil layer during the crop period varied from 65 to 130 kg N ha(-1). In these two crops nitrate leaching varied from 240 to 340 kg N ha(-1), depending on the N fertilizer treatment, and representing about 66-70% of total N input in the onion crop, and from 38 to 65% in the potato crop. Nitrate leaching losses in citrus orchards were, in general, lower than 100 kg N ha(-1) year(-1), representing about 33% of the total N input. A comparison of these results with those obtained in other studies is made. Finally, prospects for improvements in the fertilizer practice of vegetable crops and citrus orchards in the Valencian Community are discussed.


Pathologic and molecular features correlate with long-term outcome after adjuvant therapy of resected primary GI stromal tumor: the ACOSOG Z9001 trial.
The ACOSOG (American College of Surgeons Oncology Group) Z9001 (Alliance) study, a randomized, placebo-controlled trial, demonstrated that 1 year of adjuvant imatinib prolonged recurrence-free survival (RFS) after resection of primary GI stromal tumor (GIST). We sought to determine the pathologic and molecular factors associated with patient outcome. There were 328 patients assigned to the placebo arm and 317 to the imatinib arm. Median patient follow-up was 74 months. There were 645 tumor specimens available for mitotic rate or mutation analysis. RFS remained superior in the imatinib arm (hazard ratio, 0.6; 95% CI, 0.43 to 0.75; Cox model-adjusted P < .001). On multivariable analysis of patients in the placebo arm, large tumor size, small bowel location, and high mitotic rate were associated with lower RFS, whereas tumor genotype was not significantly associated with RFS. Multivariable analysis of patients in the imatinib arm yielded similar findings. When comparing the two arms, imatinib therapy was associated with higher RFS in patients with a KIT exon 11 deletion of any type, but not a KIT exon 11 insertion or point mutation, KIT exon 9 mutation, PDGFRA mutation, or wild-type tumor, although some of these patient groups were small. Adjuvant imatinib did not seem to alter overall survival. Our findings show that tumor size, location, and mitotic rate, but not tumor genotype, are associated with the natural history of GIST. Patients with KIT exon 11 deletions assigned to 1 year of adjuvant imatinib had a longer RFS.


Making medicines in the early modern household.
This article is a study of household medicine production and consumption through an examination of the papers of Elizabeth Freke (1641-1714) and a wider survey of around nine thousand medical recipes in printed and manuscript collections from seventeenth-century England. It investigates the sorts of medicines that may have been produced in early modern households and the production methods, ingredients, and equipment used. Focusing on three inventories of medicines compiled by Freke between 1710 and 1712 as well as her manuscript recipe collection and medical reading notes, I contend that she kept on hand a number of cure-alls and medicines for general weaknesses, while holding onto recipes for more-specific ailments; the recipes, in these cases, would be the "just-in-case" medicine cabinet. I also argue for a close relationship between commercial and domestic medicine, and present the idea that household practitioners purchased not only ingredients (both processed and unprocessed) and equipment, but also medical knowledge.


The Benefits of Natural Environments for Physical Activity.
Urbanisation has a profound effect on both people and the environment, as levels of physical activity decline and many natural ecosystems become lost or degraded. Here we draw on emerging research to examine the role of green spaces in providing a venue for outdoor physical activity, and in enhancing the benefit of a given amount of physical activity for urban residents. We identify critical knowledge gaps, including (1) whether (and for whom) levels of physical activity increase as new green spaces are introduced or old spaces reinvigorated; (2) which characteristics of nature promote physical activity; (3) the extent to which barriers to outdoor physical activity are environmental or social; and (4) whether the benefits of physical activity and experiences of nature accrue separately or synergistically. A clear understanding of these issues will help guide effective investment in green space provision, ecological enhancement and green exercise promotion.


GPR101 drives growth hormone hypersecretion and gigantism in mice via constitutive activation of Gs and Gq/11.
Growth hormone (GH) is a key modulator of growth and GH over-secretion can lead to gigantism. One form is X-linked acrogigantism (X-LAG), in which infants develop GH-secreting pituitary tumors over-expressing the orphan G-protein coupled receptor, GPR101. The role of GPR101 in GH secretion remains obscure. We studied GPR101 signaling pathways and their effects in HEK293 and rat pituitary GH3 cell lines, human tumors and in transgenic mice with elevated somatotrope Gpr101 expression driven by the rat Ghrhr promoter (GhrhrGpr101). Here, we report that Gpr101 causes elevated GH/prolactin secretion in transgenic GhrhrGpr101 mice but without hyperplasia/tumorigenesis. We show that GPR101 constitutively activates not only Gs, but also Gq/11 and G12/13, which leads to GH secretion but not proliferation. These signatures of GPR101 signaling, notably PKC activation, are also present in human pituitary tumors with high GPR101 expression. These results underline a role for GPR101 in the regulation of somatotrope axis function.


First Report of Tobacco ringspot virus Infecting Kudzu (Pueraria montana) in Louisiana.
Kudzu is an introduced legume commonly found growing as a perennial throughout the southeastern United States. This fast-growing vine was originally planted as an ornamental for forage and to prevent erosion (2), but is now considered an invasive species. During April 2011, a kudzu plant growing near a soybean field in Amite (Tangipahoa Parish, southeastern LA) was observed with foliar ringspot and mottle symptoms. Leaf samples were collected, and sap extracts (diluted 1:5 w/v in 0.02 M phosphate buffer pH 7.2) were mechanically inoculated onto carborundum-dusted leaves of at least five plants of the following species: kudzu, common bean (Phaseolus vulgaris) cv. Black Turtle Soup, globe amaranth (Gomphrena globosa), Nicotiana benthamiana, and soybean (Glycine max) cv. Asgrow AG 4801. Two plants of each species were also mock-inoculated. Eight to fourteen days after inoculation, all virus-inoculated plants showed virus symptoms that included foliar ringspots, mosaic, and mottle. Common bean and soybean also displayed necroses and were stunted. ELISA using antisera for Bean pod mottle virus, Cucumber mosaic virus, Soybean mosaic virus, and Tobacco ringspot virus (TRSV) (Agdia Inc., Elkhart, IN) were performed on field-collected kudzu and all inoculated plants species. ELISA tests resulted positive for TRSV but were negative for the other three viruses. All virus-inoculated plant species tested positive by ELISA. To confirm that TRSV was present in the samples, total RNA was extracted from infected and healthy plants and used in RT-PCR tests. The set of primers TRS-F (5'TATCCCTATGTGCTTGAGAG3') and TRS-R (5'CATAGACCACCAGAGTCACA3'), which amplifies a 766-bp fragment of the RdRp of TRSV, were used (3). Expected amplicons were obtained with all of the TRSV-infected plants and were cloned and sequenced. Sequence analysis confirmed that TRSV was present in kudzu. Nucleotide sequence comparisons using BLAST resulted in a 95% similarity with the bud blight strain of TRSV which infects soybeans (GenBank Accession No. U50869) (1). TRSV has been reported to infect many wild plants and crops, including soybean. In soybean, this virus can reduce yield and seed quality (4). During summer 2012, three additional kudzu plants located near soybean fields showing ringspot symptoms were also found in Morehouse, Saint Landry, and West Feliciana Parishes. These three parishes correspond to the north, central, and southeast regions, respectively. These plants also tested positive for TRSV by ELISA and RT-PCR. The results of this investigation documents that TRSV was found naturally infecting kudzu near soybean fields in different geographical locations within Louisiana. Furthermore, a TRSV strain closely related to the bud blight strain that infects soybean was identified in one location (Amite). This finding is significant because infected kudzu potentially could serve as the source of TRSV for soybean and other economically important crops. To the best of our knowledge, this is the first report of TRSV infecting kudzu. References: (1) G. L. Hartman et al. 1999. Compendium of Soybean Diseases. American Phytopathological Society, St. Paul, MN. (2) J. H. Miller and B. Edwards. S. J. Appl. Forestry 7:165, 1983. (3) S. Sabanadzovic et al. Plant Dis. 94:126, 2010. (4) P. A. Zalloua et al. Virology 219:1, 1996.


The use of electronic biofeedback for the management of post-herpetic neuralgia--a report of 3 cases.
The purpose of these case reports is to describe treatment of three consecutive patients with post-herpetic neuralgia using a bioelectronical device (SCENAR). The instrument is approved as a Class II device in the United States. The electrode of the device was stroked gently over the involved skin area for up to 15 minutes per session. No more than 5 sessions over a 3-week period was required. All patients experienced substantial relief of pain from the first treatment. One patient required only 1 treatment lasting 10 minutes. The other 2 patients required 4 to 5 treatments over a 3-week period. One patient required a treatment for skin itch after one year with a follow up period of 6 months to 24 months. An electronic biofeedback device (SCENAR) may be successfully utilized in the management of post-herpetic neuralgia.


A telescope GWAS analysis strategy, based on SNPs-genes-pathways ensamble and on multivariate algorithms, to characterize late onset Alzheimer's disease.
Genome-wide association studies (GWAS) have revealed a plethora of putative susceptibility genes for Alzheimer's disease (AD), with the sole exception of APOE gene unequivocally validated in independent study. Considering that the etiology of complex diseases like AD could depend on functional multiple genes interaction network, here we proposed an alternative GWAS analysis strategy based on (i) multivariate methods and on a (ii) telescope approach, in order to guarantee the identification of correlated variables, and reveal their connections at three biological connected levels. Specifically as multivariate methods, we employed two machine learning algorithms and a genetic association test and we considered SNPs, Genes and Pathways features in the analysis of two public GWAS dataset (ADNI-1 and ADNI-2). For each dataset and for each feature we addressed two binary classifications tasks: cases vs. controls and the low vs. high risk of developing AD considering the allelic status of APOEe4. This complex strategy allowed the identification of SNPs, genes and pathways lists statistically robust and meaningful from the biological viewpoint. Among the results, we confirm the involvement of TOMM40 gene in AD and we propose GRM7 as a novel gene significantly associated with AD.


Cerebrospinal fluid p-tau217 performs better than p-tau181 as a biomarker of Alzheimer's disease.
Cerebrospinal fluid (CSF) p-tau181 (tau phosphorylated at threonine 181) is an established biomarker of Alzheimer's disease (AD), reflecting abnormal tau metabolism in the brain. Here we investigate the performance of CSF p-tau217 as a biomarker of AD in comparison to p-tau181. In the Swedish BioFINDER cohort (n = 194), p-tau217 shows stronger correlations with the tau positron emission tomography (PET) tracer [18F]flortaucipir, and more accurately identifies individuals with abnormally increased [18F]flortaucipir retention. Furthermore, longitudinal increases in p-tau217 are higher compared to p-tau181 and better correlate with [18F]flortaucipir uptake. P-tau217 correlates better than p-tau181 with CSF and PET measures of neocortical amyloid-β burden and more accurately distinguishes AD dementia from non-AD neurodegenerative disorders. Higher correlations between p-tau217 and [18F]flortaucipir are corroborated in an independent EXPEDITION3 trial cohort (n = 32). The main results are validated using a different p-tau217 immunoassay. These findings suggest that p-tau217 might be more useful than p-tau181 in the diagnostic work up of AD.


Phase I/II study of AT-101 with topotecan in relapsed and refractory small cell lung cancer.
AT-101 is an oral, pan Bcl-2 family protein inhibitor that has demonstrated activity in small cell lung cancer (SCLC) models. A phase I/II study was conducted combining AT-101 with topotecan in relapsed and refractory SCLC. An open-labeled multicenter phase I/II study was conducted of oral AT-101 with intravenous topotecan in patients with SCLC who had progressed on prior platinum-containing chemotherapy. The phase II portion was a two-stage design, and two cohorts of patients, sensitive relapsed and refractory, were analyzed. Primary endpoint in the two-stage phase II portion was response rate; secondary endpoints were duration of response and time to progression. Thirty-six patients were enrolled. The most common toxicities were hematologic, as would be expected with topotecan and AT-101. The recommended phase II dose was 40 mg AT-101 days 1 to 5 with topotecan 1.25 mg/m(2) days 1 to 5 on a 21-day cycle. In the sensitive-relapsed cohort (n = 18), there were 0 complete response (CR), three partial response (PR), 10 stable disease (SD), and four progressive disease (PD). In the refractory cohort (n = 12), there were 0 CR/PR, five SD, and five PD. The study did not meet its prespecified endpoints to continue enrollment in the second stage of the phase II study. Median time to progression in the sensitive-relapsed cohort was 17.4 weeks and 11.7 weeks in the refractory cohort. AT-101 can be safely combined with topotecan at a reduced dose of 1.25 mg/m(2). The response rates observed did not meet the criteria for additional enrollment; however, many patients had a best response of SD and the median time to progression in both cohorts was favorable. Additional trials of AT-101 in SCLC are ongoing.


Literacy education as treatment for depression in patients with limited literacy and depression: a randomized controlled trial.
Individuals with limited literacy and those with depression share many characteristics, including low self-esteem, feelings of worthlessness, and shame. To determine whether literacy education, provided along with standard depression treatment to adults with depression and limited literacy, would result in greater improvement in depression than would standard depression treatment alone. Randomized clinical trial with patients assigned either to an intervention group that received standard depression treatment plus literacy education, or a control group that received only standard depression treatment. Seventy adult patients of a community health center who tested positive for depression using the 9-question Patient Health Questionnaire (PHQ-9) and had limited literacy based on the Rapid Estimate of Adult Literacy in Medicine (REALM). Depression severity was assessed with PHQ-9 scores at baseline and at 3 follow-up evaluations that took place up to 1 year after study enrollment. Changes in PHQ-9 scores between baseline and follow-up evaluations were compared between the intervention and control groups. The median PHQ-9 scores were similar in both the intervention and control groups at baseline (12.5 and 14, respectively). Nine-question Patient Health Questionnaire scores improved in both groups, but the improvement was significantly larger in the intervention group. The final follow-up PHQ-9 scores declined to 6 in the intervention group but only to 10 in the control group. There may be benefit to assessing the literacy skills of patients who are depressed, and recommending that patients with both depression and limited literacy consider enrolling in adult education classes as an adjuvant treatment for depression.


Neural population-level memory traces in the mouse hippocampus.
One of the fundamental goals in neurosciences is to elucidate the formation and retrieval of brain's associative memory traces in real-time. Here, we describe real-time neural ensemble transient dynamics in the mouse hippocampal CA1 region and demonstrate their relationships with behavioral performances during both learning and recall. We employed the classic trace fear conditioning paradigm involving a neutral tone followed by a mild foot-shock 20 seconds later. Our large-scale recording and decoding methods revealed that conditioned tone responses and tone-shock association patterns were not present in CA1 during the first pairing, but emerged quickly after multiple pairings. These encoding patterns showed increased immediate-replay, correlating tightly with increased immediate-freezing during learning. Moreover, during contextual recall, these patterns reappeared in tandem six-to-fourteen times per minute, again correlating tightly with behavioral recall. Upon traced tone recall, while various fear memories were retrieved, the shock traces exhibited a unique recall-peak around the 20-second trace interval, further signifying the memory of time for the expected shock. Therefore, our study has revealed various real-time associative memory traces during learning and recall in CA1, and demonstrates that real-time memory traces can be decoded on a moment-to-moment basis over any single trial.


Action after Adverse Events in Healthcare: An Integrative Literature Review.
Adverse events are common in healthcare. Three types of victims of patient-related adverse events can be identified. The first type includes patients and their families, the second type includes healthcare professionals involved in an adverse event and the third type includes healthcare organisations in which an adverse event occurs. The purpose of this integrative review is to synthesise knowledge, theory and evidence regarding action after adverse events, based on literature published in the last ten years (2009-2018). In the studies critically evaluated (n = 25), key themes emerged relating to the first, second and third victim elements. The first victim elements comprise attention to revealing an adverse event, communication after an event, first victim support and complete apology. The second victim elements include second victim support types and services, coping strategies, professional changes after adverse events and learning about adverse event phenomena. The third victim elements consist of organisational action after adverse events, strategy, infrastructure and training and open communication about adverse events. There is a lack of comprehensive models for action after adverse events. This requires understanding of the phenomenon along with ambition to manage adverse events as a whole. When an adverse event is identified and a concern expressed, systematic damage preventing and ameliorating actions should be immediately launched. System-wide development is needed.


Mutational analysis of Saccharomyces cerevisiae U4 small nuclear RNA identifies functionally important domains.
U4 small nuclear RNA (snRNA) is essential for pre-mRNA splicing, although its role is not yet clear. On the basis of a model structure (C. Guthrie and B. Patterson, Annu. Rev. Genet. 22:387-419, 1988), the molecule can be thought of as having six domains: stem II, 5' stem-loop, stem I, central region, 3' stem-loop, and 3'-terminal region. We have carried out extensive mutagenesis of the yeast U4 snRNA gene (SNR14) and have obtained information on the effect of mutations at 105 of its 160 nucleotides. Fifteen critical residues in the U4 snRNA have been identified in four domains: stem II, the 5' stem-loop, stem I, and the 3'-terminal region. These domains have been shown previously to be insensitive to oligonucleotide-directed RNase H cleavage (Y. Xu, S. Petersen-Bjørn, and J. D. Friesen, Mol. Cell. Biol. 10:1217-1225, 1990), suggesting that they are involved in intra- or intermolecular interactions. Stem II, a region that base pairs with U6 snRNA, is the most sensitive to mutation of all U4 snRNA domains. In contrast, stem I is surprisingly insensitive to mutational change, which brings into question its role in base pairing with U6 snRNA. All mutations in the putative Sm site of U4 snRNA yield a lethal or conditional-lethal phenotype, indicating that this region is important functionally. Only two nucleotides in the 5' stem-loop are sensitive to mutation; most of this domain can tolerate point mutations or small deletions. The 3' stem-loop, while essential, is very tolerant of change. A large portion of the central domain can be removed or expanded with only minor effects on phenotype, suggesting that it has little function of its own. Analysis of conditional mutations in stem II and stem I indicates that although these single-base changes do not have a dramatic effect on U4 snRNA stability, they are defective in RNA splicing in vivo and in vitro, as well as in spliceosome assembly. These results are discussed in the context of current knowledge of the interactions involving U4 snRNA.


Predictions and maps of county mean indoor radon concentrations in the mid-Atlantic states.
Measured surface radium content, geologic province information, information on the fraction of homes with basements and with living-area basements, and measurements from the EPA/State Residential Radon Surveys, were used in a Bayesian mixed effects regression to predict the distributions of short-term winter and annual living-area average radon concentrations by county in the mid-Atlantic states. The information provided by those explanatory variables is roughly equivalent to collecting an extra 12 observations per county, effectively doubling the amount of information in a typical county. Predicted county geometric means are subject to standard errors of 15% to 30% for typical counties, with the uncertainty in a given county depending on the number of radon measurements in the county and the amount of information about the geologic province that contains the county. After controlling for soil radium concentration and the effect of measuring in a basement vs. the first floor, typical geologic provinces are found to be associated with elevation or depression of indoor radon concentrations by 30% on average, with some provinces having effects of considerably larger magnitude.


Tuberculosis Biomarkers: From Diagnosis to Protection.
New approaches to control tuberculosis (TB) worldwide are needed. In particular, new tools for diagnosis and new biomarkers are required to evaluate both pathogen and host key elements of the response to infection. Non-sputum based diagnostic tests, biomarkers predictive of adequate responsiveness to treatment, and biomarkers of risk of developing active TB disease are major goals. Here, we review the current state of the field. Although reports on new candidate biomarkers are numerous, validation and independent confirmation are rare. Efforts are needed to reduce the gap between the exploratory up-stream identification of candidate biomarkers, and the validation of biomarkers against clear clinical endpoints in different populations. This will need a major commitment from both scientists and funding bodies.


Effect of endothelin-1 on the transmesothelial resistance of isolated visceral sheep peritoneum.
The mesothelium is part of the peritoneal barrier that manages the water and ion transport essential for peritoneal dialysis (PD) treatment. In addition, it has a central role in the pathogenesis of peritoneal fibrosis and the resulting ultrafiltration failure observed in many PD patients. Endothelin-1 (ET-1) is a potent vasoactive peptide originally described as an endothelial cell-derived factor In addition, ET-1 has been shown to stimulate fibrogenic activity in various organs by regulating the production and turnover of matrix components. The aim of the present study was to investigate, by means of Ussing chamber experiments, the effect of ET-1 on the transmesothelial electrical resistance (RTM) of isolated visceral sheep peritoneum. Intact sheets of visceral sheep peritoneum were obtained from 12 adult sheep. The samples were collected from the slaughterhouse immediately after the deaths of the animals and, within 30 minutes, were transferred in oxygenated Krebs-Ringer bicarbonate (KRB) solution at 4 degrees C to the laboratory to be mounted in an Ussing-type chamber. Endothelin-1 (10(-7) mol/L) was then added to the KRB solution apically or basolaterally, and the RTM was measured before and serially for 10 minutes after the addition of the ET-1. The control RTM (before addition of ET-1) was 22.8 +/- 0.56 Omega x cm2. Addition of ET-1 apically significantly increased the RTM by 63.82% +/- 16.93% (p < 0.05) within 1 minute. After addition of ET-1 basolaterally, the RTM also increased significantly by 90.91% +/- 57.31% within 1 minute (p < 0.05). In both cases, these values persisted throughout the experiment. These results clearly indicate an inhibitory effect of ET-1 on the ionic permeability of visceral sheep peritoneum. The rapid increase in RTM observed after the addition of ET-1 suggests the existence of endothelin receptors (ET-A or ET-B, or both) on visceral sheep peritoneum. Previous studies demonstrated that ET-1, acting on ET-B receptors, potently inhibits epithelial sodium channels in mammalian cell cultures. Nevertheless, the exact pathways that underlie these findings remain unclear; their elucidation requires further investigation.


Blinded randomised controlled trial of low-dose Adjuvant Steroids in Adults admitted to hospital with Pandemic influenza (ASAP): a trial 'in hibernation', ready for rapid activation.
There are no completed randomised trials of the use of corticosteroids in patients with severe influenza infection. Corticosteroid use in influenza is widespread, non-systematic and marked by controversy. A recent meta-analysis of observational studies of adjuvant corticosteroids in influenza found an association with increased mortality but there were important concerns regarding the risks of bias. To (1) evaluate whether or not low-dose corticosteroids given as an adjunct to standard treatment is beneficial in patients who are hospitalised with severe pandemic influenza and (2) develop an 'off-the-shelf' clinical trial that is ready to be activated in a future pandemic. Multicentre, pragmatic, blinded, randomised placebo-controlled trial. Thirty to 40 hospitals in the UK. Adults (≥ 16 years) admitted to hospital with an influenza-like illness during a pandemic. Five-day course of dexamethasone (Dexsol®, Rosemont Pharmaceuticals Ltd) 6 mg daily, started within 24 hours of admission. Admission to Intensive Care Unit, or death, within 30 days of admission to hospital. This trial has not yet been activated. It is currently set up with full ethics and regulatory approvals in place, ready for rapid activation at the onset of the next pandemic. Hurdles to setting up a pandemic trial include planning for pandemic-level pressures on UK NHS resources and co-enrolment of patients to multiple pandemic studies, ensuring adequate geographical distribution of participating sites, maintaining long-term low-level engagement with site investigators, addressing future trial-specific training needs of local investigators and resilience planning in trial management. Identified threats to trial delivery include changes to research capabilities or policies during the hibernation phase, lack of staff resources during a pandemic and the influence of media at the time of a pandemic. A mismatch in the approach to informed consent required by current regulations to that preferred by patients and the public was identified. This study demonstrates that advance set-up of a trial to be conducted during a pandemic, with full regulatory approvals in place, is possible. Regular review during the hibernation phase will be required. This study serves as a model for the development of other 'off-the-shelf' trials as part of preparedness planning for public health emergencies. Current Controlled Trials ISRCTN72331452. European Union Drug Regulating Authorities Clinical Trials number: 2013-001051-12. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 16. See the NIHR Journals Library website for further project information.


Expression and clinicopathological significance of notch signaling and cell-fate genes in biliary tract cancer.
Biliary tract cancer (BTC) is a fatal cancer originating from epithelial cells of the intra- and extra-hepatic biliary duct system and the gallbladder. Genes and pathways regulating stem and progenitor cells as well as cell-fate decisions are increasingly recognized in tumorigenesis. We evaluated the expression of Notch1, Notch2, and HES1 (hairy and enhancer of split 1), as well as the biliary cell-fate regulators SOX9 (SRY (sex determining region Y)-box 9) and HNF1β (hepatocyte nuclear factor 1β), in BTC for correlation with clinicopathological parameters. Tissue microarrays including normal bile ducts and 111 BTCs consisting of 17 intrahepatic cholangiocarcinomas, 58 extrahepatic cholangiocarcinomas, and 36 gallbladder carcinomas were analyzed using immunohistochemistry. Lack of cytoplasmic SOX9 expression was associated with a higher tumor grade (P=0.010) and a significantly reduced overall survival (P=0.002; median 6 months vs. 24 months) in univariate survival analysis, whereas lack of nuclear SOX9 expression was associated with a higher tumor stage (P=0.003). Notch pathway members showed high expression in BTC. However, no correlation was found between cytoplasmic or nuclear Notch1, Notch2, and HES1, as well as HNF1β expression, and any of the clinicopathological parameters. In multivariate analysis, cytoplasmic SOX9 expression was an independent prognostic factor for overall survival (P=0.031, relative risk=0.571). We show strong Notch pathway activation and identify SOX9 as a prognostic marker in BTC. These results substantiate diagnostic and therapeutic approaches targeting developmentally active genes and pathways.


Assessment of human gene diversity and expression patterns using expressed sequence tags.
ESTs provide a cheap and effective short-cut for identifying the majority of an organism's genes. Surveys of ESTs can provide a global view of the gene-expression patterns that distinguish different tissues or cell types. The large collection of human ESTs will soon permit the majority of genes to be placed on a chromosomal map.


A Mesothelial Inclusion Cyst Presenting in a 40-Year-Old Woman as Abdominal Pain and Bloating - A Rare Diagnosis.
Cystic mesotheliomas (also called mesothelial inclusion cysts) are rare benign neoplasms that occur more often in young women. Symptoms are usually non-specific, demanding a thorough work-up. We report a case of a 40-year-old female patient with 2 prior caesarean sections presenting with a 3-month history of abdominal pain. Laboratory tests revealed microcytic hypochromic anaemia and an elevated tumour marker CA-125. An investigation identified a large cystic abdominal mass, mostly in the left side of the abdomen. A laparotomy was performed with total resection of the lesion. Histological assessment resulted in a diagnosis of a mesothelial inclusion cyst. The patient had no recurrence after 3 years. Peritoneal mesotheliomas are rare conditions, and with benign features are even rarer.Mesothelial inclusion cysts, also known as benign cystic mesothelioma, occur more often in young to middle-aged women with excellent prognosis, although there are high rates of local recurrence.Investigation unmasks large abdominal lesions. A timely diagnosis is of the utmost importance, to prevent a dramatic change in outcome if severe complications develop.


Factors driving the abundance of ixodes ricinus ticks and the prevalence of zoonotic I. ricinus-borne pathogens in natural foci.
Environmental factors may drive tick ecology and therefore tick-borne pathogen (TBP) epidemiology, which determines the risk to animals and humans of becoming infected by TBPs. For this reason, the aim of this study was to analyze the influence of environmental factors on the abundance of immature-stage Ixodes ricinus ticks and on the prevalence of two zoonotic I. ricinus-borne pathogens in natural foci of endemicity. I. ricinus abundance was measured at nine sites in the northern Iberian Peninsula by dragging the vegetation with a cotton flannelette, and ungulate abundance was measured by means of dung counts. In addition to ungulate abundance, data on variables related to spatial location, climate, and soil were gathered from the study sites. I. ricinus adults, nymphs, and larvae were collected from the vegetation, and a representative subsample of I. ricinus nymphs from each study site was analyzed by PCR for the detection of Borrelia burgdorferi sensu lato and Anaplasma phagocytophilum DNA. Mean prevalences of these pathogens were 4.0% ± 1.8% and 20.5% ± 3.7%, respectively. Statistical analyses confirmed the influence of spatial factors, climate, and ungulate abundance on I. ricinus larva abundance, while nymph abundance was related only to climate. Interestingly, cattle abundance rather than deer abundance was the main driver of B. burgdorferi sensu lato and A. phagocytophilum prevalence in I. ricinus nymphs in the study sites, where both domestic and wild ungulates coexist. The increasing abundance of cattle seems to increase the risk of other hosts becoming infected by A. phagocytophilum, while reducing the risk of being infected by B. burgdorferi sensu lato. Controlling ticks in cattle in areas where they coexist with wild ungulates would be more effective for TBP control than reducing ungulate abundance.


Tertiary and quaternary structures of photoreactive Fe-type nitrile hydratase from Rhodococcus sp. N-771: roles of hydration water molecules in stabilizing the structures and the structural origin of the substrate specificity of the enzyme.
The crystal structure analysis of the Fe-type nitrile hydratase from Rhodococcus sp. N-771 revealed the unique structure of the enzyme composed of the alpha- and beta-subunits and the unprecedented structure of the non-heme iron active center [Nagashima, S., et al. (1998) Nat. Struct. Biol. 5, 347-351]. A number of hydration water molecules were identified both in the interior and at the exterior of the enzyme. The study presented here investigated the roles of the hydration water molecules in stabilizing the tertiary and the quaternary structures of the enzyme, based on the crystal structure and the results from a laser light scattering experiment for the enzyme in solution. Seventy-six hydration water molecules between the two subunits significantly contribute to the alphabeta heterodimer formation by making up the surface shape, forming extensive networks of hydrogen bonds, and moderating the surface charge of the beta-subunit. In particular, 20 hydration water molecules form the extensive networks of hydrogen bonds stabilizing the unique structure of the active center. The amino acid residues hydrogen-bonded to those hydration water molecules are highly conserved among all known nitrile hydratases and even in the homologous enzyme, thiocyanate hydrolase, suggesting the structural conservation of the water molecules in the NHase family. The crystallographic asymmetric unit contained two heterodimers connected by 50 hydration water molecules. The heterotetramer formation in crystallization was clearly explained by the concentration-dependent aggregation state of NHase found in the light scattering measurement. The measurement proved that the dimer-tetramer equilibrium shifted toward the heterotetramer dominant state in the concentration range of 10(-2)-1.0 mg/mL. In the tetramer dominant state, 50 water molecules likely glue the two heterodimers together as observed in the crystal structure. Because NHase exhibits a high abundance in bacterial cells, the result suggests that the heterotetramer is physiologically relevant. In addition, it was revealed that the substrate specificity of this enzyme, recognizing small aliphatic substrates rather than aromatic ones, came from the narrowness of the entrance channel from the bulk solvent to the active center. This finding may give a clue for changing the substrate specificity of the enzyme. Under the crystallization condition described here, one 1,4-dioxane molecule plugged the channel. Through spectroscopic and crystallographic experiments, we found that the molecule prevented the dissociation of the endogenous NO molecule from the active center even when the crystal was exposed to light.


Modeling and simulation of biological systems from image data.
This essay provides an introduction to the terminology, concepts, methods, and challenges of image-based modeling in biology. Image-based modeling and simulation aims at using systematic, quantitative image data to build predictive models of biological systems that can be simulated with a computer. This allows one to disentangle molecular mechanisms from effects of shape and geometry. Questions like "what is the functional role of shape" or "how are biological shapes generated and regulated" can be addressed in the framework of image-based systems biology. The combination of image quantification, model building, and computer simulation is illustrated here using the example of diffusion in the endoplasmic reticulum.


Goosecoid and the organizer.
The molecular nature of Spemann's organizer phenomenon has long attracted the attention of embryologists. goosecoid is a homeobox gene with a DNA-binding specificity similar to that of Drosophila bicoid. Xenopus goosecoid is expressed on the dorsal side of the embryo before the dorsal lip is formed. Cells expressing goosecoid are fated to become pharyngeal endoderm, head mesoderm and notochord. Transplantation of goosecoid mRNA to the ventral side of Xenopus embryos by microinjection mimics the properties of Spemann's organizer, leading to the formation of twinned body axes, goosecoid is activated by dorsal inducers and not affected by ventral inducers. In the mouse, goosecoid is expressed in the anterior tip of the primitive streak. The availability of two early markers, goosecoid and Brachyury, opens the way for the comparative analysis of the vertebrate gastrula. The results suggest that the goosecoid homeodomain protein is an integral component of the biochemical pathway leading to Spemman's organizer phenomenon.


Psychological distress among older adolescents and young adults in Australia.
Youth mental health has been specially targeted in the National Health Goals and Targets process for mental health. The incidence of suicide among Australia's youth is one of the highest in the world. Yet there is little information on the mental health of young people in Australia. The most recent national data come from the longitudinal Australian Youth Survey conducted by the Department of Education, Employment and Training. IN the 1994 wave of the survey, 8350 adolescents and young adults aged between 16 and 24 were surveyed. Psychological distress was measured by the 12-item General Health Questionnaire (GHQ). High levels of psychological distress were evident, with girls being more distressed than boys at all ages. Forty-one per cent of girls were classified by the GHQ as mild or moderate cases, compared with 26 per cent of boys. Levels of distress peaked at age 17 for both boys and girls and tended to decrease with age for girls, but to be relatively stable over time for boys.


Blood lipid and lipoprotein concentrations and colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition.
To examine the association between serum concentrations of total cholesterol, high density lipoprotein cholesterol (HDL), low density lipoprotein cholesterol, triglycerides, apolipoprotein A-I (apoA), apolipoprotein B and the incidence of colorectal cancer (CRC). Nested case-control study. The study was conducted within the European Prospective Investigation into Cancer and Nutrition (EPIC), a cohort of more than 520,000 participants from 10 western European countries. 1238 cases of incident CRC, which developed after enrolment into the cohort, were matched with 1238 controls for age, sex, centre, follow-up time, time of blood collection and fasting status. Serum concentrations were quantitatively determined by colorimetric and turbidimetric methods. Dietary and lifestyle data were obtained from questionnaires. Conditional logistic regression models were used to estimate incidence rate ratios (RRs) and 95% CIs which were adjusted for height, weight, smoking habits, physical activity, education, consumption of fruit, vegetables, meat, fish, alcohol, fibre and energy. After adjustments, the concentrations of HDL and apoA were inversely associated with the risk of colon cancer (RR for 1 SD increase of 16.6 mg/dl in HDL and 32.0 mg/dl in apoA of 0.78 (95% CI 0.68 to 0.89) and 0.82 (95% CI 0.72 to 0.94), respectively). No association was observed with the risk of rectal cancer. Additional adjustment for biomarkers of systemic inflammation, insulin resistance and oxidative stress or exclusion of the first 2 years of follow-up did not influence the association between HDL and risk of colon cancer. These findings show that high concentrations of serum HDL are associated with a decreased risk of colon cancer. The mechanism behind this association needs further elucidation.


Ranking of Business Process Simulation Software Tools with DEX/QQ Hierarchical Decision Model.
The omnipresent need for optimisation requires constant improvements of companies' business processes (BPs). Minimising the risk of inappropriate BP being implemented is usually performed by simulating the newly developed BP under various initial conditions and "what-if" scenarios. An effectual business process simulations software (BPSS) is a prerequisite for accurate analysis of an BP. Characterisation of an BPSS tool is a challenging task due to the complex selection criteria that includes quality of visual aspects, simulation capabilities, statistical facilities, quality reporting etc. Under such circumstances, making an optimal decision is challenging. Therefore, various decision support models are employed aiding the BPSS tool selection. The currently established decision support models are either proprietary or comprise only a limited subset of criteria, which affects their accuracy. Addressing this issue, this paper proposes a new hierarchical decision support model for ranking of BPSS based on their technical characteristics by employing DEX and qualitative to quantitative (QQ) methodology. Consequently, the decision expert feeds the required information in a systematic and user friendly manner. There are three significant contributions of the proposed approach. Firstly, the proposed hierarchical model is easily extendible for adding new criteria in the hierarchical structure. Secondly, a fully operational decision support system (DSS) tool that implements the proposed hierarchical model is presented. Finally, the effectiveness of the proposed hierarchical model is assessed by comparing the resulting rankings of BPSS with respect to currently available results.


Research use in the care of older people: a survey among healthcare staff.
Background. Sweden has one of the largest proportions of older people in the world. To manage the healthcare needs of an aging population, there has been an alteration from hospital care to community-based care. In these settings, the majority of staff is enrolled nurses (EN) and nurse aides (NA) without university education. Aim and design. The overall aim of this cross-sectional survey was to explore staff perceptions of factors related to research utilization in the care of older people. Method. Questionnaires covering research utilization and demographics were sent to all staff (n = 132) working in seven units in older people care. The response rate was 67% (n = 89). The respondents consisted of ENs/NAs (n = 63), Registered Nurses (RN) and rehabilitation professionals (RP) as physiotherapists and occupational therapists (RN/RP n = 26). Results. Most of staff reported positive attitudes towards research. The RNs/RPs stated more often than the ENs/NAs that they wanted to base their practice on research (81% vs. 25%; P = 0.001). The RNs/RPs also reported a greater extent of research use in daily practice (54% vs. 17%; P = 0.001). Support from colleagues (77% vs. 22%; P < 0.001) and unit managers (73% vs. 10%; P < 0.001) for implementing research findings was also more frequently reported by the RNs/RPs compared with the ENs/NAs. The majority of the ENs/NAs stated Do not know on many items concerning attitudes towards research, support for research utilization and actual use of research. Conclusions. Despite overall positive attitudes towards research, the majority of staff did not use research findings in daily practice. This was particularly valid for the EN/NA group. Relevance to clinical practice. There is an urgent need for managers and others in the care of older people to develop strategies for implementing evidence-based practice that involves the EN/NA group.


Leptin's effect on puberty in mice is relayed by the ventral premammillary nucleus and does not require signaling in Kiss1 neurons.
Studies in humans and rodents indicate that a minimum amount of stored energy is required for normal pubertal development. The adipocyte-derived hormone leptin is a key metabolic signal to the neuroendocrine reproductive axis. Humans and mice lacking leptin or the leptin receptor (LepR) (ob/ob and db/db mice, respectively) are infertile and fail to enter puberty. Leptin administration to leptin-deficient subjects and ob/ob mice induces puberty and restores fertility, but the exact site or sites of leptin action are unclear. Here, we found that genetic deletion of LepR selectively from hypothalamic Kiss1 neurons in mice had no effect on puberty or fertility, indicating that direct leptin signaling in Kiss1 neurons is not required for these processes. However, bilateral lesions of the ventral premammillary nucleus (PMV) of ob/ob mice blunted the ability of exogenous leptin to induce sexual maturation. Moreover, unilateral reexpression of endogenous LepR in PMV neurons was sufficient to induce puberty and improve fertility in female LepR-null mice. This LepR reexpression also normalized the increased hypothalamic GnRH content characteristic of leptin-signaling deficiency. These data suggest that the PMV is a key site for leptin's permissive action at the onset of puberty and support the hypothesis that the multiple actions of leptin to control metabolism and reproduction are anatomically dissociated.


The development and validation of a multivariable model to predict whether patients referred for total knee replacement are suitable surgical candidates at the time of initial consultation.
In previous studies, 50%-70% of patients referred to orthopedic surgeons for total knee replacement (TKR) were not surgical candidates at the time of initial assessment. The purpose of our study was to identify and cross-validate patient self-reported predictors of suitability for TKR and to determine the clinical utility of a predictive model to guide the timing and appropriateness of referral to a surgeon. We assessed pre-consultation patient data as well as the surgeon's findings and post-consultation recommendations. We used multivariate logistic regression to detect self-reported items that could identify suitable surgical candidates. Patients' willingness to undergo surgery, higher rating of pain, greater physical function, previous intra-articular injections and patient age were the factors predictive of patients being offered and electing to undergo TKR. The application of the model developed in our study would effectively reduce the proportion of nonsurgical referrals by 25%, while identifying the vast majority of surgical candidates (> 90%). Using patient-reported information, we can correctly predict the outcome of specialist consultation for TKR in 70% of cases. To reduce long waits for first consultation with a surgeon, it may be possible to use these items to educate and guide referring clinicians and patients to understand when specialist consultation is the next step in managing the patient with severe osteoarthritis of the knee.


Insulin-like growth factor-1 suppresses the Myostatin signaling pathway during myogenic differentiation.
Myogenic differentiation is a complex and well-coordinated process for generating mature skeletal muscle fibers. This event is autocrine/paracrine regulated by growth factors, principally Myostatin (MSTN) and Insulin-like Growth Factor-1 (IGF-1). Myostatin, a member of the transforming growth factor-β superfamily, is a negative regulator of skeletal muscle growth in vertebrates that exerts its inhibitory function by activating Smad transcription factors. In contrast, IGF-1 promotes the differentiation of skeletal myoblasts by activating the PI3K/Akt signaling pathway. This study reports on a novel functional crosstalk between the IGF-1 and MSTN signaling pathways, as mediated through interaction between PI3K/Akt and Smad3. Stimulation of skeletal myoblasts with MSTN resulted in a transient increase in the pSmad3:Smad3 ratio and Smad-dependent transcription. Moreover, MSTN inhibited myod gene expression and myoblast fusion in an Activin receptor-like kinase/Smad3-dependent manner. Preincubation of skeletal myoblasts with IGF-1 blocked MSTN-induced Smad3 activation, promoting myod expression and myoblast differentiation. This inhibitory effect of IGF-1 on the MSTN signaling pathway was dependent on IGF-1 receptor, PI3K, and Akt activities. Finally, immunoprecipitation assay analysis determined that IGF-1 pretreatment increased Akt and Smad3 interaction. These results demonstrate that the IGF-1/PI3K/Akt pathway may inhibit MSTN signaling during myoblast differentiation, providing new insight to existing knowledge on the complex crosstalk between both growth factors.