Isolation and comparative characterization of Ki-67 equivalent antibodies from the HuCAL phage display library.
It has been shown that a repetitive motif with the sequence FKEL(F) within the Ki-67 antigen (pKi-67) serves as an epitope for the Ki-67 antibody and equivalent clones. However, no direct correlation between reactivity towards Ki-67 epitopes and reactivity in formalin-fixed paraffin-embedded (FFPE) tissue could be found. In this study our aim was the isolation and characterization of new monoclonal Ki-67 equivalent antibodies in an in vitro approach. To select pKi-67 reactive phage antibodies, we used a large naive Fab-phage library (Human Combinatorial Antibody Library; HuCAL). We implemented a panning strategy against two different overlapping peptides, both containing the 'FKELF' epitope. ELISA screening of randomly picked phage antibody clones after the third selection round yielded six highly reactive clones against the 'FKELF' epitope, of which five were found to be reactive in FFPE tissue, showing a Ki-67 equivalent staining pattern. Substitutional epitope analysis on peptide arrays of the new recombinant pKi-67 binders and of the established murine clones Ki-67, Mib-1 and Mib-5 were carried out to compare their fine specificities. The results suggest that the lysine residue in the epitope is critical for recognition of Ki-67 antigen in FFPE tissue.


QTL mapping and phenotypic variation for root architectural traits in maize (Zea mays L.).
QTL were identified for root architectural traits in maize. Root architectural traits, including the number, length, orientation, and branching of the principal root classes, influence plant function by determining the spatial and temporal domains of soil exploration. To characterize phenotypic patterns and their genetic control, three recombinant inbred populations of maize were grown for 28 days in solid media in a greenhouse and evaluated for 21 root architectural traits, including length, number, diameter, and branching of seminal, primary and nodal roots, dry weight of embryonic and nodal systems, and diameter of the nodal root system. Significant phenotypic variation was observed for all traits. Strong correlations were observed among traits in the same root class, particularly for the length of the main root axis and the length of lateral roots. In a principal component analysis, relationships among traits differed slightly for the three families, though vectors grouped together for traits within a given root class, indicating opportunities for more efficient phenotyping. Allometric analysis showed that trajectories of growth for specific traits differ in the three populations. In total, 15 quantitative trait loci (QTL) were identified. QTL are reported for length in multiple root classes, diameter and number of seminal roots, and dry weight of the embryonic and nodal root systems. Phenotypic variation explained by individual QTL ranged from 0.44% (number of seminal roots, NyH population) to 13.5% (shoot dry weight, OhW population). Identification of QTL for root architectural traits may be useful for developing genotypes that are better suited to specific soil environments.


Cancer diagnosis is associated with a lower burden of dementia and less Alzheimer's-type neuropathology.
Cancer and Alzheimer's disease are common diseases in ageing populations. Previous research has reported a lower incidence of Alzheimer's disease-type (amnestic) dementia among individuals with a diagnosis of cancer. Both cancer and amnestic dementia are prevalent and potentially lethal clinical syndromes. The current study was conducted to investigate the association of cancer diagnosis with neuropathological and cognitive features of dementia. Data were analysed from longitudinally evaluated participants in a community-based cohort study of brain ageing who came to autopsy at the University of Kentucky Alzheimer's Disease Research Center. These data were linked to the Kentucky Cancer Registry, a population-based state cancer surveillance system, to obtain cancer-related data. We examined the relationship between cancer diagnosis, clinical dementia diagnosis, Mini-Mental State Examination scores and neuropathological features using inverse probability weighting to address bias due to confounding and missing data. To address bias due to inclusion of participants with dementia at cohort baseline, we repeated all analyses restricted to the participants who were cognitively normal at baseline. Included participants (n = 785) had a mean ± standard deviation age of death of 83.8 ± 8.6 years; 60.1% were female. Cancer diagnosis was determined in 190 (24.2%) participants, and a diagnosis of mild cognitive impairment or dementia was determined in 539 (68.7%). APOE ɛ4 allele dosage was lower among participants with cancer diagnosis compared to cancer-free participants overall (P = 0.0072); however, this association was not observed among those who were cognitively normal at baseline. Participants with cancer diagnosis had lower odds of mild cognitive impairment or dementia, and higher cognitive test scores (e.g. Mini-Mental State Examination scores evaluated 6 and ≤2 years ante-mortem, P < 0.001 for both comparisons). Cancer diagnosis also associated with lower odds of higher Braak neurofibrillary tangle stages (III/IV) or (V/VI), moderate/frequent neuritic plaques, moderate/frequent diffuse plaques and moderate/severe cerebral amyloid angiopathy (all P < 0.05). By contrast, TDP-43, α-synuclein and cerebrovascular pathologies were not associated with cancer diagnosis. Cancer diagnosis was associated with a lower burden of Alzheimer's disease pathology and less cognitive impairment. These findings from a community-based cohort with neuropathological confirmation of substrates support the hypothesis that there is an inverse relationship between cancer and Alzheimer's disease.


Same law, diverging practice: Comparative analysis of Endangered Species Act consultations by two federal agencies.
Evaluating how wildlife conservation laws are implemented is critical for safeguarding biodiversity. Two agencies, the U.S. Fish and Wildlife Service and National Marine Fisheries Service (FWS and NMFS; Services collectively), are responsible for implementing the U.S. Endangered Species Act (ESA), which requires federal protection for threatened and endangered species. FWS and NMFS' comparable role for terrestrial and marine taxa, respectively, provides the opportunity to examine how implementation of the same law varies between agencies. We analyzed how the Services implement a core component of the ESA, section 7 consultations, by objectively assessing the contents of >120 consultations on sea turtle species against the requirements in the Services' consultation handbook, supplemented with in-person observations from Service biologists. Our results showed that NMFS consultations were 1.40 times as likely to have higher completeness scores than FWS consultations given the standard in the handbook. Consultations tiered from an FWS programmatic consultation inherited higher quality scores of generally more thorough programmatic consultations, indicating that programmatic consultations could increase the quality of consultations while improving efficiency. Both agencies commonly neglected to account for the effects of previous consultations and the potential for compounded effects on species. From these results, we recommend actions that can improve quality of consultation, including the use of a single database to track and integrate previously authorized harm in new analyses and the careful but more widespread use of programmatic consultations. Our study reveals several critical shortfalls in the current process of conducting ESA section 7 consultations that the Services could address to better safeguard North America's most imperiled species.


Evaluating the Impact of Florida's "Stand Your Ground" Self-defense Law on Homicide and Suicide by Firearm: An Interrupted Time Series Study.
In 2005, Florida amended its self-defense laws to provide legal immunity to individuals using lethal force in self-defense. The enactment of "stand your ground" laws in the United States has been controversial and their effect on rates of homicide and homicide by firearm is uncertain. To estimate the impact of Florida's stand your ground law on rates of homicide and homicide by firearm. Using an interrupted time series design, we analyzed monthly rates of homicide and homicide by firearm in Florida between 1999 and 2014. Data were collected from the Wide-ranging Online Data for Epidemiologic Research (WONDER) web portal at the Centers for Disease Control and Prevention. We used seasonally adjusted segmented Poisson regression models to assess whether the onset of the law was associated with changes in the underlying trends for homicide and homicide by firearm in Florida. We also assessed the association using comparison states without stand your ground laws (New York, New Jersey, Ohio, and Virginia) and control outcomes (all suicides and suicides by firearm in Florida). October 1, 2005, the effective date of the law, was used to define homicides before and after the change. Monthly rates of homicide, firearm-related homicide, suicide, and suicide by firearm in Florida and the 4 comparison states. Prior to the stand your ground law, the mean monthly homicide rate in Florida was 0.49 deaths per 100 000 (mean monthly count, 81.93), and the rate of homicide by firearm was 0.29 deaths per 100 000 (mean monthly count, 49.06). Both rates had an underlying trend of 0.1% decrease per month. After accounting for underlying trends, these results estimate that after the law took effect there was an abrupt and sustained increase in the monthly homicide rate of 24.4% (relative risk [RR], 1.24; 95%CI, 1.16-1.33) and in the rate of homicide by firearm of 31.6% (RR, 1.32; 95% CI, 1.21-1.44). No evidence of change was found in the analyses of comparison states for either homicide (RR, 1.06; 95% CI, 0.98-1.13) or homicide by firearm (RR, 1.08; 95% CI, 0.99-1.17). Furthermore, no changes were observed in control outcomes such as suicide (RR, 0.99; 95% CI, 0.94-1.05) and suicide by firearm (RR, 0.98; 95% CI, 0.91-1.06) in Florida between 2005 and 2014. The implementation of Florida's stand your ground self-defense law was associated with a significant increase in homicides and homicides by firearm but no change in rates of suicide or suicide by firearm.


Immune recognition of Streptococcus pyogenes by dendritic cells.
Streptococcus pyogenes is one of the most frequent human pathogens. Recent studies have identified dendritic cells (DCs) as important contributors to host defense against S. pyogenes. The objective of this study was to identify the receptors involved in immune recognition of S. pyogenes by DCs. To determine whether Toll-like receptors (TLRs) were involved in DC sensing of S. pyogenes, we evaluated the response of bone marrow-derived DCs obtained from mice deficient in MyD88, an adapter molecule used by almost all TLRs, following S. pyogenes stimulation. Despite the fact that MyD88(-/-) DCs did not differ from wild-type DCs in the ability to internalize and kill S. pyogenes, the up-regulation of maturation markers, such as CD40, CD80, and CD86, and the production of inflammatory cytokines, such as interleukin-12 (IL-12), IL-6, and tumor necrosis factor alpha, were dramatically impaired in S. pyogenes-stimulated MyD88(-/-) DCs. These results suggest that signaling through TLRs is the principal pathway by which DCs sense S. pyogenes and become activated. Surprisingly, DCs deficient in signaling through each of the TLRs reported as potential receptors for gram-positive cell components, such as TLR1, TLR2, TLR4, TLR9, and TLR2/6, were not impaired in the secretion of proinflammatory cytokines and the up-regulation of costimulatory molecules after S. pyogenes stimulation. In conclusion, our results exclude a major involvement of a single TLR or the heterodimer TLR2/6 in S. pyogenes sensing by DCs and argue for a multimodal recognition in which a combination of several different TLR-mediated signals is essential for a rapid and effective response to the pathogen.


Transient receptor potential (TRP) channels: a clinical perspective.
Transient receptor potential (TRP) channels are important mediators of sensory signals with marked effects on cellular functions and signalling pathways. Indeed, mutations in genes encoding TRP channels are the cause of several inherited diseases in humans (the so-called 'TRP channelopathies') that affect the cardiovascular, renal, skeletal and nervous systems. TRP channels are also promising targets for drug discovery. The initial focus of research was on TRP channels that are expressed on nociceptive neurons. Indeed, a number of potent, small-molecule TRPV1, TRPV3 and TRPA1 antagonists have already entered clinical trials as novel analgesic agents. There has been a recent upsurge in the amount of work that expands TRP channel drug discovery efforts into new disease areas such as asthma, cancer, anxiety, cardiac hypertrophy, as well as obesity and metabolic disorders. A better understanding of TRP channel functions in health and disease should lead to the discovery of first-in-class drugs for these intractable diseases. With this review, we hope to capture the current state of this rapidly expanding and changing field.


Is Firearm Threat in Intimate Relationships Associated with Posttraumatic Stress Disorder Symptoms Among Women?
In the context of intimate partner violence (IPV), firearms may be used to threaten, coerce, and intimidate. Yet, what little research exists on firearms among IPV victims has focused almost exclusively on homicide or near homicide. Thus, the deleterious health consequences of firearms more broadly remain unknown. The goals of the current study were (1) to document the prevalence of firearm threat in a community sample of female IPV victims, and (2) to identify the extent to which threat with a firearm, independent of other forms of IPV, is related to women's posttraumatic stress disorder (PTSD) symptom severity. Participants were 298 women who had been a victim in a criminal domestic violence case with a male intimate partner (Mage = 36.39 years; 50.0% African American; 51.3% unemployed). Retrospective data on firearm threat, fear of firearm violence, other IPV victimization (i.e., physical, psychological, and sexual), and PTSD symptoms were collected during in-person individual interviews. Approximately one-quarter of the sample (24.2%) experienced threat with a firearm during the course of their relationship, and 12.5% were afraid that their partners would use a firearm against them in the 30 days prior to the study interview. Firearm threat and fear of firearm violence emerged as significant and unique predictors of PTSD symptom severity, controlling for age and physical, psychological, and sexual IPV victimization severity. The findings underscore firearm threat as a key factor for identifying and intervening with criminal justice involved women who experience IPV.


Intravenous etidronate in the management of malignant hypercalcemia.
The treatment of hypercalcemia remains a common problem in the management of many patients with cancer. We have used intravenously administered etidronate disodium as a therapy for hypercalcemia in 26 patients with malignant disease. Patients with persistent hypercalcemia despite adequate hydration and a serum creatinine level less than or equal to 1.5 mg/dL were allowed on study. Treatment consisted of intravenously administered etidronate disodium at 7.5 mg/kg/day in 250 mL of saline infused over two hours on 1, 2, 3, or 4 consecutive days. The serum calcium level in 19 (73%) of 26 patients returned to the normal range with a mean response time of 3 +/- 2 days. Similar response rates were seen in patients with a variety of tumors, including breast cancer, non-small-cell lung cancer, and multiple myeloma. Intravenously administered etidronate appears to be safe and effective therapy for hypercalcemia in patients with malignant disease.


Circulating activin A is a novel prognostic biomarker in malignant pleural mesothelioma - A multi-institutional study.
The deregulation of activin expression is often observed in various malignancies. Previous studies indicate that activin A plays a protumourigenic role in malignant pleural mesothelioma (MPM). The aim of the study was to evaluate circulating activin A level as a biomarker in MPM. Plasma samples were collected from 129 MPM patients in four institutions at the time of diagnosis or before surgical resection. Samples from 45 healthy individuals and from 16 patients with non-malignant pleural diseases served as controls. Circulating activin A was measured by enzyme-linked immunosorbent assay and correlated to clinicopathological variables. Plasma activin A level was significantly elevated in MPM patients (862 ± 83 pg/ml) when compared to healthy controls (391 ± 21 pg/ml; P < 0.0001). Patients with pleuritis or fibrosis only showed a modest increase (versus controls; 625 ± 95 pg/ml; P = 0.0067). Sarcomatoid (n = 10, 1629 ± 202 pg/ml, P = 0.0019) and biphasic (n = 23, 1164 ± 233 pg/ml, P = 0.0188) morphology were associated with high activin A levels when compared to epithelioid histology (n = 94, 712 ± 75 pg/ml). The tumour volume showed a positive correlation with increased circulating activin A levels. MPM patients with below median activin A levels had a significantly longer overall survival when compared to those with high activin A levels (median survival 735 versus 365 d, P < 0.0001). Importantly, circulating activin A levels were exclusively prognostic in epithelioid MPM. Our findings suggest that the measurement of circulating activin A may support the histological classification of MPM and at the same time help to identify epithelioid MPM patients with poor prognosis.


Television viewing, computer use, and BMI among U.S. children and adolescents.
To examine the prevalence of television (TV) viewing, computer use, and their combination and associations with demographic characteristics and body mass index (BMI) among U.S. youth. The 1999 to 2006 National Health and Nutrition Examination Survey (NHANES) was used. Time spent yesterday sitting and watching television or videos (TV viewing) and using the computer or playing computer games (computer use) were assessed by questionnaire. Prevalence (%) of meeting the U.S. objective for TV viewing (< or =2 hours/day) ranged from 65% to 71%. Prevalence of no computer use (0 hours/day) ranged from 23% to 45%. Non-Hispanic Black youth aged 2 to 15 years were less likely than their non-Hispanic White counterparts to meet the objective for TV viewing. Overweight or obese school-age youth were less likely than their normal weight counterparts to meet the objective for TV viewing. Computer use is prevalent among U.S. youth; more than half of youth used a computer on the previous day. The proportion of youth meeting the U.S. objective for TV viewing is less than the target of 75%. Time spent in sedentary behaviors such as viewing TV may contribute to overweight and obesity among U.S. youth.


Lpa2 is a negative regulator of both dendritic cell activation and murine models of allergic lung inflammation.
Negative regulation of innate immune responses is essential to prevent excess inflammation and tissue injury and promote homeostasis. Lysophosphatidic acid (LPA) is a pleiotropic lipid that regulates cell growth, migration, and activation and is constitutively produced at low levels in tissues and in serum. Extracellular LPA binds to specific G protein-coupled receptors, whose function in regulating innate or adaptive immune responses remains poorly understood. Of the classical LPA receptors belonging to the Edg family, lpa2 (edg4) is expressed by dendritic cells (DC) and other innate immune cells. In this article, we show that DC from lpa2(-/-) mice are hyperactive compared with their wild-type counterparts and are less susceptible to inhibition by different LPA species. In transient-transfection assays, we found that lpa2 overexpression inhibits NF-κB-driven gene transcription. Using an adoptive-transfer approach, we found that allergen-pulsed lpa2(-/-) DC induced substantially more lung inflammation than did wild-type DC after inhaled allergen challenge. Finally, lpa2(-/-) mice develop greater allergen-driven lung inflammation than do their wild-type counterparts in models of allergic asthma involving both systemic and mucosal sensitization. Taken together, these findings identify LPA acting via lpa2 as a novel negative regulatory pathway that inhibits DC activation and allergic airway inflammation.


Six host-range restricted poxviruses from three genera induce distinct gene expression profiles in an in vivo mouse model.
Host-range restricted poxviruses make promising vaccine vectors due to their safety profile and immunogenicity. An understanding of the host innate immune responses produced by different poxvirus vectors would aid in the assessment, selection and rational design of improved vaccines for human and veterinary applications. Novel avipoxviruses are being assessed to determine if they are different from other poxvirus vectors. Analysis of the transcriptome induced in a mouse model would aid in determining if there were significant differences between different poxvirus vectors which may reflect different adjuvant potential as well as establish if they should be further evaluated as vaccine vectors. We compared host transcript abundance in the spleens of BALB/c mice twenty four hours after intravenous infection (10(5) pfu/mouse) with six host-restricted poxvirus species from three genera, namely Lumpy Skin Disease virus (LSDV), Canarypox virus (CNPV), Fowlpox virus (FWPV), modified vaccinia Ankara (MVA) and two novel South African avipoxviruses, Feral Pigeonpox virus (FeP2) and Penguinpox virus (PEPV). These six viruses produced qualitatively and quantitatively distinct host responses with LSDV, followed by MVA, inducing the greatest interferon (IFN) response. FeP2 and PEPV caused very little change to host transcript abundance compared to the other 4 viruses tested. CNPV and FWPV induced the up regulation of two immunoglobulin genes (Ighg and Ighg3 (IgG3)) with CNPV inducing a third, Ighm (IgM). HIV-1-specific IgG3 antibodies have been correlated with decreased risk of HIV-1 infection in the RV144 trial, which included a CNPV-based vector (Yates et al. (Sci Transl Med, 6(228) p228, 2014). Up regulation of IgG3 by CNPV and FWPV but not the other poxviruses tested in vivo, implies that these two avipoxvirus-vector backbones may be involved in stimulation of the clinically important IgG3 antibody subclass. Differential transcript abundance associated with the different poxviruses is further discussed with particular emphasis on responses related to immune responses. Six, genetically diverse host-restricted poxviruses produce different responses in a mouse model early after infection. These differences may affect the immune response induced to vaccine antigen in vectors based on these viruses. The two novel avipoxviruses were clearly distinguishable from the other viruses.


Monoamine oxidase A gene (MAOA) predicts behavioral aggression following provocation.
Monoamine oxidase A gene (MAOA) has earned the nickname "warrior gene" because it has been linked to aggression in observational and survey-based studies. However, no controlled experimental studies have tested whether the warrior gene actually drives behavioral manifestations of these tendencies. We report an experiment, synthesizing work in psychology and behavioral economics, which demonstrates that aggression occurs with greater intensity and frequency as provocation is experimentally manipulated upwards, especially among low activity MAOA (MAOA-L) subjects. In this study, subjects paid to punish those they believed had taken money from them by administering varying amounts of unpleasantly hot (spicy) sauce to their opponent. There is some evidence of a main effect for genotype and some evidence for a gene by environment interaction, such that MAOA is less associated with the occurrence of aggression in a low provocation condition, but significantly predicts such behavior in a high provocation situation. This new evidence for genetic influences on aggression and punishment behavior complicates characterizations of humans as "altruistic" punishers and supports theories of cooperation that propose mixed strategies in the population. It also suggests important implications for the role of individual variance in genetic factors contributing to everyday behaviors and decisions.


Niche versus neutrality: a dynamical analysis.
Understanding the forces shaping ecological communities is of crucial importance for basic science and conservation. After 50 years in which ecological theory has focused on either stable communities driven by niche-based forces or nonstable "neutral" communities driven by demographic stochasticity, contemporary theories suggest that ecological communities are driven by the simultaneous effects of both types of mechanisms. Here we examine this paradigm using the longest available records for the dynamics of tropical trees and breeding birds. Applying a macroecological approach and fluctuation analysis techniques borrowed from statistical physics, we show that both stabilizing mechanisms and demographic stochasticity fail to play a dominant role in shaping assemblages over time. Rather, community dynamics in these two very different systems is predominantly driven by environmental stochasticity. Clearly, the current melding of niche and neutral theories cannot account for such dynamics. Our results highlight the need for a new theory of community dynamics integrating environmental stochasticity with weak stabilizing forces and suggest that such theory may better describe the dynamics of ecological communities than current neutral theories, deterministic niche-based theories, or recent hybrids.


Combined use of exhaled nitric oxide and airway hyperresponsiveness in characterizing asthma in a large population survey.
The aim of the present study was to see whether measurements of airway hyperresponsiveness (AHR) and nitric oxide (NO) in exhaled air (ENO) either separately or in combination, could differentiate between asthmatics and healthy control subjects in a population based survey. In central Norway 8,571 adolescents participated in a large-scale epidemiological survey (Young Helseundersøkelsen i Nord-Trøndelag (Health Survey in North-Trøndelag; HUNT). Asthmatic symptoms when exposed to pollen, pets or house-dust were reported by 7.8% (suspected asthmatics), while 56% reported no asthmatic or allergic symptoms (control subjects). From these respective groups 151 and 213 adolescents were investigated with allergy screening, measurements of exhaled and nasal NO, and methacholine challenge test. AHR (provocative dose of methacholine causing a 20% fall in forced expiratory volume in one second (PD20) <2 mg) was confirmed in 75% of the suspected asthmatics versus 25% of the control subjects, whereas 52% versus 20% had elevated levels of ENO (> or =8 parts per billion (ppb)). ENO and dose response ratio to methacholine (DRR) were positively correlated (r=0.41, p<0.001). ENO was significantly elevated in atopic versus nonatopic suspected asthmatics (11.7 ppb and 5.6 ppb respectively, p<0.001). Suspected asthmatics with both AHR and atopy had the highest levels of ENO (14.2 ppb). It is concluded that measurements of nitric oxide in exhaled air alone are not a useful tool in diagnosing asthma in population surveys, but that the combination of airway hyperresponsiveness and elevated nitric oxide in exhaled air is a very specific finding for allergic asthma. The use of dose response ratio to methacholine did not provide any additional information to the provocative dose of methacholine causing a 20% fall in forced expiratory volume in one second in this study.


Timing of heparin and perfusion temperature during procurement of organs with extracorporeal support in donors after circulatory determination of death.
Despite successful resuscitation of donors after circulatory determination of death (DCD) with extracorporeal support (ECS), the technique is limited by ethical concerns about donor management (heparinization) and the complexity to operate the ECS circuit. This work studies different timing of heparin administration and the effects of ECS-perfusion temperature. Cardiac arrest (CA) was induced in swine. Heparin studies, three groups: 1) PRE5, heparin 5 minutes before CA; 2) POST5, heparin 5 minutes after CA, plus 2 minutes external chest compressions; and 3) POST30, heparin with the initiation of ECS after 30 minutes CA. Perfusion temperature study, two groups: 1) normothermic, ECS-38.5°C after 30 minutes CA and 2) room temperature, ECS-25.5°C for the first 90 minutes, followed by ECS-38.5°C. Heparin studies: ECS target flows (>50 ml/kg/min) were not achieved in the POST30 group, affecting local organ perfusion as observed with poor bile (<4 ml/min) and urine output (<25 ml/min), when compared with the other groups (normal values). Temperature study: In both groups, ECS target flows were reached, and urine/bile output was restored. Heparinization 5 minutes after CA is equivalent to premortem heparinization in this ECS-DCD model. Heparinization after CA could reduce ethical concerns. Donors after circulatory determination of death were successfully resuscitated at both temperatures, suggesting that the heat exchanger/water heater can be removed to simplify the ECS circuit.


Revisiting annual screening for latent tuberculosis infection in healthcare workers: a cost-effectiveness analysis.
In North America, tuberculosis incidence is now very low and risk to healthcare workers has fallen. Indeed, recent cohort data question routine annual tuberculosis screening in this context. We compared the cost-effectiveness of three potential strategies for ongoing screening of North American healthcare workers at risk of exposure. The analysis did not evaluate the cost-effectiveness of screening at hiring, and considered only workers with negative baseline tests. A decision analysis model simulated a hypothetical cohort of 1000 workers following negative baseline tests, considering duties, tuberculosis exposure, testing and treatment. Two tests were modelled, the tuberculin skin test (TST) and QuantiFERON®-TB-Gold In-Tube (QFT). Three screening strategies were compared: (1) annual screening, where workers were tested yearly; (2) targeted screening, where workers with high-risk duties (e.g. respiratory therapy) were tested yearly and other workers only after recognised exposure; and (3) post exposure-only screening, where all workers were tested only after recognised exposure. Workers with high-risk duties had 1% annual risk of infection, while workers with standard patient care duties had 0.3%. In an alternate higher-risk scenario, the corresponding annual risks of infection were 3% and 1%, respectively. We projected costs, morbidity, quality-adjusted survival and mortality over 20 years after hiring. The analysis used the healthcare system perspective and a 3% annual discount rate. Over 20 years, annual screening with TST yielded an expected 2.68 active tuberculosis cases/1000 workers, versus 2.83 for targeted screening and 3.03 for post-exposure screening only. In all cases, annual screening was associated with poorer quality-adjusted survival, i.e. lost quality-adjusted life years, compared to targeted or post-exposure screening only. The annual TST screening strategy yielded an incremental cost estimate of $1,717,539 per additional case prevented versus targeted TST screening, which in turn cost an incremental $426,678 per additional case prevented versus post-exposure TST screening only. With the alternate "higher-risk" scenario, the annual TST strategy cost an estimated $426,678 per additional case prevented versus the targeted TST strategy, which cost an estimated $52,552 per additional case prevented versus post-exposure TST screening only. In all cases, QFT was more expensive than TST, with no or limited added benefit. Sensitivity analysis suggested that, even with limited exposure recognition, annual screening was poorly cost-effective. For most North American healthcare workers, annual tuberculosis screening appears poorly cost-effective. Reconsideration of screening practices is warranted.


Composition of the lambda plasmid heritable replication complex.
Previous studies indicated during replication of plasmids derived from bacteriophage lambda (the so-called lambda plasmids), that, once assembled, replication complex can be inherited by one of the two daughter plasmid copies after each replication round, and may function in subsequent replication rounds. It seems that similar processes occur during replication of other DNA molecules, including chromosomes of the yeast Saccharomyces cerevisiae. However, apart from some suggestions based on genetic experiments, composition of the lambda heritable replication complex remains unknown. In amino acid-starved Escherichia coli relA mutants, replication of lambda plasmid DNA is carried out exclusively by the heritable replication complex as assembly of new complexes is impaired due to inhibition of protein synthesis. Here, using a procedure based on in vivo cross-linking, cell lysis, immunoprecipitation with specific sera, de-cross-linking and PCR analysis, we demonstrate that the lambda heritable replication complex consists of O, P, DnaB and, perhaps surprisingly, DnaK proteins.


Exogenous melatonin for sleep disorders in neurodegenerative diseases: a meta-analysis of randomized clinical trials.
The purpose of this work is to investigate the efficacy of exogenous melatonin in the treatment of sleep disorders in patients with neurodegenerative disease. We searched Pubmed, the Cochrane Library, and ClinicalTrials.gov, from inception to July 2015. We included randomized clinical trials (RCTs) that compared melatonin with placebo and that had the primary aim of improving sleep in people with neurodegenerative diseases, particularly Alzheimer's disease (AD) and Parkinson's disease (PD). We pooled data with the weighted mean difference in sleep outcomes. To assess heterogeneity in results of individual studies, we used Cochran's Q statistic and the I (2) statistic. 9 RCTs were included in this research. We found that the treatment with exogenous melatonin has positive effects on sleep quality as assessed by the Pittsburgh Sleep Quality Index (PSQI) in PD patients (MD: 4.20, 95 % CI: 0.92-7.48; P = 0.01), and by changes in PSQI component 4 in AD patients (MD: 0.67, 95 % CI: 0.04-1.30; P = 0.04), but not on objective sleep outcomes in both AD and PD patients. Treatment with melatonin effectively improved the clinical and neurophysiological aspects of rapid eye movement (REM) sleep behavior disorder (RBD), especially elderly individuals with underlying neurodegenerative disorders. This meta-analysis provided some evidence that melatonin improves sleep quality in patients with AD and PD, and melatonin can be considered as a possible sole or add-on therapy in neurodegenerative disorders patients with RBD.


Context and strain-dependent behavioral response to stress.
This study posed the question whether strain differences in stress-reactivity lead to differential behavioral responses in two different tests of anxiety. Strain differences in anxiety-measures are known, but strain differences in the behavioral responses to acute prior stress are not well characterized. We studied male Fisher 344 (F344) and Wistar Kyoto (WKY) rats basally and immediately after one hour restraint stress. To distinguish between the effects of novelty and prior stress, we also investigated behavior after repeated exposure to the test chamber. Two behavioral tests were explored; the elevated plus maze (EPM) and the open field (OFT), both of which are thought to measure activity, exploration and anxiety-like behaviors. Additionally, rearing, a voluntary behavior, and grooming, a relatively automatic, stress-responsive stereotyped behavior were measured in both tests. Prior exposure to the test environment increased anxiety-related measures regardless of prior stress, reflecting context-dependent learning process in both tests and strains. Activity decreased in response to repeated testing in both tests and both strains, but prior stress decreased activity only in the OFT which was reversed by repeated testing. Prior stress decreased anxiety-related measures in the EPM, only in F344s, while in the OFT, stress led to increased freezing mainly in WKYs. Data suggest that differences in stressfulness of these tests predict the behavior of the two strains of animals according to their stress-reactivity and coping style, but that repeated testing can overcome some of these differences.


Brief mindfulness training increased glutamate metabolism in the anterior cingulate cortex.
Mindfulness meditation has become a promising intervention for promoting health and well-being. Neuroimaging studies have shown its beneficial effects on brain functional activity, connectivity, and structures following months to years of practice. A series of randomized controlled trials indicated that one form of mindfulness meditation, the integrative body-mind training (IBMT) induces brain functional and structural changes in brain regions related to self-control networks such as the anterior cingulate cortex (ACC) after 2-10 h of practice. However, whether IBMT could change brain metabolism in the ACC remains unexplored. Utilizing a noninvasive 3T proton magnetic resonance spectroscopy, our results showed a significant increase in glutamate metabolism in the rostral ACC following 10 h of IBMT, suggesting that brief training not only increases ACC activity and structure, but also induces neurochemical changes in regions of the self-control networks. To our knowledge, this is the first study demonstrating the positive effects on brain metabolism in the ACC following brief intervention, suggesting a potential mechanism and implications of mindfulness meditation in ameliorating disorders such as addiction, depression and schizophrenia, which often involve the dysfunction of self-control networks and glutamatergic system (i.e. lower glutamate metabolism).


Shifting dominance of riparian Populus and Tamarix along gradients of flow alteration in western North American rivers.
Tamarix ramosissima is a naturalized, nonnative plant species which has become widespread along riparian corridors throughout the western United States. We test the hypothesis that the distribution and success of Tamarix result from human modification of river-flow regimes. We conducted a natural experiment in eight ecoregions in arid and semiarid portions of the western United States, measuring Tamarix and native Populus recruitment and abundance at 64 sites along 13 perennial rivers spanning a range of altered flow regimes. We quantified biologically relevant attributes of flow alteration as an integrated measure (the index of flow modification, IFM), which was then used to explain between-site variation in abundance and recruitment of native and nonnative riparian plant species. We found the likelihood of successful recruitment of Tamarix to be highest along unregulated river reaches and to remain high across a gradient of regulated flows. Recruitment probability for Populus, in contrast, was highest under free-flowing conditions and declined abruptly under even slight flow modification (IFM > 0.1). Adult Tamarix was most abundant at intermediate levels of IFM. Populus abundance declined sharply with modest flow regulation (IFM > 0.2) and was not present at the most flow-regulated sites. Dominance of Tamarix was highest along rivers with the most altered flow regimes. At the 16 least regulated sites, Tamarix and Populus were equally abundant. Given observed patterns of Tamarix recruitment and abundance, we infer that Tamarix would likely have naturalized, spread, and established widely in riparian communities in the absence of dam construction, diversions, and flow regulation in western North America. However, Tamarix dominance over native species would likely be less extensive in the absence of human alteration of river-flow regimes. Restoration that combines active mechanical removal of established stands of Tamarix with a program of flow releases conducive to native species establishment and persistence is hypothesized to facilitate the codominance of Populus in reaches where it has become rare. Our findings have implications for planning flow-related stream restoration, for developing realistic expectations for yield on investment in prescribed flow releases, and for planning flow-related interventions that might be possible if control and management of invasive plant species along rivers is a goal.


Interplay of the physical microenvironment, contact guidance, and intracellular signaling in cell decision making.
The peritumoral physical microenvironment consists of complex topographies that influence cell migration. Cell decision making, upon encountering anisotropic, physiologically relevant physical cues, has yet to be elucidated. By integrating microfabrication with cell and molecular biology techniques, we provide a quantitative and mechanistic analysis of cell decision making in a variety of well-defined physical microenvironments. We used MDA-MB-231 breast carcinoma and HT1080 fibrosarcoma as cell models. Cell decision making after lateral confinement in 2-dimensional microcontact printed lines is governed by branch width at bifurcations. Cells confined in narrow feeder microchannels prefer to enter wider branches at bifurcations. In contrast, in feeder channels that are wider than the cell body, cells elongate along one side wall of the channel and are guided by contact with the wall to the contiguous branch channel independent of its width. Knockdown of β1-integrins or inhibition of cellular contractility suppresses contact guidance. Concurrent, but not individual, knockdown of nonmuscle myosin isoforms IIA and IIB also decreases contact guidance, which suggests the existence of a compensatory mechanism between myosin IIA and myosin IIB. Conversely, knockdown or inhibition of cell division control protein 42 homolog promotes contact guidance-mediated decision making. Taken together, the dimensionality, length scales of the physical microenvironment, and intrinsic cell signaling regulate cell decision making at intersections.-Paul, C. D., Shea, D. J., Mahoney, M. R., Chai, A., Laney, V., Hung, W.-C., Konstantopoulos, K. Interplay of the physical microenvironment, contact guidance, and intracellular signaling in cell decision making.


Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9.
We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable. Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.


Residency work-hours reform. A cost analysis including preventable adverse events.
In response to proposed federal legislation, the Accreditation Council for Graduate Medical Education limited resident work-hours in July 2003. The cost may be substantial but, if successful, the reform might lower preventable adverse event costs in hospital and after discharge. This study sought to estimate the reform's net cost in 2001 dollars, and to determine the reduction in preventable adverse events needed to make reform cost neutral from teaching hospital and societal perspectives. Cost analysis using published literature and data. Net costs were determined for 4 reform strategies and over a range of potential effects on preventable adverse events. Nationwide, transferring excess work to task-tailored substitutes (the lowest-level providers appropriate for noneducational tasks) would cost 673 million dollars; mid-level providers would cost 1.1 billion dollars. Reform strategies promoting adverse events would increase net teaching hospital and societal costs as well as mortality. If task-tailored substitutes decrease events by 5.1% or mid-level providers decrease them by 8.5%, reform would be cost neutral for society. Events must fall by 18.5% and 30.9%, respectively, to be cost neutral for teaching hospitals. Because most preventable adverse event costs occur after discharge, a modest decline (5.1% to 8.5%) in them might make residency work-hours reform cost neutral for society but only a much larger drop (18.5% to 30.9%) would make it cost neutral for teaching hospitals, unless additional funds are allocated. Future research should evaluate which reform approaches prevent adverse events and at what cost.


Residential greenness and prevalence of major depressive disorders: a cross-sectional, observational, associational study of 94 879 adult UK Biobank participants.
Increased urbanisation and the associated reduced contact of individuals with natural environments have led to a rise in mental disorders, including depression. Residential greenness, a fundamental component of urban design, has been shown to reduce the public health burden of mental disorders. The present study investigates the association between residential green exposure and prevalence of major depressive disorders using a large and diverse cross-sectional dataset from the UK Biobank. In this cross-sectional, observational, associational study, we used baseline data from the UK Biobank cohort of participants aged 37-73 years from across the UK. Environmental exposure data were derived from a modelled and linked built environment database. Residential greenness was assessed with a 0·5 m resolution Normalised Difference Vegetation Index, which is derived from spectral reflectance measurements in remotely sensed colour infrared data and measured within geocoded dwelling catchments. Other environment metrics included street-level movement density, terrain, and fine particulate exposures. A series of logistic models examined associations between residential greenness and odds of major depressive disorder after adjusting for activity-influencing environments and individual covariates. Of 122 993 participants with data on major depressive disorder, the study analytical sample comprised 94 879 (77·1%) participants recruited across ten UK Biobank assessment centres between April 29, 2009, and Oct 1, 2010. A protective effect of greenness on depression was consistently observed, with 4·0% lower odds of major depressive disorder per interquartile increment in Normalised Difference Vegetation Index greenness (odds ratio 0·960, 95% CI 0·93-0·99; p=0·0044). Interaction analyses indicated that the beneficial effects of greenness were more pronounced among women, participants younger than 60 years, and participants residing in areas with low neighbourhood socioeconomic status or high urbanicity. The results point to the benefits of well designed green environments on mental health. Further longitudinal studies are needed to decipher causal pathways. In the UK, policies aimed at optimising allocation and design of green spaces might help preserve psychological ecosystem services, thereby, improving the mental wellbeing of populations and enhancing the mental capital of cities. University of Hong Kong, UK Biobank, and the UK Economic & Social Research Council.


Magnetic resonance imaging of intracranial malformations in dogs and cats.
Intracranial malformations may occur because of an inherent developmental defect or secondary to in utero injury to the brain with subsequent hypoplasia and atrophy. They can cause neurologic deficits in growing animals, although some anomalies may not produce clinical signs until adulthood. Malformations of the brain include hydrocephalus, hydranencephaly/porencephaly, holoprosencephaly, corpus callosum agenesis/dysgenesis, lissencephaly, polymicrogyria, meningoencephalocele, intracranial cysts, cerebellar malformations, and hamartomas. These conditions are defined and reviewed with an emphasis on their features in magnetic resonance images.


Quaternary deepwater paleoceanography.
During the past decade, geochemical paleoceanographers have begun to explore the changes in the circulation of the deep ocean that occurred during the glacial-interglacial cycles of the earth's recent history. The deep ocean was significantly colder during the glacial maximum. The distributions of biologically utilized elements (such as carbon and phosphorus) were significantly different as well; higher concentrations of these elements occurred in the deep (>2500 meters depth) North Atlantic, and lower concentrations occurred in the upper (<2500 meters depth) waters of the North Atlantic and possibly in all of the major ocean basins. In contrast, relatively subtle changes have been observed in the radiocarbon ages of deep waters. Slow deepwater changes are statistically linked to variations in the earth's orbit, but rapid changes in deepwater circulation also have occurred. Deepwater chemistry and circulation changes may control the variability in atmospheric CO(2) levels that have been documented from studies of air bubbles in polar ice cores.


Development of NanoLuc-PEST expressing Leishmania mexicana as a new drug discovery tool for axenic- and intramacrophage-based assays.
The protozoan parasite Leishmania causes leishmaniasis; a spectrum of diseases of which there are an estimated 1 million new cases each year. Current treatments are toxic, expensive, difficult to administer, and resistance to them is emerging. New therapeutics are urgently needed, however, screening the infective amastigote form of the parasite is challenging. Only certain species can be differentiated into axenic amastigotes, and compound activity against these does not always correlate with efficacy against the parasite in its intracellular niche. Methods used to assess compound efficacy on intracellular amastigotes often rely on microscopy-based assays. These are laborious, require specialist equipment and can only determine parasite burden, not parasite viability. We have addressed this clear need in the anti-leishmanial drug discovery process by producing a transgenic L. mexicana cell line that expresses the luciferase NanoLuc-PEST. We tested the sensitivity and versatility of this transgenic strain, in comparison with strains expressing NanoLuc and the red-shifted firefly luciferase. We then compared the NanoLuc-PEST luciferase to the current methods in both axenic and intramacrophage amastigotes following treatment with a supralethal dose of Amphotericin B. NanoLuc-PEST was a more dynamic indicator of cell viability due to its high turnover rate and high signal:background ratio. This, coupled with its sensitivity in the intramacrophage assay, led us to validate the NanoLuc-PEST expressing cell line using the MMV Pathogen Box in a two-step process: i) identify hits against axenic amastigotes, ii) screen these hits using our bioluminescence-based intramacrophage assay. The data obtained from this highlights the potential of compounds active against M. tuberculosis to be re-purposed for use against Leishmania. Our transgenic L. mexicana cell line is therefore a highly sensitive and dynamic system suitable for Leishmania drug discovery in axenic and intramacrophage amastigote models.


Single-cell atlas of colonic CD8+ T cells in ulcerative colitis.
Colonic antigen-experienced lymphocytes such as tissue-resident memory CD8+ T cells can respond rapidly to repeated antigen exposure. However, their cellular phenotypes and the mechanisms by which they drive immune regulation and inflammation remain unclear. Here we compiled an unbiased atlas of human colonic CD8+ T cells in health and ulcerative colitis (UC) using single-cell transcriptomics with T-cell receptor repertoire analysis and mass cytometry. We reveal extensive heterogeneity in CD8+ T-cell composition, including expanded effector and post-effector terminally differentiated CD8+ T cells. While UC-associated CD8+ effector T cells can trigger tissue destruction and produce tumor necrosis factor (TNF)-α, post-effector cells acquire innate signatures to adopt regulatory functions that may mitigate excessive inflammation. Thus, we identify colonic CD8+ T-cell phenotypes in health and UC, define their clonal relationships and characterize terminally differentiated dysfunctional UC CD8+ T cells expressing IL-26, which attenuate acute colitis in a humanized IL-26 transgenic mouse model.


Functional polymers: scanning force microscopy insights.
Scanning force microscopy (SFM) and related techniques make it possible to visualize polymer systems with a molecular resolution. Beyond imaging, they also enable the unveiling of a variety of (dynamic) physico-chemical properties of both isolated polymer chains and their supramolecular architectures, including structural, mechanical and electronic properties. This article reviews recent progress in the use of SFM on polymers, with a particular emphasis on the mechanical properties of copolymers and single polymer chains, as well as on the bottom-up fabrication of supramolecular polymeric (helical) nanostructures in particular based upon pi-conjugated macromolecules as building blocks for nanoelectronics. Through a detailed understanding of the polymer behavior, we propose solutions for the generation of organic functional (nano)systems.


Controlled, dose-response study of sertindole and haloperidol in the treatment of schizophrenia. Sertindole Study Group.
This multicenter, double-blind, placebo-controlled study evaluated the efficacy and safety of three doses of sertindole (12, 20, and 24 mg/day) and haloperidol (4, 8, and 16 mg/day) in the treatment of psychotic symptoms for 497 hospitalized patients with schizophrenia. The patients were randomly assigned to one of the medication groups and received treatment for 8 weeks. Changes in Positive and Negative Syndrome Scale, Scale for the Assessment of Negative Symptoms, Brief Psychiatric Rating Scale, and Clinical Global Impression scores were used as evaluations of treatment efficacy. Three rating scales were used to assess extrapyramidal symptoms as well as the occurrence of adverse events and the use of medications related to extrapyramidal symptoms. Both sertindole and haloperidol were comparably effective in the treatment of psychosis, and all dose levels were significantly more effective than placebo. For the treatment of negative symptoms, only sertindole, 20 mg/day, was significantly more effective than placebo. For all extrapyramidal symptom measures, sertindole was clinically and statistically indistinguishable from placebo, and rates of extrapyramidal symptoms were not dose related. All dose levels of haloperidol produced significantly more extrapyramidal symptoms than placebo or sertindole. Adverse events associated with sertindole treatment were mild in severity. Sertindole is a new antipsychotic agent effective for the treatment of both the positive and negative symptoms of schizophrenia, with motor side effects that are indistinguishable from those associated with placebo.


Individual tree damage dominates mortality risk factors across six tropical forests.
The relative importance of tree mortality risk factors remains unknown, especially in diverse tropical forests where species may vary widely in their responses to particular conditions. We present a new framework for quantifying the importance of mortality risk factors and apply it to compare 19 risks on 31 203 trees (1977 species) in 14 one-year periods in six tropical forests. We defined a condition as a risk factor for a species if it was associated with at least a doubling of mortality rate in univariate analyses. For each risk, we estimated prevalence (frequency), lethality (difference in mortality between trees with and without the risk) and impact ('excess mortality' associated with the risk, relative to stand-level mortality). The most impactful risk factors were light limitation and crown/trunk loss; the most prevalent were light limitation and small size; the most lethal were leaf damage and wounds. Modes of death (standing, broken and uprooted) had limited links with previous conditions and mortality risk factors. We provide the first ranking of importance of tree-level mortality risk factors in tropical forests. Future research should focus on the links between these risks, their climatic drivers and the physiological processes to enable mechanistic predictions of future tree mortality.


X chromosome monosomy: a common mechanism for autoimmune diseases.
The majority of human autoimmune diseases are characterized by female predominance. Although sex hormone influences have been suggested to explain this phenomenon, the mechanism remains unclear. In contrast to the role of hormones, it has been suggested, based on pilot data in primary biliary cirrhosis, that there is an elevation of monosomy X in autoimmune disease. Using peripheral white blood cells from women with systemic sclerosis (SSc), autoimmune thyroid disease (AITD), or healthy age-matched control women, we studied the presence of monosomy X rates using fluorescence in situ hybridization. We also performed dual-color fluorescence in situ hybridization analysis with a chromosome Y alpha-satellite probe to determine the presence of the Y chromosome in the monosomic cells. In subsets of patients and controls, we determined X monosomy rates in white blood cell subpopulations. The rates of monosomy X increased with age in all three populations. However, the rate of monosomy X was significantly higher in patients with SSc and AITD when compared with healthy women (6.2 +/- 0.3% and 4.3 +/- 0.3%, respectively, vs 2.9 +/- 0.2% in healthy women, p < 0.0001 in both comparisons). Importantly, X monosomy rate was more frequent in peripheral T and B lymphocytes than in the other blood cell populations, and there was no evidence for the presence of male fetal microchimerism. These data highlight the thesis that chromosome instability is common to women with SSc and AITD and that haploinsufficiency for X-linked genes may be a critical factor for the female predominance of autoimmune diseases.


Temporal requirement for high SMN expression in SMA mice.
Spinal muscular atrophy (SMA) is caused by loss of the survival motor neuron 1 gene (SMN1) and retention of the SMN2 gene, resulting in reduced SMN. SMA mice can be rescued with high expression of SMN in neurons, but when is this high expression required? We have developed a SMA mouse with inducible expression of SMN to address the temporal requirement for high SMN expression. Both embryonic and early postnatal induction of SMN resulted in a dramatic increase in survival with some mice living greater than 200 days. The mice had no marked motor deficits and neuromuscular junction (NMJ) function was near normal thus it appears that induction of SMN in postnatal SMA mice rescues motor function. Early postnatal SMN induction, followed by a 1-month removal of induction at 28 days of age, resulted in no morphological or electrophysiological abnormalities at the NMJ and no overt motor phenotype. Upon removal of SMN induction, five mice survived for just over 1 month and two female mice have survived past 8 months of age. We suggest that there is a postnatal period of time when high SMN levels are required. Furthermore, two copies of SMN2 provide the minimal amount of SMN necessary to maintain survival during adulthood. Finally, in the course of SMA, early induction of SMN is most efficacious.


Medical Cannabis: The Oncology Nurse's Role in Patient Education About the Effects of Marijuana on Cancer Palliation .
Cannabis, also known as marijuana, is legal either medicinally or recreationally in 29 states and the District of Columbia, with a majority of the U.S. adult population now living in states where cannabis is legal for medicinal use. As an advocate for patient autonomy and informed choice, the oncology nurse has an ethical responsibility to educate patients about and support their use of cannabis for palliation. . This article aims to discuss the human endocannabinoid system as a basis for better understanding the palliative and curative nature of cannabis as a medicine, as well as review cannabis delivery methods and the emerging role of the oncology nurse in this realm. . This article examines the literature and uses a theoretical-conceptual method to explore the oncology nurse's role in supporting the use of medicinal cannabis by patients with cancer. . The oncology nurse can play a pivotal role in supporting patients' use of cannabis for palliation.


The ethical implications of verbal autopsy: responding to emotional and moral distress.
Verbal autopsy is a pragmatic approach for generating cause-of-death data in contexts without well-functioning civil registration and vital statistics systems. It has primarily been conducted in health and demographic surveillance systems (HDSS) in Africa and Asia. Although significant resources have been invested to develop the technical aspects of verbal autopsy, ethical issues have received little attention. We explored the benefits and burdens of verbal autopsy in HDSS settings and identified potential strategies to respond to the ethical issues identified. This research was based on a case study approach centred on two contrasting HDSS in Kenya and followed the Mapping-Framing-Shaping Framework for empirical bioethics research. Data were collected through individual interviews, focus group discussions, document reviews and non-participant observations. 115 participants were involved, including 86 community members (HDSS residents and community representatives), and 29 research staff (HDSS managers, researchers, census field workers and verbal autopsy interviewers). The use of verbal autopsy data for research and public health was described as the most common potential benefit of verbal autopsy in HDSS. Community members mentioned the potential uses of verbal autopsy data in addressing immediate public health problems for the local population while research staff emphasized the benefits of verbal autopsy to research and the wider public. The most prominent burden associated with the verbal autopsy was emotional distress for verbal autopsy interviewers and respondents. Moral events linked to the interview, such as being unsure of the right thing to do (moral uncertainty) or knowing the right thing to do and being constrained from acting (moral constraint), emerged as key causes of emotional distress for verbal autopsy interviewers. The collection of cause-of-death data through verbal autopsy in HDSS settings presents important ethical and emotional challenges for verbal autopsy interviewers and respondents. These challenges include emotional distress for respondents and moral distress for interviewers. This empirical ethics study provides detailed accounts of the distress caused by verbal autopsy and highlights ethical tensions between potential population benefits and risks to individuals. It includes recommendations for policy and practice to address emotional and moral distress in verbal autopsy.


You see what you look for: Targets and distractors in visual search can cause opposing serial dependencies.
Visual perception is, at any given moment, strongly influenced by its temporal context-what stimuli have recently been perceived and in what surroundings. We have previously shown that to-be-ignored items produce a bias upon subsequent perceptual decisions that acts in parallel with other biases induced by attended items. However, our previous investigations were confined to biases upon the perceived orientation of a visual search target, and it is unclear whether these biases influence perceptual decisions in a more general sense. Here, we test whether the biases from visual search targets and distractors affect the perceived orientation of a neutral test line, one that is neither a target nor a distractor. To do so, we asked participants to search for an oddly oriented line among distractors and report its location for a few trials and next presented a test line irrelevant to the search task. Participants were asked to report the orientation of the test line. Our results indicate that in tasks involving visual search, targets induce a positive bias upon a neutral test line if their orientations are similar, whereas distractors produce an attractive bias for similar test lines and a repulsive bias if the orientations of the test line and the average orientation of the distractors are far apart in feature space. In sum, our results show that both attentional role and proximity in feature space between previous and current stimuli determine the direction of biases in perceptual decisions.


Solidification of a Charged Colloidal Dispersion Investigated Using Microfluidic Pervaporation.
We investigate the dynamics of solidification of a charged colloidal dispersion using an original microfluidic technique referred to as micropervaporation. This technique exploits pervaporation within a microfluidic channel to extract the solvent of a dilute colloidal dispersion. Pervaporation concentrates the colloids in a controlled way up to the tip of the channel until a wet solid made of closely packed colloids grows and invades the microfluidic channel. For the charged dispersion under study, we however evidence a liquid to solid transition (LST) preceding the formation of the solid, owing to the presence of long-range electrostatic interactions. This LST is associated with the nucleation and growth of domains confined in the channel. These domains are then compacted anisotropically up to forming a wet solid of closely packed colloids. This solid then invades the whole channel as in directional drying with a growth rate which depends on the microfluidic geometry. In the final steps of the solidification, we observed the occurrence of cracks and shear bands, the delamination of the wet solid from the channel walls, and its invasion by a receding air front. Interestingly, this air front follows specific patterns within the solid which reveal different microscopic colloidal organizations.


Secretory leukocyte protease inhibitor: a human saliva protein exhibiting anti-human immunodeficiency virus 1 activity in vitro.
Infection of adherent primary monocytes with HIV-1Ba-L is significantly suppressed in the presence of human saliva. By reverse transcriptase (RT) levels, saliva, although present for only 1 h during monocyte viral exposure, inhibited HIV-1 infectivity for 3 wk after infection, whereas human plasma and synovial fluid failed to inhibit HIV-1 infectivity. Antiviral activity was identified in the saliva soluble fraction, and to determine the factor(s) responsible, individual saliva proteins were examined. Of those proteins examined, only secretory leukocyte protease inhibitor (SLPI) was found to possess anti-HIV-1 activity at physiological concentrations. SLPI anti-HIV-1 activity was dose dependent, with maximal inhibition at 1-10 micrograms/ml (> 90% inhibition of RT activity). SLPI also partially inhibited HIV-1IIIB infection in proliferating human T cells. SLPI appears to target a host cell-associated molecule, since no interaction with viral proteins could be demonstrated. However, SLPI anti-HIV-1 activity was not due to direct interaction with or downregulation of the CD4 antigen. Partial depletion of SLPI in whole saliva resulted in decreased anti-HIV-1 activity of saliva. These data indicate that SLPI has antiretroviral activity and may contribute to the important antiviral activity of saliva associated with the infrequent oral transmission of HIV-1.


Three-layer model with absorption for conservative estimation of the maximum acoustic transmission coefficient through the human skull for transcranial ultrasound stimulation.
Transcranial ultrasound stimulation (TUS) has been shown to be a safe and effective technique for non-invasive superficial and deep brain stimulation. Safe and efficient translation to humans requires estimating the acoustic attenuation of the human skull. Nevertheless, there are no international guidelines for estimating the impact of the skull bone. A tissue independent, arbitrary derating was developed by the U.S. Food and Drug Administration to take into account tissue absorption (0.3 dB/cm-MHz) for diagnostic ultrasound. However, for the case of transcranial ultrasound imaging, the FDA model does not take into account the insertion loss induced by the skull bone, nor the absorption by brain tissue. Therefore, the estimated absorption is overly conservative which could potentially limit TUS applications if the same guidelines were to be adopted. Here we propose a three-layer model including bone absorption to calculate the maximum pressure transmission through the human skull for frequencies ranging between 100 kHz and 1.5 MHz. The calculated pressure transmission decreases with the frequency and the thickness of the bone, with peaks for each thickness corresponding to a multiple of half the wavelength. The 95th percentile maximum transmission was calculated over the accessible surface of 20 human skulls for 12 typical diameters of the ultrasound beam on the skull surface, and varies between 40% and 78%. To facilitate the safe adjustment of the acoustic pressure for short ultrasound pulses, such as transcranial imaging or transcranial ultrasound stimulation, a table summarizes the maximum pressure transmission for each ultrasound beam diameter and each frequency.


Glucose metabolism and energy homeostasis in mouse hearts overexpressing dominant negative alpha2 subunit of AMP-activated protein kinase.
AMP-activated protein kinase (AMPK) is an energy-sensing enzyme that plays a pivotal role in regulating cellular metabolism for sustaining energy homeostasis under stress conditions. Activation of AMPK has been observed in the heart during acute and chronic stresses, but its functional role has not been completely understood because of the lack of effective activators and inhibitors of this kinase in the heart. We generated transgenic mice (TG) with cardiac-specific overexpression of a dominant negative mutant of the AMPK alpha2 catalytic subunit to clarify the functional role of this kinase in myocardial ischemia. In isolated perfused hearts subjected to a 10-min ischemia, AMPK alpha2 activity in wild type (WT) increased substantially (by 4.5-fold), whereas AMPK alpha2 activity in TG was similar to the level of WT at base line. Basal AMPK alpha1 activity was unchanged in TG and increased normally during ischemia. Ischemia stimulated a 2.5-fold increase in 2-deoxyglucose uptake over base line in WT, whereas the inactivation of AMPK alpha2 in TG significantly blunted this response. Using 31P NMR spectroscopy, we found that ATP depletion was accelerated in TG hearts during no-flow ischemia, and these hearts developed left ventricular dysfunction manifested by an early and more rapid increase in left ventricular end-diastolic pressure. The exacerbated ATP depletion could not be attributed to impaired glycolytic ATP synthesis because TG hearts consumed slightly more glycogen during this period of no-flow ischemia. Thus, AMPK alpha2 is necessary for maintaining myocardial energy homeostasis during ischemia. It is likely that the functional role of AMPK in myocardial energy metabolism resides both in energy supply and utilization.


Determination of minimum alveolar concentration and cardiovascular effects of desflurane in positive-pressure ventilated sheep.
OBJECTIVE To determine the minimum alveolar concentration of desflurane (MACDES) and effects on cardiovascular variables in positive-pressure ventilated sheep. ANIMALS 13 adult female sheep. PROCEDURES Anesthesia was induced with desflurane. After a 30-minute equilibration at an end-tidal concentration of desflurane (etDES) of 10.5%, an electrical stimulus (5 Hz/ms and 50 mA) was applied for 1 minute or until gross purposeful movement occurred. The etDES was then changed by 0.5% (modified up-down method), depending on whether a positive motor response had been elicited, and stimulation was repeated. The MACDES was the etDES midway between a positive and negative response. After MACDES was determined, etDES was increased to 1.3 and 1.6 MACDES. Animals were allowed to equilibrate for 15 minutes, and cardiovascular, blood gas, acid-base, and hematologic variables were measured. Times to induction of anesthesia, extubation, attainment of sternal position, and standing and duration of anesthesia were recorded. RESULTS Mean ± SD MACDES was 9.81 ± 0.79%. Times to intubation, extubation, and standing were 4.81 ± 2.21 minutes, 14.09 ± 4.05 minutes, and 32.4 ± 12.5 minutes, respectively. Duration of anesthesia was 226 ± 22 minutes. Heart rate increased significantly at induction of anesthesia but otherwise remained at preanesthetic rates. Arterial blood pressures progressively decreased with increasing etDES; pressures increased slightly only in response to noxious stimulation. CONCLUSIONS AND CLINICAL RELEVANCE The MACDES determined here compared favorably with that determined for other sheep populations and indicated similar anesthetic potency as in other species. Desflurane caused dose-dependent arterial hypotension, which indicated the need for careful blood pressure monitoring.


Trauma in the neighborhood: a geospatial analysis and assessment of social determinants of major injury in North America.
We sought to identify and characterize areas with high rates of major trauma events in 9 diverse cities and counties in the United States and Canada. We analyzed a prospective, population-based cohort of injured individuals evaluated by 163 emergency medical service agencies transporting patients to 177 hospitals across the study sites between December 2005 and April 2007. Locations of injuries were geocoded, aggregated by census tract, assessed for geospatial clustering, and matched to sociodemographic measures. Negative binomial models were used to evaluate population measures. Emergency personnel evaluated 8786 major trauma patients, and data on 7326 of these patients were available for analysis. We identified 529 (13.7%) census tracts with a higher than expected incidence of major trauma events. In multivariable models, trauma events were associated with higher unemployment rates, larger percentages of non-White residents, smaller percentages of foreign-born residents, lower educational levels, smaller household sizes, younger age, and lower income levels. Major trauma events tend to cluster in census tracts with distinct population characteristics, suggesting that social and contextual factors may play a role in the occurrence of significant injury events.


Effects of Military Load Carriage on Susceptibility to Enemy Fire During Tactical Combat Movements.
Current military operations require soldiers to carry heavy external loads that are widely acknowledged to impair the ability to move tactically on the battlefield. However, to date, the effect of load on susceptibility to enemy fire (the probability of being hit) has not been examined. Nineteen soldiers completed a break contact simulation (five 30-m sprints commencing every 44 seconds) and a fire and movement simulation (sixteen 6-m bounds commencing every 20 seconds) in each of the 5 load conditions (ranging from 9.8 to 30.1 kg). For each simulation, the impact of load on exposure time and peak movement velocity was examined. In addition, the 6 fastest and 6 slowest soldiers (determined by exposure time in the heaviest condition) were parsed into subgroups to examine interindividual differences in response to load. Susceptibility for the 2 subgroups was modeled using exposure time for the 2 simulations and the assumed reaction time, shooting cadence, and shooting accuracy of the enemy. Susceptibility increased as a function of load for both the break contact and fire and movement simulations and became more pronounced when the participant population was parsed into fast and slow groups. When the impact of personal protection systems was isolated and analyzed, it was found that not only were the slower participants more vulnerable (as a result of not wearing the personal protection system) but also more susceptible than the faster participants who carried 11.2 kg more load. Large interindividual differences in response to external load have meaningful consequences for battlefield susceptibility, and it is therefore critical that personnel are afforded tailored training such that they maximize their proficiency in the execution of tactical combat movements.


Review paper on research ethics in Ethiopia: experiences and lessons learnt from Addis Ababa University College of Health Sciences 2007-2012.
Health research in Ethiopia is increasing both in volume and type, accompanied with expansion of higher education and research since the past few years. This calls for a proportional competence in the governance of medical research ethics in Ethiopia in the respective research and higher learning institutes. The paper highlights the evolution and progress ofthe ethics review at Addis Ababa University - College of Health Sciences (AAU-CHS) in the given context of health research review system in Ethiopia. Reflections are made on the key lessons to be drawnfrom the formative experiences of the Institutional Review Board (IRB) and their implications to the Ethiopian health research review system. This article is a review paper based on review of published and un published documents on research ethics in Ethiopia and the AAU-CHS (2007-2012). Thematic summaries of review findings are presented in thematic areas - formation of ethics review and key factors in the evolution of ethics review and implications. The IRB at AAU-CHS has been pivotal in providing review and follow-up for important clinical studies in Ethiopia. It has been one of the first IRBs to get WHO/SIDCER recognition from Africa and Ethiopia. Important factors in the successes of the IRB among others included leadership commitment, its placement in institutional structure, and continued capacity building. Financial challenges and sustainability issues need to be addressed for the sustained gains registered so far. Similar factors are considered important for the new and younger IRBs within the emergent Universities and research centers in the country.


The use of monoclonal antibodies for studying the biological properties of Staphylococcus aureus endo-beta-N-acetylglucosaminidase.
Staphylococcus aureus endo-beta-N-acetylglucosaminidase (SaG) has been suggested to function as a virulence determinant which interferes with the host cellular immune response. To further characterize the biological properties of SaG, monoclonal antibodies (mAbs) were raised against purified SaG. Four IgG1 subclass mAbs were obtained, none of which reacted with the reduced, sodium dodecyl sulphate pretreated or boiled enzyme. The ability of the mAbs to react with the enzymes present in supernatants obtained from 197 S. aureus strains indicated that they recognized epitopes which are highly conserved; bacteriolytic enzymes produced by staphylococci other than S. aureus did not show any cross-reactivity. After pretreatment of SaG with mAbs (mAb-SaG molar ratios varying from 1 to 20), it was shown that all selected mAbs caused, at a mAb:SaG molar ratio of 10, a 90% inhibition of SaG bacteriolytic activity and a statistically significant reduction of its ability to interfere with phagocytosis by human polymorphonuclear leukocytes. All selected mAbs reacted with several commercially available exo-beta-N-acetylglucosaminidases; mAb C1/10-11 also reacted with chicken and turkey egg muramidases and, at a mAb:SaG molar ratio of 10, inhibited their bacteriolytic activity by 97%. This suggests that one or more epitopes present in the above exo-glucosaminidases and muramidases share some degree of homology with others present in SaG.


Pigeons (Columba livia) learn a four-item list by trial and error.
The aim of the current study was to assess whether pigeons could acquire a four-item list by trial and error. Pigeons received either extensive list training prior to being tested on a novel four-item list (i.e., the full-training group) or very limited training (i.e., the limited-training group). Specifically, subjects in the full-training group were trained to acquire a large set of two-item lists by trial and error, then a large set of three-item lists, and finally a large set of four-item lists. In addition, within each set, the number of training phases was gradually reduced. In contrast, the limited-training group were trained on a single four-item list prior to testing. Only one of the eight subjects (12.5%) in the limited-training group learned the novel four-item list. In contrast, all five subjects (100%) in the full-training group learned the novel four-item list. We suggest that the difference between groups reflects the fact that subjects in the full-training group acquired a learning set over the course of their extensive training. The current study is the first to demonstrate pigeons can learn a four-item list without phased training. (PsycINFO Database Record


Eye movements in visual search indicate impaired saliency processing in Parkinson's disease.
Previous studies have produced contradictory evidence on the nature of the visual search impairment in patients with Parkinson's disease (PD). Eye movements were measured during multi-target search in nine individuals with mild-to-moderate PD. Subjects were asked to click on a response button whenever they judged they were fixating a target for the first time. Compared to age-matched healthy volunteers, PD patients were impaired at efficient search (detecting "+"s amongst "L"s) but not inefficient search ("T"s amongst "L"s). However, these patients had normal memory for locations as indexed by their rate of re-clicking on previously inspected locations. We suggest that the pattern of gaze for efficient search may reflect impaired saliency processing in PD.


Concentration-dependent patterning of the Xenopus ectoderm by BMP4 and its signal transducer Smad1.
Morphogens are thought to establish pattern in early embryos by specifying several cell fates along a gradient of concentration; a well-studied example is the Drosophila protein decapentaplegic (DPP) acting in the wing disc. Recent work has established that bone morphogenetic protein 4 (BMP4), the vertebrate homologue of DPP, controls the fundamental choice between neural and epidermal fates in the vertebrate ectoderm, under the control of antagonists secreted by the organizer region of the mesoderm. We now show that BMP4 can act as a morphogen, evoking distinct responses in Xenopus ectodermal cells at high and low concentrations, in a pattern consistent with the positions of the corresponding cell types in the embryo. Moreover, this complex cellular response to extracellular BMP4 concentration does not require subsequent cell-cell communication and is thus direct, as required of a classical morphogen. We also show that the same series of cell types--epidermis, cement gland and neural tissue--can be produced by progressively inhibiting endogenous BMP signaling with specific antagonists, including the organizer factor noggin. Finally, expression of increasing doses of the signal transduction molecule Smad1 accurately reproduces the response to BMP4 protein. Since Smads have been shown to act in the nucleus, this finding implies a direct translation of extracellular morphogen concentration into transcription factor activity. We propose that a graded distribution of BMP activity controls the specification of several cell types in the gastrula ectoderm and that this extracellular gradient acts by establishing an intracellular and then nuclear gradient of Smad activity.


Screening mammography beliefs and recommendations: a web-based survey of primary care physicians.
The appropriateness and cost-effectiveness of screening mammography (SM) for women younger than 50 and older than 74 years is debated in the clinical research community, among health care providers, and by the American public. This study explored primary care physicians' (PCPs) perceptions of the influence of clinical practice guidelines for SM; the recommendations for SM in response to hypothetical case scenarios; and the factors associated with perceived SM effectiveness and recommendations in the US from June to December 2009 before the United States Preventive Services Task Force (USPSTF) recently revised guidelines. A nationally representative sample of 11,922 PCPs was surveyed using a web-based questionnaire. The response rate was 5.7% (684); (41%) 271 family physicians (FP), (36%) 232 general internal medicine physicians (IM), (23%) 150 obstetrician-gynaecologists (OBG), and (0.2%) 31 others. Cross-sectional analysis examined PCPs perceived effectiveness of SM, and recommendation for SM in response to hypothetical case scenarios. PCPs responses were measured using 4-5 point adjectival scales. Differences in perceived effectiveness and recommendations for SM were examined after adjusting for PCPs specialty, race/ethnicity, and the US region. Compared to IM and FP, OBG considered SM more effective in reducing breast cancer mortality among women aged 40-49 years (p = 0.003). Physicians consistently recommended mammography to women aged 50-69 years with no differences by specialty (p = 0.11). However, 94% of OBG "always recommended" SM to younger and 86% of older women compared to 81% and 67% for IM and 84% and 59% for FP respectively (p = < .001). In ordinal regression analysis, OBG specialty was a significant predictor for perceived higher SM effectiveness and recommendations for younger and older women. In evaluating hypothetical scenarios, overall PCPs would recommend SM for the 80 year woman with CHF with a significant variation by specialty (38% of OBG, 18% of FP, 17% of IM; p = < .001). A majority of physicians, especially OBG, favour aggressive breast cancer screening for women from 40 through 79 years of age, including women with short life expectancy. Policy interventions should focus on educating providers to provide tailored recommendations for mammography based on individualized cancer risk, health status, and preferences.


Change through persuasion.
Faced with the need for a massive change, most managers respond predictably. They revamp the organization's strategy, shift around staff, and root out inefficiencies. They then wait patiently for performance to improve--only to be bitterly disappointed because they've failed to adequately prepare employees for the change. In this article, the authors contend that to make change stick, leaders must conduct an effective persuasion campaign-one that begins weeks or months before the turn-around plan is set in concrete. Like a political campaign, a persuasion campaign is largely one of differentiation from the past. Turnaround leaders must convince people that the organization is truly on its deathbed-or, at the very least, that radical changes are required if the organization is to survive and thrive. (This is a particularly difficult challenge when years of persistent problems have been accompanied by few changes in the status quo.) And they must demonstrate through word and deed that they are the right leaders with the right plan. Accomplishing all this calls for a four-part communications strategy. Prior to announcing a turnaround plan, leaders need to set the stage for employees' acceptance of it. At the time of delivery, they must present a framework through which employees can interpret information and messages about the plan. As time passes, they must manage the mood so that employees' emotional states support implementation and follow-through. And at critical intervals, they must provide reinforcement to ensure that the desired changes take hold and that there's no backsliding. Using the example of the dramatic turn-around at Boston's Beth Israel Deaconess Medical Center, the authors elucidate the inner workings of a successful change effort.


Binding of the N-terminal domain of the lactococcal bacteriophage TP901-1 CI repressor to its target DNA: a crystallography, small angle scattering, and nuclear magnetic resonance study.
In most temperate bacteriophages, regulation of the choice of lysogenic or lytic life cycle is controlled by a CI repressor protein. Inhibition of transcription is dependent on a helix-turn-helix motif, often located in the N-terminal domain (NTD), which binds to specific DNA sequences (operator sites). Here the crystal structure of the NTD of the CI repressor from phage TP901-1 has been determined at 1.6 Å resolution, and at 2.6 Å resolution in complex with a 9 bp double-stranded DNA fragment that constitutes a half-site of the OL operator. This N-terminal construct, comprising residues 2-74 of the CI repressor, is monomeric in solution as shown by nuclear magnetic resonance (NMR), small angle X-ray scattering, and gel filtration and is monomeric in the crystal structures. The binding interface between the NTD and the half-site in the crystal is very similar to the interface that can be mapped by NMR in solution with a full palindromic site. The interactions seen in the complexes (in the crystal and in solution) explain the observed affinity for the OR site that is lower than that for the OL site and the specificity for the recognized DNA sequence in comparison to that for other repressors. Compared with many well-studied phage repressor systems, the NTD from TP901-1 CI has a longer extended scaffolding helix that, interestingly, is strongly conserved in putative repressors of Gram-positive pathogens. On the basis of sequence comparisons, we suggest that these bacteria also possess repressor/antirepressor systems similar to that found in phage TP901-1.


Influence of electronic and molecular structure on the fragmentation dynamic of even-electron carbocationic triangulenes and helicenes in the gas phase.
Stable, long-lived organic cations are directly transferred by electrospray ionization (ESI) from solution into the gas phase where their collision-induced dissociations (CID) are studied by tandem mass spectrometry. Three related types of triphenyl carbenium ions are investigated, in which the meta positions are either substituted by methoxy groups or tertiary nitrogen bridges, including tetramethoxyphenylacridinium (TMPA+ ), dimethoxyquinacridinium (DMQA+ ), and triazatriangulenium (TATA+ ) cations. These ions are triangular in shape with increasing degrees of planarity. Fragmentation occurs at the periphery of the triangular molecule, involving the methoxy groups and the substituent of the nitrogen bridge. Each initial precursor cation is an even electron (EE) system and shows competing dissociations into both even (EE) and odd electron (OE) fragment ions. The latter reaction is a breach of the classic 'even-electron rule' in mass spectrometry. While the EE fragment dissociates similar to the precursor, the OE fragment ion shows a rich radical-induced fragmentation pattern. Two driving forces direct the fragmentation of the EE precursor ion toward OE fragment ions, including the release of stabilized radicals and the extension of the π-system by increasing planarization of the triangulene core. Copyright © 2017 John Wiley & Sons, Ltd.


Homocysteine and cardiovascular disease.
Research over the past decade has shown that elevated levels of homocysteine have a strong association with all forms of atherothrombotic disease and venous thromboembolism. This association is particularly strong for coronary disease and newer data indicate that screening for homocysteine levels may be warranted in those with unexplained thrombotic tendencies and in young patients who develop coronary events or disease without the usual predisposing factors such as hypertension, smoking, hypercholesterolemia, or diabetes. Although the link between hyperhomocysteinemia and cardiac disease has not been conclusively shown to be causal as yet, data are emerging that lowering homocysteine levels may be beneficial in patients at high risk. Such lowering can be done safely and inexpensively with increased intake of fruits and vegetables and in those patients who are particularly at high risk using supplementation with folic acid and the B vitamins. Preliminary studies have shown that lowering homocysteine levels in this manner may slow the progression of atherosclerosis in coronary and carotid vessels. No mortality data exist yet showing that reducing homocysteine reduces cardiac or total mortality, although it is likely that ongoing and planned trials that are underway will shed light on these important questions soon.


Neuroimaging and psychophysiological investigation of the link between anxiety, enhanced affective reactivity and interoception in people with joint hypermobility.
Anxiety is associated with increased physiological reactivity and also increased "interoceptive" sensitivity to such changes in internal bodily arousal. Joint hypermobility, an expression of a common variation in the connective tissue protein collagen, is increasingly recognized as a risk factor to anxiety and related disorders. This study explored the link between anxiety, interoceptive sensitivity and hypermobility in a sub-clinical population using neuroimaging and psychophysiological evaluation. Thirty-six healthy volunteers undertook interoceptive sensitivity tests, a clinical examination for hypermobility and completed validated questionnaire measures of state anxiety and body awareness tendency. Nineteen participants also performed an emotional processing paradigm during functional neuroimaging. We confirmed a significant relationship between state anxiety score and joint hypermobility. Interoceptive sensitivity mediated the relationship between state anxiety and hypermobility. Hypermobile, compared to non-hypermobile, participants displayed heightened neural reactivity to sad and angry scenes within brain regions implicated in anxious feeling states, notably insular cortex. Our findings highlight the dependence of anxiety state on bodily context, and increase our understanding of the mechanisms through which vulnerability to anxiety disorders arises in people bearing a common variant of collagen.


An Australian longitudinal pilot study examining health determinants of cardiac outcomes 12 months post percutaneous coronary intervention.
Percutaneous coronary intervention (PCI) is a very common revascularisation procedure for coronary artery disease (CAD). The purpose of this study was to evaluate cardiac outcomes, health related quality of life (HRQoL), resilience and adherence behaviours in patients who have undergone a PCI at two time points (6 and 12 months) following their procedure. A longitudinal pilot study was conducted to observe the cardiac outcomes across a cohort of patients who had undergone a percutaneous coronary intervention (PCI). Participants who had undergone PCI 6 months prior were invited. Those participants who met the inclusion criteria and provided consent then completed a telephone survey (time point 1). These participants were then contacted 6 months later (i.e. 12 months post-intervention, time point 2) and the measures were repeated. All patients (n = 51) were recorded as being alive at time point 1. The multiple model indicated that controlling for other factors, gender was significantly associated with a linear combination of outcome measures (p = 0.004). The effect was moderate in magnitude (partial-η(2) = 0.303), where males performed significantly better than females 6 months after the PCI procedure physically and with mood. Follow-up univariate ANOVAs indicated that gender differences were grounded in the scale measuring depression (PHQ9) (p = 0.005) and the physical component score of the short form measuring HRQoL (SF12-PCS) (p = 0.003). Thirteen patients were lost to follow-up between time points 1 and 2. One patient was confirmed to have passed away. The pattern of correlations between outcome measures at time point 2 revealed statistically significant negative correlation between the PHQ instrument and the resilience scale (CD-RISC) (r = -0.611; p < 0.001); and the physical component score of the SF-12 instrument (r = -0.437; p = 0.054). Men were performing better than women in the 6 months post-PCI, particularly in the areas of mood (depression) and physical health. This pilot results indicate gender-sensitive practices are recommended particularly up to 6 months post-PCI. Any gender differences observed at 6 month appear to disappear at 12 months post-PCI. Further research into the management of mood particularly for women post-PCI is warranted. A more detailed inquiry related to access/attendance to secondary prevention is also warranted.


Flame spray-pyrolyzed vanadium oxide nanoparticles for lithium battery cathodes.
Vanadium pentoxide (V2O5) nanoparticles (30-60 nm) were made by a one-step and scalable flame spray pyrolysis (FSP) process. Optimization of the FSP processing conditions (precursor concentration and injection rate) enhanced the electrochemical performance of these nanoparticles. Increasing the cut-off potential for discharging from 1.5 to 2.5 V vs. Li/Li+ improved the cycle life of these V2O5 nanoparticles. Particles with the lowest specific surface area (approximately 32 m2 g(-1)) and highest phase purity (up to 98 wt%) showed excellent cyclability between 2.5 and 4.0 V vs. Li/Li+, retaining a specific charge of 110 mAh g(-1) beyond 100 cycles at a specific current of 100 mA g(-1), and also superior specific charge of 100 mAh g(-1) at specific current up to 20C rate (or 2000 mA g(-1)).