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Parkinson's disease (PD) is an idiopathic disease of the nervous system characterized by progressive tremor, bradykinesia, rigidity, and postural instability. It has been postulated that exogenous toxicants, including pesticides, might be involved in the etiology of PD. In this article we present a comprehensive review of the published epidemiologic and toxicologic literature and critically evaluate whether a relationship exists between pesticide exposure and PD. From the epidemiologic literature, there does appear to be a relatively consistent relationship between pesticide exposure and PD. This relationship appears strongest for exposure to herbicides and insecticides, and after long durations of exposure. Toxicologic data suggest that paraquat and rotenone may have neurotoxic actions that potentially play a role in the development of PD, with limited data for other pesticides. However, both the epidemiology and toxicology studies were limited by methodologic weaknesses. Particular issues of current and future interest include multiple exposures (both pesticides and other exogenous toxicants), developmental exposures, and gene-environment interactions. At present, the weight of evidence is sufficient to conclude that a generic association between pesticide exposure and PD exists but is insufficient for concluding that this is a causal relationship or that such a relationship exists for any particular pesticide compound or combined pesticide and other exogenous toxicant exposure. [ABSTRACT FROM AUTHOR]

Exertional rhabdomyolysis is an uncommon diagnosis, but because its complications can be severe, clinicians need a thorough understanding of this syndrome. When skeletal muscle cell membranes are damaged, their intracellular contents enter the bloodstream and can cause potentially serious sequelae, even death. Intense exercise, some viral infections, and certain genetic disorders increase the risk. Serum creatine kinase levels are the diagnostic gold standard. The treatment of rhabdomyolysis consists of early detection, therapy for the underlying cause, measures to prevent renal failure, and correction of metabolic complications. [ABSTRACT FROM AUTHOR]

BACKGROUND: A sulphur dioxide (SO(2)) episode occurred in the United Kingdom in 1998. The worst affected area was the city of Nottingham. METHODS: Emergency hospital admissions in Nottingham in the episode week were compared with those in the previous week. RESULTS: A statistically significant increase in admissions for all respiratory diseases occurred in the episode week (odds ratio (OR) = 1.40, 95 per cent confidence interval (CI) = 1.00-1.94). Ten of the 25 excess admissions were for asthma, although the excess for asthma alone was not statistically significant (OR = 1.90, 95 per cent CI = 0.87-4.15). CONCLUSIONS: The excess admissions for respiratory diseases could have been caused by exposure to SO(2), to other pollutants present in increased concentrations during the pollution episode, or by seasonal variations in the frequency of asthma symptoms, or prevailing weather conditions. This study shows how simple analyses of routinely collected health data can be used to assess public health impacts of pollution episodes. [ABSTRACT FROM AUTHOR]

Oxidized lipids arising from oxidative stress are associated with many serious health conditions, including cardiovascular diseases. For example, KDdiA-PC and KOdiA-PC are two oxidized phosphatidylcholines (oxPC) directly linked to atherosclerosis, which precipitate heart failure, stroke, aneurysms, and chronic kidney disease. These oxPCs are well-characterized in small particles such as low-density lipoprotein, but how their presence affects the biophysical properties of larger bilayer membranes is unclear. It is also unclear how membrane mediators, such as cholesterol, affect lipid bilayers containing these oxPCs. Here, we characterize supported lipid bilayers (SLBs) containing POPC, KDdiA-PC, or KOdiA-PC, and cholesterol. We used a quartz crystal microbalance with dissipation monitoring (QCM-D), fluorescence microscopy, and all-atom molecular dynamics (MD) to examine the formation process, biophysical properties, and specific lipid conformations in simulated bilayers. Experimentally, we show that liposomes containing either oxPC form SLBs by rupturing on contact with SiO 2 substrates, which differs from the typical adsorption-rupture pathway observed with nonoxidized liposomes. We also show that increasing the oxPC concentration in SLBs results in thinner bilayers that contain defects. Simulations reveal that the oxidized sn -2 tails of KDdiA-PC and KOdiA-PC bend out of the hydrophobic membrane core into the hydrophilic headgroup region and beyond. The altered conformations of these oxPC, which are affected by cholesterol content and protonation state of the oxidized functional groups, contribute to trends of decreasing membrane thickness and increasing membrane area with increasing oxPC concentration. This combined approach provides a comprehensive view of the biophysical properties of membranes containing KDdiA-PC and KOdiA-PC at the molecular level, which is crucial to understanding the role of lipid oxidation in cardiovascular disease and related immune responses.

Harmonized global collaborations are crucial to improving outcomes in hormone sensitive operable breast cancer.

Oxidative stress leads to the production of oxidized phospholipids (oxPLs) that modulate the biophysical properties of phospholipid monolayers and bilayers. As many immune cells are responsible for surveilling cells and tissues for the presence of oxPLs, oxPL-dependent mechanisms have been suggested as targets for treating chronic kidney disease, atherosclerosis, diabetes, and cancer metastasis. This review details recent experimental and computational studies that characterize oxPLs' behaviors in various monolayers and bilayers. These studies investigate how the tail length and polar functional groups of OxPLs impact membrane properties, how oxidized membranes can be stabilized, and how membrane integrity is generally affected by oxidized lipids. In addition, for oxPL-containing membrane modeling and simulation, CHARMM-GUI Membrane Builder has been extended to support a variety of oxPLs, accelerating the simulation system building process for these biologically relevant lipid bilayers., Competing Interests: Declaration of competing interest W.I. is the co-founder and CEO of MolCube INC., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The distributions of vegetation and fire activity are changing rapidly in response to climate warming. In many regions, climate effects on dead fuel moisture content (FMC) are expected to increase future wildfire activity. However, forest FMC is largely driven by microclimate conditions, which are moderated from open weather by vegetation canopies. As shifts in vegetation increase under climate warming, the extent to which future fire activity will be driven by climate directly or associated vegetation shifts remains unresolved. Here, we present a study aimed at quantifying the relative magnitudes of (i) direct climate warming, and (ii) vegetation change, on FMC. Field sites to evaluate these effects were established in a natural laboratory of altered forest states to mature wet temperate forest in south-eastern Australia. FMC was estimated using a process-based model and 48 years of reconstructed climate data. Canopy effects on microclimate were captured by transferring inputs from climate to microclimate using models parameterised with field observations. To evaluate the relative magnitude of climate and vegetation effects, we calculated the maximum difference in mean annual FMC across annual climate replicates and compared this to FMC differences across reorganising forest sites. Our results show vegetation effects on FMC can exceed those related to expected climate change. Changes to forest structure and composition increased (+15.7%) and decreased (-12.3%) mean annual FMC, with a larger negative effect when forest cover was completely removed (-18.5%). In contrast, the largest climate effect on FMC was -6.6% across 48-years of data. Our study demonstrates that the magnitude of vegetation effects on FMC can exceed expected climate change effects. Models of future fire activity that do not account for changing vegetation effects on microclimate are omitting a key biophysical control on FMC and therefore may not be accurately predicting future fire activity., (© 2023 John Wiley & Sons Ltd.)

Many inhaler devices are currently used in clinical practice to deliver medication, with each inhaler device offering different benefits to overcome technique issues. Inhaler technique remains poor, contributing to reduced airway drug deposition and consequently poor disease control. Scoring inhaler technique has been used within research as an outcome measure of inhaler technique assessment, and this systematic review collates and evaluates these scoring methods. The review protocol was prospectively registered in PROSPERO (CRD42020218869). A total of 172 articles were screened with 77 included, and the results presented using narrative synthesis due to the heterogeneity of the study design and data. The most frequently used scoring method awarded one point per step in the inhaler technique checklist and was included in 59/77 (77%) of articles; however limited and varied guidance was provided for score interpretation. Other inhaler technique scoring methods included grading the final inhaler technique score, expressing the total score as a percentage/ratio, deducting points from the final score when errors were made, and weighting steps within the checklist depending on how crucial the step was. Vast heterogeneity in the number of steps and content in the inhaler technique checklists was observed across all device types (range 5-19 steps). Only 4/77 (5%) of the inhaler technique measures had undertaken fundamental steps required in the scale development process for use in real world practice. This review demonstrates the demand for a tool that measures inhaler technique and highlights the current unmet need for one that has undergone validation., Competing Interests: Declaration of competing interest There is no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Among people living with HIV (PLWH), 50% report substance use disorders (SUDs), and 30-61% report posttraumatic stress disorder (PTSD). Comorbid PTSD/SUD/HIV has been linked to faster HIV progression and twice the rate of death, lower medical adherence and retention, and increased viral load compared to PLWH without co-occurring PTSD or SUD. A critical first step in establishing comprehensive mental health services for PLWH is the implementation of an evidence-based screening protocol for PTSD and SUDs to facilitate referrals to specialty mental health providers. Guided by the Consolidated Framework for Implementation Research, this mixed-methods study aimed to examine the feasibility of delivering the REACH (Resiliency, Engagement, and Accessibility for Comorbid HIV/PTSD/SUD populations) Screening protocol. Three case managers were instructed to provide the REACH screening electronically to all patients that they saw for enrollment or re-enrollment appointments over 3 months (n=102). Of the 70 patients who completed the screener, 27% had clinically significant PTSD symptoms and 48.6% had SUD concerns. Qualitative feedback revealed themes related to beliefs about SU and PTSD, attitudes toward screening, comfort in the discussion of SU and PTSD, and referral and treatment considerations. Discussion includes lessons learned for implementation of this assessment of PTSD/SUD in PLWH as a novel approach to increase mental health engagement and promote health equity, with the potential long-term impact of improving HIV care outcomes via ameliorating mental health/SUD, and implications for prevention of HIV transmission. Implementation science can be leveraged to understand the gap in the utilization of existing evidence-based screening tools in HIV care settings., (© 2023. National Council for Mental Wellbeing.)

Supporting self-management is key in improving disease control, with technology increasingly utilised. We hypothesised the addition of telehealth support following assessment in an integrated respiratory clinic could reduce unscheduled healthcare visits in patients with asthma and COPD. Following treatment optimisation, exacerbation-prone participants or those with difficulty in self-management were offered telehealth support. This comprised automated twice-weekly telephone calls, with a specialist nurse triaging alerts. We performed a matched cohort study assessing additional benefits of the telehealth service, matching by: confirmed diagnosis, age, sex, FEV 1 percent predicted, smoking status and ≥1 exacerbation in the last year. Thirty-four telehealth participants were matched to twenty-nine control participants. The telehealth cohort generated 165 alerts, with 29 participants raising at least one alert; 88 (53.5%) alerts received a call discussing self-management, of which 35 (21%) received definitive advice that may otherwise have required an unscheduled healthcare visit. There was a greater reduction in median exacerbation rate across both telehealth groups at 6 months post-intervention (1 to 0, p < 0.001) but not in control groups (0.5 to 0.0, p = 0.121). Similarly, there was a significant reduction in unscheduled GP visits across the telehealth groups (1.5 to 0.0, p < 0.001), but not the control groups (0.5 to 0.0, p = 0.115). These reductions led to cost-savings across all groups, but greater in the telehealth cohorts. The addition of telehealth support to exacerbation-prone patients with asthma or COPD, following comprehensive assessment and treatment optimisation, proved beneficial in reducing exacerbation frequency and unscheduled healthcare visits and thus leads to significant cost-savings for the NHS.Clinical Trial Registration: ClinicalTrials.gov: NCT03096509., (© 2022. The Author(s).)

What Is Known and Object: Aspiration pneumonia is a clinically important infectious process that can result in increased morbidity and mortality. Empiric antimicrobial therapy with activity against anaerobes has been a standard practice based on previous studies, which isolated anaerobes from respiratory cultures. Recent studies have failed to identify anaerobes as causative pathogens, however, these studies did not assess patient outcomes based on the presence or absence of anaerobic coverage., Methods: This retrospective cohort study evaluated patients at least 18 years of age requiring mechanical ventilation diagnosed with aspiration pneumonia between 1 October 2020 and 31 July 2021. The primary outcome was the incidence of clinical failure. Secondary outcomes included the time to clinical failure, the incidence of Clostridioides difficile infections and development of multidrug-resistant infections, as well as time on mechanical ventilation and intensive care unit length of stay., Results: A total of 141 patients were included with 83 patients initially receiving anaerobic coverage and 58 patients treated without anaerobic coverage. There was no difference in the incidence of clinical failure between cohorts (18.1% vs. 22.4%; p = 0.41). There was a statistically significant difference in anaerobic escalations with more escalations in the cohort without anaerobic coverage (0% vs. 20.7%; p < 0.0001). Patients initially treated with drugs with anaerobic activity had a higher incidence of multidrug resistant infections on current admission (7.2% vs. 0%; p = 0.04) and a longer length of intensive care unit stay., What Is New and Conclusion: In critically ill adults with aspiration pneumonia, our study found no difference in clinical failure based on the presence or absence of empiric anaerobic coverage adding to evolving literature suggesting that anaerobic coverage is not routinely warranted in this patient population. Interpretation of the results needs to consider, however, that the retrospective design led to the inclusion of sicker patients in the anaerobic cohort. The frequency of empiric anaerobic coverage demonstrates the need for a prospective randomized control trial to confirm these findings., (© 2022 John Wiley & Sons Ltd.)

Introduction: This study sought to identify the availability of automated external defibrillators (AEDs) in schools in the region served by West Midlands Ambulance Service University NHS Trust (WMAS), United Kingdom, and the number of out-of-hospital cardiac arrests (OHCA) that occurred at or near to schools. A secondary aim was to explore the cost effectiveness of school-based defibrillators., Methods: This observational study used data from the national registry for OHCA (University of Warwick) to identify cases occurring at or near schools between January 2014 and December 2016 in WMAS region (n = 11,399). A school survey (n = 2,453) was carried out in September 2017 to determine the presence of AEDs and their registration status with WMAS. Geographical Information System mapping software identified OHCAs occurring within a 300-metre radius of a school. An economic analysis calculated the cost effectiveness of school-based AEDs., Results: A total of 39 (0.34%) of all OHCAs occurred in schools, although 4,250 (37.3%) of OHCAs in the region were estimated to have occurred within 300 metres of a school. Of 323 school survey responses, 184 (57%) had an AED present, of which 24 (13.0%) were available 24 h/day. Economic modelling of a school-based AED programme showed additional quality-adjusted life years (QALY) of 0.26 over the lifetime of cardiac arrest survivors compared with no AED programme. The incremental cost-effectiveness ratio (ICER) was £8,916 per QALY gained., Conclusion: Cardiac arrests in schools are rare. Registering AEDs with local Emergency Medical Services and improving their accessibility within their local community would increase their utility., (© 2022 The Author(s).)

Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Claire A. Hawkes, Inès Kander, Terry P. Brown, Scott Booth, Abraham Contreras and Chen Ji, and Gavin D. Perkins are employed by the University of Warwick, which receives grants from the British Heart Foundation (BHF) and the Resuscitation Council (UK) for the conduct of the Out-of-Hospital Cardiac Arrest outcomes project. Terry P. Brown is supported by the National Institute for Health Research (NIHR) Applied Research Collaboration (ARC) West Midlands. A. Niroshan Siriwardena currently receives research funding from the NIHR, the Medical Research Council, Health and Care Research Wales, and Health Education England. Rachael T. Forthergill is employed by the London Ambulance Service NHS Trust. Estelle Stephenson is employed by the British Hearth Foundation. Gavin D. Perkins is an Editorial Board Member for Resuscitation Plus and is supported by the National Institute for Health Research (NIHR) Applied Research Collaboration (ARC) West Midlands and Director of Research for the Intensive Care Foundation. The remaining authors have no disclosures to report. The views expressed in this paper are those of the authors and not necessarily those of the NIHR, Department of Health and Social Care, the BHF, or the Resuscitation Council UK.

Background: Early defibrillation is an essential element of the chain of survival for out-of-hospital cardiac arrest (OHCA). Public access defibrillation (PAD) programmes aim to place automated external defibrillators (AED) in areas with high OHCA incidence, but there is sometimes a mismatch between AED density and OHCA incidence., Objectives: This study aimed to assess whether there were any disparities in the characteristics of areas that have an AED and those that do not in England., Methods: Details of the location of AEDs registered with English Ambulance Services were obtained from individual services or internet sources. Neighbourhood characteristics of lower layer super output areas (LSOA) were obtained from the Office for National Statistics. Comparisons were made between LSOAs with and without a registered AED., Results: AEDs were statistically more likely to be in LSOAs with a lower residential but higher workplace population density, with people predominantly from a white ethnic background and working in higher socio-economically classified occupations (p < 0.05). There was a significant correlation between AED coverage and the LSOA Index of Multiple Deprivation (IMD) (r = 0.79, p = 0.007), with only 27.4% in the lowest IMD decile compared to about 45% in highest. AED density varied significantly across the country from 0.82/km 2 in the north east to 2.97/km 2 in London., Conclusions: In England, AEDs were disproportionately placed in more affluent areas, with a lower residential population density. This contrasts with locations where OHCAs have previously occurred. Future PAD programmes should give preference to areas of higher deprivation and be tailored to the local community., Competing Interests: Declaration of Competing Interest Terry Brown and Gavin Perkins are affiliated to the National Institute for Health Research (NIHR) Applied Research Collaboration (ARC) West Midlands. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. Gavin Perkins is co-chair of International Liaison Committee for Resuscitation, Director of Science and Research at European Resuscitation Council, and Chair of Community and Ambulance Research Committee of Resuscitation Council UK. Charles Deakin is a trustee of the Resuscitation Council UK, domain leader for defibrillation with the International Liaison Committee for Resuscitation, and member of the Advanced Life Support Working Group at European Resuscitation Council., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Aim: Bystander CPR rates have steadily increased in England between 2014 and 2018. In West Yorkshire, there have been two important developments during this time. We aimed to describe whether postcode districts (PCDs) with more cumulative annual 'Restart a Heart' (RSAH) and/or Community First Responder (CFR) scheme activity between 2014 and 2018 were associated with greater improvements in non-EMS bystander CPR rates for out-of-hospital cardiac arrest (OHCA) when compared with PCDs in the same region with lesser or no such historic activity during the same time period., Method: We collated data from the OHCA Outcomes Registry for all non-EMS witnessed OHCA in West Yorkshire treated by Yorkshire Ambulance Service. We analysed clusters of PCDs with high and low levels of RSAH and CFR activity between 2014 and 2018 using descriptive statistics, and comparisons were made between groups using chi-square and t-test., Results: The reported bystander CPR rate for non-EMS witnessed OHCA cases for West Yorkshire rose from 38.4% in 2014 to 69.7% in 2018. The largest increases were seen in PCDs with high RSAH activity (+34.3%) and in the combination of high RSAH and low CFR activity (+38.5%). There was no significant difference when considering the interaction between RSAH and CFR groups., Conclusion: The data infers the possibility of a non-significant association between improved non-EMS bystander CPR rates and RSAH training and CFR scheme activity. We recommend coordinated mass training, in particular for children in regions where CPR is not a mandatory part of the school curriculum., (© 2021 The Author(s).)

Aims: The out-of-hospital cardiac arrest (OHCA) outcomes project is a national research registry. One of its aims is to explore sources of variation in OHCA survival outcomes. This study reports the development and validation of risk prediction models for return of spontaneous circulation (ROSC) at hospital handover and survival to hospital discharge., Methods and Results: The study included OHCA patients who were treated during 2014 and 2015 by emergency medical services (EMS) from seven English National Health Service ambulance services. The 2014 data were used to identify important variables and to develop the risk prediction models, which were validated using the 2015 data. Model prediction was measured by area under the curve (AUC), Hosmer-Lemeshow test, Cox calibration regression, and Brier score. All analyses were conducted using mixed-effects logistic regression models. Important factors included age, gender, witness/bystander cardiopulmonary resuscitation (CPR) combined, aetiology, and initial rhythm. Interaction effects between witness/bystander CPR with gender, aetiology and initial rhythm and between aetiology and initial rhythm were significant in both models. The survival model achieved better discrimination and overall accuracy compared with the ROSC model (AUC = 0.86 vs. 0.67, Brier score = 0.072 vs. 0.194, respectively). Calibration tests showed over- and under-estimation for the ROSC and survival models, respectively. A sensitivity analysis individually assessing Index of Multiple Deprivation scores and location in the final models substantially improved overall accuracy with inconsistent impact on discrimination., Conclusion: Our risk prediction models identified and quantified important pre-EMS intervention factors determining survival outcomes in England. The survival model had excellent discrimination., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Background : Allergen avoidance is important in allergic asthma management. Nocturnal treatment with Temperature-controlled Laminar Airflow (TLA) has been shown to provide a significant reduction in the exposure to allergens in the breathing zone, leading to a long-term reduction in airway inflammation and improvement in Quality of life (QoL). Allergic asthma patients symptomatic on Global Initiative for Asthma (GINA) step 4/5 were found to benefit the most as measured by Asthma Quality of Life Questionnaire (AQLQ). However, the effect of TLA on severe asthma exacerbations is uncertain and therefore a meta-analysis was performed. Methods : Patients with severe allergic asthma (GINA 4/5) were extracted from two 1-year randomised, double-blind, placebo-controlled trials conducted with TLA. A meta-analysis of the effect on severe exacerbations was performed by negative binomial regression in a sequential manner, defined by baseline markers of asthma control (symptoms and QoL scores). Results : The pooled dataset included 364patients. Patients with more symptoms at baseline (ACT<18 or ACQ7>3; N=179), had a significant mean 41% reduction in severe exacerbations (RR=0.59 (0.38-0.90); p=0.015) in favour of TLA. Higher ACQ7 cut-points of 3.5-4.5 resulted in significant reductions of 48-59%.More uncontrolled patients based on AQLQ total and symptom domains ≤3.0 at baseline also showed a significant reduction in severe exacerbations for TLA vs. placebo ((47% (p=0.037) and 53% (p=0.011), respectively). The meta-analysis also confirmed a significant difference in AQLQ-responders ((Minimal Clinically Important Difference)≥0.5; 74% vs. 43%, p=0.04). Conclusion : This meta-analysis of individual patient data shows a beneficial effect on severe exacerbations and quality of life for TLA over placebo in more symptomatic patients with severe allergic asthma. These outcomes support the national management recommendations for patients with symptomatic severe allergic asthma. The actual effect of TLA on severe exacerbations should be confirmed in a prospective study with larger numbers of patients., Competing Interests: AJC was Chief Investigator of the LASER Trial and currently conducting the LASER-48 trial funded by Airsonett. He has been on advisory boards for Sanofi Genzyme, Novartis, XIM, Glyconics and Exhalation Technology. TPB and WS have no conflicts to declare. LBJ was on the scientific advisory board and an investigator on the 4As trial. He has given paid lectures during Airsonett symposia at international conferences. GE has been on a scientific advisory board and has consulted for Airsonett and other companies. FR has no conflicts of interest to report. SP has consulted for Airsonett and other companies. JOW has been a member of scientific advisory boards and/or run clinical trials with funding from Airsonett, UCB pharma, AstraZeneca, Novartis, Allergy Therapeutics, Merck and Danone/Nutricia., (© 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

COVID-19 is frequently accompanied by a hypercoagulable inflammatory state with microangiopathic pulmonary changes that can precede the diffuse alveolar damage characteristic of typical acute respiratory distress syndrome (ARDS) seen in other severe pathogenic infections. Parallels with systemic inflammatory disorders such as atypical hemolytic uremic syndrome (aHUS) have implicated the complement pathway in the pathogenesis of COVID-19, and particularly the anaphylatoxins C3a and C5a released from cleavage of C3 and C5, respectively. C5a is a potent cell signalling protein that activates a cytokine storm-a hyper-inflammatory phenomenon-within hours of infection and the innate immune response. However, excess C5a can result in a pro-inflammatory environment orchestrated through a plethora of mechanisms that propagate lung injury, lymphocyte exhaustion, and an immune paresis. Furthermore, disruption of the homeostatic interactions between complement and extrinsic and intrinsic coagulation pathways contributes to a net pro-coagulant state in the microvasculature of critical organs. Fatal COVID-19 has been associated with a systemic inflammatory response accompanied by a pro-coagulant state and organ damage, particularly microvascular thrombi in the lungs and kidneys. Pathologic studies report strong evidence of complement activation. C5 blockade reduces inflammatory cytokines and their manifestations in animal studies, and has shown benefits in patients with aHUS, prompting investigation of this approach in the treatment of COVID-19. This review describes the role of the complement pathway and particularly C5a and its aberrations in highly pathogenic virus infections, and therefore its potential as a therapeutic target in COVID-19., (© 2020 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

SLC6A14 is a Na+/Cl--coupled transporter for neutral and cationic amino acids. It is expressed at basal levels in the normal colon but is up-regulated in colon cancer. However, the relevance of this up-regulation to cancer progression and the mechanisms involved in the up-regulation remain unknown. Here, we show that SLC6A14 is essential for colon cancer and that its up-regulation involves, at least partly, Wnt signaling. The up-regulation of the transporter is evident in most human colon cancer cell lines and also in a majority of patient-derived xenografts. These findings are supported by publicly available TCGA (The Cancer Genome Atlas) database. Treatment of colon cancer cells with α-methyltryptophan (α-MT), a blocker of SLC6A14, induces amino acid deprivation, decreases mTOR activity, increases autophagy, promotes apoptosis, and suppresses cell proliferation and invasion. In xenograft and syngeneic mouse tumor models, silencing of SLC6A14 by shRNA or blocking its function by α-MT reduces tumor growth. Similarly, the deletion of Slc6a14 in mice protects against colon cancer in two different experimental models (inflammation-associated colon cancer and genetically driven colon cancer). In colon cancer cells, expression of the transporter is reduced by Wnt antagonist or by silencing of β-catenin whereas Wnt agonist or overexpression of β-catenin shows the opposite effect. Finally, SLC6A14 as a target for β-catenin is confirmed by chromatin immunoprecipitation. These studies demonstrate that SLC6A14 plays a critical role in the promotion of colon cancer and that its up-regulation in cancer involves Wnt signaling. These findings identify SLC6A14 as a promising drug target for the treatment of colon cancer., (© 2020 The Author(s).)

GPR81 is a G-protein-coupled receptor for lactate, which is upregulated in breast cancer and plays an autocrine role to promote tumor growth by tumor cell-derived lactate. Here we asked whether lactate has any paracrine role via activation of GPR81 in cells present in tumor microenvironment to help tumor growth. First, we showed that deletion of Gpr81 suppresses breast cancer growth in a constitutive breast cancer mouse model (MMTV-PyMT-Tg). We then used a syngeneic transplant model by monitoring tumor growth from a mouse breast cancer cell line (AT-3, Gpr81-negative) implanted in mammary fat pad of wild-type mice and Gpr81-null mice. Tumor growth was suppressed in Gpr81-null mice compared with wild-type mice. There were more tumor-infiltrating T cells and MHCII hi -immune cells in tumors from Gpr81-null mice compared with tumors from wild-type mice. RNA-seq analysis of tumors indicated involvement of immune cells and antigen presentation in Gpr81-dependent tumor growth. Antigen-presenting dendritic cells expressed Gpr81 and activation of this receptor by lactate suppressed cell-surface presentation of MHCII. Activation of Gpr81 in dendritic cells was associated with decreased cAMP, IL-6 and IL-12. These findings suggest that tumor cell-derived lactate activates GPR81 in dendritic cells and prevents presentation of tumor-specific antigens to other immune cells. This paracrine mechanism is complementary to the recently discovered autocrine mechanism in which lactate induces PD-L1 in tumor cells via activation of GPR81 in tumor cells, thus providing an effective means for tumor cells to evade immune system. As such, blockade of GPR81 signaling could boost cancer immunotherapy.

Reprogramming of biochemical pathways is a hallmark of cancer cells, and generation of lactic acid from glucose/glutamine represents one of the consequences of such metabolic alterations. Cancer cells export lactic acid out to prevent intracellular acidification, not only increasing lactate levels but also creating an acidic pH in extracellular milieu. Lactate and protons in tumor microenvironment are not innocuous bystander metabolites but have special roles in promoting tumor-cell proliferation and growth. Lactate functions as a signaling molecule by serving as an agonist for the G-protein-coupled receptor GPR81, involving both autocrine and paracrine mechanisms. In the autocrine pathway, cancer cell-generated lactate activates GPR81 on cancer cells; in the paracrine pathway, cancer cell-generated lactate activates GPR81 on immune cells, endothelial cells, and adipocytes present in tumor stroma. The end result of GPR81 activation is promotion of angiogenesis, immune evasion, and chemoresistance. The acidic pH creates an inwardly directed proton gradient across the cancer-cell plasma membrane, which provides driving force for proton-coupled transporters in cancer cells to enhance supply of selective nutrients. There are several molecular targets in the pathways involved in the generation of lactic acid by cancer cells and its role in tumor promotion for potential development of novel anticancer therapeutics., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Severe asthma exacerbations are costly to patients and the NHS, and occur frequently in severely allergic patients., Objective: To ascertain whether or not nocturnal temperature-controlled laminar airflow (TLA) device usage over 12 months can reduce severe exacerbations and improve asthma control and quality of life compared with a placebo device, while being cost-effective and acceptable to adults with severe allergic asthma., Design: A pragmatic, multicentre, randomised, double-blind, placebo-controlled, parallel-group, superiority trial with qualitative interviews. The trial included an internal pilot with qualitative focus groups., Setting: Fourteen hospitals in the UK that manage patients with severe asthma., Participants: Adults (16-75 years) with severe, poorly controlled, exacerbation-prone asthma despite high-intensity treatment, and who are sensitised to a perennial indoor aeroallergen., Intervention: Nocturnal, home-based TLA treatment using an Airsonett ® (Airsonett AB, Ängelholm, Sweden) device. The comparator was a placebo device that was identical to the active device except that it did not deliver the laminar airflow. Participants were allocated 1 : 1 to TLA therapy or placebo, minimised by site, origin of case, baseline severe exacerbation frequency, maintenance oral corticosteroid use and pre-bronchodilator forced expiratory volume in 1 second., Main Outcome Measures: Primary outcome - frequency of severe asthma exacerbations occurring within the 12-month follow-up period, defined as worsening of asthma requiring systemic corticosteroids [≥ 30 mg of prednisolone or equivalent daily (or ≥ 50% increase in dose if on maintenance dose of ≥ 30 mg of prednisolone)] for ≥ 3 days. Secondary outcomes - changes in asthma control, lung function, asthma-specific and global quality of life for participants, adherence to the intervention, device acceptability, health-care resource use and cost-effectiveness., Results: Between May 2014 and January 2016, 489 patients consented to participate in the trial, of whom 249 failed screening and 240 were randomised ( n  = 119 in the treatment group and n  = 121 in the placebo group); all were analysed. In total, 202 participants (84%) reported use of the device for 9-12 months. Qualitative analyses showed high levels of acceptability. The mean [standard deviation (SD)] rate of severe exacerbations did not differ between groups [active 1.39 (1.57), placebo 1.48 (2.03); risk ratio 0.92, 95% CI 0.66 to 1.27; p  = 0.616]. There were no significant differences in secondary outcomes for lung function, except for a reduction in mean daily peak expiratory flow [mean (SD) difference 14.7 l/minute (7.35 l/minute), 95% CI 0.32 to 29.1 l/minute; p  = 0.045) for those in the active device group. There were no differences in asthma control or airway inflammation and no serious harms related to the device. No significant difference between the groups in quality-adjusted life-years gained over 1 year was observed. In addition, there was no difference in generic or disease-specific health-related quality of life overall, although statistically significant higher quality of life at month 6 was observed. Increases in quality of life were not sufficient to offset the annual costs associated with use of the TLA device., Limitations: Missing outcome data could have resulted in an underestimation of exacerbations and rendered the study inconclusive., Conclusions: Within the limits of the data, no consistent benefits of the active device were demonstrated, and the differences observed were not sufficient to make the device cost-effective. The types of patients who may benefit from the TLA device, and the reasons for large reductions in exacerbation frequency in severe asthma trials, which also incorporate other methods of recording exacerbations, need to be explored., Trial Registration: Current Controlled Trials ISRCTN46346208., Funding: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 23, No. 29. See the NIHR Journals Library website for further project information., Competing Interests: Claire Roberts reports grants, in addition to non-financial support, from Novartis Pharmaceuticals UK Ltd (Frimley, UK), outside the submitted work. Peter Howarth reports part-time employment with GlaxoSmithKline plc (London, UK) as a global medical expert.

Background Bystander cardiopulmonary resuscitation ( CPR ) and public access defibrillator ( PAD ) use can save the lives of people who experience out-of-hospital cardiac arrest. Little is known about the proportions of UK adults trained, their characteristics and willingness to act if witnessing an out-of-hospital cardiac arrest, or the public's knowledge regarding where the nearest PAD is located. Methods and Results An online survey was administered by YouGov to a nonprobabilistic purposive sample of UK adults, achieving 2084 participants, from a panel that was matched to be representative of the population. We used descriptive statistics and multivariate logistic regression modeling for analysis. Almost 52% were women, 61% were aged <55 years, and 19% had witnessed an out-of-hospital cardiac arrest. Proportions ever trained were 57% in chest-compression-only CPR, 59% in CPR , and 19.4% in PAD use. Most with training in any resuscitation technique had trained at work (54.7%). Compared with people not trained, those trained in PAD use said they were more likely to use one (odds ratio: 2.61), and those trained in CPR or chest-compression-only CPR were more likely to perform it (odds ratio: 5.39). Characteristics associated with being trained in any resuscitation technique included youth, female sex, higher social grade, and full-time employment. Conclusions In the United Kingdom, training makes a difference in people's willingness to act in the event of a cardiac arrest. Although there is considerable opportunity to increase the proportion of the general population trained in CPR , consideration should be also given to encouraging training in PAD use and targeting training for those who are older or from lower social grades.

Aims: The aim of the project was to identify the neighbourhood characteristics of areas in England where out-of-hospital cardiac arrest (OHCA) incidence was high and bystander cardiopulmonary resuscitation (BCPR) was low using registry data., Methods and Results: Analysis was based on 67 219 cardiac arrest events between 1 April 2013 and 31 December 2015. Arrest locations were geocoded to give latitude/longitude. Postcode district was chosen as the proxy for neighbourhood. High-risk neighbourhoods, where OHCA incidence based on residential population was >127.6/100 000, or based on workday population was >130/100 000, and BCPR in bystander witnessed arrest was <60% were observed to have: a greater mean residential population density, a lower workday population density, a lower rural-urban index, a higher proportion of people in routine occupations and lower proportion in managerial occupations, a greater proportion of population from ethnic minorities, a greater proportion of people not born in UK, and greater level of deprivation. High-risk areas were observed in the North-East, Yorkshire, South-East, and Birmingham., Conclusion: The study identified neighbourhood characteristics of high-risk areas that experience a high incidence of OHCA and low bystander resuscitation rate that could be targeted for programmes of training in cardiopulmonary resuscitation and automated external defibrillator use.

Background: Asthma and Chronic Obstructive Pulmonary Disease (COPD) are common conditions that affect over 5 million people in the United Kingdom. These groups of patients suffer significantly from breathlessness and recurrent exacerbations that can be difficult to diagnose and go untreated. A common feature of COPD and asthma is airway inflammation that increases before and during exacerbations. Current methods of assessing airway inflammation can be invasive, difficult to perform, and are often inaccurate. In contrast, measurement of exhaled breath condensate (EBC) hydrogen peroxide (H 2 O 2 ) is performed during normal tidal breathing and is known to reflect the level of global inflammation in the airways. There is a need for novel tools to diagnose asthma and COPD earlier and to detect increased airway inflammation that precedes an exacerbation., Objective: The aim of this study was to explore the use of a new handheld device (called Inflammacheck) in measuring H 2 O 2 levels in EBC. We will study whether it can measure EBC H 2 O 2 levels consistently and whether it can be used to differentiate asthma and COPD from healthy controls., Methods: We will perform a cross-sectional, feasibility, pilot study of EBC H 2 O 2 levels, as measured by Inflammacheck, and other markers of disease severity and symptom control in patients with asthma and COPD and volunteers with no history of lung disease. Participants will be asked to provide an exhaled breath sample for measurement of their EBC H 2 O 2 using Inflammacheck. The result will be correlated with disease stage, spirometry, fractional exhaled nitric oxide (FeNO), and symptom control scores., Results: This study's recruitment is ongoing; it is anticipated that the results will be available in 2018., Conclusions: The EXhaled Hydrogen peroxide As a marker of Lung diseasE (EXHALE) pilot study will provide an evaluation of a new method of measuring EBC H 2 O 2 . It will assess the device's consistency and ability to distinguish airway inflammation in asthma and COPD compared with healthy controls., (©Daniel M Neville, Carole Fogg, Thomas P Brown, Thomas L Jones, Eleanor Lanning, Paul Bassett, Anoop J Chauhan. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 30.01.2018.)

Objectives: The Out-of-Hospital Cardiac Arrest Outcomes (OHCAO) project aims to understand the epidemiology and outcomes of out-of-hospital cardiac arrest (OHCA) across the UK. This data linkage study is a subproject of OHCAO. The aim was to establish the feasibility of linking OHCAO data to National Health Service (NHS) patient demographic data and Office for National Statistics (ONS) date of death data held on the NHS Personal Demographics Service (PDS) database to improve OHCAO demographic data quality and enable analysis of 30-day survival from OHCA., Design and Setting: Data were collected from 1 January 2014 to 31 December 2014 as part of a prospective, observational study of OHCA attended by 10 English NHS Ambulance Services. 28 729 OHCA cases had resuscitation attempted by Emergency Medical Services and were included in the study. Data linkage was carried out using a data linkage service provided by NHS Digital, a national provider of health-related data. To assess data linkage feasibility a random sample of 3120 cases was selected. The sample was securely transferred to NHS Digital to be matched using OHCAO patient demographic data to return previously missing demographic data and provide ONS date of death data., Results: A total of 2513 (80.5%) OHCAO cases were matched to patients in the NHS PDS database. Using the linkage process, missing demographic data were retrieved for 1636 (72.7%) out of 2249 OHCAO cases that had previously incomplete demographic data. Returned ONS date of death data allowed analysis of 30-day survival status. The results showed a 30-day survival rate of 9.3%, reducing unknown survival status from 46.1% to 8.5%., Conclusions: In this sample, data linkage between the OHCAO registry and NHS PDS database was shown to be feasible, improving demographic data quality and allowing analysis of 30-day survival status., Competing Interests: Competing interests: SJB, TPB, CJ, CH, SJBM and GDP are employed by the University of Warwick, which receives grants from the British Heart Foundation and the Resuscitation Council (UK) for the conduct of the OHCAO project., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Fibroblast growth factor 23 (FGF23) is the causative factor of X-linked hypophosphatemia (XLH), a genetic disorder effecting 1:20,000 that is characterized by excessive phosphate excretion, elevated FGF23 levels and a rickets/osteomalacia phenotype. FGF23 inhibits phosphate reabsorption and suppresses 1α,25-dihydroxyvitamin D (1,25D) biosynthesis, analytes that differentially contribute to bone integrity and deleterious soft-tissue mineralization. As inhibition of ligand broadly modulates downstream targets, balancing efficacy and unwanted toxicity is difficult when targeting the FGF23 pathway. We demonstrate that a FGF23 c-tail-Fc fusion molecule selectively modulates the phosphate pathway in vivo by competitive antagonism of FGF23 binding to the FGFR/α klotho receptor complex. Repeated injection of FGF23 c-tail Fc in Hyp mice, a preclinical model of XLH, increases cell surface abundance of kidney NaPi transporters, normalizes phosphate excretion, and significantly improves bone architecture in the absence of soft-tissue mineralization. Repeated injection does not modulate either 1,25D or calcium in a physiologically relevant manner in either a wild-type or disease setting. These data suggest that bone integrity can be improved in models of XLH via the exclusive modulation of phosphate. We posit that the selective modulation of the phosphate pathway will increase the window between efficacy and safety risks, allowing increased efficacy to be achieved in the treatment of this chronic disease. © 2017 American Society for Bone and Mineral Research., (© 2017 American Society for Bone and Mineral Research.)

Pure autonomic failure is a degenerative disorder of the peripheral autonomic nervous system. Patients experience symptomatic hypotension that requires them to sit, squat or lie down to prevent syncope. It is associated with characteristic histopathological findings, resulting in neuronal cytoplasmic inclusions in the peripheral autonomic nerves. These lesions are responsible for defects in the synthesis and release of norepinephrine from sympathetic nerve terminals, resulting in significant hypotension. Patients with autonomic failure also have exaggerated blood pressure responses to common stimuli such as food or fluid intake, heat, exercise and medications. Tilt table (head-up) testing is probably the test most commonly used to establish the diagnosis. However, simple office testing is also useful, such as having the patient stand after lying supine with blood pressure monitoring. Treatment options range from simply increasing fluid and salt intake, and using compressive garments, to medications administered orally, subcutaneously or intravenously in more severe cases., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

ZSF1 rats exhibit spontaneous nephropathy secondary to obesity, hypertension, and diabetes, and have gained interest as a model system with potentially high translational value to progressive human disease. To thoroughly characterize this model, and to better understand how closely it recapitulates human disease, we performed a high resolution longitudinal analysis of renal disease progression in ZSF1 rats spanning from early disease to end stage renal disease. Analyses included metabolic endpoints, renal histology and ultrastructure, evaluation of a urinary biomarker of fibrosis, and transcriptome analysis of glomerular-enriched tissue over the course of disease. Our findings support the translational value of the ZSF1 rat model, and are provided here to assist researchers in the determination of the model's suitability for testing a particular mechanism of interest, the design of therapeutic intervention studies, and the identification of new targets and biomarkers for type 2 diabetic nephropathy.

Chronic prostatitis characterized on light microscopic examination by moderate, multifocal, predominantly lymphocytic inflammation associated with epithelial atypia and intranuclear and cytoplasmic inclusion-like material was identified in the prostate gland of 2 Wistar Han rats administered an immunomodulatory test article in a 6-month chronic toxicity study. Transmission electron microscopy of the prostate glands identified 45-nm, nonenveloped, icosahedral virions arranged in paracrystalline array within the cell nuclei in 1 of the 2 rats. The size, shape, location, and array pattern were most consistent with a polyomavirus. The light and electron microscopic findings after immunosuppression in our case have a resemblance to a polyomavirus recently reported to affect prostate gland epithelium in a colony of immunocompromised X-linked severe combined immune deficiency rats. To the best of our knowledge, this is the first report of light and electronic microscopic lesions in the reproductive tract associated with polyomavirus following chronic immunosuppression in a widely used, wild-type Wistar Han rat.

Detecting and monitoring exocrine pancreatic damage during nonclinical and clinical testing is challenging because classical biomarkers amylase and lipase have limited sensitivity and specificity. Novel biomarkers for drug-induced pancreatic injury are needed to improve safety assessment and reduce late-stage attrition rates. In a series of studies, miR-216a and miR-217 were evaluated as potential biomarkers of acute exocrine pancreatic toxicity in rats. Our results revealed that miR-216a and miR-217 were almost exclusively expressed in rat pancreas and that circulating miR-216a and miR-217 were significantly increased in rats following administration of established exocrine pancreatic toxicants caerulein (CL) and 1-cyano-2-hydroxy-3-butene (CHB) as well as in rats administered a proprietary molecule known to primarily affect the exocrine pancreas. Conversely, neither microRNA was increased in rats administered a proprietary molecule known to cause a lesion at the pancreatic endocrine-exocrine interface (EEI) or in rats administered an established renal toxicant. Compared with amylase and lipase, increases in miR-216a and miR-217 were of greater magnitude, persisted longer, and/or correlated better with microscopic findings within the exocrine pancreas. Our findings demonstrate that in rats, miR-216a and miR-217 are sensitive and specific biomarkers of acute exocrine pancreatic toxicity that may add value to the measurement of classical pancreatic biomarkers.

Introduction: This study reports the epidemiology and outcomes from out-of-hospital cardiac arrest (OHCA) in England during 2014., Methods: Prospective observational study from the national OHCA registry. The incidence, demographic and outcomes of patients who were treated for an OHCA between 1st January 2014 and 31st December 2014 in 10 English ambulance service (EMS) regions, serving a population of almost 54 million, are reported in accordance with Utstein recommendations., Results: 28,729 OHCA cases of EMS treated cardiac arrests were reported (53 per 100,000 of resident population). The mean age was 68.6 (SD=19.6) years and 41.3% were female. Most (83%) occurred in a place of residence, 52.7% were witnessed by either the EMS or a bystander. In non-EMS witnessed cases, 55.2% received bystander CPR whilst public access defibrillation was used rarely (2.3%). Cardiac aetiology was the leading cause of cardiac arrest (60.9%). The initial rhythm was asystole in 42.4% of all cases and was shockable (VF or pVT) in 20.6%. Return of spontaneous circulation at hospital transfer was evident in 25.8% (n=6302) and survival to hospital discharge was 7.9%., Conclusion: Cardiac arrest is an important cause of death in England. With less than one in ten patients surviving, there is scope to improve outcomes. Survival rates were highest amongst those who received bystander CPR and public access defibrillation., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Two 6-month repeat-dose toxicity studies in cynomolgus monkeys illustrated immune complex-mediated adverse findings in individual monkeys and identified parameters that potentially signal the onset of immune complex-mediated reactions following administration of RN6G, a monoclonal antibody (mAb). In the first study, 3 monkeys exhibited nondose-dependent severe clinical signs accompanied by decreased erythrocytes with increased reticulocytes, neutrophilia, monocytosis, thrombocytopenia, coagulopathy, decreased albumin, azotemia, and increased serum levels of activated complement products, prompting unscheduled euthanasia. Histologically, immunohistochemical localization of RN6G was associated with monkey immunoglobulin and complement components in glomeruli and other tissues, attributable to immune complex disease (ICD). All 3 animals also had anti-RN6G antibodies and decreased plasma levels of RN6G. Subsequently, an investigational study was designed and conducted with regulatory agency input to detect early onset of ICD and assess reversibility to support further clinical development. Dosing of individual animals ceased when biomarkers of ICD indicated adverse findings. Of the 12 monkeys, 1 developed anti-RN6G antibodies and decreased RN6G exposure that preceded elevations in complement products, interleukin-6, and coagulation parameters and decreases in albumin and fibrinogen. All findings in this monkey, except for antidrug antibody (ADA), reversed after cessation of dosing without progressing to adverse sequelae typically associated with ICD., (© 2014 by The Author(s).)

Refractory ceramic fibres (RCF) and alkaline earth silicate (AES) wools are types of man-made vitreous fibre (MMVF) that are used in demanding high-temperature industrial applications, generally above 900 °C and up to 1400 °C. When exposed to prolonged high temperatures, MMVF can devitrify with the formation of cristobalite and other crystalline silica species, which is of potential concern because crystalline silica (CS) is classified as carcinogenic. This article reviews the chemico-physical processes and morphological consequences of fibre devitrification, the forms and micro-location of CS produced, and the toxicity of devitrified fibres and the CS species formed in this way. It also examines scenarios for worker exposure to the products of fibre devitrification in industries using RCF and/or AES wools. We identify gaps in knowledge and make recommendations for future research., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: We evaluated the immunological responses of African green monkeys immunized with multiple F and G protein-based vaccines and assessed protection against the Memphis 37 strain of respiratory syncytial virus (RSV)., Methods: Monkeys were immunized with F and G proteins adjuvanted with immunostimulatory (CpG) oligodeoxyribonucleotides admixed with either Alhydrogel or ISCOMATRIX adjuvant. Delivery of F and G proteins via replication incompetent recombinant vesicular stomatitis viruses (VSVs) and human adenoviruses was also evaluated. Mucosally or parenterally administered recombinant adenoviruses were used in prime-boost regimens with adjuvanted proteins or recombinant DNA., Results: Animals primed by intranasal delivery of recombinant adenoviruses, and boosted by intramuscular injection of adjuvanted F and G proteins, developed neutralizing antibodies and F/G protein-specific T cells and were protected from RSV infection. Intramuscular injections of Alhydrogel (plus CpG) adjuvanted F and G proteins reduced peak viral loads in the lungs of challenged monkeys. Granulocyte numbers were not significantly elevated, relative to controls, in postchallenge bronchoalveolar lavage samples from vaccinated animals., Conclusions: This study has validated the use of RSV (Memphis 37) in an African green monkey model of intranasal infection and identified nonreplicating vaccines capable of eliciting protection in this higher species challenge model.

Histamine and tumor necrosis factor-α (TNF-α) are critical mediators of acute and chronic inflammation that are generated by mast cells and macrophages in atherosclerotic lesions or systemically during allergic attacks. Both of them induce activation of vascular endothelium and thus may play a role in thrombosis. Here we studied the interplay between histamine and TNF-α in glycoprotein (GP) Ibα-mediated platelet adhesion to cultured human vascular endothelial cells under static and shear flow conditions. The stimulation of endothelial cells with histamine or TNF-α increased the number of adherent or slow rolling GP Ibα-coated microbeads or washed human platelets. However, the application of histamine to endothelium pre-activated by TNF-α inhibited GP Ibα-mediated platelet adhesion. These effects were found to be associated with changes in the concentration of ultra large von Willebrand factor (ULVWF) strings anchored to endothelium. The results of this study indicate that histamine released during mast cell degranulation may cause or inhibit thrombosis, depending on whether it acts on resting endothelial cells or on cells pre-activated by other inflammatory stimuli., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Cerebral vasogenic edema and microhemorrhages are potential safety concerns for compounds intended to treat subjects with Alzheimer's disease (AD) by targeting amyloid β (Aβ). Ponezumab (PF-04360365) is an investigational anti-Aβ monoclonal antibody. Two hundred female mice (APP(K670N;M671L); Tg2576) 16-19 months old received an aglycosylated CHO-derived murine surrogate of ponezumab by intraperitoneal administration once weekly for up to 26 weeks at doses of 0, 10, 30, or 100 mg/kg. Drug exposure and plasma Aβ levels increased with increasing dose. After 26 weeks, the 100 mg/kg group had significantly greater plasma levels of Aβ(1-x) and Aβ(x-40) than the vehicle group (p < 0.001). Brain microhemorrhages were identified histologically using hematoxylin and eosin and/or Perls' Prussian blue iron staining. The incidence in the vehicle group was equal to or higher than those of the treated groups. There was no evidence of vasogenic edema. In summary, intraperitoneal administration of a murine surrogate of ponezumab to aged Tg2576 mice for up to 6 months did not produce any compound-related brain microhemorrhage or other pathologies.

Many diagnostic tests in a conventional clinical laboratory are performed on blood plasma because changes in its composition often reflect the current status of pathological processes throughout the body. Recently, a significant research effort has been invested into the development of microfluidic paper-based analytical devices (μPADs) implementing these conventional laboratory tests for point-of-care diagnostics in resource-limited settings. This paper describes the use of red blood cell (RBC) agglutination for separating plasma from finger-prick volumes of whole blood directly in paper, and demonstrates the utility of this approach by integrating plasma separation and a colorimetric assay in a single μPAD. The μPAD was fabricated by printing its pattern onto chromatography paper with a solid ink (wax) printer and melting the ink to create hydrophobic barriers spanning through the entire thickness of the paper substrate. The μPAD was functionalized by spotting agglutinating antibodies onto the plasma separation zone in the center and the reagents of the colorimetric assay onto the test readout zones on the periphery of the device. To operate the μPAD, a drop of whole blood was placed directly onto the plasma separation zone of the device. RBCs in the whole blood sample agglutinated and remained in the central zone, while separated plasma wicked through the paper substrate into the test readout zones where analyte in plasma reacted with the reagents of the colorimetric assay to produce a visible color change. The color change was digitized with a portable scanner and converted to concentration values using a calibration curve. The purity and yield of separated plasma was sufficient for successful operation of the μPAD. This approach to plasma separation based on RBC agglutination will be particularly useful for designing fully integrated μPADs operating directly on small samples of whole blood.

"Animal Models of Neural Disease" was the focus of General Session 5 at a 2010 scientific symposium that was sponsored jointly by the Society of Toxicologic Pathology (STP) and the International Federation of Societies of Toxicologic Pathologists (IFSTP). The objective was to consider issues that dictate the choice of animal models for neuropathology-based studies used to investigate neurological diseases and novel therapeutic agents to treat them. In some cases, no animal model exists that recapitulates the attributes of the human disease (e.g., fibromyalgia syndrome). Alternatively, numerous animal models are available for other conditions, so an essential consideration is selecting the most appropriate experimental system (e.g., Alzheimer's disease). New technologies (e.g., genetically engineered rodent models) promise the opportunity to generate suitable animal models for syndromes that currently lack any in vivo animal model, while in vitro models offer the opportunity to evaluate xenobiotic effects in specific neural cell populations. The complex nature of neurological disease requires regular reassessment of available and potential options to ensure that animal-derived data sets support translational medicine efforts to improve public health.