Mucosal-associated invariant T (MAIT) cells are innate sensors of viruses and can augment early immune responses and contribute to protection. We hypothesized that MAIT cells may have inherent ...adjuvant activity in vaccine platforms that use replication-incompetent adenovirus vectors. In mice and humans, ChAdOx1 (chimpanzee adenovirus Ox1) immunization robustly activated MAIT cells. Activation required plasmacytoid dendritic cell (pDC)-derived interferon (IFN)-α and monocyte-derived interleukin-18. IFN-α-induced, monocyte-derived tumor necrosis factor was also identified as a key secondary signal. All three cytokines were required in vitro and in vivo. Activation of MAIT cells positively correlated with vaccine-induced T cell responses in human volunteers and MAIT cell-deficient mice displayed impaired CD8
T cell responses to multiple vaccine-encoded antigens. Thus, MAIT cells contribute to the immunogenicity of adenovirus vectors, with implications for vaccine design.
Since the mid-1980s, our understanding of nutrient limitation of oceanic primary production has radically changed. Mesoscale iron addition experiments (FeAXs) have unequivocally shown that iron ...supply limits production in one-third of the world ocean, where surface macronutrient concentrations are perennially high. The findings of these 12 FeAXs also reveal that iron supply exerts controls on the dynamics of plankton blooms, which in turn affect the biogeochemical cycles of carbon, nitrogen, silicon, and sulfur and ultimately influence the Earth climate system. However, extrapolation of the key results of FeAXs to regional and seasonal scales in some cases is limited because of differing modes of iron supply in FeAXs and in the modern and paleo-oceans. New research directions include quantification of the coupling of oceanic iron and carbon biogeochemistry.
Abstract Autoantibodies to nodal/paranodal proteins have been reported in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN). To determine ...the frequency of anti-paranodal antibodies in our cohort of CIDP patients and to validate the presence anti-nodal antibodies in MMN, sera were screened for IgG against human neurofascin 155, contactin-1, neurofascin 186 and gliomedin using ELISA. In CIDP patients, 7% were anti-NF155 IgG4 positive and 7% were anti-CNTN1 IgG4 positive. Positive results were confirmed using cell based assays and indirect immunofluorescence on teased nerve fibres. We did not detect IgG autoantibodies against these nodal/paranodal antigens in MMN patients.
Methane (CH4) emission by carbon-rich cryosols at the high latitudes in Northern Hemisphere has been studied extensively. In contrast, data on the CH4 emission potential of carbon-poor cryosols is ...limited, despite their spatial predominance. This work employs CH4 flux measurements in the field and under laboratory conditions to show that the mineral cryosols at Axel Heiberg Island in the Canadian high Arctic consistently consume atmospheric CH4. Omics analyses present the first molecular evidence of active atmospheric CH4-oxidizing bacteria (atmMOB) in permafrost-affected cryosols, with the prevalent atmMOB genotype in our acidic mineral cryosols being closely related to Upland Soil Cluster α. The atmospheric (atm) CH4 uptake at the study site increases with ground temperature between 0 °C and 18 °C. Consequently, the atm CH4 sink strength is predicted to increase by a factor of 5-30 as the Arctic warms by 5-15 °C over a century. We demonstrate that acidic mineral cryosols are a previously unrecognized potential of CH4 sink that requires further investigation to determine its potential impact on larger scales. This study also calls attention to the poleward distribution of atmMOB, as well as to the potential influence of microbial atm CH4 oxidation, in the context of regional CH4 flux models and global warming.
Abstract Increasing evidence supports a role for the environment in the development of autoimmune diseases, as reviewed in the accompanying three papers from the National Institute of Environmental ...Health Sciences Expert Panel Workshop. An important unresolved issue, however, is the development of criteria for identifying autoimmune disease phenotypes for which the environment plays a causative role, herein referred to as environmentally associated autoimmune diseases. There are several different areas in which such criteria need to be developed, including: 1) identifying the necessary and sufficient data to define environmental risk factors for autoimmune diseases meeting current classification criteria; 2) establishing the existence of and criteria for new environmentally associated autoimmune disorders that do not meet current disease classification criteria; and 3) identifying in clinical practice specific environmental agents that induce autoimmune disease in individual patients. Here we discuss approaches that could be useful for developing criteria in these three areas, as well as factors that should be considered in evaluating the evidence for criteria that can distinguish individuals with such disorders from individuals without such disorders with high sensitivity and specificity. Current studies suggest that multiple lines of complementary evidence will be important and that in many cases there will be clinical, serologic, genetic, epigenetic, and/or other laboratory features that could be incorporated as criteria for environmentally associated autoimmune diseases to improve diagnosis and treatment and possibly allow for preventative strategies in the future.
Summary Objectives Outer membrane vesicle (OMV) vaccines are used against outbreaks of capsular group B Neisseria meningitidis (MenB) caused by strains expressing particular PorA outer membrane ...proteins (OMPs). Ferric enterobactin receptor (FetA) is another variable OMP that induces type-specific bactericidal antibodies, and the combination of judiciously chosen PorA and FetA variants in vaccine formulations is a potential approach to broaden protection of such vaccines. Methods The OMV vaccine MenPF-1 was generated by genetically modifying N. meningitidis strain 44/76 to constitutively express FetA. Three doses of 25 μg or 50 μg of MenPF-1 were delivered intra-muscularly to 52 healthy adults. Results MenPF-1 was safe and well tolerated. Immunogenicity was measured by serum bactericidal assay (SBA) against wild-type and isogenic mutant strains. After 3 doses, the proportion of volunteers with SBA titres ≥1:4 (the putative protective titre) was 98% for the wild-type strain, and 77% for the strain 44/76 FetA on PorA off compared to 51% in the strain 44/76 FetA off PorA off , demonstrating that vaccination with MenPF-1 simultaneously induced FetA and PorA bactericidal antibodies. Conclusion This study provides a proof-of-concept for generating bactericidal antibodies against FetA after OMV vaccination in humans. Prevalence-based choice of PorA and FetA types can be used to formulate a vaccine for broad protection against MenB disease.
Quantitative measurements are commonly implemented to objectively evaluate heart size in dogs. However, recent studies suggest that the phase of cardiac cycle can impact vertebral heart score, ...thereby potentially influencing clinical management. This study used fluoroscopy to assess the impact of the cardiac cycle on quantitative cardiovascular measurements in healthy dogs of various breeds.
This was a prospective study. Multiple cardiac and respiratory cycles were recorded fluoroscopically. Peak inspiratory end-systole and end-diastole frames were captured from 49 dogs in right lateral recumbency. Vertebral heart score (VHS), cardiothoracic ratio (CTR), vertebral left atrial size (VLAS), and caudal vena cava diameter ratio (CVCDR) measurements were performed. Mean cardiac measurements were compared between cardiac cycle phases, and the impact of body condition score (BCS), weight, thoracic conformation, sex, and age was evaluated.
Cardiac cycle had a significant impact on VHS (mean difference: 0.36 ± 0.14 vertebral units between systole and diastole; p < 0.001) and CTR (mean difference: 2.2 ± 1.2% between systole and diastole; p < 0.001). Cardiac cycle had no significant impact on VLAS or CVCDR. Increasing BCS significantly increased variation between systole and diastole in CTR measurements (p = 0.024).
The cardiac cycle has a significant effect on VHS and CTR but does not impact VLAS or CVCDR. These findings should be taken into consideration during clinical use of these measurements, especially if a patient is being monitored for cardiac changes over time via serial radiographs.
To determine long-term seroprotection after serogroup C meningococcal (MenC) vaccination at the age of 9-12 years, with or without booster vaccination at the age of 13-15 years.
Observational cohort ...study; follow-on from randomised study.
Participants were recruited from English secondary schools (in Oxfordshire and Buckinghamshire).
Participants were primed with MenC CRM-glycoconjugate vaccine at the age of 9-12 years in the UK routine immunisation campaign. In previous studies they were randomised at 13 to 15 years of age to receive a booster dose of MenC-CRM glycoconjugate vaccine (CRM-group) or bivalent meningococcal serogroup A/C polysaccharide vaccine (PS-group), or they received no additional doses of MenC vaccine (control group). In this follow-on study, a blood sample was obtained 11 years after primary immunisation. Of 531 individuals eligible to participate, 134 were enrolled, and 124 were included in the analysis.
MenC serum bactericidal antibody (SBA) geometric mean titre; proportion of participants with SBA titre ≥8 (putative protective threshold).
Median ages at priming, boosting and blood sampling were 10.61, 14.42 and 22.11 years, respectively. Geometric mean titres for MenC SBA were: CRM group 1373 (95% CI 954 to 1977); PS group 1024 (687 to 1526); and controls 284 (167 to 483). SBA titres ≥8 were present in 50/54 (92.6%) controls and 70/70 (100%) boosted individuals.
The planned introduction in the UK of an adolescent booster of MenC conjugate vaccine in 2013 is likely to provide sustained protection against MenC disease.
Registered on ClinicalTrials.gov (NCT01459432).
IntroductionRespiratory syncytial virus (RSV) infection causes respiratory disease throughout life, with infants and the elderly at risk of severe disease and death. RSV001 is a phase 1 ...(first-in-man), open-label, dose-escalation, clinical trial of novel genetic viral-vectored vaccine candidates PanAd3-RSV and modified vaccinia virus Ankara (MVA)-RSV. The objective of RSV001 is to characterise the (primary objective) safety and (secondary objective) immunogenicity of these vaccines in healthy younger and older adults.Methods and analysisHeterologous and homologous ‘prime’/boost combinations of PanAd3-RSV and single-dose MVA-RSV are evaluated in healthy adults. 40 healthy adults aged 18–50 years test one of four combinations of intramuscular (IM) or intranasal (IN) PanAd3-RSV prime and IM PanAd3 or IM MVA-RSV boost vaccination, starting at a low dose for safety. The following year an additional 30 healthy adults aged 60–75 years test either a single dose of IM MVA-RSV, one of three combinations of IN or IM PanAd3-RSV prime and PanAd3-RSV or MVA-RSV boost vaccination used in younger volunteers, and a non-vaccinated control group. Study participants are self-selected volunteers who satisfy the eligibility criteria and are assigned to study groups by sequential allocation. Safety assessment includes the daily recording of solicited and unsolicited adverse events for 1 week after vaccination, as well as visit (nursing) observations and safety bloods obtained at all scheduled attendances. Laboratory measures of RSV-specific humoral and cellular immune responses after vaccination will address the secondary end points. All study procedures are performed at the Centre for Clinical Vaccinology and Tropical Medicine (CCVTM), Oxford, UK.Ethics and disseminationRSV001 has clinical trial authorisation from the Medicines and Healthcare Products Regulatory Agency (MHRA) and ethics approval from NRES Berkshire (reference 13/SC/0023). All study procedures adhere to International Conference on Harmonisation (ICH) Good Clinical Practice guidelines. The results of the trial are to be published in peer-reviewed journals, conferences and academic forums.Trial registration numberNCT01805921.
Background
Current methods available for assessing alterations in lung mechanics require sophisticated equipment and are of limited availability. A method that could assess lung area change with ...respiration might be a clinically useful surrogate for assessing lung compliance.
Objective
To use fluoroscopy to determine percent change in thoracic and lung areas in healthy dogs.
Animals
Forty‐four client‐owned dogs with no evidence of respiratory disease.
Methods
Prospective study. Resting respiration was recorded fluoroscopically, and peak inspiratory and expiratory frames were captured for 3 typical respiratory cycles. The number of intrathoracic pixels in the entire thoracic cavity was measured for both inspiration and expiration, and the average percent change in intrathoracic area was determined for each dog. This process was repeated by a hemithorax measurement of lung area that excluded the mediastinum and cardiac silhouette. Proposed reference ranges (and 95% confidence intervals CI) were computed by a nonparametric percentile distribution.
Results
Median percent change in thoracic dimension for the total thorax measurement was 12.5% (CI, 8.9–24.0%). Median percent change for the hemithorax measurement was significantly (P < 0.001) larger (20.8%, CI, 14.3–37.6%). Both measurement techniques were correlated with body weight but not with age, sex, thoracic conformation, body condition score (BCS), or breed.
Conclusions and Clinical Importance
Fluoroscopy allows a noninvasive and repeatable measure of lung area changes during respiration that must be corrected for body weight. Additional studies in dogs with respiratory diseases are needed to determine its utility in detecting clinically useful alterations in lung area changes.
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