Impaired natural killer cell phenotype and function in idiopathic and heritable pulmonary arterial hypertension

BACKGROUND: Beyond their role as innate immune effectors, natural killer (NK) cells are emerging as important regulators of angiogenesis and vascular remodeling. Pulmonary arterial hypertension (PAH) is characterized by severe pulmonary vascular remodeling and has long been associated with immune dysfunction. Despite this association, a role for NK cells in disease pathology has not yet been described. METHODS AND RESULTS: Analysis of whole blood lymphocytes and isolated NK cells from PAH patients revealed an expansion of the functionally defective CD56(-)/CD16(+) NK subset that was not observed in patients with chronic thromboembolic pulmonary hypertension. NK cells from PAH patients also displayed decreased levels of the activating receptor NKp46 and the killer immunoglobulin-like receptors 2DL1/S1 and 3DL1, reduced secretion of the cytokine macrophage inflammatory protein-1β, and a significant impairment in cytolytic function associated with decreased killer immunoglobulin-like receptor 3DL1 expression. Genotyping patients (n=222) and controls (n=191) for killer immunoglobulin-like receptor gene polymorphisms did not explain these observations. Rather, we show that NK cells from PAH patients exhibit increased responsiveness to transforming growth factor-β, which specifically downregulates disease-associated killer immunoglobulin-like receptors. NK cell number and cytotoxicity were similarly decreased in the monocrotaline rat and chronic hypoxia mouse models of PAH, accompanied by reduced production of interferon-γ in NK cells from hypoxic mice. NK cells from PAH patients also produced elevated quantities of matrix metalloproteinase 9, consistent with a capacity to influence vascular remodeling. CONCLUSIONS: Our work is the first to identify an impairment of NK cells in PAH and suggests a novel and substantive role for innate immunity in the pathobiology of this disease

Clinical trial protocol for TRANSFORM-UK: A therapeutic open-label study of tocilizumab in the treatment of pulmonary arterial hypertension.

Our aim is to assess the safety and potential efficacy of a novel treatment paradigm in pulmonary arterial hypertension (PAH), immunomodulation by blocking interleukin-6 (IL6) signaling with the IL6 receptor antagonist, tocilizumab. Inflammation and autoimmunity are established as important in PAH pathophysiology. One of the most robust observations across multiple cohorts in PAH has been an increase in IL6, both in the lung and systemically. Tocilizumab is an IL-6 receptor antagonist established as safe and effective, primarily in rheumatoid arthritis, and has shown promise in scleroderma. In case reports where the underlying cause of PAH is an inflammatory process such as systemic lupus erythematosus, mixed connective tissue disease (MCTD), and Castleman's disease, there have been case reports of regression of PAH with tocilizumab. TRANSFORM-UK is an open-label study of intravenous (IV) tocilizumab in patients with group 1 PAH. The co-primary outcome measures will be safety and the change in resting pulmonary vascular resistance (PVR). Clinically relevant secondary outcome measurements include 6-minute walk distance, WHO functional class, quality of life score, and N-terminal pro-brain natriuretic peptide (NT-proBNP). If the data support a potentially useful therapeutic effect with an acceptable risk profile, the study will be used to power a Phase III study to properly address efficacy

LSQ13ddu: a rapidly evolving stripped-envelope supernova with early circumstellar interaction signatures

This paper describes the rapidly evolving and unusual supernova LSQ13ddu, discovered by the La Silla-QUEST survey. LSQ13ddu displayed a rapid rise of just 4.8 ± 0.9 d to reach a peak brightness of −19.70 ± 0.02 mag in the LSQgr band. Early spectra of LSQ13ddu showed the presence of weak and narrow HeI features arising from interaction with circumstellar material (CSM). These interaction signatures weakened quickly, with broad features consistent with those seen in stripped-envelope SNe becoming dominant around two weeks after maximum. The narrow HeI velocities are consistent with the wind velocities of luminous blue variables but its spectra lack the typically seen hydrogen features. The fast and bright early light curve is inconsistent with radioactive ⁵⁶Ni powering but can be explained through a combination of CSM interaction and an underlying ⁵⁶Ni decay component that dominates the later time behaviour of LSQ13ddu. Based on the strength of the underlying broad features, LSQ13ddu appears deficient in He compared to standard SNe Ib

Luminous Type II Short-Plateau Supernovae 2006Y, 2006ai, and 2016egz: A Transitional Class from Stripped Massive Red Supergiants

The diversity of Type II supernovae (SNe II) is thought to be driven mainly by differences in their progenitor's hydrogen-rich (H-rich) envelope mass, with SNe IIP having long plateaus ($\sim100$ days) and the most massive H-rich envelopes. However, it is an ongoing mystery why SNe II with short plateaus (tens of days) are rarely seen. Here we present optical/near-infrared photometric and spectroscopic observations of luminous Type II short-plateau SNe 2006Y, 2006ai, and 2016egz. Their plateaus of about $50$--$70$ days and luminous optical peaks ($\lesssim-18.4$ mag) indicate significant pre-explosion mass loss resulting in partially-stripped H-rich envelopes and early circumstellar material (CSM) interaction. We compute a large grid of MESA+STELLA single-star progenitor and light-curve models with various progenitor zero-age main-sequence (ZAMS) masses, mass-loss efficiencies, explosion energies, $^{56}$Ni masses, and CSM densities. Our model grid shows a continuous population of SNe IIP--IIL--IIb-like light-curve morphology in descending order of H-rich envelope mass. With large $^{56}$Ni masses ($\gtrsim0.05\,M_\odot$), short-plateau SNe II lie in a confined parameter space as a transitional class between SNe IIL and IIb. For SNe 2006Y, 2006ai, and 2016egz, our findings suggest high-mass red supergiant (RSG) progenitors ($M_{\rm ZAMS} \simeq 18$--$22\,M_{\odot}$) with small H-rich envelope masses ($M_{\rm H_{\rm env}} \simeq 1.7\,M_{\odot}$) that experience enhanced mass loss ($\dot{M} \simeq 10^{-2}\,M_{\odot}\,{\rm yr}^{-1}$) for the last few decades before the explosion. If high-mass RSGs result in rare short-plateau SNe II, then these events might ease some of the apparent under-representation of higher-luminosity RSGs in observed SN II progenitor samples.Comment: 26 pages, 16 figures, submitted to Ap

Baseline factors predictive of serious suicidality at follow-up: findings focussing on age and gender from a community-based study

The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1471-244X/10/41Background: Although often providing more reliable and informative findings relative to other study designs, longitudinal investigations of prevalence and predictors of suicidal behaviour remain uncommon. This paper compares 12-month prevalence rates for suicidal ideation and suicide attempt at baseline and follow-up; identifies new cases and remissions; and assesses the capacity of baseline data to predict serious suicidality at follow-up, focusing on age and gender differences. Methods: 6,666 participants aged 20-29, 40-49 and 60-69 years were drawn from the first (1999-2001) and second (2003-2006) waves of a general population survey. Analyses involved multivariate logistic regression. Results: At follow-up, prevalence of suicidal ideation and suicide attempt had decreased (8.2%-6.1%, and 0.8%-0.5%, respectively). However, over one quarter of those reporting serious suicidality at baseline still experienced it four years later. Females aged 20-29 never married or diagnosed with a physical illness at follow-up were at greater risk of serious suicidality (OR = 4.17, 95% CI = 3.11-5.23; OR = 3.18, 95% CI = 2.09-4.26, respectively). Males aged 40-49 not in the labour force had increased odds of serious suicidality (OR = 4.08, 95% CI = 1.6-6.48) compared to their equivalently-aged and employed counterparts. Depressed/anxious females aged 60-69 were nearly 30% more likely to be seriously suicidal. Conclusions: There are age and gender differentials in the risk factors for suicidality. Life-circumstances contribute substantially to the onset of serious suicidality, in addition to symptoms of depression and anxiety. These findings are particularly pertinent to the development of effective population-based suicide prevention strategies.A Kate Fairweather-Schmidt, Kaarin J Anstey, Agus Salim and Bryan Rodger

Luminous Type II Short-Plateau Supernovae 2006Y, 2006ai, and 2016egz: A Transitional Class from Stripped Massive Red Supergiants

The diversity of Type II supernovae (SNe II) is thought to be driven mainly by differences in their progenitor's hydrogen-rich (H-rich) envelope mass, with SNe IIP having long plateaus (similar to 100 days) and the most massive H-rich envelopes. However, it is an ongoing mystery why SNe II with short plateaus (tens of days) are rarely seen. Here, we present optical/near-infrared photometric and spectroscopic observations of luminous Type II short-plateau SNe 2006Y, 2006ai, and 2016egz. Their plateaus of about 50-70 days and luminous optical peaks (less than or similar to-18.4 mag) indicate significant pre-explosion mass loss resulting in partially stripped H-rich envelopes and early circumstellar material (CSM) interaction. We compute a large grid of MESA+STELLA single-star progenitor and light-curve models with various progenitor zero-age main-sequence (ZAMS) masses, mass-loss efficiencies, explosion energies, Ni-56 masses, and CSM densities. Our model grid shows a continuous population of SNe IIP-IIL-IIb-like light-curve morphology in descending order of H-rich envelope mass. With large Ni-56 masses (greater than or similar to 0.05M(circle dot)), short-plateau SNe II lie in a confined parameter space as a transitional class between SNe IIL and IIb. For SNe 2006Y, 2006ai, and 2016egz, our findings suggest high-mass red supergiant (RSG) progenitors (M-ZAMS similar or equal to 18-22M(circle dot)) with small H-rich envelope masses (M-Henv similar or equal to 1.7 M-circle dot) that have experienced enhanced mass loss (M similar or equal to 10(-2) M-circle dot yr(-1)) for the last few decades before the explosion. If high-mass RSGs result in rare short-plateau SNe II, then these events might ease some of the apparent underrepresentation of higher-luminosity RSGs in observed SN II progenitor samples

LSQ13ddu: a rapidly evolving stripped-envelope supernova with early circumstellar interaction signatures

This paper describes the rapidly evolving and unusual supernova LSQ13ddu, discovered by the La Silla-QUEST survey. LSQ13ddu displayed a rapid rise of just 4.8 +/- 0.9 d to reach a peak brightness of -19.70 +/- 0.02 mag in the LSQgr band. Early spectra of LSQ13ddu showed the presence of weak and narrow He I features arising from interaction with circumstellar material (CSM). These interaction signatures weakened quickly, with broad features consistent with those seen in stripped-envelope SNe becoming dominant around two weeks after maximum. The narrow He I velocities are consistent with the wind velocities of luminous blue variables but its spectra lack the typically seen hydrogen features. The fast and bright early light curve is inconsistent with radioactive Ni-56 powering but can be explained through a combination of CSM interaction and an underlying Ni-56 decay component that dominates the later time behaviour of LSQ13ddu. Based on the strength of the underlying broad features, LSQ13ddu appears deficient in He compared to standard SNe Ib

Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 (BMPR2) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene (EIF2AK4) are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH. METHODS: Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource-Rare Diseases study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of <1:10 000 in control data sets and predicted to be deleterious (by combined annotation-dependent depletion, PolyPhen-2, and sorting intolerant from tolerant predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured. RESULTS: Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (Kco; 33% [interquartile range, 30%-35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23-38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. Patients with PAH with biallelic EIF2AK4 mutations had a shorter survival. CONCLUSIONS: Biallelic EIF2AK4 mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low Kco and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation

Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease

Inherited retinal disease is a common cause of visual impairment and represents a highly heterogeneous group of conditions. Here, we present findings from a cohort of 722 individuals with inherited retinal disease, who have had whole-genome sequencing (n = 605), whole-exome sequencing (n = 72), or both (n = 45) performed, as part of the NIHR-BioResource Rare Diseases research study. We identified pathogenic variants (single-nucleotide variants, indels, or structural variants) for 404/722 (56%) individuals. Whole-genome sequencing gives unprecedented power to detect three categories of pathogenic variants in particular: structural variants, variants in GC-rich regions, which have significantly improved coverage compared to whole-exome sequencing, and variants in non-coding regulatory regions. In addition to previously reported pathogenic regulatory variants, we have identified a previously unreported pathogenic intronic variant in $\textit{CHM}$ in two males with choroideremia. We have also identified 19 genes not previously known to be associated with inherited retinal disease, which harbor biallelic predicted protein-truncating variants in unsolved cases. Whole-genome sequencing is an increasingly important comprehensive method with which to investigate the genetic causes of inherited retinal disease.This work was supported by The National Institute for Health Research England (NIHR) for the NIHR BioResource – Rare Diseases project (grant number RG65966). The Moorfields Eye Hospital cohort of patients and clinical and imaging data were ascertained and collected with the support of grants from the National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital, National Health Service Foundation Trust, and UCL Institute of Ophthalmology, Moorfields Eye Hospital Special Trustees, Moorfields Eye Charity, the Foundation Fighting Blindness (USA), and Retinitis Pigmentosa Fighting Blindness. M.M. is a recipient of an FFB Career Development Award. E.M. is supported by UCLH/UCL NIHR Biomedical Research Centre. F.L.R. and D.G. are supported by Cambridge NIHR Biomedical Research Centre

Phenotypic Characterization of <i>EIF2AK4</i> Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension

Background: Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 ( BMPR2 ) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene ( EIF2AK4 ) are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH. Methods: Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource–Rare Diseases study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of &lt;1:10 000 in control data sets and predicted to be deleterious (by combined annotation-dependent depletion, PolyPhen-2, and sorting intolerant from tolerant predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured. Results: Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (K co ; 33% [interquartile range, 30%–35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23–38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. Patients with PAH with biallelic EIF2AK4 mutations had a shorter survival. Conclusions: Biallelic EIF2AK4 mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low K co and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation. </jats:sec