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1.
J Pain Symptom Manage ; 58(2): e2-e3, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30904417
2.
J Pain Symptom Manage ; 57(6): 1051-1061.e1, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30802635

RESUMO

CONTEXT: The battery-operated hand-held fan ("fan") and the Calming Hand (CH), a cognitive strategy, are interventions used in clinical practice to relieve chronic breathlessness. OBJECTIVE: To test the feasibility of a Phase III randomized controlled trial (RCT) evaluating the impact of the fan and/or CH compared with exercise advice alone for the relief of chronic breathlessness due to respiratory conditions. METHODS: A single-site, feasibility "2 × 2" factorial, nonblinded, mixed-methods RCT was performed. Participants randomly allocated to four groups: fan + exercise advice, CH + exercise advice, fan + CH + exercise advice, and exercise advice alone. Measures included recruitment, acceptability, data quality and study outcomes (baseline and day 28), modified Incremental Shuttle Walk Test (mISWT), recovery time from exertion-induced breathlessness, life-space questionnaire, General Self-Efficacy Scale, and breathlessness numerical rating scales. Willing participants and carers were interviewed at study end. RESULTS: Recruitment/acceptability/data completion: 53 people were screened, 40 randomized and completed (mean age 72 years (SD 9.8), 70% male). There were few missing data (mISWT, n = 2). Recovery time (seconds) from exertion-induced breathlessness showed most improvement for the fan; mean reduction from baseline -33.5 vs. CH mean increase from baseline 5.7. This represents a recovery speed at day 28 (-20.4%) faster for the fan vs. 4.1% slower for the CH. Qualitative data indicated participants valued the faster recovery and identified the fan as a useful "medical" device but found the CH unhelpful. CONCLUSION: A Phase III RCT is feasible. Mixed-methods data synthesis supports recovery time as a novel, meaningful outcome measure.

3.
Proc Natl Acad Sci U S A ; 116(6): 2112-2117, 2019 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-30659157

RESUMO

Increasing evidence for rapid evolution suggests that the maintenance of species diversity in ecological communities may be influenced by more than purely ecological processes. Classic theory shows that interspecific competition may select for traits that increase niche differentiation, weakening competition and thus promoting species coexistence. While empirical work has demonstrated trait evolution in response to competition, if and how evolution affects the dynamics of the competing species-the key step for completing the required eco-evolutionary feedback-has been difficult to resolve. Here, we show that evolution in response to interspecific competition feeds back to change the course of competitive population dynamics of aquatic plant species over 10-15 generations in the field. By manipulating selection imposed by heterospecific competitors in experimental ponds, we demonstrate that (i) interspecific competition drives rapid genotypic change, and (ii) this evolutionary change in one competitor, while not changing the coexistence outcome, causes the population trajectories of the two competing species to converge. In contrast to the common expectation that interspecific competition should drive the evolution of niche differentiation, our results suggest that genotypic evolution resulted in phenotypic changes that altered population dynamics by affecting the competitive hierarchy. This result is consistent with theory suggesting that competition for essential resources can limit opportunities for the evolution of niche differentiation. Our finding that rapid evolution regulates the dynamics of competing species suggests that ecosystems may rely on continuous feedbacks between ecology and evolution to maintain species diversity.


Assuntos
Biodiversidade , Evolução Biológica , Seleção Genética , Algoritmos , Análise de Variância , Modelos Teóricos , Dinâmica Populacional , Característica Quantitativa Herdável
4.
Platelets ; : 1-5, 2018 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-30365337

RESUMO

It is widely believed that assays of platelet activation are susceptible to preanalytical variables related to blood draw technique. We assessed platelet activation by whole blood flow cytometry and investigated the effects of: (1) drawing blood into vacuum tubes or manually aspirated syringes, and (2) discarding the first drawn blood sample (discard tube). Platelet P-selectin expression and platelet-monocyte complexes were measured by flow cytometry under both basal conditions and following stimulation with 0.1, 1, or 10 µM ADP. Bland-Altman plots demonstrated agreement between results for vacuum tube and syringe-aspirated samples with an a priori-defined clinically relevant agreement limit of 5%. Agreement of results was also observed between discard tube and second draw samples for both vacuum-driven and manually aspirated blood. We conclude that a vacuum tube or a manually-aspirated syringe can be used when assessing platelet activation by flow cytometry and that there is no need for a discard tube.

9.
Lancet Respir Med ; 5(11): 869-880, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-29066090

RESUMO

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease with high mortality, uncertain cause, and few treatment options. Studies have identified a significant genetic risk associated with the development of IPF; however, mechanisms by which genetic risk factors promote IPF remain unclear. We aimed to identify genetic variants associated with IPF susceptibility and provide mechanistic insight using gene and protein expression analyses. METHODS: We used a two-stage approach: a genome-wide association study in patients with IPF of European ancestry recruited from nine different centres in the UK and controls selected from UK Biobank (stage 1) matched for age, sex, and smoking status; and a follow-up of associated genetic variants in independent datasets of patients with IPF and controls from two independent US samples from the Chicago consortium and the Colorado consortium (stage 2). We investigated the effect of novel signals on gene expression in large transcriptomic and genomic data resources, and examined expression using lung tissue samples from patients with IPF and controls. FINDINGS: 602 patients with IPF and 3366 controls were selected for stage 1. For stage 2, 2158 patients with IPF and 5195 controls were selected. We identified a novel genome-wide significant signal of association with IPF susceptibility near A-kinase anchoring protein 13 (AKAP13; rs62025270, odds ratio [OR] 1·27 [95% CI 1·18-1·37], p=1·32 × 10-9) and confirmed previously reported signals, including in mucin 5B (MUC5B; rs35705950, OR 2·89 [2·56-3·26], p=1·12 × 10-66) and desmoplakin (DSP; rs2076295, OR 1·44 [1·35-1·54], p=7·81 × 10-28). For rs62025270, the allele A associated with increased susceptibility to IPF was also associated with increased expression of AKAP13 mRNA in lung tissue from patients who had lung resection procedures (n=1111). We showed that AKAP13 is expressed in the alveolar epithelium and lymphoid follicles from patients with IPF, and AKAP13 mRNA expression was 1·42-times higher in lung tissue from patients with IPF (n=46) than that in lung tissue from controls (n=51). INTERPRETATION: AKAP13 is a Rho guanine nucleotide exchange factor regulating activation of RhoA, which is known to be involved in profibrotic signalling pathways. The identification of AKAP13 as a susceptibility gene for IPF increases the prospect of successfully targeting RhoA pathway inhibitors in patients with IPF. FUNDING: UK Medical Research Council, National Heart, Lung, and Blood Institute of the US National Institutes of Health, Agencia Canaria de Investigación, Innovación y Sociedad de la Información, Spain, UK National Institute for Health Research, and the British Lung Foundation.


Assuntos
Proteínas de Ancoragem à Quinase A/genética , Grupo com Ancestrais do Continente Europeu/genética , Predisposição Genética para Doença/genética , Variação Genética , Fibrose Pulmonar Idiopática/genética , Antígenos de Histocompatibilidade Menor/genética , Proteínas Proto-Oncogênicas/genética , Idoso , Células Epiteliais Alveolares/metabolismo , Estudos de Casos e Controles , Europa (Continente) , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/metabolismo , Fatores de Troca de Nucleotídeo Guanina Rho/fisiologia , Transdução de Sinais/genética , Estruturas Linfoides Terciárias/genética , Proteína rhoA de Ligação ao GTP/fisiologia
10.
Nat Ecol Evol ; 1(9): 1411, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29046538

RESUMO

An error during production led to a truncation of the final two sentences in the abstract, which should have read 'In so doing, this framework substantially reframes current approaches to spatial community ecology. Quantifying the spatial scales of species coexistence will permit the next important advance in our understanding of the maintenance of diversity in nature, and should improve the contribution of community ecology to biodiversity conservation.' These have been corrected in all versions of the Perspective.

11.
Nat Ecol Evol ; 1(8): 1066-1073, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29046584

RESUMO

Understanding how species diversity is maintained is a foundational problem in ecology and an essential requirement for the discipline to be effective as an applied science. Ecologists' understanding of this problem has rapidly matured, but this has exposed profound uncertainty about the spatial scales required to maintain species diversity. Here we define and develop this frontier by proposing the coexistence-area relationship-a real relationship in nature that can be used to understand the determinants of the scale-dependence of diversity maintenance. The coexistence-area relationship motivates new empirical techniques for addressing important, unresolved problems about the influence of demographic stochasticity, environmental heterogeneity and dispersal on scale-dependent patterns of diversity. In so doing, this framework substantially reframes current approaches to spatial community ecology. Quantifying the spatial scales of species coexistence will permit the next important advance in our understanding of the maintenance of diversity in nature, and should improve the contribution of community ecology to biodiversity conservation.


Assuntos
Biodiversidade , Conservação dos Recursos Naturais , Ecologia/métodos , Animais , Invertebrados , Plantas , Vertebrados
13.
ERJ Open Res ; 3(1)2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28344981

RESUMO

Chronic inflammatory diseases of the airways are associated with gastro-oesophageal reflux (GOR) and aspiration events. The observation of lipid-laden macrophages (LLMs) within the airway may indicate aspiration secondary to GOR. The proposed mechanism, that lipid droplets from undigested or partially digested food are aspirated leading to accumulation in scavenging macrophages, led us to hypothesise that an activated population of LLMs could interact with other immune cells to induce bronchial inflammation. To test this, we generated an in vitro model using differentiated THP-1 cells, which were treated with a high-fat liquid feed. Here, we show that THP-1 cells can take up lipid from the high-fat feed independent of actin polymerisation or CD36-dependent phagocytosis. These cells did not exhibit M1 or M2 polarisation. Gene array analysis confirmed over 8000 genes were upregulated by at least twofold following high fat exposure, and IL-8 was the most upregulated gene. Pathway analysis revealed upregulation of genes known to be involved in chronic obstructive pulmonary disease (COPD) pathophysiology. We suggest that aspiration and macrophage phagocytosis may be important mechanisms in the aetiology of diseases such as COPD and cystic fibrosis that are characterised by high levels of IL-8 within the airways.

14.
J Allergy Clin Immunol Pract ; 5(4): 938-945, 2017 Jul - Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28351785

RESUMO

A proportion of people living with common variable immunodeficiency disorders develop granulomatous-lymphocytic interstitial lung disease (GLILD). We aimed to develop a consensus statement on the definition, diagnosis, and management of GLILD. All UK specialist centers were contacted and relevant physicians were invited to take part in a 3-round online Delphi process. Responses were graded as Strongly Agree, Tend to Agree, Neither Agree nor Disagree, Tend to Disagree, and Strongly Disagree, scored +1, +0.5, 0, -0.5, and -1, respectively. Agreement was defined as greater than or equal to 80% consensus. Scores are reported as mean ± SD. There was 100% agreement (score, 0.92 ± 0.19) for the following definition: "GLILD is a distinct clinico-radio-pathological ILD occurring in patients with [common variable immunodeficiency disorders], associated with a lymphocytic infiltrate and/or granuloma in the lung, and in whom other conditions have been considered and where possible excluded." There was consensus that the workup of suspected GLILD requires chest computed tomography (CT) (0.98 ± 0.01), lung function tests (eg, gas transfer, 0.94 ± 0.17), bronchoscopy to exclude infection (0.63 ± 0.50), and lung biopsy (0.58 ± 0.40). There was no consensus on whether expectant management following optimization of immunoglobulin therapy was acceptable: 67% agreed, 25% disagreed, score 0.38 ± 0.59; 90% agreed that when treatment was required, first-line treatment should be with corticosteroids alone (score, 0.55 ± 0.51).


Assuntos
Imunodeficiência de Variável Comum , Granuloma , Doenças Pulmonares Intersticiais , Instituições de Caridade , Imunodeficiência de Variável Comum/diagnóstico , Imunodeficiência de Variável Comum/diagnóstico por imagem , Imunodeficiência de Variável Comum/tratamento farmacológico , Imunodeficiência de Variável Comum/patologia , Consenso , Granuloma/diagnóstico , Granuloma/diagnóstico por imagem , Granuloma/tratamento farmacológico , Granuloma/patologia , Humanos , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Doenças Pulmonares Intersticiais/tratamento farmacológico , Doenças Pulmonares Intersticiais/patologia , Sociedades Médicas , Reino Unido
15.
Sci Rep ; 6: 38689, 2016 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-27929051

RESUMO

In sarcoidosis, the proinflammatory cytokines interferon gamma, tumour necrosis factor and interleukin-6 are released by monocyte-derived macrophages and lymphocytes in the lungs and other affected tissues. Regulatory receptors expressed on monocytes and macrophages act to suppress cytokine production, and reduced expression of regulatory receptors may thus promote tissue inflammation. The aim of this study was to characterise the role of regulatory receptors on blood monocytes in patients with sarcoidosis. Cytokine release in response to stimulation of whole blood was measured in healthy controls and Caucasian non-smoking patients with sarcoidosis who were not taking disease modifying therapy. Expression of the regulatory molecules IL-10R, SIRP-α/ß, CD47, CD200R, and CD200L was measured by flow cytometry, and functional activity was assessed using blocking antibodies. Stimulated whole blood and monocytes from patients with sarcoidosis produced more TNF and IL-6 compared with healthy controls. 52.9% of sarcoidosis patients had monocytes characterised by low expression of CD200R, compared with 11.7% of controls (p < 0.0001). Patients with low monocyte CD200R expression produced higher levels of proinflammatory cytokines. In functional studies, blocking the CD200 axis increased production of TNF and IL-6. Reduced expression of CD200R on monocytes may be a mechanism contributing to monocyte and macrophage hyper-activation in sarcoidosis.


Assuntos
Antígenos de Superfície/genética , Citocinas/metabolismo , Regulação da Expressão Gênica , Mediadores da Inflamação/metabolismo , Monócitos/metabolismo , Receptores de Superfície Celular/genética , Sarcoidose/genética , Sarcoidose/metabolismo , Adulto , Idoso , Antígenos CD/metabolismo , Biomarcadores , Feminino , Humanos , Imunofenotipagem , Contagem de Leucócitos , Linfopenia , Masculino , Pessoa de Meia-Idade , Fenótipo , Ligação Proteica , Radiografia Torácica , Sarcoidose/diagnóstico , Linfócitos T/imunologia , Linfócitos T/metabolismo , Adulto Jovem
16.
Exp Lung Res ; 42(8-10): 397-407, 2016 Oct - Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27797602

RESUMO

AIM OF THE STUDY: Bleomycin-induced lung disease is a serious complication of therapy characterized by alveolar injury, cytokine release, inflammatory cell recruitment, and eventually pulmonary fibrosis. The mechanisms underlying bleomycin-induced pulmonary fibrosis may be relevant to other progressive scarring diseases of the lungs. Pulmonary vascular endothelial cells are critically involved in immune cell extravasation at sites of injury through adhesion molecule expression and cytokine release. We sought to determine the effects of bleomycin on adhesion molecule expression and cytokine release by pulmonary vascular endothelial cells, and their functional relevance to inflammatory cell recruitment. MATERIALS AND METHODS: The effects of pharmacologically relevant concentrations of bleomycin on adhesion molecule expression and cytokine release by human vascular endothelial cells in vitro were studied by flow cytometry, quantitative polymerase chain reaction, and enzyme-linked immunosorbent assay. A flow chamber model was used to assess the functional consequences on adhesion of flowing human neutrophils to endothelial cell monolayers. RESULTS: Bleomycin increased intercellular adhesion molecule 1 (ICAM-1; CD54), vascular cell adhesion molecule (VCAM-1; CD106), and E-selectin (CD62E) expression, and increased monocyte chemoattractant protein (MCP-1) and interleukin (IL-8) release by endothelial cells. Increases in protein expression were accompanied by increased mRNA transcription. In contrast, there was no direct effect of bleomycin on the profibrotic cytokines transforming growth factor-beta (TGF-ß), platelet-derived growth factor-BB (PDGF-BB), or endothelin-1. Under flow conditions, endothelial cells exposed to bleomycin supported increased neutrophil adhesion which was independent of ICAM-1 or E-selectin. CONCLUSION: Our findings demonstrate that bleomycin promotes endothelial-mediated inflammation and neutrophil adhesion. These mechanisms may contribute to the development of pulmonary fibrosis by supporting immune cell recruitment in the lungs.


Assuntos
Bleomicina/farmacologia , Adesão Celular/efeitos dos fármacos , Células Endoteliais/metabolismo , Neutrófilos/metabolismo , Linhagem Celular , Selectina E/biossíntese , Células Endoteliais/patologia , Humanos , Inflamação , Molécula 1 de Adesão Intercelular/biossíntese , Fibrose Pulmonar , Regulação para Cima
17.
Trends Ecol Evol ; 31(11): 831-841, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27640784

RESUMO

Climate change will likely reshuffle ecological communities, causing novel species interactions that could profoundly influence how populations and communities respond to changing conditions. Nonetheless, predicting the impacts of novel interactions is challenging, partly because many methods of inference are contingent on the current configuration of climatic variables and species distributions. Focusing on competition, we argue that experiments designed to quantify novel interactions in ways that can inform species distribution models are urgently needed, and suggest an empirical agenda to pursue this goal, illustrated using plants. An emerging convergence of ideas from macroecology and demographically focused competition theory offers opportunities to mechanistically incorporate competition into species distribution models, while forging closer ties between experimental ecology and macroecology.


Assuntos
Mudança Climática , Ecologia , Biota , Clima , Plantas
18.
Ecol Lett ; 19(8): 825-38, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27250037

RESUMO

Although the effects of variation between individuals within species are traditionally ignored in studies of species coexistence, the magnitude of intraspecific variation in nature is forcing ecologists to reconsider. Compelling intuitive arguments suggest that individual variation may provide a previously unrecognised route to diversity maintenance by blurring species-level competitive differences or substituting for species-level niche differences. These arguments, which are motivating a large body of empirical work, have rarely been evaluated with quantitative theory. Here we incorporate intraspecific variation into a common model of competition and identify three pathways by which this variation affects coexistence: (1) changes in competitive dynamics because of nonlinear averaging, (2) changes in species' mean interaction strengths because of variation in underlying traits (also via nonlinear averaging) and (3) effects on stochastic demography. As a consequence of the first two mechanisms, we find that intraspecific variation in competitive ability increases the dominance of superior competitors, and intraspecific niche variation reduces species-level niche differentiation, both of which make coexistence more difficult. In addition, individual variation can exacerbate the effects of demographic stochasticity, and this further destabilises coexistence. Our work provides a theoretical foundation for emerging empirical interests in the effects of intraspecific variation on species diversity.


Assuntos
Ecossistema , Modelos Biológicos , Adaptação Fisiológica , Animais , Comportamento Competitivo , Dinâmica Populacional , Especificidade da Espécie
19.
Ther Clin Risk Manag ; 12: 563-74, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27114711

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease of unknown cause. Approximately 5,000 people are diagnosed with IPF in the UK every year. People with IPF suffer significant morbidity and, without any curative treatment at present, survival rates remain poor with a median survival of 3 years. While treatment remains largely supportive, many drug therapies have been trialed in IPF over the years. Pirfenidone and nintedanib are newly licensed treatments for IPF and the first drugs to have shown convincing evidence of slowing disease progression. In addition to evaluating clinical evidence, we also discuss elements affecting drug choice from the viewpoint of patients and health care professionals. We discuss pharmacological and nonpharmacological aspects of providing best supportive care for patients with IPF. However, few good quality studies exist focusing on controlling symptoms specifically in patients with IPF, and recommendations are often extrapolated from evidence in other chronic diseases. In covering these topics, we hope to provide readers with a comprehensive review of the available evidence pertaining to all aspects of care for patients suffering with IPF.

20.
J Palliat Med ; 19(5): 549-55, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26840603

RESUMO

BACKGROUND: Irrreversible interstitial lung disease (ILD) is associated with high morbidity and mortality. Palliative care needs of patients and caregivers are not routinely assessed; there is no tool to identify needs and triage support in clinical practice. OBJECTIVE: The study objective was to adapt and face/content validate a palliative needs assessment tool for people with ILD. METHODS: The Needs Assessment Tool: Progressive Disease-Cancer (NAT:PD-C) was adapted to reflect the palliative care needs identified from the ILD literature and patient/caregiver interviews. Face and content validity of the NAT:PD-ILD was tested using patient/caregiver focus groups and an expert consensus group. Participants in the study were two English tertiary health care trusts' outpatients clinics. There were four focus groups: two patient (n = 7; n = 4); one caregiver (n = 3); and one clinician (n = 8). There was a single caregiver interview, and an expert consensus group-academics (n = 3), clinicians (n = 9), patients (n = 4), and caregivers (n = 2). Each item in the tool was revised as agreed by the groups. Expert consensus was reached. RESULTS: Overall, the tool reflected participants' experience of ILD. Each domain was considered relevant. Adaptations were needed to represent the burden of ILD: respiratory symptoms (especially cough) and concerns about sexual activity were highlighted. All emphasized assessment of caregiver need as critical, and the role of caregivers in clinical consultations. CONCLUSIONS: The NAT:PD-ILD appears to have face and content validity. The inclusion of the family caregiver in the consultation as someone with their own needs as well as a source of information was welcomed. Reliability testing and construct validation of the tool are ongoing.


Assuntos
Doenças Pulmonares Intersticiais , Cuidadores , Humanos , Determinação de Necessidades de Cuidados de Saúde , Cuidados Paliativos , Reprodutibilidade dos Testes
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