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1.
BMJ Open Respir Res ; 8(1)2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34848495

RESUMO

INTRODUCTION: Respiratory high-dependency units (rHDUs) are used to manage respiratory failure in COVID-19 outside of the intensive care unit (ICU). The alpha variant of COVID-19 has been linked to increased rates of mortality and admission to ICU; however, its impact on a rHDU population is not known. We aimed to compare rHDU outcomes between the two main UK waves of COVID-19 infection and evaluate the impact of the alpha variant on second wave outcomes. METHODS: We conducted a single-centre, retrospective analysis of all patients with a diagnosis of COVID-19 admitted to the rHDU of our teaching hospital for respiratory support during the first and second main UK waves. RESULTS: In total, 348 patients were admitted to rHDU. In the second wave, mortality (26.7% s vs 50.7% first wave, χ2=14.7, df=1, p=0.0001) and intubation rates in those eligible (24.3% s vs 58.8% first wave, χ2=17.3, df=2, p=0.0002) were improved compared with the first wave. In the second wave, the alpha variant had no effect on mortality (OR 1.18, 95% CI 0.60 to 2.32, p=0.64). Continuous positive airway pressure (CPAP) (89.5%) and awake proning (85.6%) were used in most patients in the second wave. DISCUSSION: Our single-centre experience shows that rHDU mortality and intubation rates have improved over time in spite of the emergence of the alpha variant. Our data support the use of CPAP and awake proning, although improvements in outcome are likely to be multifactorial.

3.
EClinicalMedicine ; 41: 101159, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34693230

RESUMO

Background: The longitudinal trajectories of cardiopulmonary abnormalities and symptoms following infection with coronavirus disease (COVID-19) are unclear. We sought to describe their natural history in previously hospitalised patients, compare this with controls, and assess the relationship between symptoms and cardiopulmonary impairment at 6 months post-COVID-19. Methods: Fifty-eight patients and thirty matched controls (single visit), recruited between 14th March - 25th May 2020, underwent symptom-questionnaires, cardiac and lung magnetic resonance imaging (CMR), cardiopulmonary exercise test (CPET), and spirometry at 3 months following COVID-19. Of them, forty-six patients returned for follow-up assessments at 6 months. Findings: At 2-3 months, 83% of patients had at least one cardiopulmonary symptom versus 33% of controls. Patients and controls had comparable biventricular volumes and function. Native cardiac T1 (marker of fibroinflammation) and late gadolinium enhancement (LGE, marker of focal fibrosis) were increased in patients at 2-3 months. Sixty percent of patients had lung parenchymal abnormalities on CMR and 55% had reduced peak oxygen consumption (pV̇O2) on CPET. By 6 months, 52% of patients remained symptomatic. On CMR, indexed right ventricular (RV) end-diastolic volume (-4·3 mls/m2, P=0·005) decreased and RV ejection fraction (+3·2%, P=0·0003) increased. Native T1 and LGE improved and was comparable to controls. Lung parenchymal abnormalities and peak V̇O2, although better, were abnormal in patients versus controls. 31% had reduced pV̇O2 secondary to symptomatic limitation and muscular impairment. Cardiopulmonary symptoms in patients did not associate with CMR, lung function, or CPET measures. Interpretation: In patients, cardiopulmonary abnormalities improve over time, though some measures remain abnormal relative to controls. Persistent symptoms at 6 months post-COVID-19 did not associate with objective measures of cardiopulmonary health. Funding: The authors' work was supported by the NIHR Oxford Biomedical Research Centre, Oxford British Heart Foundation (BHF) Centre of Research Excellence (RE/18/3/34214), United Kingdom Research Innovation and Wellcome Trust. This project is part of a tier 3 study (C-MORE) within the collaborative research programme entitled PHOSP-COVID Post-hospitalization COVID-19 study: a national consortium to understand and improve long-term health outcomes, funded by the Medical Research Council and Department of Health and Social Care/National Institute for Health Research Grant (MR/V027859/1) ISRCTN number 10980107.

5.
EClinicalMedicine ; 31: 100683, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33490928

RESUMO

Background: The medium-term effects of Coronavirus disease (COVID-19) on organ health, exercise capacity, cognition, quality of life and mental health are poorly understood. Methods: Fifty-eight COVID-19 patients post-hospital discharge and 30 age, sex, body mass index comorbidity-matched controls were enrolled for multiorgan (brain, lungs, heart, liver and kidneys) magnetic resonance imaging (MRI), spirometry, six-minute walk test, cardiopulmonary exercise test (CPET), quality of life, cognitive and mental health assessments. Findings: At 2-3 months from disease-onset, 64% of patients experienced breathlessness and 55% reported fatigue. On MRI, abnormalities were seen in lungs (60%), heart (26%), liver (10%) and kidneys (29%). Patients exhibited changes in the thalamus, posterior thalamic radiations and sagittal stratum on brain MRI and demonstrated impaired cognitive performance, specifically in the executive and visuospatial domains. Exercise tolerance (maximal oxygen consumption and ventilatory efficiency on CPET) and six-minute walk distance were significantly reduced. The extent of extra-pulmonary MRI abnormalities and exercise intolerance correlated with serum markers of inflammation and acute illness severity. Patients had a higher burden of self-reported symptoms of depression and experienced significant impairment in all domains of quality of life compared to controls (p<0.0001 to 0.044). Interpretation: A significant proportion of patients discharged from hospital reported symptoms of breathlessness, fatigue, depression and had limited exercise capacity. Persistent lung and extra-pulmonary organ MRI findings are common in patients and linked to inflammation and severity of acute illness. Funding: NIHR Oxford and Oxford Health Biomedical Research Centres, British Heart Foundation Centre for Research Excellence, UKRI, Wellcome Trust, British Heart Foundation.

6.
BMJ Open Respir Res ; 7(1)2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32928787

RESUMO

The SARS-CoV-2 can lead to severe illness with COVID-19. Outcomes of patients requiring mechanical ventilation are poor. Awake proning in COVID-19 improves oxygenation, but on data clinical outcomes is limited. This single-centre retrospective study aimed to assess whether successful awake proning of patients with COVID-19, requiring respiratory support (continuous positive airways pressure (CPAP) or high-flow nasal oxygen (HFNO)) on a respiratory high-dependency unit (HDU), is associated with improved outcomes. HDU care included awake proning by respiratory physiotherapists. Of 565 patients admitted with COVID-19, 71 (12.6%) were managed on the respiratory HDU, with 48 of these (67.6%) requiring respiratory support. Patients managed with CPAP alone 22/48 (45.8%) were significantly less likely to die than patients who required transfer onto HFNO 26/48 (54.2%): CPAP mortality 36.4%; HFNO mortality 69.2%, (p=0.023); however, multivariate analysis demonstrated that increasing age and the inability to awake prone were the only independent predictors of COVID-19 mortality. The mortality of patients with COVID-19 requiring respiratory support is considerable. Data from our cohort managed on HDU show that CPAP and awake proning are possible in a selected population of COVID-19, and may be useful. Further prospective studies are required.


Assuntos
Pressão Positiva Contínua nas Vias Aéreas/métodos , Infecções por Coronavirus/terapia , Oxigenoterapia/métodos , Posicionamento do Paciente/métodos , Pneumonia Viral/terapia , Decúbito Ventral , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus , COVID-19 , Infecções por Coronavirus/mortalidade , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ventilação não Invasiva/métodos , Razão de Chances , Pandemias , Pneumonia Viral/mortalidade , Estudos Retrospectivos , SARS-CoV-2 , Resultado do Tratamento , Reino Unido , Vigília
7.
BMJ Open Respir Res ; 7(1)2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32565444

RESUMO

BACKGROUND: Increased iron availability modifies cardiorespiratory function in healthy volunteers and improves exercise capacity and quality of life in patients with heart failure or pulmonary hypertension. We hypothesised that intravenous iron would produce improvements in oxygenation, exercise capacity and quality of life in patients with chronic obstructive pulmonary disease (COPD). METHODS: We performed a randomised, placebo-controlled, double-blind trial in 48 participants with COPD (mean±SD: age 69±8 years, haemoglobin 144.8±13.2 g/L, ferritin 97.1±70.0 µg/L, transferrin saturation 31.3%±15.2%; GOLD grades II-IV), each of whom received a single dose of intravenous ferric carboxymaltose (FCM; 15 mg/kg bodyweight) or saline placebo. The primary endpoint was peripheral oxygen saturation (SpO2) at rest after 1 week. The secondary endpoints included daily SpO2, overnight SpO2, exercise SpO2, 6 min walk distance, symptom and quality of life scores, serum iron indices, spirometry, echocardiographic measures, and exacerbation frequency. RESULTS: SpO2 was unchanged 1 week after FCM administration (difference between groups 0.8%, 95% CI -0.2% to 1.7%). However, in secondary analyses, exercise capacity increased significantly after FCM administration, compared with placebo, with a mean difference in 6 min walk distance of 12.6 m (95% CI 1.6 to 23.5 m). Improvements of ≥40 m were observed in 29.2% of iron-treated and 0% of placebo-treated participants after 1 week (p=0.009). Modified MRC Dyspnoea Scale score was also significantly lower after FCM, and fewer participants reported scores ≥2 in the FCM group, compared with placebo (33.3% vs 66.7%, p=0.02). No significant differences were observed in other secondary endpoints. Adverse event rates were similar between groups, except for hypophosphataemia, which occurred more frequently after FCM (91.7% vs 8.3%, p<0.001). CONCLUSIONS: FCM did not improve oxygenation over 8 weeks in patients with COPD. However, this treatment was well tolerated and produced improvements in exercise capacity and functional limitation caused by breathlessness. These effects on secondary endpoints require confirmation in future studies. TRIAL REGISTRATION NUMBER: ISRCTN09143837.


Assuntos
Dispneia/reabilitação , Tolerância ao Exercício/efeitos dos fármacos , Compostos Férricos/administração & dosagem , Maltose/análogos & derivados , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Administração Intravenosa , Idoso , Método Duplo-Cego , Feminino , Hemoglobinas/análise , Humanos , Masculino , Maltose/administração & dosagem , Pessoa de Meia-Idade , Oxigênio/sangue , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Qualidade de Vida , Teste de Caminhada
8.
BMJ Open Respir Res ; 7(1)2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32161066

RESUMO

INTRODUCTION: In asthma, lung function measures are often discordant with clinical features such as disease activity or control. METHODS: We investigated a novel technique that provides a measure (σCL) of unevenness (inhomogeneity) in lung inflation/deflation. In particular, we compared σCL with FEV1% predicted (FEV1%pred) as measures of disease activity in the asthmatic lung. RESULTS: σCL correlated modestly with FEV1%pred. However, σCL is not simply a proxy for FEV1%pred as the effects of salbutamol on the two parameters were unrelated. Importantly, σCL reflected disease control better than FEV1. DISCUSSION: We conclude that σCL shows promise as an objective measure of disease activity in asthma.


Assuntos
Asma/fisiopatologia , Volume Expiratório Forçado , Pulmão/fisiopatologia , Troca Gasosa Pulmonar , Índice de Gravidade de Doença , Adulto , Idoso , Albuterol/administração & dosagem , Broncodilatadores/administração & dosagem , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Espirometria/métodos
10.
Physiol Rep ; 7(13): e14164, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31270967

RESUMO

In older individuals, pulmonary artery pressure rises markedly during exercise, probably due in part to increased pulmonary vascular resistance and in part to an increase in left-heart filling pressure. Older individuals also show more marked pulmonary vascular response to hypoxia at rest. Treatment with intravenous iron reduces the rise in pulmonary artery pressure observed during hypoxia. Here, we test the hypothesis that intravenous iron administration may also attenuate the rise in pulmonary artery pressure with exercise in older individuals. In a randomized double-blind placebo-controlled physiology study in 32 healthy participants aged 50-80 years, we explored the hypothesis that iron administration would deliver a fall in systolic pulmonary artery pressure (SPAP) during moderate cycling exercise (20 min duration; increase in heart rate of 30 min-1 ) and a change in maximal cycling exercise capacity ( V ˙ O 2 m a x ). Participants were studied before, and at 3 h to 8 weeks after, infusion. SPAP was measured using Doppler echocardiography. Iron administration resulted in marked changes in indices of iron homeostasis over 8 weeks, but no significant change in hemoglobin concentration or inflammatory markers. Resting SPAP was also unchanged, but SPAP during exercise was lower by ~3 mmHg in those receiving iron (P < 0.0001). This effect persisted for 8 weeks. Although V ˙ O 2 m a x remained unaffected in the iron-replete healthy participants studied here, this study demonstrates for the first time the ability of intravenous iron supplementation to reduce systolic pulmonary artery pressure during exercise.


Assuntos
Pressão Sanguínea , Exercício Físico , Hipertensão Pulmonar/tratamento farmacológico , Ferro/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Hipertensão Pulmonar/prevenção & controle , Injeções Intravenosas , Ferro/administração & dosagem , Masculino , Pessoa de Meia-Idade , Consumo de Oxigênio , Artéria Pulmonar/fisiologia
11.
Thorax ; 74(8): 797-805, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31036773

RESUMO

Chronic airways diseases, including asthma, COPD and cystic fibrosis, cause significant morbidity and mortality and are associated with high healthcare expenditure, in the UK and worldwide. For patients with these conditions, improvements in clinical outcomes are likely to depend on the application of precision medicine, that is, the matching of the right treatment to the right patient at the right time. In this context, the identification and targeting of 'treatable traits' is an important priority in airways disease, both to ensure the appropriate use of existing treatments and to facilitate the development of new disease-modifying therapy. This requires not only better understanding of airway pathophysiology but also an enhanced ability to make physiological measurements of disease activity and lung function and, if we are to impact on the natural history of these diseases, reliable measures in early disease. In this article, we outline some of the key challenges faced by the respiratory community in the management of airways diseases, including early diagnosis, disease stratification and monitoring of therapeutic response. In this context, we review the advantages and limitations of routine physiological measurements of respiratory function including spirometry, body plethysmography and diffusing capacity and discuss less widely used methods such as forced oscillometry, inert gas washout and the multiple inert gas elimination technique. Finally, we highlight emerging technologies including imaging methods such as quantitative CT and hyperpolarised gas MRI as well as quantification of lung inhomogeneity using precise in-airway gas analysis and mathematical modelling. These emerging techniques have the potential to enhance existing measures in the assessment of airways diseases, may be particularly valuable in early disease, and should facilitate the efforts to deliver precision respiratory medicine.


Assuntos
Pneumopatias/fisiopatologia , Gases Nobres/análise , Testes de Função Respiratória/métodos , Asma/fisiopatologia , Testes Respiratórios/métodos , Fibrose Cística/fisiopatologia , Humanos , Pneumopatias/diagnóstico por imagem , Imageamento por Ressonância Magnética , Oscilometria , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Análise Espectral , Tomografia Computadorizada por Raios X/métodos
13.
Am J Respir Crit Care Med ; 199(2): 211-219, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30025470

RESUMO

RATIONALE: Obstructive sleep apnea (OSA) is associated with systemic hypertension. Either overnight intermittent hypoxia, or the recurrent arousals that occur in OSA, could cause the daytime increases in blood pressure (BP). OBJECTIVES: To establish the role of intermittent hypoxia in the increased morning BP in patients with OSA. METHODS: Randomized, double-blinded, crossover trial assessing the effects of overnight supplemental oxygen versus air (sham) on morning BP, after continuous positive airway pressure (CPAP) withdrawal in patients with moderate to severe OSA. The primary outcome was the change in home morning BP after CPAP withdrawal for 14 nights, oxygen versus air. Secondary outcomes included oxygen desaturation index (ODI), apnea-hypopnea index (AHI), subjective sleepiness (Epworth Sleepiness Scale score), and objective sleepiness (Oxford Sleep Resistance Test). MEASUREMENTS AND MAIN RESULTS: Supplemental oxygen virtually abolished the BP rise after CPAP withdrawal and, compared with air, significantly reduced the rise in mean systolic BP (-6.6 mm Hg; 95% confidence interval [CI], -11.3 to -1.9; P = 0.008), mean diastolic BP (-4.6 mm Hg; 95% CI, -7.8 to -1.5; P = 0.006), and median ODI (-23.8/h; interquartile range, -31.0 to -16.3; P < 0.001) after CPAP withdrawal. There was no significant difference, oxygen versus air, in AHI, subjective sleepiness, or objective sleepiness. CONCLUSIONS: Supplemental oxygen virtually abolished the rise in morning BP during CPAP withdrawal. Supplemental oxygen substantially reduced intermittent hypoxia, but had a minimal effect on markers of arousal (including AHI), subjective sleepiness, or objective sleepiness. Therefore intermittent hypoxia, and not recurrent arousals, appears to be the dominant cause of daytime increases in BP in OSA.


Assuntos
Pressão Positiva Contínua nas Vias Aéreas , Hipertensão/prevenção & controle , Oxigenoterapia/métodos , Apneia Obstrutiva do Sono/fisiopatologia , Apneia Obstrutiva do Sono/terapia , Idoso , Pressão Sanguínea , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Hipertensão/complicações , Hipertensão/fisiopatologia , Hipóxia/complicações , Hipóxia/fisiopatologia , Hipóxia/terapia , Masculino , Pessoa de Meia-Idade , Oxigênio , Índice de Gravidade de Doença , Apneia Obstrutiva do Sono/complicações
14.
Artigo em Inglês | MEDLINE | ID: mdl-30188794

RESUMO

Intravenous (iv) iron administration is typically indicated in individuals who have iron deficiency refractory to oral iron. However, in certain chronic disease states, it may be beneficial to administer iv iron to individuals who are not strictly iron deficient. The purpose of this study was to define a dose-response relationship between clinical indices of iron status and modest loading with iv iron in healthy, iron-replete participants. This was a double-blind, controlled study involving 18 male participants. Participants were block randomised 2:1 to the iron and saline (control) groups. Participants in the iron group received 250 mg of iv iron, once a month for six months, provided that their ferritin remained < 300 µg/L and their transferrin saturation remained < 45%. Otherwise they received a saline infusion, as did the control participants. Iron indices were measured monthly during the study. The pulmonary vascular response to sustained hypoxia and total hemoglobin mass were measured before, at three months (hemoglobin mass only) and at six months, as variables that may be affected by iron loading. Serum ferritin was robustly elevated by iv iron by 0.21 µg/L/mg of iron delivered (95% CI: 0.15-0.26 µg/L/mg), but the effects on all other iron indices did not reach statistical significance. The pulmonary vascular response to sustained hypoxia was significantly suppressed by iron loading at six months, but the hemoglobin mass was unaffected. We conclude that the robust effect on ferritin provides a quantitative measure for the degree of iron loading in iron-replete individuals.

15.
Physiol Rep ; 5(17)2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28899910

RESUMO

Exposure to sustained hypoxia of 8 h duration increases the sensitivity of the pulmonary vasculature to acute hypoxia, but it is not known whether exposure to sustained hyperoxia affects human pulmonary vascular control. We hypothesized that exposure to 8 h of hyperoxia would diminish the hypoxic pulmonary vasoconstriction (HPV) that occurs in response to a brief exposure to hypoxia. Eleven healthy volunteers were studied in a crossover protocol with randomization of order. Each volunteer was exposed to acute isocapnic hypoxia (end-tidal PO2 = 50 mmHg for 10 min) before and after 8 h of hyperoxia (end-tidal PO2 = 420 mmHg) or euoxia (end-tidal PO2 = 100 mmHg). After at least 3 days, each volunteer returned and was exposed to the other condition. Systolic pulmonary artery pressure (an index of HPV) and cardiac output were measured, using Doppler echocardiography. Eight hours of hyperoxia had no effect on HPV or the response of cardiac output to acute hypoxia.


Assuntos
Hiperóxia/fisiopatologia , Hipóxia/fisiopatologia , Oxigenoterapia/métodos , Artéria Pulmonar/fisiologia , Vasoconstrição , Adolescente , Adulto , Pressão Sanguínea , Dióxido de Carbono/sangue , Feminino , Humanos , Hipóxia/terapia , Masculino , Oxigenoterapia/efeitos adversos , Circulação Pulmonar
16.
PLoS Genet ; 13(4): e1006675, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28448578

RESUMO

The indigenous people of the Tibetan Plateau have been the subject of much recent interest because of their unique genetic adaptations to high altitude. Recent studies have demonstrated that the Tibetan EPAS1 haplotype is involved in high altitude-adaptation and originated in an archaic Denisovan-related population. We sequenced the whole-genomes of 27 Tibetans and conducted analyses to infer a detailed history of demography and natural selection of this population. We detected evidence of population structure between the ancestral Han and Tibetan subpopulations as early as 44 to 58 thousand years ago, but with high rates of gene flow until approximately 9 thousand years ago. The CMS test ranked EPAS1 and EGLN1 as the top two positive selection candidates, and in addition identified PTGIS, VDR, and KCTD12 as new candidate genes. The advantageous Tibetan EPAS1 haplotype shared many variants with the Denisovan genome, with an ancient gene tree divergence between the Tibetan and Denisovan haplotypes of about 1 million years ago. With the exception of EPAS1, we observed no evidence of positive selection on Denisovan-like haplotypes.


Assuntos
Adaptação Fisiológica/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Genoma Humano , Seleção Genética/genética , Altitude , Sistema Enzimático do Citocromo P-450/genética , Feminino , Haplótipos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Prolina Dioxigenases do Fator Induzível por Hipóxia/genética , Masculino , Anotação de Sequência Molecular , Proteínas/genética , Receptores de Calcitriol/genética , Tibet
17.
BMC Genomics ; 18(1): 102, 2017 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-28103797

RESUMO

BACKGROUND: We set out to describe the fine-scale population structure across the Eastern region of Nepal. To date there is relatively little known about the genetic structure of the Sherpa residing in Nepal and their genetic relationship with the Nepalese. We assembled dense genotype data from a total of 1245 individuals representing Nepal and a variety of different populations resident across the greater Himalayan region including Tibet, China, India, Pakistan, Kazakhstan, Uzbekistan, Tajikistan and Kirghizstan. We performed analysis of principal components, admixture and homozygosity. RESULTS: We identified clear substructure across populations resident in the Himalayan arc, with genetic structure broadly mirroring geographical features of the region. Ethnic subgroups within Nepal show distinct genetic structure, on both admixture and principal component analysis. We detected differential proportions of ancestry from northern Himalayan populations across Nepalese subgroups, with the Nepalese Rai, Magar and Tamang carrying the greatest proportions of Tibetan ancestry. CONCLUSIONS: We show that populations dwelling on the Himalayan plateau have had a clear impact on the Northern Indian gene pool. We illustrate how the Sherpa are a remarkably isolated population, with little gene flow from surrounding Nepalese populations.


Assuntos
/genética , /genética , Cromossomos Humanos Y/genética , DNA/isolamento & purificação , DNA/metabolismo , DNA Mitocondrial/genética , Fluxo Gênico , Genótipo , Humanos , Leucócitos/metabolismo , Funções Verossimilhança , Nepal , Análise de Componente Principal
18.
Respirology ; 22(4): 793-799, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-27860068

RESUMO

BACKGROUND AND OBJECTIVE: Obstructive sleep apnoea (OSA) is associated with cardiovascular disease. Intermittent hypoxia, endothelial dysfunction and adipose tissue-mediated inflammation have all been linked to cardiovascular disease in OSA. We therefore explored the effect of OSA on relevant associated blood markers: adrenomedullin (ADM), endocan, endothelin-1 (ET-1), resistin and vascular endothelial growth factor (VEGF). METHODS: Patients with OSA, established on and compliant with continuous positive airways pressure (CPAP) therapy for >1 year were included from three randomized controlled trials, conducted at two centres. Patients were randomized to either continued therapeutic CPAP or sham CPAP (CPAP withdrawal) for 2 weeks. Blood markers were measured at baseline and at 14 days and the treatment effect between sham CPAP and therapeutic CPAP was analysed. RESULTS: A total of 109 patients were studied (therapeutic CPAP n = 54, sham CPAP n = 55). Sham CPAP was associated with a return of OSA (between-group difference in oxygen desaturation index (ODI) 36.0/h, 95% CI 29.9-42.2, P < 0.001). Sham CPAP was associated with a reduction in ADM levels at 14 days (-26.0 pg/mL, 95% CI -47.8 to -4.3, P = 0.02), compared to therapeutic CPAP. Return of OSA was not associated with changes in endocan, ET-1, resistin or VEGF. CONCLUSION: Whilst CPAP withdrawal was associated with return of OSA, it was associated with an unexpected significant reduction in the vasodilator ADM and not with expected increases in hypoxia-induced markers, markers of endothelial function or resistin. We propose that the vascular effects occurring in OSA may be brought about by other mechanisms, perhaps partly through a reduction in ADM.


Assuntos
Adrenomedulina/sangue , Biomarcadores/sangue , Pressão Positiva Contínua nas Vias Aéreas/métodos , Endotelina-1/sangue , Proteínas de Neoplasias/sangue , Proteoglicanas/sangue , Resistina/sangue , Apneia Obstrutiva do Sono/fisiopatologia , Fator A de Crescimento do Endotélio Vascular/sangue , Desmame do Respirador/métodos , Adulto , Idoso , Feminino , Humanos , Hipóxia/metabolismo , Inflamação/metabolismo , Masculino , Pessoa de Meia-Idade , Cooperação do Paciente
19.
Haematologica ; 101(11): 1306-1318, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27651169

RESUMO

Erythrocytosis is a rare disorder characterized by increased red cell mass and elevated hemoglobin concentration and hematocrit. Several genetic variants have been identified as causes for erythrocytosis in genes belonging to different pathways including oxygen sensing, erythropoiesis and oxygen transport. However, despite clinical investigation and screening for these mutations, the cause of disease cannot be found in a considerable number of patients, who are classified as having idiopathic erythrocytosis. In this study, we developed a targeted next-generation sequencing panel encompassing the exonic regions of 21 genes from relevant pathways (~79 Kb) and sequenced 125 patients with idiopathic erythrocytosis. The panel effectively screened 97% of coding regions of these genes, with an average coverage of 450×. It identified 51 different rare variants, all leading to alterations of protein sequence, with 57 out of 125 cases (45.6%) having at least one of these variants. Ten of these were known erythrocytosis-causing variants, which had been missed following existing diagnostic algorithms. Twenty-two were novel variants in erythrocytosis-associated genes (EGLN1, EPAS1, VHL, BPGM, JAK2, SH2B3) and in novel genes included in the panel (e.g. EPO, EGLN2, HIF3A, OS9), some with a high likelihood of functionality, for which future segregation, functional and replication studies will be useful to provide further evidence for causality. The rest were classified as polymorphisms. Overall, these results demonstrate the benefits of using a gene panel rather than existing methods in which focused genetic screening is performed depending on biochemical measurements: the gene panel improves diagnostic accuracy and provides the opportunity for discovery of novel variants.


Assuntos
Mutação , Policitemia/genética , Variação Genética , Humanos , Técnicas de Diagnóstico Molecular/métodos , Técnicas de Diagnóstico Molecular/normas , Policitemia/diagnóstico , Policitemia/etiologia , Análise de Sequência de DNA
20.
J Appl Physiol (1985) ; 121(2): 537-44, 2016 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-27418684

RESUMO

Sustained hypoxia over several hours induces a progressive rise in pulmonary artery systolic pressure (PASP). Administration of intravenous iron immediately prior to the hypoxia exposure abrogates this effect, suggesting that manipulation of iron stores may modify hypoxia-induced pulmonary hypertension. Iron (ferric carboxymaltose) administered intravenously has a plasma half-life of 7-12 h. Thus any therapeutic use of intravenous iron would require its effect on PASP to persist long after the iron-sugar complex has been cleared from the blood. To examine this, we studied PASP during sustained (6 h) hypoxia on 4 separate days (days 0, 1, 8, and 43) in 22 participants. On day 0, the rise in PASP with hypoxia was well matched between the iron and saline groups. On day 1, each participant received either 1 g of ferric carboxymaltose or saline in a double-blind manner. After administration of intravenous iron, the rise in PASP with hypoxia was attenuated by ∼50%, and this response remained suppressed on both days 8 and 43 (P < 0.001). Following administration of intravenous iron, values for ferritin concentration, transferrin saturation, and hepcidin concentration rose significantly (P < 0.001, P < 0.005, and P < 0.001, respectively), and values for transferrin concentration fell significantly (P < 0.001). These changes remained significant at day 43 We conclude that the attenuation of the pulmonary vascular response to hypoxia by elevation of iron stores persists long after the artificial iron-sugar complex has been eliminated from the blood. The persistence of this effect suggests that intravenous iron may be of benefit in some forms of pulmonary hypertension.


Assuntos
Hipertensão Pulmonar/prevenção & controle , Hipertensão Pulmonar/fisiopatologia , Hipóxia/tratamento farmacológico , Hipóxia/fisiopatologia , Ferro/administração & dosagem , Ferro/sangue , Artéria Pulmonar/fisiopatologia , Adulto , Pressão Sanguínea/efeitos dos fármacos , Feminino , Humanos , Hipertensão Pulmonar/etiologia , Hipóxia/complicações , Injeções Intravenosas , Masculino , Taxa de Depuração Metabólica , Artéria Pulmonar/efeitos dos fármacos , Resultado do Tratamento , Vasoconstrição/efeitos dos fármacos
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