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European Respiratory Journal 10/2009; 34(4):1001-3. · 5.89 Impact Factor
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S J Chapman,
C C Khor,
F O Vannberg,
A Rautanen,
S Segal,
C E Moore, R J O Davies,
N P Day,
N Peshu,
D W Crook,
J A Berkley,
T N Williams,
J A Scott,
A V S Hill
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ABSTRACT: The proinflammatory transcription factor nuclear factor-kappaB (NF-kappaB) has a central role in host defence against pneumococcal disease. Both rare mutations and common polymorphisms in the NFKBIA gene encoding the NF-kappaB inhibitor, IkappaB-alpha, associate with susceptibility to bacterial disease, but the possible role of polymorphisms within the related IkappaB-zeta gene NFKBIZ in the development of invasive pneumococcal disease (IPD) has not been reported previously. To investigate this further, we examined the frequencies of 22 single-nucleotide polymorphisms spanning NFKBIZ in two case-control studies, comprising UK Caucasian (n=1008) and Kenyan (n=723) individuals. Nine polymorphisms within a single UK linkage disequilibrium (LD) block and all four polymorphisms within the equivalent, shorter Kenyan LD block displayed either a significant association with IPD or a trend towards association. For each polymorphism, heterozygosity was associated with protection from IPD when compared with the combined homozygous states (for example, for rs600718, Mantel-Haenszel 2 x 2 chi(2)=7.576, P=0.006, odds ratio (OR)=0.67, 95% confidence interval (95% CI) for OR: 0.51-0.88; for rs616597, Mantel-Haenszel 2 x 2 chi(2)=8.715, P=0.003, OR=0.65, 95% CI: 0.49-0.86). We conclude that multiple NFKBIZ polymorphisms associate with susceptibility to IPD in humans. The study of multiple populations may aid in fine mapping of associations within extensive regions of strong LD ('transethnic mapping').
Genes and immunity 10/2009; 11(4):319-25. · 4.22 Impact Factor
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ABSTRACT: Obstructive sleep apnoea syndrome (OSAS) has been associated with hypertension, stroke and myocardial ischaemia in epidemiological and observational studies. Continuous positive airway pressure (CPAP) is the treatment of choice for OSAS, but the impact of this intervention on established risk factors for cardiovascular disease remains incompletely understood. A total of 102 males with moderate-to-severe OSAS were randomised to therapeutic (n = 51) or subtherapeutic (n = 51) CPAP treatment for 4 weeks to investigate the effects of active treatment on 24-h urinary catecholamine excretion, baroreflex sensitivity (BRS), arterial stiffness (augmentation index) and 24-h ambulatory blood pressure (ABP). After 4 weeks of therapeutic CPAP, significant reductions were seen in urine normetanephrine excretion (from mean+/-sd 179.7+/-80.1 to 132.7+/-46.5 micromol x mol(-1) creatinine) and augmentation index (from 14.5+/-11.3 to 9.1+/-13.8%) compared with the subtherapeutic control group. Furthermore, therapeutic CPAP significantly improved BRS (from 7.1+/-3.3 to 8.8+/-4.2 ms x mmHg(-1)) and reduced mean arterial ABP by 2.6+/-5.4 mmHg. In conclusion, treatment of obstructive sleep apnoea with continuous positive airway pressure may lower cardiovascular risk by reducing sympathetic nerve activity, ambulatory blood pressure and arterial stiffness and by increasing sensitivity of the arterial baroreflex.
European Respiratory Journal 12/2008; 32(6):1488-96. · 5.89 Impact Factor
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BMJ (Clinical research ed.). 02/2007; 334(7586):206-7.
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ABSTRACT: Obstructive sleep apnoea (OSA) is associated with high cardiovascular morbidity and mortality. Several randomised controlled trials have shown that continuous positive airway pressure (CPAP) treatment of OSA reduces blood pressure (BP). This randomised, sham-placebo controlled crossover trial assesses whether CPAP produces a similar clinically significant fall in BP in hypertensive OSA patients, but without hypersomnolence. Thirty-five, nonsleepy, hypertensive patients with OSA were treated with CPAP for 1 month, randomised first to either therapeutic or sham-placebo (subtherapeutic CPAP, about 1 cmH(2)O pressure). The second months' alternative treatment followed a 2-week washout period. BP was measured over 24 h, before and at the end of the two treatment periods: mean 24-h BP was the primary outcome variable. There was no overall significant difference in mean 24-h BP: the change in mean 24-h BP on therapeutic CPAP was -2.1 mmHg (sd 8.1), and -1.1 mmHg (sd 8.1) on subtherapeutic CPAP, with a difference of 0.7 mmHg (95% confidence interval (CI) +2.9- -4.4). There was a small significant fall in Epworth Sleepiness Score, therapeutic (-1.4) versus sham (-0.3), and difference -1.2 (95% CI -2.0- -0.4), but no change in objective sleepiness. In nonhypersomnolent hypertensive patients with obstructive sleep apnoea, there is no significant fall in mean 24-h blood pressure with continuous positive airway pressure, in contrast to the fall seen in hypersomnolent patients with obstructive sleep apnoea.
European Respiratory Journal 07/2006; 27(6):1229-35. · 5.89 Impact Factor
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ABSTRACT: Pneumocystis jirovecii is the cause of Pneumocystis pneumonia (PCP) in immunosuppressed humans. Asymptomatic colonisation with P jirovecii may occur in patients with minor immunosuppression or chronic lung disease. The aim of this study was to describe the molecular epidemiology of P jirovecii in Britain over a period of 12.5 years.
Between January 1989 and July 2001 161 samples of P jirovecii were obtained from patients with PCP (n = 119), patients colonised by P jirovecii (n = 35), and from air spora (n = 6). Genotyping of samples was performed at the mitochondrial large subunit rRNA (mt LSU rRNA).
Genotype 1 (38%) was the most frequently identified genotype: genotypes 2 (26.6%), 3 (20.3%), and 4 (5%) were less common. Mixed infection (more than one genotype) was identified in 10% of samples. While genotype 1 was the most frequently detected type in both patients with PCP and those colonised by P jirovecii (38% and 42%, respectively), these groups differed in the relatively lower rate of detection of genotype 4 (2% v 17%) and the higher detection of mixed infection in those with PCP (13% v 3%). Detection of specific genotypes of P jirovecii was associated with the patient's place of residence (p = 0.02). There was no association between specific genotypes and severity of PCP as measured by arterial oxygen tension (p = 0.3).
The evidence of clustering of specific genotypes with patient's postcode of residence is consistent with the hypothesis of person to person transmission of P jirovecii via the airborne route. The lack of association between specific mt LSU rRNA genotypes and severity of PCP suggests that this locus is not implicated in the virulence of the organism.
Thorax 09/2005; 60(8):679-82. · 6.84 Impact Factor
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ABSTRACT: The use of CPAP to control excessive daytime sleepiness in OSAHS probably also produces a substantial reduction in vascular risk. This is reviewed with particular reference to hypertension.
Thorax 01/2005; 59(12):1089-94. · 6.84 Impact Factor
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Histopathology 12/2004; 45(5):542-4. · 3.08 Impact Factor
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ABSTRACT: Obstructive sleep apnoea (OSA) is associated with high cardiovascular morbidity and mortality and is an independent risk factor for hypertension. Novel circulating cardiovascular risk markers enabling a more accurate prediction of cardiovascular risk have been identified. Examination of these markers may clarify the increased risk in OSA and contribute to an analysis of the benefits of treatment.
Plasma levels of total cholesterol and triglyceride and activated coagulation factors XIIa and VIIa, factors VII, VIII, XII, fibrinogen, thrombin-antithrombin (TAT), von Willebrand factor antigen (vWFAg), soluble P-selectin (sP-sel), and homocysteine were measured before and after treatment for 1 month with therapeutic or subtherapeutic (control) continuous positive airways pressure (CPAP) in 220 patients with OSA.
Levels of activated coagulation factors XIIa, VIIa, TAT and sP-sel were higher in OSA patients at baseline than in unmatched controls, but did not fall with 1 month of therapeutic CPAP treatment. The raised sP-sel levels correlated only with body mass index (p = 0.002). There was a trend towards a significant fall in total cholesterol with therapeutic CPAP (p = 0.06) compared with the control group. In the therapeutic group there was a clinically significant mean fall in total cholesterol of 0.28 mmol/l (95% confidence interval 0.11 to 0.45, p = 0.001) which may reduce cardiovascular risk by about 15%.
A number of activated coagulation factors are increased in untreated OSA patients, potentially contributing to vascular risk, but they do not fall with 1 month of CPAP treatment. Nasal CPAP may produce a clinically relevant fall in total cholesterol level, potentially reducing cardiovascular risk, but this needs to be verified in a larger prospective study.
Thorax 10/2004; 59(9):777-82. · 6.84 Impact Factor
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Thorax 03/2004; 59(2):180. · 6.84 Impact Factor
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ABSTRACT: Arguments over the definition of obstructive sleep apnoea/hypopnoea syndrome (OSAHS) have still not been satisfactorily resolved. As a result, robust estimates of the prevalence of OSAHS are not possible. New approaches are needed to identify those who have "CPAP responsive" disease, enabling more accurate estimates to be made of the prevalence of the sleep apnoea syndrome in the community.
Thorax 02/2004; 59(1):73-8. · 6.84 Impact Factor
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ABSTRACT: Obstructive sleep apnoea (OSA) is a relatively common condition producing disabling somnolence and profound physiological responses to hypoxaemic episodes during sleep, including significant oscillations in blood pressure. This study aimed to provide controlled data on the interaction between OSA and endocrine axes to establish whether overrepresentation of pathology such as hypertension and hypogonadism in OSA subjects might have an endocrine basis.
Parallel randomized sham placebo controlled 1-month trial of nasal continuous positive airway pressure (nCPAP) in 101 male subjects with OSA presenting to a respiratory sleep clinic.
Analysis of gonadotrophins, testosterone, sex hormone binding protein (SHBG), prolactin, cortisol, thyroid stimulating hormone (TSH), free thyroxine (free T4), insulin-like growth factor-1 (IGF-1), renin and aldosterone were performed at baseline and after 1 month's active or placebo nCPAP intervention. Quality of life questionnaire scoring was also recorded over the same time period.
Testosterone and SHBG showed significant negative correlations with baseline OSA severity. Active treatment of OSA produced SHBG elevation and TSH reduction (P< or =0.03). Both groups showed an increase in aldosterone (P<0.001) and IGF-1 (P< or =0.03), associated with a large improvement in subjective quality of life scoring.
These findings demonstrate significant changes in endocrine axes not previously reported in a placebo-controlled trial. OSA is a recognized reversible cause of testosterone reduction; SHBG suppression correlating to baseline OSA severity supports a diagnosis of secondary hypogonadism. Significant rises in aldosterone and IGF-1 on treatment coincide with increased physical activity and an improved quality of life score.
Journal of Internal Medicine 11/2003; 254(5):447-54. · 5.48 Impact Factor
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ABSTRACT: Randomised trials show that treatment of obstructive sleep apnoea (OSA) with nasal continuous positive airway pressure (CPAP) greatly improves sleepiness and also lowers diurnal systemic blood pressures (BP). Such patients consume more coffee than controls (presumably to combat their sleepiness) and might reduce their consumption following effective treatment, thus lowering BP by this mechanism rather than via a direct effect of alleviating OSA.
Plasma caffeine levels before and after treatment with either therapeutic (n=52) or subtherapeutic (control, n=49) CPAP were measured in stored blood samples from a previous randomised controlled trial of CPAP for 4 weeks in patients with OSA.
There was a small significant rise in caffeine levels when the two groups were analysed as a whole (p=0.02), but not individually. Despite the fall in sleepiness measured objectively in the therapeutic CPAP group, there was no difference in absolute (or change in) caffeine levels between the two groups (mean (SE) micro mol/l; therapeutic CPAP 9.2 (1.2), 10.2 (1.0), subtherapeutic 6.7 (0.9), 8.6 (0.9) before and after treatment, respectively).
Reduced coffee consumption is unlikely to be the explanation for the falls in BP following treatment of OSA.
Thorax 10/2003; 58(9):801-2. · 6.84 Impact Factor
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ABSTRACT: The opportunistic fungus Pneumocystis jiroveci is a common cause of respiratory infection in immunocompromised patients. By contrast, pneumocystis pneumonia (PCP) occurs only rarely in immunocompetent individuals. Asymptomatic colonisation with P jiroveci has recently been described in patients who are either minimally immunosuppressed or who have underlying lung disorders such as bronchiectasis. We sought to determine the prevalence of asymptomatic colonisation by P jiroveci in a cohort of adult patients undergoing diagnostic bronchoscopy.
A prospective observational cohort study was performed in patients who required bronchoscopy and bronchoalveolar lavage (BAL) as part of their routine clinical assessment. All the samples underwent standard microbiological analysis and a Grocott methenamine silver stain was performed where clinically indicated to detect the presence of P jiroveci. Polymerase chain reaction for detection of P jiroveci specific DNA was also performed.
Ninety three consecutive BAL fluid samples were analysed, 17 (18%) of which contained P jiroveci DNA. Of the potential predictors examined, only glucocorticoid use was significantly associated with detectable P jiroveci DNA. Eighteen patients were receiving oral glucocorticoids (equivalent to >20 mg/day prednisolone) at the time of bronchoscopy, of whom eight (44%) had detectable P jiroveci DNA. In contrast, P jiroveci was detected in only nine of 75 patients (12%) who were not receiving glucocorticoids (difference between proportions 32%, 95% CI 8 to 57; p=0.004, two tailed Fisher's exact test).
P jiroveci colonisation, as determined by detection of P jiroveci DNA in BAL fluid, is common in HIV negative patients with primary respiratory disorders undergoing bronchoscopy and BAL. The higher prevalence in patients receiving corticosteroids suggests that oral glucocorticoid therapy is an independent risk factor for colonisation. In contrast, underlying lung cancer or COPD did not appear to be risk factors.
Thorax 07/2003; 58(7):594-7. · 6.84 Impact Factor
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Thorax 06/2003; 58 Suppl 2:ii18-28. · 6.84 Impact Factor
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Thorax 06/2003; 58 Suppl 2:ii1-7. · 6.84 Impact Factor
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ABSTRACT: The Department of Health recently issued guidance on how Local Research Ethics Committees (LRECs) should handle an Multi-centre Research Ethics Committee (MREC)-approved application. This process is intended as a rapid standardized approval process, facilitating the execution of clinical trials.
To evaluate if this guidance had led to an efficient process for obtaining local ethical approval.
Questionnaires were sent by post to Local Investigators of the 56 centres who had obtained LREC approval for the Multi-centre Intrapleural Streptokinase Trial.
Replies were received from 51 centres (91%). A total of 25 296 pieces of paper and 62 h of photocopying time were required to meet the 51 LRECs' requirements. LREC meetings ranged from weekly to bimonthly, with only 24 (47%) having a 'fast track' system in place. Applications took a median of 27 (1-90) days from submission to first being considered, with local investigators spending 3.27 (0.5-15) h on each submission. Nineteen (37%) of the local investigators felt the LREC/MREC interface did not work well and 17 (33%) were at least partly deterred from participating in future trials.
The guidelines do not seem to have been implemented by all LREC committees, leading to wide variation in local experience.
QJM: monthly journal of the Association of Physicians 05/2003; 96(4):305-7. · 2.33 Impact Factor
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ABSTRACT: Over 200000 pleural effusions are attributable to cancer in the UK and USA every year. Cytological examination of pleural fluid classifies about 60% of malignant effusions. Pleural biopsy needs to be done in the remaining cases. We aimed to assess whether CT-guided biopsy is an improvement over standard pleural biopsy in this setting.
50 consecutive patients with cytologically negative suspected malignant pleural effusions were recruited. All had a contrast-enhanced thoracic CT scan to assess pleural thickening. Patients were randomly allocated, stratified by baseline pleural thickening, to either Abrams' pleural biopsy (standard care; n=25) or CT-guided cutting needle biopsy (n=25). Sensitivity for pleural malignancy from the biopsy specimen was the primary endpoint, with the patient's clinical outcome after 1 year being the diagnostic gold standard. Analysis was per protocol.
Three patients did not undergo biopsy. Abrams' biopsy correctly diagnosed malignancy in eight of 17 patients (sensitivity 47%, specificity 100%, negative predictive value 44%, positive predictive value 100%). CT-guided biopsy correctly diagnosed malignancy in 13 of 15 (sensitivity 87%, specificity 100%, negative predictive value 80%, positive predictive value 100%; difference in sensitivity between Abrams' and CT-guided 40%, 95% CI 10-69, p=0.02). Diagnostic advantage was similar in patients proving to have mesothelioma.
Primary use of CT-guided biopsy would avoid doing at least one Abrams' biopsy for every 2.5 CT-guided biopsies undertaken. In cytology-negative suspected malignant pleural effusions, CT-guided pleural biopsy is a better diagnostic test than Abrams' pleural biopsy.
The Lancet 05/2003; 361(9366):1326-30. · 38.28 Impact Factor
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ABSTRACT: Sleep studies have grown to encompass a broad range of technologies employed to study and diagnose a variety of sleep disorders. From their inception in neurophysiology laboratories interested in investigating primary disorders of sleep architecture from psychiatric illness, their remit has widened such that their most common role is currently to diagnose secondary sleep disruption from respiratory, cardiovascular or other systemic causes. This review outlines the pathophysiology of obstructive sleep apnoea in particular and how sleep studies have improved our understanding of the complex dynamic changes in blood gas tensions, cardiovascular control and cerebral arousal that occur with these repetitive events. We review the historical development of standard laboratory-based sleep studies and discuss their limitations in staging sleep, reflecting the episodes of increased upper airway resistance that underlie these disorders and their ability to predict individuals' symptoms or response to medical or surgical therapies. We then describe some alternative signals that have been employed to monitor the physiological changes in upper airway resistance and arousal with a discussion of some of the evidence that these 'limited' studies may provide diagnostic information that can guide clinical decision making and may predict the outcome without the need, in some cases, for more complex and costly laboratory-based studies.
Physiological Measurement 06/2002; 23(2):R39-74. · 1.68 Impact Factor
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