A Mal functional variant is associated with protection against invasive pneumococcal disease, bacteremia, malaria and tuberculosis.

Toll-like receptors (TLRs) and members of their signaling pathway are important in the initiation of the innate immune response to a wide variety of pathogens. The adaptor protein Mal (also known as TIRAP), encoded by TIRAP (MIM 606252), mediates downstream signaling of TLR2 and TLR4 (refs. 4-6). We report a case-control study of 6,106 individuals from the UK, Vietnam and several African countries with invasive pneumococcal disease, bacteremia, malaria and tuberculosis. We genotyped 33 SNPs, including rs8177374, which encodes a leucine substitution at Ser180 of Mal. We found that heterozygous carriage of this variant associated independently with all four infectious diseases in the different study populations. Combining the study groups, we found substantial support for a protective effect of S180L heterozygosity against these infectious diseases (N = 6,106; overall P = 9.6 x 10(-8)). We found that the Mal S180L variant attenuated TLR2 signal transduction.

Effect of Opioids vs NSAIDs and Larger vs Smaller Chest Tube Size on Pain Control and Pleurodesis Efficacy Among Patients With Malignant Pleural Effusion: The TIME1 Randomized Clinical Trial.

IMPORTANCE: For treatment of malignant pleural effusion, nonsteroidal anti-inflammatory drugs (NSAIDs) are avoided because they may reduce pleurodesis efficacy. Smaller chest tubes may be less painful than larger tubes, but efficacy in pleurodesis has not been proven. OBJECTIVE: To assess the effect of chest tube size and analgesia (NSAIDs vs opiates) on pain and clinical efficacy related to pleurodesis in patients with malignant pleural effusion. DESIGN, SETTING, AND PARTICIPANTS: A 2×2 factorial phase 3 randomized clinical trial among 320 patients requiring pleurodesis in 16 UK hospitals from 2007 to 2013. INTERVENTIONS: Patients undergoing thoracoscopy (n = 206; clinical decision if biopsy was required) received a 24F chest tube and were randomized to receive opiates (n = 103) vs NSAIDs (n = 103), and those not undergoing thoracoscopy (n = 114) were randomized to 1 of 4 groups (24F chest tube and opioids [n = 28]; 24F chest tube and NSAIDs [n = 29]; 12F chest tube and opioids [n = 29]; or 12F chest tube and NSAIDs [n = 28]). MAIN OUTCOMES AND MEASURES: Pain while chest tube was in place (0- to 100-mm visual analog scale [VAS] 4 times/d; superiority comparison) and pleurodesis efficacy at 3 months (failure defined as need for further pleural intervention; noninferiority comparison; margin, 15%). RESULTS: Pain scores in the opiate group (n = 150) vs the NSAID group (n = 144) were not significantly different (mean VAS score, 23.8 mm vs 22.1 mm; adjusted difference, -1.5 mm; 95% CI, -5.0 to 2.0 mm; P = .40), but the NSAID group required more rescue analgesia (26.3% vs 38.1%; rate ratio, 2.1; 95% CI, 1.3-3.4; P = .003). Pleurodesis failure occurred in 30 patients (20%) in the opiate group and 33 (23%) in the NSAID group, meeting criteria for noninferiority (difference, -3%; 1-sided 95% CI, -10% to ∞; P = .004 for noninferiority). Pain scores were lower among patients in the 12F chest tube group (n = 54) vs the 24F group (n = 56) (mean VAS score, 22.0 mm vs 26.8 mm; adjusted difference, -6.0 mm; 95% CI, -11.7 to -0.2 mm; P = .04) and 12F chest tubes vs 24F chest tubes were associated with higher pleurodesis failure (30% vs 24%), failing to meet noninferiority criteria (difference, -6%; 1-sided 95% CI, -20% to ∞; P = .14 for noninferiority). Complications during chest tube insertion occurred more commonly with 12F tubes (14% vs 24%; odds ratio, 1.91; P = .20). CONCLUSIONS AND RELEVANCE: Use of NSAIDs vs opiates resulted in no significant difference in pain scores but was associated with more rescue medication. NSAID use resulted in noninferior rates of pleurodesis efficacy at 3 months. Placement of 12F chest tubes vs 24F chest tubes was associated with a statistically significant but clinically modest reduction in pain but failed to meet noninferiority criteria for pleurodesis efficacy. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN33288337.

Intrapleural use of tissue plasminogen activator and DNase in pleural infection.

BACKGROUND: More than 30% of patients with pleural infection either die or require surgery. Drainage of infected fluid is key to successful treatment, but intrapleural fibrinolytic therapy did not improve outcomes in an earlier, large, randomized trial. METHODS: We conducted a blinded, 2-by-2 factorial trial in which 210 patients with pleural infection were randomly assigned to receive one of four study treatments for 3 days: double placebo, intrapleural tissue plasminogen activator (t-PA) and DNase, t-PA and placebo, or DNase and placebo. The primary outcome was the change in pleural opacity, measured as the percentage of the hemithorax occupied by effusion, on chest radiography on day 7 as compared with day 1. Secondary outcomes included referral for surgery, duration of hospital stay, and adverse events. RESULTS: The mean (±SD) change in pleural opacity was greater in the t-PA-DNase group than in the placebo group (-29.5±23.3% vs. -17.2±19.6%; difference, -7.9%; 95% confidence interval [CI], -13.4 to -2.4; P=0.005); the change observed with t-PA alone and with DNase alone (-17.2±24.3 and -14.7±16.4%, respectively) was not significantly different from that observed with placebo. The frequency of surgical referral at 3 months was lower in the t-PA-DNase group than in the placebo group (2 of 48 patients [4%] vs. 8 of 51 patients [16%]; odds ratio for surgical referral, 0.17; 95% CI, 0.03 to 0.87; P=0.03) but was greater in the DNase group (18 of 46 patients [39%]) than in the placebo group (odds ratio, 3.56; 95% CI, 1.30 to 9.75; P=0.01). Combined t-PA-DNase therapy was associated with a reduction in the hospital stay, as compared with placebo (difference, -6.7 days; 95% CI, -12.0 to -1.9; P=0.006); the hospital stay with either agent alone was not significantly different from that with placebo. The frequency of adverse events did not differ significantly among the groups. CONCLUSIONS: Intrapleural t-PA-DNase therapy improved fluid drainage in patients with pleural infection and reduced the frequency of surgical referral and the duration of the hospital stay. Treatment with DNase alone or t-PA alone was ineffective. (Funded by an unrestricted educational grant to the University of Oxford from Roche UK and by others; Current Controlled Trials number, ISRCTN57454527.).

Characterization of a new mouse model of empyema and the mechanisms of pleural invasion by Streptococcus pneumoniae.

Although empyema affects more than 65,000 people each year in the United States and in the United Kingdom, there are limited data on the pathogenesis of pleural infection. We investigated the pathogenesis of empyema using animal and cell culture models of Streptococcus pneumoniae infection. The pathological processes during the development of empyema associated with murine pneumonia due to S. pneumoniae (strain D39) were investigated. Lungs were examined using histology, and pleural fluid and blood bacterial colony-forming units, cytokine levels, and cellular infiltrate were determined over time. Bacterial migration across mesothelial monolayers was investigated using cell culture techniques, flow cytometry, and confocal microscopy. After intranasal inoculation with 10(7) S. pneumoniae D39 strain, mice developed pneumonia associated with rapid bacterial invasion of the pleural space; raised intrapleural IL-8, VEGF, MCP-1, and TNF-α levels; and caused significant intrapleural neutrophilia followed by the development of fibrinous pleural adhesions. Bacterial clearance from the pleural space was poor, and in vitro assays demonstrated that S. pneumoniae crossed mesothelial layers by translocation through cells rather than by a paracellular route. This study describes key events during the development of S. pneumoniae empyema using a novel murine model of pneumonia-associated empyema that closely mimics human disease. The model allows for future assessment of molecular mechanisms involved in the development of empyema and evaluation of potential new therapies. The data suggest that transmigration of bacteria through mesothelial cells could be important in empyema development. Furthermore, upon entry the pleural cavity offers a protected compartment for the bacteria.

Effect of an indwelling pleural catheter vs chest tube and talc pleurodesis for relieving dyspnea in patients with malignant pleural effusion: the TIME2 randomized controlled trial.

CONTEXT: Malignant pleural effusion causes disabling dyspnea in patients with a short life expectancy. Palliation is achieved by fluid drainage, but the most effective first-line method has not been determined. OBJECTIVE: To determine whether indwelling pleural catheters (IPCs) are more effective than chest tube and talc slurry pleurodesis (talc) at relieving dyspnea. DESIGN: Unblinded randomized controlled trial (Second Therapeutic Intervention in Malignant Effusion Trial [TIME2]) comparing IPC and talc (1:1) for which 106 patients with malignant pleural effusion who had not previously undergone pleurodesis were recruited from 143 patients who were treated at 7 UK hospitals. Patients were screened from April 2007-February 2011 and were followed up for a year. INTERVENTION: Indwelling pleural catheters were inserted on an outpatient basis, followed by initial large volume drainage, education, and subsequent home drainage. The talc group were admitted for chest tube insertion and talc for slurry pleurodesis. MAIN OUTCOME MEASURE: Patients completed daily 100-mm line visual analog scale (VAS) of dyspnea over 42 days after undergoing the intervention (0 mm represents no dyspnea and 100 mm represents maximum dyspnea; 10 mm represents minimum clinically significant difference). Mean difference was analyzed using a mixed-effects linear regression model adjusted for minimization variables. RESULTS: Dyspnea improved in both groups, with no significant difference in the first 42 days with a mean VAS dyspnea score of 24.7 in the IPC group (95% CI, 19.3-30.1 mm) and 24.4 mm (95% CI, 19.4-29.4 mm) in the talc group, with a difference of 0.16 mm (95% CI, −6.82 to 7.15; P = .96). There was a statistically significant improvement in dyspnea in the IPC group at 6 months, with a mean difference in VAS score between the IPC group and the talc group of −14.0 mm (95% CI, −25.2 to −2.8 mm; P = .01). Length of initial hospitalization was significantly shorter in the IPC group with a median of 0 days (interquartile range [IQR], 0-1 day) and 4 days (IQR, 2-6 days) for the talc group, with a difference of −3.5 days (95% CI, −4.8 to −1.5 days; P < .001). There was no significant difference in quality of life. Twelve patients (22%) in the talc group required further pleural procedures compared with 3 (6%) in the IPC group (odds ratio [OR], 0.21; 95% CI, 0.04-0.86; P = .03). Twenty-one of the 52 patients in the catheter group experienced adverse events vs 7 of 54 in the talc group (OR, 4.70; 95% CI, 1.75-12.60; P = .002). CONCLUSION: Among patients with malignant pleural effusion and no previous pleurodesis, there was no significant difference between IPCs and talc pleurodesis at relieving patient-reported dyspnea. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN87514420.

Blood culture bottle culture of pleural fluid in pleural infection.

BACKGROUND: Pleural infection is common, and has a >30% major morbidity and mortality-particularly when infection is caused by Gram-negative, Staphylococcus aureus or mixed aerobic pathogens. Standard pleural fluid culture is negative in ∼40% of cases. Culturing pleural fluid in blood culture bottles may increase microbial yield, and is cheap and easy to perform. OBJECTIVES: To determine whether inoculating pleural fluid into blood culture bottles increases the culture positivity of pleural infection over standard laboratory culture, and to assess the optimum volume of inoculum to introduce. METHODS: 62 patients with pleural infection were enrolled. Pairs of aerobic and anaerobic blood culture bottles were inoculated at the bedside with 2, 5 or 10 ml of pleural fluid, and two pleural fluid specimens were sent for standard culture. Pleural fluid from nine control patients was cultured to test for 'false-positive' results. RESULTS: The addition of blood culture bottle culture to standard culture increased the proportion of patients with identifiable pathogens by 20.8% (20/53 (37.7%) to 31/53 (58.5%) (difference 20.8%, 95% CI difference 8.9% to 20.8%, p<0.001)). The second standard culture did not similarly improve the culture positivity (19/49 (38.8%) to 22/49 (44.9%) (difference 6.1%, 95% CI difference -2.5% to 6.1%, p=0.08)). The culture inoculum volume did not influence bacterial isolation frequency. The control fluids were culture negative. CONCLUSIONS: Blood culture bottle culture of infected pleural fluid increases microbial yield when used in addition to standard culture. This technique should be part of routine care.

Setting up a respiratory trials unit.

Clinical trials are essential in advancing our knowledge and treatment of patients with respiratory disease. Conducting well-designed clinical studies which accurately and reliably answer important clinical questions is challenging. The expertise required to deliver such studies is increasingly concentrated in clinical trials units. This article will describe some of the challenges associated with clinical studies and the methods and personnel involved in a clinical trials unit.

Diagnostic accuracy, safety and utilisation of respiratory physician-delivered thoracic ultrasound.

BACKGROUND Thoracic ultrasound-guided pleural procedures are associated with fewer adverse events than 'blind' procedures for patients with pleural effusion. Ultrasound is increasingly practised by respiratory physicians but there has been no prospective assessment of its safety and diagnostic accuracy when delivered by respiratory physicians. METHODS The activity level, safety and diagnostic accuracy of thoracic ultrasound delivered by respiratory physicians were prospectively assessed. Diagnostic accuracy was assessed using a stepwise pragmatic approach (recording if pleural fluid was obtained or effusion was present on another radiological modality). In the absence of the above, ultrasound clips were reviewed by a blinded radiologist. The number of ultrasounds referred to radiologists and adverse events within 1 week were recorded. The complication rate was compared with the published literature. RESULTS 960 ultrasound scans occurred over a 3 year period. The activity of the service increased over time, as a result of increased use of interventional ultrasound. The referral rate to radiology remained constant over the study period (mean proportion 4.0%). Physician-delivered ultrasound correctly identified the presence/absence of pleural fluid in 951 of 955 evaluable scans (99.6% CI 98.9% to 99.9%). The major complication rate was 3/558=0.5% (95% CI 0.1% to 1.6%), which compared favourably with the identified published literature. CONCLUSION Respiratory physician-delivered thoracic ultrasound appears to be safe and effective in the diagnosis/intervention of pleural effusion, and is associated with a major complication rate comparable with that of published studies. Continued liaison with the radiology service has here been demonstrated as a requirement for a physician-based service.

Mannose-binding lectin genotypes: lack of association with susceptibility to thoracic empyema.

BACKGROUND: The role of the innate immune protein mannose-binding lectin (MBL) in host defence against severe respiratory infection remains controversial. Thoracic empyema is a suppurative lung infection that arises as a major complication of pneumonia and is associated with a significant mortality. Although the pathogenesis of thoracic empyema is poorly understood, genetic susceptibility loci for this condition have recently been identified. The possible role of MBL genotypic deficiency in susceptibility to thoracic empyema has not previously been reported. METHODS: To investigate this further we compared the frequencies of the six functional MBL polymorphisms in 170 European individuals with thoracic empyema and 225 healthy control individuals. RESULTS: No overall association was observed between MBL genotypic deficiency and susceptibility to thoracic empyema (2 x 2 Chi square = 0.02, P = 0.87). Furthermore, no association was seen between MBL deficiency and susceptibility to the Gram-positive or pneumococcal empyema subgroups. MBL genotypic deficiency did not associate with progression to death or requirement for surgery. CONCLUSIONS: Our results suggest that MBL genotypic deficiency does not associate with susceptibility to thoracic empyema in humans.

Common NFKBIL2 polymorphisms and susceptibility to pneumococcal disease: a genetic association study.

INTRODUCTION: Streptococcus pneumoniae remains a major global health problem and a leading cause of death in children worldwide. The factors that influence development of pneumococcal sepsis remain poorly understood, although increasing evidence points towards a role for genetic variation in the host's immune response. Recent insights from the study of animal models, rare human primary immunodeficiency states, and population-based genetic epidemiology have focused attention on the role of the proinflammatory transcription factor NF-κB in pneumococcal disease pathogenesis. The possible role of genetic variation in the atypical NF-κB inhibitor IκB-R, encoded by NFKBIL2, in susceptibility to invasive pneumococcal disease has not, to our knowledge, previously been reported upon. METHODS: An association study was performed examining the frequencies of nine common NFKBIL2 polymorphisms in two invasive pneumococcal disease case-control groups: European individuals from hospitals in Oxfordshire, UK (275 patients and 733 controls), and African individuals from Kilifi District Hospital, Kenya (687 patients with bacteraemia, of which 173 patients had pneumococcal disease, together with 550 controls). RESULTS: Five polymorphisms significantly associated with invasive pneumococcal disease susceptibility in the European study, of which two polymorphisms also associated with disease in African individuals. Heterozygosity at these loci was associated with protection from invasive pneumococcal disease (rs760477, Mantel-Haenszel 2 × 2 χ(2) = 11.797, P = 0.0006, odds ratio = 0.67, 95% confidence interval = 0.53 to 0.84; rs4925858, Mantel-Haenszel 2 × 2 χ(2) = 9.104, P = 0.003, odds ratio = 0.70, 95% confidence interval = 0.55 to 0.88). Linkage disequilibrium was more extensive in European individuals than in Kenyans. CONCLUSIONS: Common NFKBIL2 polymorphisms are associated with susceptibility to invasive pneumococcal disease in European and African populations. These findings further highlight the importance of control of NF-κB in host defence against pneumococcal disease.

The approach to the patient with a parapneumonic effusion.

Parapneumonic effusions are seen in up to 57% of patients with pneumonia. The majority of these effusions are noninfected and resolve with standard antibiotic treatment for the associated pneumonia. However, parapneumonic effusions in a minority of cases become infected and require prompt chest tube drainage and occasionally thoracic surgery. Patients may present in a variety of ways from florid sepsis to weight loss and anorexia; such diversity mandates a high index of suspicion among physicians. The role of the combination of intrapleural deoxyribonuclease (DNase) and tissue plasminogen activator (t-PA) to aid fluid drainage shows promise but needs further assessment in large trials with surgery and mortality as primary end points.

Clinical impact and reliability of pleural fluid mesothelin in undiagnosed pleural effusions.

RATIONALE: Serum mesothelin is a new biomarker for the diagnosis of mesothelioma. Patients with mesothelioma commonly present with pleural effusions. To define the clinical utility of mesothelin quantification in pleural fluid, we assessed its additional value over pleural fluid cytology and its short-term reproducibility and reliability after pleural inflammatory processes, including pleurodesis. OBJECTIVES: To assess the diagnostic role of pleural fluid mesothelin and the effect of common clinical factors that may influence measurement accuracy. METHODS: Mesothelin was quantified in 424 pleural fluid and 64 serum samples by ELISA. Fluid was collected prospectively from 167 patients who presented with pleural effusions for investigation. Serial pleural fluid samples were obtained from patients (n = 33) requiring repeated drainage. Mesothelin levels were also measured in patients (n = 32) prepleurodesis and postpleurodesis. MEASUREMENTS AND MAIN RESULTS: Pleural fluid mesothelin concentrations were significantly higher in patients with mesothelioma (n = 24) relative to those with metastatic carcinomas (n = 67) and benign effusions (n = 75): median (interquartile range, 25th-75th percentile) = 40.3 (18.3-68.1) versus 6.1 (1.5-13.2) versus 3.7 (0.0-12.4) nM, respectively, P < 0.0001. Mesothelin measurement was superior to cytological examination in the diagnosis and exclusion of mesothelioma (sensitivity, 71 vs. 35%; specificity, 89 vs. 100%; negative predictive value, 95 vs. 82%, respectively). In patients with "suspicious" cytology, pleural fluid mesothelin was 100% specific for mesothelioma, and in cytology-negative effusions (n = 105) offered a negative predictive value of 94%. Intraindividual reproducibility of pleural fluid mesothelin was excellent: mean (+/-SD) variation, -0.15 (+/-8.41) nM in samples collected within 7 days from patients with mesothelioma. Measurements remained reliable after pleurodesis and were not affected by the presence of bacteria. CONCLUSIONS: Pleural fluid mesothelin provides additional diagnostic value relative to cytological examination. Mesothelin measurements are reproducible and not affected by inflammatory pleural processes.

Safety and immunogenicity of a new tuberculosis vaccine, MVA85A, in Mycobacterium tuberculosis-infected individuals.

RATIONALE: An effective new tuberculosis (TB) vaccine regimen must be safe in individuals with latent TB infection (LTBI) and is a priority for global health care. OBJECTIVES: To evaluate the safety and immunogenicity of a leading new TB vaccine, recombinant Modified Vaccinia Ankara expressing Antigen 85A (MVA85A) in individuals with LTBI. METHODS: An open-label, phase I trial of MVA85A was performed in 12 subjects with LTBI recruited from TB contact clinics in Oxford and London or by poster advertisements in Oxford hospitals. Patients were assessed clinically and had blood samples drawn for immunological analysis over a 52-week period after vaccination with MVA85A. Thoracic computed tomography scans were performed at baseline and at 10 weeks after vaccination. Safety of MVA85A was assessed by clinical, radiological, and inflammatory markers. The immunogenicity of MVA85A was assessed by IFNgamma and IL-2 ELISpot assays and FACS. MEASUREMENTS AND MAIN RESULTS: MVA85A was safe in subjects with LTBI, with comparable adverse events to previous trials of MVA85A. There were no clinically significant changes in inflammatory markers or thoracic computed tomography scans after vaccination. MVA85A induced a strong antigen-specific IFN-gamma and IL-2 response that was durable for 52 weeks. The magnitude of IFN-gamma response was comparable to previous trials of MVA85A in bacillus Calmette-Guérin-vaccinated individuals. Antigen 85A-specific polyfunctional CD4(+) T cells were detectable prior to vaccination with statistically significant increases in cell numbers after vaccination. CONCLUSIONS: MVA85A is safe and highly immunogenic in individuals with LTBI. These results will facilitate further trials in TB-endemic areas. Clinical trial registered with www.clinicaltrials.gov (NCT00456183).

Continuous positive airway pressure treatment for obstructive sleep apnoea reduces resting heart rate but does not affect dysrhythmias: a randomised controlled trial.

Obstructive sleep apnoea (OSA) is associated with cardiovascular morbidity and may precipitate cardiac dysrhythmias. Uncontrolled reports suggest that continuous positive airway pressure (CPAP) may reduce dysrhythmia frequency and resting heart rate. We undertook a randomised controlled trial of therapeutic CPAP and compared with a subtherapeutic control which included an exploration of changes in dysrhythmia frequency and heart rate. Values are expressed as mean (SD). Eighty-three men [49.5 (9.6) years] with moderate-severe OSA [Oxygen Desaturation Index, 41.2 (24.3) dips per hour] underwent 3-channel 24-h electrocardiograms during normal daily activities, before and after 1 month of therapeutic (n = 43) or subtherapeutic (n = 40) CPAP. Recordings were manually analysed for mean heart rate, pauses, bradycardias, supraventricular and ventricular dysrhythmias. The two groups were well matched for age, body mass index, OSA severity, cardiovascular risk factors and history. Supraventricular ectopics and ventricular ectopics were frequently found in 95.2% and 85.5% of patients, respectively. Less common were sinus pauses (42.2%), episodes of bradycardia (12%) and ventricular tachycardias (4.8%). Compared with subtherapeutic control, CPAP reduced mean 24-h heart rate from 83.0 (11.5) to 79.7 (9.8) (P < 0.002) in the CPAP group compared with a non-significant rise (P = 0.18) from 79.0 (10.4) to 79.9 (10.4) in the subtherapeutic group; this was also the case for the day period analysed separately. There was no significant change in the frequencies of dysrhythmias after CPAP. Four weeks of CPAP therapy reduces mean 24-h heart rate possibly due to reduced sympathetic activation but did not result in a significant decrease in dysrhythmia frequency.

Pleural procedures and pleuroscopy.

Pleural procedures are commonly performed by physicians from a range of specialities. These procedures vary in complexity, from relatively straightforward pleural aspiration to more challenging procedures such as pleuroscopy. After appropriate training, even complex pleural procedures have a low risk of complications. Nevertheless, an appreciation of procedural risks is essential for physician training and forms the crux of a valid patient consent process. This review presents a systematic evaluation of the potential complications of common pleural procedures.

Continuous positive airway pressure and liver enzymes in obstructive sleep apnoea: data from a randomized controlled trial.

BACKGROUND: Obstructive sleep apnoea syndrome (OSAS) has been suggested to be an independent risk factor for non-alcoholic fatty liver disease (NAFLD), possibly via intermittent hypoxia that influences blood pressure, lipid levels and insulin resistance, factors themselves known to cause NAFLD. In observational studies, OSAS has been associated with elevated levels of liver enzymes. Continuous positive airway pressure (CPAP) is the treatment for OSAS, but the effects of CPAP on liver enzymes have not been studied in a randomized controlled trial. OBJECTIVE: To determine if 4 weeks of CPAP influence alanine-aminotransferase (ALT) and aspartate-aminotranferase (AST) levels. METHODS: 94 patients with moderate-to-severe OSAS were randomized to therapeutic or sub-therapeutic CPAP treatment. Plasma ALT and AST were measured before and after 4 weeks of CPAP. RESULTS: Results are means +/- SD. ALT levels decreased from 39.1 +/- 26.3 to 30.3 +/- 16.4 IU/l in patients treated with therapeutic CPAP, but also decreased from 36.9 +/- 20.7 to 31.5 +/- 16.5 IU/l in patients treated with sub-therapeutic CPAP (difference between mean changes -3.4, 95% CI -7.8 to 1.0 IU/l, p = 0.13 between groups). AST levels did not change significantly with therapeutic CPAP (from 29.1 +/- 14.7 to 30.2 +/- 13.6 IU/l), nor with sub-therapeutic CPAP (from 28.2 +/- 16.2 to 29.5 +/- 12.6 IU/l; difference between mean changes -0.2, 95% CI -3.0 to 2.6 IU/l, p = 0.87 between groups). CONCLUSIONS: Four weeks of active CPAP has no beneficial effect on aminotransferase levels when compared to sub-therapeutic CPAP in patients with OSAS. Therefore, CPAP does not seem to improve biochemical markers of potential NAFLD in OSAS patients.

Endothelial function and arterial stiffness in minimally symptomatic obstructive sleep apnea.

RATIONALE: Moderate-severe obstructive sleep apnea (OSA) is associated with endothelial dysfunction, increased arterial stiffness, and hypertension. It is not known whether minimally symptomatic OSA is also associated with impaired vascular function. OBJECTIVES: To determine whether minimally symptomatic OSA is associated with impaired vascular function. METHODS: In 64 patients (7 females) with minimally symptomatic OSA (oxygen desaturation index, 23.1 [SD, 15.6]; Epworth Sleepiness Scale score, 8 [SD, 3.8]), and 15 matched control subjects without OSA, endothelial function was assessed by ultrasonographic measurement of flow-mediated dilatation, and by applanation tonometry-derived pulse wave analysis (forearm ischemia and salbutamol-induced changes in augmentation index, AI(x)). Arterial stiffness was assessed by AI(x) and ambulatory blood pressure (ABP) was measured over 1 week. MEASUREMENTS AND MAIN RESULTS: In patients with OSA, flow-mediated dilatation was significantly lower than in control subjects (5.0% [SD, 2.7%] and 7.5% [SD, 3.3%], respectively; P = 0.003). AI(x) was significantly higher in the OSA group compared with the control group (26.0% [interquartile range (IQR), 19.0-29.5%] and 21.0% [IQR, 8.0-27.0%], respectively; P = 0.04). Change in AI(x) after both forearm ischemia and salbutamol was significantly smaller in patients with OSA (-2.0% [IQR, -5.0 to +4.0%] and -3.0% [IQR, -7.0 to 0.0%], respectively), than in control subjects (-6.0% [IQR, -8.0 to -5.0%] and -7.0% [IQR, -10.0 to -3.0%]; P = 0.005 and P = 0.04, respectively). ABP was similar (97.6 mm Hg [SD, 7.9 mm Hg] and 94.8 mm Hg [SD, 7.4 mm Hg], OSA and control groups, respectively; P = 0.21). CONCLUSIONS: In patients with minimally symptomatic OSA, diverse properties of endothelial function are impaired and arterial stiffness is increased. Although this was not associated with a significantly increased ABP, the findings suggest that patients with minimally symptomatic OSA are at increased cardiovascular risk.

Clinically important factors influencing the diagnostic measurement of pleural fluid pH and glucose.

RATIONALE: Accurate pleural fluid pH and glucose measurement is a key component in the diagnosis and management of patients with pleural effusion. Standardized methods of pleural fluid collection have not been defined. OBJECTIVES: To assess the effect of common clinical factors that may distort measurement accuracy of pleural fluid pH and glucose. METHODS: Ninety-two exudative pleural aspirates were collected in commercially available blood gas syringes. MEASUREMENTS AND MAIN RESULTS: Samples were analyzed immediately using a blood gas analyzer. The effects of residual air, lidocaine, heparin, and delay in analysis (24 h) on pH and glucose measurement accuracy were assessed. Pleural fluid pH was significantly increased by residual air (mean +/- SD, 0.08 +/- 0.07; 95% confidence interval [CI], 0.06 to 0.09; P < 0.001) and significantly decreased by residual lidocaine (0.2 ml; mean change in pH, -0.15 +/- 0.09; 95% CI, -0.13 to -0.18; P < 0.001) and residual heparin (mean change in pH, -0.02 +/- 0.05; 95% CI, -0.01 to -0.04; P = 0.027). Pleural fluid pH was stable at room temperature for 1 hour and significantly increased at 4 (mean +/- SD, 0.03 +/- 0.07; 95% CI, 0.01 to 0.04; P = 0.003) and 24 hours (0.05 +/- 0.12; 95% CI, 0.03 to 0.08; P < 0.001). Pleural fluid glucose concentration was not clinically significantly altered by residual air, lidocaine (up to 0.4 ml), or 24-hour analysis delay. CONCLUSIONS: Accuracy of measured pleural pH is critically dependent on sample collection method. Residual air, lidocaine, and analysis delay significantly alter pH and may impact on clinical management. Pleural fluid glucose concentration is not significantly influenced by these factors. Protocols defining appropriate sampling and analysis methods are needed.

Use of lipoteichoic acid-T for pleurodesis in malignant pleural effusion: a phase I toxicity and dose-escalation study.

BACKGROUND: Bacterial infection of the pleural space often causes adherence of the pleural membranes by fibrous tissue, probably mediated by inflammation initiated by bacterial cell-wall motifs, including lipoteichoic acid-T (LTA-T). We postulated that therapeutically administered LTA-T might produce a similar effect, achieving control of malignant pleural effusion (pleurodesis). METHODS: Patients with histocytologically proven symptomatic malignant pleural effusions were included in this phase I toxicity and dose-escalation study, An indwelling pleural catheter was placed in the pleural effusion to drain the fluid fully. A control dose of intrapleural saline was administered after complete drainage (day 1) and pleural-fluid production was recorded for 7 days. On day 7 a single dose of intrapleural LTA-T (increasing in each patient) was administered and pleural-fluid production was monitored for a further 7 days. Long-term fluid control was recorded. This study is registered as an International Standard Randomised Controlled Trial, ISRCTN44367564. FINDINGS: Between November, 2004, and November, 2005, 14 patients were enrolled on the trial at the Oxford Centre for Respiratory Medicine (Oxford, UK). 13 of 14 patients received escalated doses of LTA-T. A dose-limiting toxic effect (ie, systemic inflammation) occurred at 3000 microg, and a therapeutic dose of 750-1500 microg was established. Toxic effects were mild and had no consistent pattern at the therapeutic dose. Pleural-fluid production decreased significantly after a dose of at least 750 microg LTA-T, compared with saline control (mean fluid production after saline control 1244 mL [SD 933], mean fluid production after LTA-T 394 mL [SD 375], mean difference -850 mL [SD 699], p=0.028), and six of seven (86%) patients achieved pleural-fluid control at 1 month with no further intervention. INTERPRETATION: The toxic effects of intrapleural LTA-T seem to be mild and favourable when compared with the toxicity profiles of standard pleurodesis agents. There is early evidence of LTA-T-induced pleurodesis efficacy, suggesting that this might be a viable therapeutic strategy for the control of malignant pleural effusion.