Search

The proinflammatory transcription factor nuclear factor-kappaB (NF-κB) plays a central role in host defence against pneumococcal disease. Both rare mutations and common polymorphisms in the NFKBIA gene encoding the NF-κB inhibitor IκB-α associate with susceptibility to bacterial disease, but the possible role of polymorphisms within the related IκB-ζ gene NFKBIZ in the development of invasive pneumococcal disease has not previously been reported. 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 block and all four polymorphisms within the equivalent, shorter Kenyan linkage disequilibrium block displayed either significant association with invasive pneumococcal disease or a trend towards association. For each polymorphism, heterozygosity was associated with protection from invasive pneumococcal disease when compared to the combined homozygous states (e.g. for rs600718, Mantel-Haenszel 2×2 χ2=7.576, P=0.006, OR=0.67, 95% CI for OR: 0.51-0.88; for rs616597, Mantel-Haenszel 2×2 χ2=8.715, P=0.003, OR=0.65, 95% CI: 0.49-0.86). We conclude that multiple NFKBIZ polymorphisms associate with susceptibility to invasive pneumococcal disease in humans. The study of multiple populations may aid fine-mapping of associations within extensive regions of strong linkage disequilibrium (‘transethnic mapping’).

Nocturnal hypoxaemia is inaccurately assessed by one night's sleep study which will artifactually reduce its relationship with blood pressure through regression dilution bias. This study aims to quantify this effect. Two data sets were analysed. 893 normal men aged 35-60, studied during a survey of OSA and mean blood pressure (MBP) (BMJ: 1990:300:75) and 204 subjects (162M, 42F, Age 49SD10.8, >4%SaO2 diprate 14SD20.3) referred with possible sleep apnoea to centre 2. The normal subjects received one night of arterial pulse oximetry (Biox 3700) at home, and the sleep clinic group two nights (Pulsox 5). The severity of nocturnal hypoxaemia was quantified as the number of >4% falls in SaO2 per recording hour (>4% diprate). To describe how regression to the mean affects nocturnal hypoxaemia, the log10>4% diprate on the first night's oximetry in the 204 sleep clinic patients was sorted into ascending order and divided into 12, 0.25 range cells with the first two cells collapsed. For the resulting 11 cells, the difference between the average log10>4% diprates on the first and second nights was calculated. Above log10>4% diprate of 1.2 (=16hr-1) regression to the mean is minor as nocturnal hypoxaemia is reproducible. Below this threshold regression to the mean changes in an approximately linear way: diff log10diprate = -0.29 x mean first night log10diprate +0.12(r2=0.81) Since only 4 of the 893 (4% diprate >16 hr-1 this equation was used to correct the normal data for regression dilution bias. These 893 subjects were sorted into ascending log10>4% diprate and grouped into 9, 0.20 range cells with the first two cells collapsed. The cell average MBP was plotted against the cell average log10>4% diprate and the corrected cell average log10>4% diprate and their linear relationships described: MBP = 5.4 x log10>4%diprate+103.6 (r2=0.75) MBP = 7.0 x corrected log10>4%diprate+102.8 (r2=0.83) Correction for regression dilution bias strengthens the relationship between MBP and nocturnal hypoxaemia severity. This previously unconsidered effect may have distorted apparent relationships between OSA, MBP and obesity in community studies.

Background. Anti-streptokinase immunoglobulin (IgG) induced by intravenous (IV) streptokinase (SK) can reduce the effectiveness of repeated SK use, or lead to an increased incidence of immune mediated adverse reactions. It is therefore advised that IV SK exposed patients receive an alternative fibrinolytic for later exposures. It is not known whether intra-pleural streptokinase (IPSK) induces a similar response. Methods. We studied 18 patients (age 35-81) receiving IPSK for drainage of multiloculated pleural effusion (13 infected; 5 malignant). All patients received 250,000i.u. IPSK twice daily to a maximum of 1,500,000i.u. The development of functionally important circulating antibodies against SK was assessed by comparing the inhibition of SK-induced fibrinolytic activity (Streptokinase-Resistance test) before SK administration with that 10-14 days later. Serial dilution's of SK (20μL) were added to citrated plasma (160μL) containing thrombin (20μL). The lowest concentration of SK achieving complete lysis was noted and expressed as the SK resistance titre. Results. SK resistance titres rose in 7/18 patients (39%) and in 4/18 (22%) there was at least a four-fold rise in titres. No patients had allergic reactions following IPSK administration. Conclusions. A minority of patients receiving IPSK experience a rise in functionally significant anti-streptokinase antibodies. The frequency of this rise is less than that seen following IV SK, but is sufficient to warrant the use of an alternative fibrinolytic if this is subsequently indicated.

L-ficolin is a pattern-recognition molecule which binds lipoteichoic acid and Gram-positive bacteria and activates the lectin pathway of complement. Five common functional polymorphisms have recently been identified in the FCN2 gene which encodes L-ficolin: three promoter polymorphisms (at positions -986, -602 and -4) which affect serum L-ficolin concentration, and two non-synonymous polymorphisms (Thr236Met and Ala258Ser) which influence carbohydrate binding. We studied the frequencies of these polymorphisms in individuals with invasive pneumococcal disease (IPD) and a control group. Although the five FCN2 polymorphisms were each present in the UK Caucasian population studied, no significant associations were observed between the FCN2 polymorphisms and susceptibility to IPD. This is in contrast to mannose-binding lectin deficiency, which we have previously shown to be associated with increased susceptibility to IPD. Although we are unable to exclude small effects of FCN2 genetic variation on susceptibility to IPD, the result suggests that L-ficolin may not be critical for host defence against pneumococcal infection.

© 2006 Elsevier Ltd. All rights reserved. Development of a sterile, exudative pleural effusion (simple parapneumonic effusion) is a common complication of bacterial pneumonia, and the majority of cases resolve with antibiotic treatment alone. A minority become secondarily infected (complex parapneumonic effusions), and require chest drainage for clinical resolution. Infected pleural fluid is characterized biochemically by a low pH and glucose, and an elevated lactate dehydrogenase. Pleural infection is associated with activation of the coagulation cascade, and the subsequent deposition of fibrin within the pleural space results in the formation of septations and impedes drainage. Ongoing infection leads to the accumulation of pus in the pleural cavity (empyema). Treatment of pleural infection comprises appropriate antibiotics, chest drainage, nutritional support, and in some cases surgery; intrapleural fibrinolytics are ineffective. Tuberculous pleural effusions develop as a result of a delayed hypersensitivity reaction to mycobacteria in the pleural space. Diagnosis is based on mycobacterial culture of pleural fluid or pleural tissue, or may be inferred from the finding of granulomas on pleural biopsy. Treatment of tuberculous pleurisy involves the same antimicrobial regimen as that used for pulmonary tuberculosis. The use of steroids to treat tuberculous pleurisy is controversial, although they may lead to symptomatic benefit by hastening pleural fluid absorption.

In the last few years substantial progress has been made in unravelling the genetic basis of susceptibility to Crohn’s disease. Three CARD 15 (previously called NOB2) genetic variants, resulting in proteins with modified carboxy terminal regions, have been implicated.1,2 43% of patients with Crohn’s disease carry at least one of these CARD 15 mutations (compared with 15% of healthy controls).1 Mutations in CARD 15 have also been identified in affected members of families with Blau syndrome.3,4 This is a rare autosomal dominant disorder, sometimes referred to as familial sarcoidosis, characterised by granuloma formation in joints, skin, and uvea. Card 15 is a microbial sensing protein involved in innate immunity. It recognises conserved structural components of microorganisms (bacterial muramyl dipeptide, MDP and peptidoglycan, PGN) and is part of the danger signal pattern recognition network which forms the front line of protective immunity. Mutations associated with Crohn’s disease render the molecule insensitive to MDP and interfere with the downstream activation of NF-κB. One …

Background The intercostal artery is thought to be shielded in the groove of the superior rib; however, the course and variability of the intercostal artery, and factors which may influence these, have not been described in vivo. Describing these variables in vivo has potentially important implications for avoiding complications during common pleural procedures. Methods Maximum intensity projection (MIP) reformats in the coronal plane were produced from CT pulmonary angiograms, to identify the posterolateral course of the contrast opacified intercostal artery. A novel semi-automated computer segmentation algorithm was used to identify and measure distances between the lower border of the superior rib, the upper border of the inferior rib and the position of the intercostal artery when exposed in the intercostal space, and manually verified by a radiologist. Position and variability of the artery were described and then analysed for association with clinical factors using a random effects regression model. Results 298 arteries were analysed from 48 patients (mean age 60 years). The mean lateral distance from the spine over which the artery was exposed within the intercostal space (‘unsafe artery length’) was 39 mm with wide variability (SD=10 mm, 10th to 90th centile 28 mm to 51 mm, Abstract P64 Figure 1A). At 3 cm lateral distance from the spine 16.6% of arteries were shielded by the superior rib, compared to 96.6% at 6 cm. Unsafe artery length was not associated with age, sex, rib space or side. Using regression modelling, variability of arterial position (as SD and coefficient of variation) was significantly associated with age (coeff 0.91, p Conclusions The intercostal artery is exposed within the intercostal space in the first 6 cm lateral to the spine; variability of its vertical position is greater in older patients and more cephalad rib spaces. This implies that pleural interventions within 6 cm lateral to the spine should be conducted with caution and that the risk of intercostal artery laceration is potentially higher in older patients and more cephalad rib spaces.

The raised rate of road accidents in OSA has stimulated a search for predictors of driving performance. 34 patients investigated for possible OSA (age 47.8 SD10.1, BMI 29.6 SD 6.3, ESS 11.9 SD4.0, >4%SaO2 dips/hr 10.4 SD 13.1) performed a steering simulation, including responses to peripheral events. Subjects performed a modified maintenance of wakefulness test (MWT 28.5 SD9.9 mins). The eventual diagnosis ranged from normal to severe OSA. Two steering simulation parameters (SD of steering error from the theoretical perfect path, and reaction time) were correlated against age, measures of sleepiness (ESS, MWT) and measures of OSA severity (autonomic arousals/hr, >4%SaO2 dips/hr, and body movements/hr). R age ESS MWT autonomic >4% body values arousals SaO2 movements /h dips/h /h steering 0.39* 0.28 -0.36* 0.23 0.22 0.40* error reaction 0.11 0.33 -0.04 0.35* 0.32 0.27 time * p

A number of studies have demonstrated a relationship between the clinical syndrome of obstructive sleep apnoea (OSA) and hypertension. There is also an excess of cardiovascular morbidity and mortality in subjects with OSA, but studies examining important clinical endpoints of cardiovascular disease, e.g. left ventricular hypertrophy (LVH) in OSA subjects have produced conflicting results. Cerebral magnetic resonance imaging (MRI) detects clinically silent abnormalities relating to hypertensive cerebrovascular disease, which are seen as small areas of high signal foci in deep white matter (DWM) and lacunae. These lesions are permanent and known to be associated with stroke, age, hypertension, LVH and carotid atherosclerosis. We performed a case control study of cerebral MRI in patients with OSA and closely matched controls. 37 sleep clinic patients with moderate to severe OSA and excessive daytime sleepiness were matched to 37 controls without evidence of OSA on a sleep study. Matched variables included age, body mass index (BMI), alcohol and cigarette consumption, treated hypertension and history of ischaemic heart disease. 24-hour ABP recordings were performed in all subjects, and before treatment in the patients with OSA. All subjects underwent standard sagittal T1 and axial T2 MRI imaging, which were analysed for high signal abnormalities. Lacunae/high signal foci in DWM were present in 15 (40%) OSA subjects and 19 (51%) controls, despite significant increases in mean daytime diastolic blood pressure (5.0mmHg,p