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.