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The role of female sex steroid hormones in asthma is still unclear, although there is much Background -A study was undertaken to investigate the influence of the menstrual circumstantial evidence to suggest that they may be important. Up to 40% of female asthcycle on airway responsiveness and 2 adrenoceptor function in female asthmatic matic subjects report a premenstrual deterioration in their condition. 1-4 Indeed, a patients. It has previously been shown that normal women exhibit cyclical changes in premenstrual fall in peak expiratory flow rate (PEFR) has been demonstrated even in those 2 adrenoceptor function with an increase in 2 adrenoceptor density in the luteal who have previously not been aware of this phenomenon. 4 An effect of sex steroid horphase during the premenstrual period. Methods -Fifteen women with stable, well mones has been shown by the observation that, in a few patients, intramuscular supplementary controlled asthma (mean forced expiratory volume in one second (FEV 1 ) 2.97 l progesterone eliminated the premenstrual fall in PEFR and allowed better control of asthma (93.8% predicted)) were evaluated. Measurements were made at the follicular phase with lower doses of systemic steroids.5 However, the pathophysiology of this phenomenon (days 1-6) and the luteal phase (days 21-24) of the menstrual cycle. Airway re-remains unclear. Female sex steroid hormones have a regulatory role on 2 adrenoceptor funcsponsiveness was assessed using adenosine 5′-monophosphate (AMP) and expressed tion and it has been postulated that abnormal 2 adrenoceptor regulation may be a possible as PC 20 AMP. Beta 2 adrenoceptor function was evaluated by measuring lymphocyte mechanism for premenstrual asthma. We have previously shown that cyclical changes in 2 adrenoceptor parameters and constructing dose-response curves to sal-lymphocyte 2 adrenoceptor function occur during the menstrual cycle in normal women butamol (100-1600 g). The levels of female sex hormones were also measured with greater 2 adrenoceptor density and isoprenaline responsiveness in the luteal phase at both phases of the cycle. Results -There were significant increases during the premenstrual period.6 Further support for this role is provided by in vitro studies in serum levels of both oestradiol (2.2-fold, p <0.001) and progesterone (7.2-fold, p which show that female sex steroid hormones potentiate the bronchorelaxant effect of cate-<0.05) between the follicular and luteal phases. Geometric mean PC 20 AMP was cholamines. 7In this study we have investigated 2 ad-19.0 mg/ml and 7.6 mg/ml during the follicular and luteal phases, respectively (p renoceptor regulation and airway responsiveness to adenosine 5′-monophosphate <0.05), a 2.51-fold difference (95% CI 1.19 to 5.30) amounting to 1.33 doubling doses (AMP) in female asthmatic subjects. AMP was used because it is a marker of mediator release of AMP. There was no change in lymphocyte 2 adrenoceptor parameters or in from mast cells.

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In CRSwNP there is asymptomatic airway dysfunction suggestive of an asthmatic phenotype. Impairment of lung function is significantly associated with BHR and eosinophilia but not parameters of nasal disease suggesting that severity of airway dysfunction relates to the spectrum of asthma rather than rhinosinusitis. Lower airway dysfunction is common in CRSwNP but does not correlate to the severity of nasal disease. Signs and symptoms of asthma should be sought and treated in CRSwNP.

1 Up to 40% of female asthmatic subjects suffer a premenstrual deterioration in their condition which may be ameliorated by progesterone supplementation, although the mechanism responsible for this phenomenon is not understood.In vitro studies have shown that female sex-steroid hormones potentiate the bronchorelaxant effect of isoprenaline, whilst in vivo it has been shown that females exhibit greater sensitivity of systemic 02-adrenoceptor responses. 2 The aim of the present study was to determine whether cyclical alterations in P2-adrenoceptor expression, occurring under the influence of ovarian sex-steroid hormones, may offer an explanation for these findings. In vitro parameters of lymphocyte P2-adrenoceptor function were investigated in nine normal female subjects (aged 24 ± 2 years) during the follicular (day 2-4) and luteal (day 21-23) phases of their menstrual cycle, and results were compared with those of nine agematched healthy male controls studied at the same time intervals. 3 In female subjects there were significant increases in serum concentrations of oestradiol (3.3-fold) and progesterone (10.6-fold) between the follicular and luteal phases of the menstrual cycle, whereas no changes occurred in males. 4 In females during the luteal phase, the increase in sex-steroid hormones was mirrored by an increase in lymphocyte P2-adrenoceptor density (Bmax) and in maximal cyclic AMP response to isoprenaline (Emax), which were significantly higher than in male subjects. Mean differences (95% CI) between male and female subjects on visit 2 were 1.09 (0.49 to 1.69) fmol/106 cells (P = 0.001) for Bmax, and 3.42 (0.80 to 6.04) pmol/106 cells (P = 0.02) for Emax. The mean difference (95% CI) in Emax between visits 1 and 2 in females was 2.57 (0.32 to 4.82) pmol/106 cells (P = 0.03). The receptor affinity (Kd) remained unchanged in both sexes. 5 These findings suggest that lymphocyte ,2-adrenoceptors are regulated under the influence of ovarian sex-steroid hormones during the menstrual cycle, and may account for previously observed gender differences of in vivo ,32-responses.Furthermore, the rapid hormone flux and fall in P2-adrenoceptor density and cyclic AMP response between luteal and follicular phases may also provide a possible mechanism for premenstrual deterioration in asthma and its response to progesterone.

Background -C-type natriuretic peptide (CNP) is a recent addition to the family of natriuretic peptides which includes atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). Whilst the levels of ANP and BNP are increased in conditions such as congestive heart failure and cor pulmonale, abnormal levels of CNP in these conditions have not been reported. Methods -Plasma levels of CNP were measured by specific radioimmunoassay in 12 young normal controls, 12 elderly normal controls, 12 patients with NYHA grade III-IV congestive heart failure, and in 16 patients with hypoxaemic cor pulmonale. CNP levels, however, are not raised in congestive heart failure,6 and its role as a regulatory peptide in circulatory homeostasis remains unclear. We have therefore measured plasma levels of CNP in patients with cor pulmonale and congestive heart failure where the vascular natriuretic peptide system could potentially act as a functional antagonist of the vascular renin angiotensin system. Results Methods SUBJECTSNormal controls Twelve young male volunteers of mean (SE) age 25-9 (1 9) years and 12 older volunteers (10 men) aged (1-3) years were studied. None were taking regular medication and all had a normal clinical history and examination, electrocardiogram, echocardiogram, and haematological and biochemical test results.Patients with congestive heart failure Twelve (10 men) patients aged 68-6 (2 3) years with stable NYHA grade III-IV heart failure symptoms were studied. All had a left ventricular ejection fraction (LVEF) less than 40% as assessed by radionuclide ventriculography, and had been taking a constant dose of frusemide (mean dose 80 mg/day, range 40-160 mg) and ACE inhibitors for at least two weeks. Patients with clinical or radiographic evidence of chronic obstructive pulmonary disease (COPD), systemic hypertension, disturbances of cardiac rhythm, or impaired renal function (serum creatinine >170 mmol/l) were excluded. In this group mean LVEF was 21*6(1 8)%.Patients with cor pulmonale Sixteen (12 men) patients aged 68 1 (1 9) years with clinically stable cor pulmonale secondary to COPD were studied. All had spirometric results reflecting COPD (FEVI/FVC <70%), arterial hypoxaemia while breathing air (Pao2 1247

1 The aim of this study was to compare the systemic bioactivity of low and high doses of inhaled budesonide and fluticasone propionate given by respective dry powder inhaler devices. 2 A randomised, single blind cross-over design was used in nine healthy subjects who were given 800 ,ug day-1 of budesonide Turbohaler (Bsoo) for 1 week, followed by 1 week of 1600 ig day-1 (BI600), or fluticasone Diskhaler 750 jg day-1 (F750) for 1 week followed by 1 week of 1500 pg day-1 (F1500). There was a 1 week washout between treatments with fluticasone or budesonide. A twice daily dosing regime was used and mouth-rinsing was employed to reduce gut bioavailability as well as to obviate local adverse effects.

Introduction Current interferon-gamma (IFN-γ) release assays (IGRAs) are not sufficiently sensitive to be used as a "rule-out" test for tuberculosis (TB). Antigen-specific gene expression of chemokines downstream of, and amplified by, IFN-γ might demonstrate such sensitivity, and can be performed with very small volumes of blood. 1 Here we assess the performance and sensitivity of two IFN-γdependent gene expression platforms in the peripheral blood mononuclear cells of individuals with and without TB. Methods 23 individuals with active TB, 12 individuals with latent TB infection (LTBI), and 18 controls had simultaneous IFN-γ ELISpot assays and qRTPCR of CXCL-9 and CXCL-10, following stimulation with the immunodominant antigens ESAT-6, CFP-10 and EspC (6 gene expression assays in total). Test performances of the 6 gene expression assays were compared to the ELISpot. Results Gene expression of CXCL-9 and CXCL-10 was antigen specific, correlating well with each other and with the IFN-γ ELISpot (Spearman Rank Correlations ranging from r=0.648 to 0.74). Gene expression of either was not significantly different between those with active TB and LTBI. Receiver-operating characteristic curves indicated good test performances for all the gene expression assays (AUC ranging from 0.918 to 0.959) and agreements between the ELISpot and gene expression platforms was good (κ statistic ranging from 0.403-0.496). After constructing cutoffs for sensitivity for individual antigens, with cutoffs for specificity matching or exceeding that of the IFN-γ ELISpot, the sensitivity of TB diagnosis with gene expression was superior to ELISpot in 5 out of the 6 assays, although these differences were not statistically significant. Sensitivity was equivalent when antigens were combined, as in the commercially available T-Spot ® .TB. Conclusions These pilot data indicate that gene expression of IFN-γ-dependent cytokines is a robust, sensitive and specific method of TB diagnosis, and carries potential to be a more sensitive platform that the current gold standard-IFN-γ ELISpot. Larger studies with appropriate power are now required in similar populations to investigate this approach definitively. References