Sputum tumour necrosis factor-alpha and leukotriene concentrations in cystic fibrosis

It is postulated that a vigorous host inflammatory response in the cystic fibrosis lung contributes to lung injury. Tumour necrosis factor-alpha (TNF-alpha) may play a part in that process and in the generation of leukotrienes. Therefore, the relationships between sputum TNF-alpha, leukotriene concentration, and lung function abnormalities in 16 children with cystic fibrosis were investigated. Each subject provided sputum samples and performed spirometry. TNF-alpha was measured by enzyme linked immunosorbent assay; individual leukotrienes were separated using high performance liquid chromatography and quantified by radioimmunoassay. The geometric mean concentration of TNF-alpha was 129.7 pg/ml and 95% confidence interval 48.2 to 348.3. Mean (SEM) leukotriene B4 (LTB4) was 97.8 (22.9) pmol/g and total cysteinyl leukotrienes were 60.9 (14.8) pmol/g. Mean (SD) forced expiratory volume in one second (FEV1) of the group was 53 (15)% of predicted and forced vital capacity (FVC) was 65 (14)% of predicted. There was a significant positive correlation between TNF-alpha and both LTB4 and the total cysteinyl leukotriene sputum content. An inverse relationship existed between TNF-alpha and FEV1 and FVC. Moreover, a negative correlation was observed between sputum LTB4 and FEV1 and FVC. These results suggest that TNF-alpha and the leukotrienes may participate in the airways inflammation and airflow obstruction observed in cystic fibrosis subjects and support the hypothesis that TNF-alpha upregulates the 5-lipoxygenase pathway in vivo.     

Interleukin-1 alpha, soluble interleukin-2 receptor, and IgG concentrations in cystic fibrosis treated with prednisolone

The cytokines interleukin-1 and interleukin-2 participate in the inflammatory response, and may contribute to hypergammaglobulinaemia G and the development of lung injury in cystic fibrosis. Anti-inflammatory treatment with corticosteroids may attenuate this response. The effect of a 12 week course of oral prednisolone on spirometry and serum concentrations of interleukin-1 alpha (IL-1 alpha), soluble interleukin-2 receptor (sIL-2R), and IgG was investigated in 24 children with cystic fibrosis. Prednisolone was administered, in a double blind and placebo controlled manner, at an initial dose of 2 mg/kg daily for 14 days and tapered to 1 mg/kg on alternate days for 10 weeks. The treated group (n = 12) experienced an increase in forced expiratory volume in one second and forced vital capacity at 14 days, however, these changes were smaller at 12 weeks. In the treated group, change in pulmonary function was associated with decreased serum IgG and cytokine concentrations. Prednisolone suppresses serum concentrations of these cytokines, which may participate in the inflammatory response, the excessive synthesis of IgG, and airflow obstruction observed in cystic fibrosis patients.     

Pioneers in Psychopharmacology II

In 1998, the first Pioneers in Psychopharmacology Awards were presented at the XXIst CINP Meeting in Glasgow to Pierre Deniker, Joel Elkes and Heinz Lehmann. These three individuals had distinguished themselves and Psychopharmacology not only by the quality of their work but also by their ability to persuade others of the importance of the new field that was opening up (Healy, 1998). At the XXIInd CINP Meeting in Brussels in July 2000, Paul Janssen, Mogens Schou and Alec Coppen became the second group to receive such awards for distinguished achievement.     

Anthoptilides A-E, new Briarane diterpenes from the Australian sea pen Anthoptilum cf. kukenthali

The Australian sea pen Anthoptilum cf. kukenthali has afforded five new briarane-type diterpenes, anthoptilides A-E. Their structures were determined on the basis of their spectroscopic data. Single-crystal X-ray determination was performed on anthoptilide A. Anthoptilides B and C inhibited the binding of [(3)H]1, 3-dipropyl-8-cyclopentylxanthine ([(3)H]DPCPX) on adenosine A(1) receptors.     

Dopaminergic sensitivity and prediction of antidepressant response

This study was designed to examine neuroendocrine predictors of antidepressant response to the selective serotonin reuptake inhibitor (SSRI) paroxetine. We assessed the prognostic utility of the apomorphine stimulation test by examining the relationship between pretreatment change in growth hormone (GH) following apomorphine and acute response to paroxetine treatment. We hypothesized that those subjects with most marked pretreatment dopaminergic supersensitivity, as manifested by greatest change in GH, would be most likely to show an early antidepressant response and would also be more likely to develop manic or hypomanic symptoms on paroxetine. Contrary to our hypothesis, greater dopamine postsynaptic sensitivity was associated with greater resistance to paroxetine treatment. In our sample of 13 subjects with a major depressive episode, pretreatment GH response to apomorphine per unit weight was inversely correlated with change in Hamilton depression rating scale following 6 weeks of paroxetine. Within the group of subjects who showed mood elevation on paroxetine, there was a trend towards greater GH response being associated with slower antidepressant response. With regard to the development of manic or hypomanic symptoms on paroxetine, change in GH per unit weight not did distinguish the two subjects who subsequently developed paroxetine-induced hypomania from other subjects. The seven subjects with previous antidepressant-induced hypomania did not differ from the other subjects in change in GH response per unit weight. The finding that subjects who had low dopamine receptor responsivity pretreatment were more likely to have an antidepressant response with paroxetine is consistent with recent suggestions that the therapeutic effect of SSRIs may be mediated through increased dopamine receptor sensitivity in the mesolimbic system. Further work assessing pretreatment and post-treatment GH response to apomorphine will help to test the hypothesis that low dopamine receptor responsivity predicts antidepressant response to SSRIs.     

Combined aortic and visceral arterial reconstruction: risks and results

The indications, morbidity, and efficacy of combined reconstruction of the abdominal aorta and visceral arteries (renal and superior mesenteric; excluding suprarenal aortic aneurysms) were analyzed retrospectively in 29 consecutive patients who underwent surgery from June 1984 through February 1990. Seventeen men and 12 women ages 32 to 76 years (mean, 66 years) were studied. Follow-up was complete in all patients to either death or calendar year 1989 to 1990 (mean, 31.9 months; range, 2 to 66 months). All patients underwent bypass of angiographically proven severe lesions of one renal artery (19 patients), both renal arteries (8 patients), or the superior mesenteric artery and renal arteries (2 patients), in concert with synthetic distal aortic replacement for occlusive disease (10 patients) or aneurysm (19 patients). Indications for renal artery repair included severe hypertension in 13 patients, ischemic renal insufficiency in 8 patients, and lesion morphology alone in 8 patients. Operative mortality rate was 3 of 29 (10.3%), and each death was the result of multisystem organ failure. Nonfatal complications occurred in 11 of the 26 survivors (42%), and this group differed significantly from the uncomplicated 15 patients only in having a higher mean preoperative serum creatinine (2.5 +/- 1.1 mg/dl vs 1.6 +/- 0.9 mg/dl, p = 0.04, t test). The mortality rate of patients with preoperative serum creatinine greater than or equal to 2.0 mg/dl, was 15.4% (2/13 patients), compared to 6.2% (1/16) in patients with creatinine less than 2.0 mg/dl. Three late deaths occurred (2 stroke, 1 cancer). Hypertension control improved in 64% of patients overall, and in 7 of 9 patients whose major operative indication was renovascular hypertension. Renal function remained stable or improved in 12 of 15 patients (80%) with renal insufficiency, but 3 patients progressed to require dialysis. Long-term graft patency was demonstrated by angiography or on duplex scan in all studied survivors (21 patients). Although operative risks are clearly increased compared to less complex vascular procedures, careful patient selection and management will yield a favorable outcome in most patients with such combined lesions.     

Peripheral α2-adrenoceptor-mediated sympathoinhibitory effects of mivazerol

Summary— Mivazerol is a new compound that could potentially reduce perioperative cardiovascular morbidity and mortality in patients with or at risk of coronary disease and submitted to surgery. This action of mivazerol depends on a well documented centrally mediated reduction in sympathetic nerve activity, but a direct peripheral decrease in sympathetic neurotransmitter release induced by activation of prejunctional α₂-adrenoceptors located on sympathetic nerve endings could also contribute. To investigate this issue, the effects of mivazerol on the pressor, systemic and regional hemodynamic (pulsed Doppler technique) as well as on the cardiac responses to electrical stimulation of the spinal cord (SCS) were measured in pithed rats in the absence and in the presence of mivazerol. Mivazerol exerted strong sympathoinhibitory effects: SCS-induced increases in blood pressure, total peripheral resistance and heart rate were dose-dependently reduced by mivazerol, but among the regional vascular beds investigated, only the hindlimb vasoconstrictor responses were significantly drug-affected. All these sympathoinhibitory effects of mivazerol were abolished by prior yohimbine administration. Simultaneously, mivazerol did not induce any postjunctional adrenoceptor blockade as it did not affect noradrenaline cardiac and hemodynamic effects. On the contrary, through postjunctional α₂-adrenoceptor stimulation, mivazerol, in this pithed preparation, dose-dependently increased blood pressure, total peripheral and hindlimb vascular resistances, but heart rate was not affected. We conclude that, in the pithed rat, mivazerol exerts strong peripheral sympathoinhibitory effects. The mechanism involved is prejunctional α₂-adrenoceptor activation as i) mivazerol does not display any postsynaptic α-adrenoceptor blocking effect — it even behaves as a postsynaptic α₂-adrenoceptor agonist — and ii) yohimbine abolishes mivazerol's sympathoinhibitory effects. Thus, direct peripheral together with central mechanisms contribute to mivazerol's sympathoinhibitory effects and ultimately to its cardioprotective action.