Different modulation by histamine of IL-4 and interferon-gamma (IFN-γ) release according to the phenotype of human Th0, Th1 and Th2 clones

Histamine, an important inflammatory mediator in allergic diseases and asthma, has been reported to have modulator effects on T cells, suggesting that the bronchial microenvironment may regulate the function of resident T cells. We examined the effect of histamine on the release of the Th2-associated cytokines IL-4 and IL-5 and the Th1-associated cytokine IFN-γ by 30 CD4⁺ T cell clones from peripheral blood or bronchial biopsy of one atopic subject. Based on the IL-4/IFN-γ ratio, the clones were ascribed to the Th2 (ratio >1), Th0 (ratio 0.1 and 1) or Th1 (ratio <0.1) phenotype. Histamine inhibited IFN-γ production by Th1-like cells (P<0.02, Kruskall–Wallis), especially from bronchial biopsy, but had no effect on IL-4 release. Regarding Th0 clones, histamine inhibited IL-4 production (P<0.02) in a dose-dependent manner and slightly inhibited IFN-γ production, but had no effect on Th2-like cells. Histamine had a heterogeneous and insignificant effect on IL-5 production. The H₂-receptor antagonist ranitidine completely reversed the inhibition of IL-4 and IFN-γ production, whereas the agonist dimaprit mimicked this effect. In contrast, H₁- and H₃-receptor agonists and antagonists had no significant effect. These data demonstrate that histamine has different effects on IL-4 and IFN-γ release by T helper cells according to their phenotype via H₂-receptors. This study extends the immunomodulatory effects of histamine which may contribute to the perpetuation of airway inflammation in asthma.     

Sevoflurane for central catheter placement in neonatal intensive care: a randomized trial

Objective: To compare the efficacy and safety of sevoflurane deep sedation with glucose and nonnutritive sucking (GNNS) in reducing the duration of the procedure and in preventing pain‐related effects during peripherally inserted central catheter (PICC) placement. Background: PICC placement in neonatal intensive care is a delicate and stressful procedure that requires pain prevention. GNNS has been recommended in this situation but remain often inefficient. Methods: We designed a randomized controlled study in a sixteen‐bed pediatric and neonatal unit in a tertiary hospital. Fifty‐nine neonates at >28 weeks of gestation with continuous positive airway pressure or invasive mechanical ventilation and requiring PICC placement were included. Patients were randomized to receive inhaled sevoflurane (IS) or glucose and non‐nutritive sucking (GNNS). Procedural duration and conditions, hemodynamic and respiratory parameters, occurrence of movements and complications were compared ( http://clinicaltrials.gov trial register no. NCT00420693). Results: The two groups had similar demographics. There were no between‐group differences in procedural duration (P = 0.84) despite greater immobility in IS group (P = 0.017). IS was also associated with fewer episodes of hypertension (P = 0.003), tachycardia (P < 0.001), and bradycardia (P = 0.02). Occurrences of hypotension were not different between the groups (P = 0.06). The GNNS group showed more desaturation during the 4 h after the procedure (P = 0.03). Complications during intensive care stay did not differ between groups. Conclusion: Inhaled sevoflurane does not make easier catheters placement but prevent pain‐related symptoms. Because sevoflurane is responsible for hypotension, it requires careful monitoring and treatment adaptation.     

Influence of age on rectal tone and sensitivity to distension in healthy subjects

Hypersensitivity to rectal distension is frequently observed in patients with irritable bowel syndrome (IBS). However, few data are available about the influence of age on rectal sensory thresholds and tone. The aim of this study was to measure rectal sensory thresholds and tone with a barostat in 12 healthy subjects (aged 86 +/- 4 years, eight females, four males) as compared with 12 young healthy male controls (26 +/- 1 years). Isobaric phasic distensions were performed in the fasted state (increment of 4 mmHg, steps of 5 min, interval of 5 min). Rectal tone changes were then measured as changes in volume of the barostat bag, the pressure being kept constant. After a baseline recording of 1 h, a 1000-kcal meal was served and the tone recorded until return to baseline. Rectal sensory thresholds were significantly higher in aged subjects. First sensation, sensation of urge to defaecate and sensation of pain were triggered at 21.1 +/- 3.2 mmHg, 30.4 +/- 5.4 mmHg and 40.5 +/- 5.0 mmHg, respectively, in aged subjects, vs 13.3 +/- 4.6 mmHg (P < 0.05), 20.7 +/- 1.0 mmHg (P < 0.001) 31.3 +/- 1.7 mmHg (P < 0.001) in controls. Rectal compliance was not significantly different between the two groups. Mean barostat bag volume was 104 +/- 13 mL in fasting aged subjects and 125 +/- 23 mL in controls (NS). After the meal, the barostat bag volume decreased by 69 +/- 11% during 85 +/- 17 min in aged subjects and 75 +/- 14% during 89 +/- 15 min in young controls (NS). Rectal sensory thresholds triggered by distension are increased in aged healthy subjects while compliance and tone are not different. Age should be considered as a confounding factor when studying rectal sensitivity and further studies in aged patients with IBS should include a group of control subjects within the same range of age as studied patients.     

Relationship between skin reactions to common allergens and non-specific bronchial reactivity in young healthy subjects

In patients with respiratory symptoms, several studies have provided data supporting the hypothesis that there is a causal relationship between allergen exposure and variations in bronchial reactivity. In order to determine if this relationship holds when atopy is defined only on the basis of positive skin tests to common allergens, we compared bronchial reactivity in a group of twelve healthy subjects with positive skin tests and twenty-eight healthy subjects with negative tests. The two groups were comparable in terms of gender, age, smoking habits and family history of atopic diseases. The slopes of the dose-response curves, using airway conductance as an index of response, were similar in the two groups. Thus, in this healthy group of subjects, there was no relationship between skin and bronchial reactivity. It can be hypothesized that, if genetic factors determine bronchial reactivity, such reactivity might not be revealed until skin-test positive subjects have received repeated bronchial stimulation through inhalant allergens.     

1,25-DIHYDROXYCHOLECALCIFEROL INDUCES AN INCREASE IN PGE1 - AND FORSKOLIN-STIMULATED CYCLIC-AMP PRODUCTION IN T47D HUMAN BREAST CANCER CELL LINE

The effect of 1,25-dihydroxycholecalciferol [1,25(OH)2D3], the active form of vitamin D3, on cell growth, clonogenicity, and cyclic adenosine monophosphate (cAMP) production was examined in human breast cancer cell line T47D. 1,25(OH)2D3 markedly inhibited proliferation of T47D cells in a time- and concentration-dependent manner. 1,25(OH)2D3 5 X 10(-7) reduced to 70% [3H]thymidine incorporation into DNA. Specific high affinity nuclear receptors for 1,25(OH)2D3 were present in this cell line. The cAMP produced by T47D cells was measured during 10 min stimulation by effectors (prostaglandin E1 or forskolin). Without effector, T47D cells produced similar amounts of cAMP in control and 1,25(OH)2D3-treated cells. After 3 days in the presence of 1,25(OH)2D3, cAMP production was significantly increased compared to control cells when stimulated by 10(-4) M prostaglandin E1 or 5 X 10(-7) M forskolin (3.2- and 2.4-fold increase, respectively). This cAMP increase was concentration dependent within the same range that inhibited cell growth and clonogenicity. These results suggest that 1,25(OH)2D3 may indirectly affect cAMP production by modulating the target cell response to stimulatory agents of cAMP production.     

Allergy to suxamethonium: persisting abnormalities in skin tests, specific IgE antibodies and leucocyte histamine release

Twenty-one patients, who had previously experienced an anaphylactic reaction to suxamethonium during general anaesthesia, were selected for this study. Initially, skin tests with muscle relaxants were carried out in the twenty-one patients, detection of specific anti-choline IgE in nineteen, and leucocyte histamine release in seventeen. These three tests were then repeated between 1 year and 4 years after the initial evaluation. In the majority of patients, sensitization to the muscle relaxants persisted for more than 1 year after the anaphylactic reaction. Only three patients out of twenty-one (4%) had negative skin tests when retested 1–4 years later. A reduction in leucocyte histamine release was noticed in one of the seventeen retested patients (6%). Modifications of anti-choline IgE were observed in five of nineteen patients (26%). The persistence of sensitization to suxamethonium may result from repeated stimulation by occasional contacts with quaternary ammonium compounds. This study demonstrates the reliability of skin tests, leucocyte histamine release and detection of anti-choline IgE to diagnose allergic reactions to suxamethonium, even when they are performed a long time after the initial anaphylactic reaction.     

Thrombophilias and adverse pregnancy outcomes: results from the Danish National Birth Cohort

Summary. Background: Inherited thrombophilias have inconsistently been linked to adverse pregnancy outcomes. Differences in study design, size and population could explain this heterogeneity. Objective: The aim of the present study was to evaluate if factor (F)V Leiden G1691A, prothrombin mutation G20210A (PTM) and methylenetetrahydrofolate reductase C677T (MTHFR) increased the risk of severe preeclampsia, fetal growth restriction, very preterm delivery, placental abruption and a composite of these outcomes also including stillbirth. Patients and methods: In a nested case–cohort study of pregnant women in Denmark, we genotyped 2032 cases and 1851 random controls. Each of the medical records of the cases was validated. We calculated both genomic and allelic models, and present both models. We also performed sensitivity analyses adjusting for parity, age, smoking, body mass index and socioeconomic status. Results: In the allelic models, FV Leiden increased the risk of the composite outcome (odds ratio [OR] 1.4, 95% confidence interval [CI] 1.1–1.8), severe preeclampsia (OR 1.6, 95% CI 1.1–2.4), fetal growth restriction (OR 1.4, 95% CI 1.1–1.8) and placental abruption (OR=1.7 (95% CI 1.2–2.4). In the sensitivity analyses, adjustment diminished these estimates slightly. PTM was not significantly associated with any of the outcomes, and MTHFR was only significantly associated with severe preeclampsia (OR 1.3, 95% CI 1.1–1.6). Conclusion: FV Leiden predisposes to adverse pregnancy outcomes in a setting of Scandinavian women.