Effects of cigarette smoke on degranulation and NO production by mast cells and epithelial cells

Exhaled nitric oxide (eNO) is decreased by cigarette smoking. The hypothesis that oxides of nitrogen (NO(X)) in cigarette smoke solution (CSS) may exert a negative feedback mechanism upon NO release from epithelial (AEC, A549, and NHTBE) and basophilic cells (RBL-2H3) was tested in vitro. CSS inhibited both NO production and degranulation (measured as release of beta-hexosaminidase) in a dose-dependent manner from RBL-2H3 cells. Inhibition of NO production by CSS in AEC, A549, and NHTBE cells was also dose-dependent. In addition, CSS decreased expression of NOS mRNA and protein expression. The addition of NO inhibitors and scavengers did not, however, reverse the effects of CSS, nor did a NO donor (SNP) or nicotine mimic CSS. N-acetyl-cysteine, partially reversed the inhibition of beta-hexosaminidase release suggesting CSS may act via oxidative free radicals. Thus, some of the inhibitory effects of CSS appear to be via oxidative free radicals rather than a NO(X )-related negative feedback

Planned delivery or expectant management for late preterm pre-eclampsia in low-income and middle-income countries (CRADLE-4): a multicentre, open-label, randomised controlled trial

Background: Pre-eclampsia is a leading cause of maternal and perinatal mortality. Evidence regarding interventions in a low-income or middle-income setting is scarce. We aimed to evaluate whether planned delivery between 34+ 0 and 36+ 6 weeks’ gestation can reduce maternal mortality and morbidity without increasing perinatal complications in India and Zambia. / Methods: In this parallel-group, multicentre, open-label, randomised controlled trial, we compared planned delivery versus expectant management in women with pre-eclampsia from 34+ 0 to 36+ 6 weeks’ gestation. Participants were recruited from nine hospitals and referral facilities in India and Zambia and randomly assigned to planned delivery or expectant management in a 1:1 ratio by a secure web-based randomisation facility hosted by MedSciNet. Randomisation was stratified by centre and minimised by parity, single-fetus pregnancy or multi-fetal pregnancy, and gestational age. The primary maternal outcome was a composite of maternal mortality or morbidity with a superiority hypothesis. The primary perinatal outcome was a composite of one or more of: stillbirth, neonatal death, or neonatal unit admission of more than 48 h with a non-inferiority hypothesis (margin of 10% difference). Analyses were by intention to treat, with an additional per-protocol analysis for the perinatal outcome. The trial was prospectively registered with ISRCTN, 10672137. The trial is closed to recruitment and all follow-up has been completed. / Findings: Between Dec 19, 2019, and March 31, 2022, 565 women were enrolled. 284 women (282 women and 301 babies analysed) were allocated to planned delivery and 281 women (280 women and 300 babies analysed) were allocated to expectant management. The incidence of the primary maternal outcome was not significantly different in the planned delivery group (154 [55%]) compared with the expectant management group (168 [60%]; adjusted risk ratio [RR] 0·91, 95% CI 0·79 to 1·05). The incidence of the primary perinatal outcome by intention to treat was non-inferior in the planned delivery group (58 [19%]) compared with the expectant management group (67 [22%]; adjusted risk difference –3·39%, 90% CI –8·67 to 1·90; non-inferiority p<0·0001). The results from the per-protocol analysis were similar. There was a significant reduction in severe maternal hypertension (adjusted RR 0·83, 95% CI 0·70 to 0·99) and stillbirth (0·25, 0·07 to 0·87) associated with planned delivery. There were 12 serious adverse events in the planned delivery group and 21 in the expectant management group. / Interpretation: Clinicians can safely offer planned delivery to women with late preterm pre-eclampsia, in a low-income or middle-income country. Planned delivery reduces stillbirth, with no increase in neonatal unit admissions or neonatal morbidity and reduces the risk of severe maternal hypertension. Planned delivery from 34 weeks’ gestation should therefore be considered as an intervention to reduce pre-eclampsia associated mortality and morbidity in these settings. / Funding: UK Medical Research Council and Indian Department of Biotechnology

Antenatal dexamethasone for early preterm birth in low-resource countries

BACKGROUND: The safety and efficacy of antenatal glucocorticoids in women in low-resource countries who are at risk for preterm birth are uncertain. METHODS: We conducted a multicountry, randomized trial involving pregnant women between 26 weeks 0 days and 33 weeks 6 days of gestation who were at risk for preterm birth. The participants were assigned to intramuscular dexamethasone or identical placebo. The primary outcomes were neonatal death alone, stillbirth or neonatal death, and possible maternal bacterial infection; neonatal death alone and stillbirth or neonatal death were evaluated with superiority analyses, and possible maternal bacterial infection was evaluated with a noninferiority analysis with the use of a prespecified margin of 1.25 on the relative scale. RESULTS: A total of 2852 women (and their 3070 fetuses) from 29 secondary- and tertiary-level hospitals across Bangladesh, India, Kenya, Nigeria, and Pakistan underwent randomization. The trial was stopped for benefit at the second interim analysis. Neonatal death occurred in 278 of 1417 infants (19.6%) in the dexamethasone group and in 331 of 1406 infants (23.5%) in the placebo group (relative risk, 0.84; 95% confidence interval [CI], 0.72 to 0.97; P=0.03). Stillbirth or neonatal death occurred in 393 of 1532 fetuses and infants (25.7%) and in 444 of 1519 fetuses and infants (29.2%), respectively (relative risk, 0.88; 95% CI, 0.78 to 0.99; P=0.04); the incidence of possible maternal bacterial infection was 4.8% and 6.3%, respectively (relative risk, 0.76; 95% CI, 0.56 to 1.03). There was no significant between-group difference in the incidence of adverse events. CONCLUSIONS: Among women in low-resource countries who were at risk for early preterm birth, the use of dexamethasone resulted in significantly lower risks of neonatal death alone and stillbirth or neonatal death than the use of placebo, without an increase in the incidence of possible maternal bacterial infection.Fil: Oladapo, Olufemi T.. Organizacion Mundial de la Salud; ArgentinaFil: Vogel, Joshua P.. Organizacion Mundial de la Salud; ArgentinaFil: Piaggio, Gilda. Organizacion Mundial de la Salud; ArgentinaFil: Nguyen, My-Huong. Organizacion Mundial de la Salud; ArgentinaFil: Althabe, Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Epidemiología y Salud Pública. Instituto de Efectividad Clínica y Sanitaria. Centro de Investigaciones en Epidemiología y Salud Pública; ArgentinaFil: Metin Gülmezoglu, A.. Organizacion Mundial de la Salud; ArgentinaFil: Bahl, Rajiv. Organizacion Mundial de la Salud; ArgentinaFil: Rao, Suman P.N.. Organizacion Mundial de la Salud; ArgentinaFil: de Costa, Ayesha. Organizacion Mundial de la Salud; ArgentinaFil: Gupta, Shuchita. Organizacion Mundial de la Salud; ArgentinaFil: Shahidullah, Mohammod. No especifíca;Fil: Chowdhury, Saleha B.. No especifíca;Fil: Ara, Gulshan. No especifíca;Fil: Akter, Shaheen. No especifíca;Fil: Akhter, Nasreen. No especifíca;Fil: Dey, Probhat R.. No especifíca;Fil: Abdus Sabur, M.. No especifíca;Fil: Azad, Mohammad T.. No especifíca;Fil: Choudhury, Shahana F.. No especifíca;Fil: Matin, M.A.. No especifíca;Fil: Goudar, Shivaprasad S.. No especifíca;Fil: Dhaded, Sangappa M.. No especifíca;Fil: Metgud, Mrityunjay C.. No especifíca;Fil: Pujar, Yeshita V.. No especifíca;Fil: Somannavar, Manjunath S.. No especifíca;Fil: Vernekar, Sunil S.. No especifíca;Fil: Herekar, Veena R.. No especifíca;Fil: Bidri, Shailaja R.. No especifíca;Fil: Mathapati, Sangamesh S.. No especifíca;Fil: Patil, Preeti G.. No especifíca;Fil: Patil, Mallanagouda M.. No especifíca;Fil: Gudadinni, Muttappa R.. No especifíca;Fil: Bijapure, Hidaytullah R.. No especifíca;Fil: Mallapur, Ashalata A.. No especifíca;Fil: Katageri, Geetanjali M.. No especifíca;Fil: Chikkamath, Sumangala B.. No especifíca;Fil: Yelamali, Bhuvaneshwari C.. No especifíca;Fil: Pol, Ramesh R.. No especifíca;Fil: Misra, Sujata S.. No especifíca;Fil: Das, Leena. No especifíca

Biomarkers in a Taurine Trial for Succinic Semialdehyde Dehydrogenase Deficiency

We tested the hypothesis that patients with succinic semialdehyde dehydrogenase (SSADH) deficiency on taurine would have decreased cortical excitability as measured by transcranial magnetic stimulation (TMS) and improved cognition, due to taurine's partial GABA(A and B) receptor agonist effects and rescue in the null mouse model from status epilepticus and premature lethality. Biomarkers including neuropsychological testing, TMS, and CSF metabolites were studied in a cohort of patients on and off three months' taurine treatment. Seven patients (5M/2F; age range 12-33 years) were enrolled in this open-label crossover study. Baseline average full-scale IQ (FSIQ) was 44.1 (range 34-55). Of six who returned at 6-month follow-up, five completed cognitive testing (3M/2F) on therapy; average FSIQ = 43.4 (range 33-51). CSF biomarkers (n = 4 subjects) revealed elevation in taurine levels but no change in free or total GABA. Baseline cortical excitability measured with TMS agreed with previous findings in this population, with a short cortical silent period and lack of long-interval intracortical inhibition. Patients on taurine showed a decrease in cortical silent period and short-interval intracortical inhibition compared to their off taurine study. TMS demonstrated decreased inhibition in patients on taurine, in contrast to the study hypothesis, but consistent with its failure to produce clinical or cognitive improvement. TMS may be a useful biomarker for therapy in pediatric neurotransmitter disorders

Reciprocal effects of interleukin-4 and interferon-γ on immunoglobulin E-mediated mast cell degranulation: a role for nitric oxide but not peroxynitrite or cyclic guanosine monophosphate

We report that cultured rat peritoneal cells spontaneously synthesize nitric oxide and this is associated with active suppression of mast cell secretory function. Addition of interleukin-4 (IL-4) or the nitric oxide synthase inhibitor N-monomethyl-l-arginine to peritoneal cells inhibited nitric oxide synthesis and enhanced anti-IgE-mediated mast cell degranulation, measured as serotonin release. Interferon-γ (IFN-γ) completely overcame the enhancement of serotonin release and suppression of nitrite production induced by IL-4. Over several experiments, with or without IL-4 and/or IFN-γ, serotonin release correlated inversely with nitrite production. On a cell-for-cell basis, non-mast cells produced ≈30 times more nitrite than mast cells in peritoneal cell populations, with or without IFN-γ stimulation. The nitric oxide donor S-nitrosoglutathione inhibited anti-IgE-induced serotonin release from purified mast cells, whereas 8-bromo-cyclic GMP, the guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, superoxide dismutase and the peroxynitrite scavenger uric acid, were without effect. We conclude that IL-4 and IFN-γ reciprocally regulate mast cell secretory responsiveness via control of nitric oxide synthesis by accessory cells; the nitric oxide effect on mast cells is direct but does not involve cyclic GMP or peroxynitrite