Search

Congenital long QT syndrome (LQTS) is a genetically autosomal heterogeneous disorder of the ion channels and causes about 10% of sudden death infant syndrome in newborns. Its estimated prevalence is approximately 1 in 2500, probably underestimated because of its clinical heterogenicity. Few cases of neonatal LQTS have been reported. In 4% of them, life-threatening arrhythmic events can be the first manifestation of LQTS. The authors report two cases of neonatal LQTS with heterogeneous genetic mutations. Both manifested by bradycardia, one since fetal life. One case had serious arrhythmias during beta blocker therapeutic establishment needing a pacemaker implantation. Genetic mutations found were not the most frequently described in association with neonatal bradycardia, thus the importance of this report. Presentation with bradycardia is relatively frequent in neonatal period, thus LQTS should be actively investigated in neonates with unexplained bradycardia. Beta blocker therapy reduces QTc and avoids arrhythmic events and sudden death.

Fetuses exposed to warfarin during pregnancy are at an increased risk of developing an embryopathy known as fetal warfarin syndrome or warfarin embryopathy. The most consistent anomalies are nasal hypoplasia and stippling of vertebrae or bony epiphyses. Management of pregnant patients on anticoagulation is challenging. Current guidelines suggest the use of warfarin if the therapeutic dose is ≤5 mg/day. We report the case of a newborn with signs of warfarin embryopathy born from a mother anticoagulated with warfarin due to mechanical mitral and aortic heart valves. Warfarin was required at the dose of 5 mg/day and was withheld without medical advice between weeks 8 and 10 with no other anticoagulation. The newborn presented with skeletal abnormalities and a ventricular septal defect that have not required specific treatment during the first year of life. Low-dose warfarin is associated with a lower risk of warfarin-related fetopathy but the risk of embryopathy seems unchanged.

BACKGROUND: There are two isoforms of cyclo-oxygenase (COX), namely COX- 1 and COX-2. COX-1 is constitutively expressed in most tissues and in blood platelets. The metabolites derived from COX-1 are probably involved in cellular housekeeping functions. COX-2 is expressed only following cellular activation by inflammatory stimuli and is thought to be involved in inflammation. METHODS: The expression of COX-1 and COX-2 isoenzymes has been studied in the bronchial mucosa of 10 normal and 18 asthmatic subjects, 11 of whom had aspirin-sensitive asthma (ASA) and seven had non-aspirin-sensitive asthma (NASA) RESULTS: There was a significant fourfold and 14-fold increase, respectively, in the epithelial and submucosal cellular expression of COX-2, but not of COX- 1, in asthmatic patients. There was no significant difference in the total number of cells staining for either COX-1 or COX-2 between subjects with ASA and NASA, but the number and percentage of mast cells that expressed COX-2 was significantly increased sixfold and twofold, respectively, in individuals with ASA. There was a mean fourfold increase in the percentage of COX-2 expressing cells that were mast cells in subjects with ASA and the number of eosinophils expressing COX- 2 was increased 2.5-fold in these subjects. CONCLUSION: COX-2-derived metabolites may play an essential part in the inflammatory processes present in asthmatic airways and development of drugs targeted at this isoenzyme may have therapeutic potential in the treatment of asthma. Mast cells and eosinophils may also have a central role in the pathology of aspirin-sensitive asthma.

BACKGROUND: Accumulating evidence suggests that the cytokine network is central to the immunopathology of bronchial asthma and the existence of naturally occurring cytokine antagonists has added to this complexity. Upregulation of both interleukin 1 beta (IL-1 beta) and its naturally occurring receptor antagonist, interleukin 1 receptor antagonist (IL- 1ra), has previously been observed on asthmatic bronchial epithelium compared with normal airways. METHODS: The effect of inhaled beclomethasone dipropionate (BDP) on asthmatic bronchial epithelial expression of IL-1 beta and IL-1ra was studied. Frozen bronchial biopsy specimens from nine asthmatic subjects receiving 1000 micrograms BDP daily for eight weeks and from six asthmatic subjects receiving matching placebo were stained with anti-IL-1 beta and anti-IL-1ra antibodies. Hue-saturation-intensity (HSI) colour image analysis was used to quantify the brown immunoperoxidase reaction colour present on the bronchial epithelium. RESULTS: There was a significant twofold decrease in the epithelial expression of IL-1 beta after treatment with BDP but no significant change was seen in IL-1ra (P = 0.175). CONCLUSION: The selective inhibition of IL-1 beta, without effect on IL- 1ra, provides a novel mechanism for the anti-inflammatory action of glucocorticosteroids.

BACKGROUND: The aspirin-induced bronchoconstriction in patients with aspirin-sensitive asthma is caused by cysteinyl leukotriene release. The cellular source of the leukotrienes is unknown. The inflammatory cell infiltrate in bronchial biopsy samples from seven aspirin-sensitive asthmatic (ASA) subjects and eight non-ASA subjects before and after local challenge with lysine aspirin was therefore examined. METHODS: Using flexible bronchoscopy, airway mucosal biopsy samples were taken and lysine aspirin solution was placed directly onto a carina of the contralateral lung. Twenty minutes later a second series of biopsy samples was taken from the site of the local endobronchial lysine aspirin challenge. The biopsy samples were double immunostained with a rabbit polyclonal antibody to the enzyme 5-lipoxygenase and monoclonal antibodies to mast cells (AA1), neutrophils (NP57), macrophages (EBM11), T lymphocytes (anti-CD3), and total (BMK13) and activated eosinophils (EG2). RESULTS: A decrease in both absolute mast cell numbers staining with mast cell tryptase (AA1) and the percentage of mast cells co-immunostaining with 5-lipoxygenase was seen in the ASA patients after lysine aspirin challenge compared with the non-ASA control group. There was also an increase in the numbers of activated eosinophils (EG2) in the ASA subjects compared with the non-ASA group. No changes were observed in the total numbers of macrophages (EBM11), neutrophils (NP57), total eosinophils (BMK13), and T lymphocytes (anti-CD3) after challenge with lysine aspirin. CONCLUSIONS: The decrease in numbers of mast cells staining for tryptase and the increase in activated eosinophils after endobronchial challenge with lysine aspirin may represent degranulation of these cell types, and may be an early event associated with aspirin-sensitive reactions in ASA subjects.

Rationale To evaluate efficacy and safety of adding umeclidinium (UMEC), a long-acting muscarinic antagonist (LAMA), to inhaled corticosteroid (ICS)/long-acting β-agonist (LABA) in patients with moderate-to-very severe chronic obstructive pulmonary disease (COPD) for 12-weeks. Methods Multicentre, randomised, double-blind, parallel-group study. Inclusion criteria included diagnosis of COPD, modified Medical Research Council Dyspnoea Scale score ≥2 (i.e. patients symptomatic on ICS/LABA), post-salbutamol forced expiratory volume in one second (FEV 1 ) ≤70% predicted and FEV 1 /forced vital capacity ratio of 1 at Day 85; other endpoints included 0−6 h weighted mean FEV 1 , rescue medication use, COPD assessment test (CAT) score, and transition dyspnoea index (TDI) score. Adverse events (AEs) were also investigated. Results In the UMEC+ICS/LABA and PBO+ICS/LABA groups, 119 and 117 patients were randomised, respectively, receiving fluticasone/salmeterol (40%), budesonide/formoterol (43%), and other ICS/LABA, including generics (17%). Compared with PBO+ICS/LABA, UMEC+ICS/LABA resulted in statistically significant improvements in change from baseline trough FEV 1 at Day 85 and 0−6 h weighted mean FEV 1 at Day 84 (Table 1). UMEC+ICS/LABA resulted in a statistically significant reduction in change from baseline mean puffs/day of rescue salbutamol over Weeks 1–12 versus PBO+ICS/LABA, but not for percentage of rescue-free days. Change from baseline in CAT score at Day 84 was statistically significantly different for UMEC+ICS/LABA versus PBO+ICS/LABA, but TDI score was not significantly different for UMEC+ICS/LABA versus PBO+ICS/LABA; the study was not powered for these endpoints. Incidence of AEs was similar with UMEC+ICS/LABA and PBO+ICS/LABA; n = 45 (38%) and n = 49 (42%), respectively. The most common AEs were nasopharyngitis (13–15%) and headache (3–7%). Conclusions UMEC+ICS/LABA improved lung function and reduced rescue medication use (mean puffs/day) and CAT score in patients with COPD versus PBO+ICS/LABA. No additional safety concerns were identified with UMEC+ICS/LABA. Funded by GlaxoSmithKline (NCT02257372). COI Statement ARS, JR, AC, WAF, CQZ and YSP are employees of GSK and hold stocks/shares in GSK.