Glibenclamide treatment in a Cantú syndrome patient with a pathogenic ABCC9 gain‐of‐function variant: Initial experience

Cantú syndrome (CS), characterized by hypertrichosis, distinctive facial features, and complex cardiovascular abnormalities, is caused by pathogenic variants in ABCC9 and KCNJ8 genes. These genes encode gain‐of‐function mutations in the regulatory (SUR2) and pore‐forming (Kir6.1) subunits of K_ATP channels, respectively, suggesting that channel‐blocking sulfonylureas could be a viable therapy. Here we report a neonate with CS, carrying a heterozygous ABCC9 variant (c.3347G>A, p.Arg1116His), born prematurely at 32 weeks gestation. Initial echocardiogram revealed a large patent ductus arteriosus (PDA), and high pulmonary pressures with enlarged right ventricle. He initially received surfactant and continuous positive airway pressure ventilation and was invasively ventilated for 4 weeks, until PDA ligation. After surgery, he still had ongoing bilevel positive airway pressure (BiPAP) requirement, but was subsequently weaned to nocturnal BiPAP. He was treated for pulmonary hypertension with Sildenafil, but failed to make further clinical improvement. A therapeutic glibenclamide trial was commenced in week 11 (initial dose of 0.05 mg^–1 kg^–1 day^–1 in two divided doses). After 1 week of treatment, he began to tolerate time off BiPAP when awake, and edema improved. Glibenclamide was well tolerated, and the dose was slowly increased to 0.15 mg^?1 kg^?1day^?1 over the next 12 weeks. Mild transient hypoglycemia was observed, but there was no cardiovascular dysfunction. Confirmation of therapeutic benefit will require studies of more CS patients but, based on this limited experience, consideration should be given to glibenclamide as CS therapy, although problems associated with prematurity, and complications of hypoglycemia, might limit outcome in critically ill neonates with CS.     

Sleep related breathing disorders in older men: A search for underlying mechanisms

—The incidence of sleep-related breathing disorders (SRBDs) associated with hemoglobin desaturation was determined by nocturnal polygraphic evaluations in 26 healthy men, aged 55–70 years. Sixteen subjects (62%) had abnormal rates of at least 12 episodes per hour of sleep: 8 had occlusive, and 8 had central apnea or hypopnea. During waking ten of 16 SRBD subjects and only one subject without SRBDs exhibited either an elevated nasopharyngeal airway resistance (n=4) or a reduced ventilatory response to hypercapnia (n=4) and/or hypoxia (n=3). However, these abnormalities were not related to the type or severity of SRBDs, and 6 subjects with SRBDs demonstrated no respiratory defect. We conclude that SRBDs have a very high incidence in older males and are not usually secondary to pulmonary cardiac, neurological, or behavioral disorders. Additionally, we hypothesize that abnormalities in ventilatory control or upper airway resistance contribute to SRBDs, but depression of brain stem reticular formation activity during sleep plays a primary role in these disorders. Factors related to both aging and SRBDs are reviewed. These include reduced chemoreceptor responses, altered steroid hormone metabolism, and use and metabolism of hypnotic drugs and alcohol.     

Allergic airway inflammation induces tachykinin peptides expression in vagal sensory neurons innervating mouse airways

BACKGROUND: Allergic airway inflammation has been shown to induce pro-inflammatory neuropeptides such as tachykinin peptides substance P (SP) and neurokinin A (NKA) together with related peptide like calcitonin gene-related peptide (CGRP) in nodose sensory neurons innervating guinea-pig airways. OBJECTIVE: The present study was designed to examine the effects of allergen sensitization and challenge on the SP/NKA expression in the jugular-nodose ganglion neurons innervating the murine airways. METHODS: Using retrograde neuronal tracing technique in combination with double-labelling immunohistochemistry, the expression of SP/NKA was investigated in a murine model of allergic airway inflammation. RESULTS: Allergic airway inflammation was found to induce the expression of SP/NKA (13.2+/-1.43% vs. 5.8+/-0.37%, P<0.01) in large-diameter (>20 microm) vagal sensory neurons retrograde labelled with Fast blue dye from the main stem bronchi. CONCLUSION: Based on the induction of tachykinins in airway-specific large-sized jugular-nodose ganglia neurons by allergic airway inflammation, the present study suggests that allergen sensitization and challenge may lead to de novo induction of tachykinins in neurons. This may partly contribute to the pathogenesis of airways diseases such as allergic airway inflammation.     

Chronic obstructive pulmonary disease is associated with enhanced bronchial expression of FGF-1, FGF-2, and FGFR-1

An important feature of chronic obstructive pulmonary disease (COPD) is airway remodelling, the molecular mechanisms of which are poorly understood. In this study, the role of fibroblast growth factors (FGF-1 and FGF-2) and their receptor, FGFR-1, was assessed in bronchial airway wall remodelling in patients with COPD (FEV1 < 75%; n = 15) and without COPD (FEV1 > 85%; n = 16). FGF-1 and FGFR-1 were immunolocalized in bronchial epithelium, airway smooth muscle (ASM), submucosal glandular epithelium, and vascular smooth muscle. Quantitative digital image analysis revealed increased cytoplasmic expression of FGF-2 in bronchial epithelium (0.35 +/- 0.03 vs 0.20 +/- 0.04, p < 0.008) and nuclear localization in ASM (p < 0.0001) in COPD patients compared with controls. Elevated levels of FGFR-1 in ASM (p < 0.005) and of FGF-1 (p < 0.04) and FGFR-1 (p < 0.001) in bronchial epithelium were observed. In cultured human ASM cells, FGF-1 and/or FGF-2 (10 ng/ml) induced cellular proliferation, as shown by [3H]thymidine incorporation and by cell number counts. Steady-state mRNA levels of FGFR-1 were elevated in human ASM cells treated with either FGF-1 or FGF-2. The increased bronchial expression of fibroblast growth factors and their receptor in patients with COPD, and the mitogenic response of human ASM cells to FGFs in vitro suggest a potential role for the FGF/FGFR-1 system in the remodelling of bronchial airways in COPD.     

The Compliance Curve for the Flow Limiting Segments of the Airway

Maximum effort flow-static recoil curves were obtained in 5 healthy subjects breathing air, He/O₂, and SF₆/O₂ mixtures. In 4 of them maximum effort flows corresponded to really maximal flows and their curves were transformed into compliance curves for the flow limiting segments of the airway and analyzed from the point of view of a previously presented lung model (Pedersen and Nielsen 1976). The results showed, that viscosity dependent pressure losses from the alveoli to the flow limiting segments were minimal for air and SF₆/O₂, but not for He/O₂. When viscosity dependent pressure losses could be neglected, then expiration of gases of different densities gave almost identical compliance curves for the flow limiting segments. This supported the applicability of the model. The calculated compliance curves for the flow limiting segments were compared with data from the literature, and the findings indicated that flow limitation during expirations with just maximal flows throughout began in the extrapulmonary airways and moved upstream during the expiration.     

双相气道正压无创机械通气上呼吸道影像分析

目的应用多层螺旋CT对患者不同通气状态下上呼吸道放射性成像,证实在全身麻醉无自主呼吸的条件下,双相气道正压(bi-level positive airway pressure,BiPAP)无创机械通气能克服上呼吸道阻力,实施有效的机械通气。方法选择拟实施全身麻醉的择期手术患者10例,分别对患者清醒自主呼吸、麻醉诱导后自主呼吸停止、BiPAP无创通气时头颈部正位和侧位作螺旋CT扫描。监测扫描过程的无创血压(NIBP)、脉搏氧饱和度(SpO2)、心率(HR)、自主呼吸频率(RR)。测量上呼吸道各软组织区(软腭后区RP、舌根后区RG、会厌区EPG)的最窄气道横截面左右径、前后径线长度及相应横截面积。结果头部正位麻醉诱导后各软组织区的最窄横截面左右径、前后径线长度及相应横截面积均比清醒时缩小(P<0.05),BiPAP通气时各截面径线和面积与清醒期比较差异仍有统计学意义(P<0.05,P<0.01)。头部侧位BiPAP通气时各径线和截面积与清醒时比较,差异无统计学意义。EPG区和RG区在BiPAP通气期的侧位截面积明显比正位时增大(P<0.05,P<0.01)。诱导期正、侧位SpO2均明显下降(P<0.01);头部正位BiPAP通气时与诱导期的SpO2比较虽有改善,但差异无统计学意义(P>0.05);头部侧位BiPAP通气时SpO2较诱导期明显升高(P<0.01),基本恢复到清醒期水平(P>0.05)。结论麻醉诱导后上呼吸道的通气面积明显减少,气道通畅度下降;头颈部侧位时上呼吸道各软组织区最狭窄处的通气截面积比正位时显著改善,以会厌区最明显。无明显上呼吸道梗阻性病史的成年患者全身麻醉时,头部侧位BiPAP无创通气能克服上呼吸道阻力,实施有效的机械通气,保证通气和氧合正常。     

Mucosal bromodomain-containing protein 4 mediates aeroallergen-induced inflammation and remodeling

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Microenvironmental influences on inflammatory cell differentiation

Airways inflammation involves accumulation of inflammatory cells such as eosinophils, basophils and mast cells, which are derived from progenitors in marrow and blood. The inflamed tissue of the airways, through its structural (epithelium, stroma) and inflammatory cell components, produces an array of cytokines which can influence the differentiation of inflammatory cell progenitors. It is particular mechanism that we have investigated, showing that molecules such as GM-CSF, G-CSF, IL-6, IL-8 and SCF can be produced by airways epithelial cells and fibroblasts in quantities sufficient to induce hemopoietic events, either systemically or locally. Corticosteriods may act therapeutically, at least in part, to block inflammatory cell differentiation, and thus recruitment, into the allergic inflammatory process in the airways.     

Effects of Killed and Live Attenuated Influenza Vaccine on Symptoms and Specific Airway Conductance in Asthmatics and Healthy Subjects

Killed and live influenza virus vaccines were given to asthmatics and healthy subjects to investigate symptoms and alterations in their respiratory performance after vaccination. Polyvalent killed influenza virus vaccine was given to 16 asthmatics and live attenuated influenza virus vaccine to 23 asthmatics and 21 healthy subjects. Fourteen of the 16 asthmatics vaccinated with the killed vaccine displayed a significant rise in serum antibody level as measured by a single radial haemolysis in gel (SRH test). 11 of the 23 asthmatics and 14 of the 21 healthy subjects vaccinated with the live attenuated vaccine displayed a significant rise in the SRH test. Among the subjects with no measurable initial antibodies and with a significant rise in the SRH test, one asthmatic vaccinated with the killed vaccine experienced symptoms of common cold with fever and dyspnoea 1 week after vaccination. Three asthmatics and four healthy subjects vaccinated with live attenuated vaccine experienced mild symptoms, mainly rhinorrhoea, cough and sore throat 2 to 3 days after vaccination. No alterations in specific airway conductance in asthmatics or in healthy subjects were observed. We conclude that both killed and live attenuated influenza virus vaccines are tolerated well by asthmatics and appear to be safe for asthma patients.