No abstract

Clinical studies with modulators of the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) protein have demonstrated that functional restoration of the mutated CFTR can lead to substantial clinical benefit. However, studies have shown highly variable patient responses. The objective of this study was to determine a biomarker predictive of the clinical response. CFTR function was assessed in vivo via nasal potential difference (NPD) and in human nasal epithelial (HNE) cultures by the response to Forskolin/IBMX and the CFTR potentiator VX-770 in short-circuit-current (∆IscF/I+V) experiments. CFTR expression was evaluated by apical membrane fluorescence semi-quantification. Isc measurements discriminated CFTR function between controls, healthy heterozygotes, patients homozygous for the severe F508del mutation and patients with genotypes leading to absent or residual function. ∆IscF/I+V correlated with CFTR cellular apical expression and NPD measurements. The CFTR correctors lumacaftor and tezacaftor significantly increased the ∆IscF/I+V response to about 25% (SEM = 4.4) of the WT-CFTR level and the CFTR apical expression to about 22% (SEM = 4.6) of the WT-CFTR level in F508del/F508del HNE cells. The level of CFTR correction in HNE cultures significantly correlated with the FEV1 change at 6 months in 8 patients treated with CFTR modulators. We provide the first evidence that correction of CFTR function in HNE cell cultures can predict respiratory improvement by CFTR modulators.

Acute poisoning in children is still a major public health problem, and represents a frequent cause of admission in emergency departments. We carried out an epidemiological study of poisonings leading to admission to a paediatric emergency care unit (PECU). We analysed data from 2988 children who were admitted to the PECU of Bordeaux, France with acute poisoning from 1989 through 1995. During the 7-year period, the poison exposure numbers decreased slightly from 490 to 382 (6% vs. 3% of total medical emergencies). This represented a mean annual incidence of 1.4 poison exposures per 1000 children younger than 18 years of age and living in Bordeaux and its surroundings. Characteristics of the study population, circumstances of poisoning and substances involved were similar to those previously described. Eighty per cent of children were younger than 5 years of age, presented with a benign course. Forty per cent were not treated and 75% were discharged home either immediately or within 24 hours of admission. Only 1.5% of cases, mainly adolescent girls who attempted suicide, were admitted to a paediatric intensive care unit. Overall mortality rate was 0.33/1000. In children, most cases of acute poisoning are accidental, benign, and mainly attributed to the ingestion of a non-toxic substance. This points to the need for better information of the population on availability of poison control centre calling facilities, in order to decrease the number of admissions to the PECU. Patients suspected of having ingested a potentially dangerous substance can be managed in short-stay observation units, thus avoiding unnecessarily prolonged hospitalization. Acute poisoning in children remains a frequent problem, highlighting the need to develop an education programme on primary prevention in our region.

Human airway smooth muscle cells (HASMC) secrete fractalkine (FKN), a chemokine the concentration of which is increased in asthmatic patients. HASMC also induce mast cell chemotaxis, as a component of asthma inflammation. We therefore evaluated the role of smooth muscle-derived FKN in mast cell migration. We assessed the capacity of recombinant FKN to induce human mast cell chemotaxis. This effect implicates a calcium-independent pathway involving actin reorganization and protein kinase C-δ. We found that HASMC constitutively produce FKN, the synthesis of which is reinforced upon proinflammatory stimulation. Under basal experimental conditions, FKN production by HASMC is not sufficient to induce mast cell chemotaxis. However, pretreatment of mast cells with the neuropeptide vasoactive intestinal peptide (VIP) increases FKN potency to attract mast cells. Since we observed, in asthmatic patients, an increase in both FKN and VIP expression by airway smooth muscle and a positive correlation between VIP staining and mast cell infiltration of the smooth muscle layer, we conclude that HASMC-derived FKN may contribute to mast cell recruitment in asthma.

Pulmonary artery (PA) hypertension was studied in a chronic hypoxic-pulmonary hypertension model (7-21 days) in the rat. Increase in PA pressure (measured by catheterism), cardiac right ventricle hypertrophy (determined by echocardiography), and PA remodeling (evaluated by histology) were almost entirely prevented after oral dehydroepiandrosterone (DHEA) administration (30 mg͞kg every alternate day). Furthermore, in hypertensive rats, oral administration, or intravascular injection (into the jugular vein) of DHEA rapidly decreased PA hypertension. In PA smooth muscle cells, DHEA reduced the level of intracellular calcium (measured by microspectrofluorimetry). The effect of DHEA appears to involve a large conductance Ca 2؉ -activated potassium channel (BK Ca)-dependent stimulatory mechanism, at both function and expression levels (isometric contraction and Western blot), via a redox-dependent pathway. Voltage-gated potassium (Kv) channels also may be involved because the antagonist 4-amino-pyridine blocked part of the DHEA effect. The possible pathophysiological and therapeutic significance of the results is discussed.hypoxia ͉ potassium channels E xposure of animals to chronic hypoxia leads to the development of chronic hypoxic-pulmonary hypertension (CH-PHT). In human beings CH-PHT is frequently associated with severe pulmonary diseases. CH-PHT involve pulmonary arterial vasoconstriction and remodeling (1). Although the endothelium is involved in the pathogenesis of CH-PHT, the role of vascular smooth muscle cells (SMCs) is increasingly recognized (2).Both the contractile status and the proliferative status of SMCs are regulated by the levels of intracellular Ca 2ϩ ([Ca 2ϩ ] i ). The [Ca 2ϩ ] i levels are determined in part by the influx of Ca 2ϩ through the voltage-gated, L-type Ca 2ϩ channels. In pulmonary artery (PA) SMCs, the membrane potential is regulated by large conductance Ca 2ϩ -activated channels (BK Ca ) (3) and voltagegated K ϩ channels (Kv), including shaker family Kv (4, 5). K channel (BK Ca and Kv) function and expression are downregulated with development and maintenance of CH-PHT (6, 7). CH reduces K current density in PASMCs, resulting in a state of depolarization (8, 9), followed by elevation of [Ca 2ϩ ] i , which induces contraction and proliferation (10).The mechanism for K channel down-regulation is unclear, but recent work suggests that it is related to the altered redox state induced by CH (8). Lungs of rats with CH-PHT are in a more reduced redox state than those of normoxic controls, as indicated by increased levels of reduced glutathione (8). A reduced redox state has potential for both short-term effects through modulation of K ϩ channels function (11) and long-term effects by activating several oxygen-responsive genes including hypoxiainducible factor (HIF) (12).We sought to enhance expression and function of BK Ca by using DHEA, a BK Ca opener in hypoxic human pulmonary cells (13), which can shift the redox balance toward an oxidized state leading to both BK Ca and Kv activatio...

AZLI demonstrated statistical superiority in lung function and a reduction in acute pulmonary exacerbations compared to TNS over 3 treatment courses (ClinicalTrials.gov: NCT00757237).

We previously reported the French real-life experience of 1 year of add-on treatment with omalizumab in 101 severe allergic asthmatic children (6-18 years), 92 of whom were still receiving the treatment at the end of the first year [1]. The study provided complementary data to the previous randomised trials [2-6]. We showed a marked drop of 72% in the mean rate of severe exacerbations (from 4.4 per patient during the preceding year to 1.25 during the year of treatment) and of 88.5% for hospitalisations (44% of the patients during the preceding year to 6.7% during the year of treatment); a large improvement in asthma control (from 0% at initiation to 67% of well-controlled patients after 1 year); a decrease of 30% of the mean inhaled corticosteroid (ICS) dose (from 703 at initiation to 488 µg fluticasone equivalent per day after 1 year); and a forced expiratory volume in 1 s (FEV1) increase, from a mean of 88% to 92.1% of the predicted value. Treatment was discontinued in six patients due to serious adverse events attributed to omalizumab by the practitioner. Here we report the outcome of this cohort after 2 years of omalizumab treatment.

Lung infections play a critical role in cystic fibrosis (CF) pathogenesis. CF respiratory tract is now considered to be a polymicrobial niche and advances in high-throughput sequencing allowed to analyze its microbiota and mycobiota. However, no NGS studies until now have characterized both communities during CF pulmonary exacerbation (CFPE). Thirty-three sputa isolated from patients with and without CFPE were used for metagenomic high-throughput sequencing targeting 16S and ITS2 regions of bacterial and fungal rRNA. We built inter-kingdom network and adapted Phy-Lasso method to highlight correlations in compositional data. The decline in respiratory function was associated with a decrease in bacterial diversity. The inter-kingdom network revealed three main clusters organized around Aspergillus, Candida, and Scedosporium genera. Using Phy-Lasso method, we identified Aspergillus and Malassezia as relevantly associated with CFPE, and Scedosporium plus Pseudomonas with a decline in lung function. We corroborated in vitro the cross-domain interactions between Aspergillus and Streptococcus predicted by the correlation network. For the first time, we included documented mycobiome data into a version of the ecological Climax/Attack model that opens new lines of thoughts about the physiopathology of CF lung disease and future perspectives to improve its therapeutic management. Lung infections play a critical role in cystic fibrosis (CF) pathogenesis where they can lead to significant acute decrease of lung function, known as CF pulmonary exacerbation (CFPE). Developments of next-generation sequencing (NGS) approaches allowed us to understand microbiome composition that can contribute to lung physiopathology in both healthy individuals and patients with lung disease. More recently, NGS together with advances into statistical network inference tools allowed to analyze the microbial airway communities, appreciate the inter-kingdom equilibrium of respiratory floras, and therefore develop understanding of microbial communities as a whole 1-7. Acute CFPEs represent major clinical events that significantly decline the lung function, contribute to disease progression and require adapted, prompt anti-infectious treatment 8-11. Omics approaches confirmed associations between bacterial community and exacerbation 12-20. Apart from bacteria that are well known agents causing dramatic recurrent CFPEs, respiratory viruses have been recently found to be associated with CFPE, independently