Morally Problematic Situations Encountered by Adults Living With Rare Diseases.

Background: Rare diseases are generally poorly understood from scientific and medical standpoints due, to their complexity and low prevalence. As a result, individuals living with rare diseases struggle to obtain timely diagnoses and suitable care. These clinical difficulties add to the physical and psychological impacts of living with chronic and often severe medical conditions.

An Ethics Action Plan for Rare Disease Care: Participatory Action Research Approach.

Background: Owing to their low prevalence, rare diseases are poorly addressed in the scientific literature and clinical practice guidelines. Thus, health care workers are inadequately equipped to provide timely diagnoses, appropriate treatment, and support for these poorly understood conditions. These clinical tribulations are experienced as moral challenges by patients, jeopardizing their life trajectories, dreams, and aspirations.

Understanding Rare Disease Experiences Through the Concept of Morally Problematic Situations.

Rare diseases, defined as having a prevalence inferior to 1/2000, are poorly understood scientifically and medically. Appropriate diagnoses and treatments are scarce, adding to the burden of living with chronic medical conditions. The moral significance of rare disease experiences is often overlooked in qualitative studies conducted with adults living with rare diseases.

Association of low-density neutrophils with lung function and disease progression in adult cystic fibrosis.

Background: Cystic fibrosis (CF) neutrophils fail to eradicate infection despite their massive recruitment into the lung. While studies mostly focus on pathogen clearance by normal density neutrophils in CF, the contribution of low-density neutrophil (LDNs) subpopulations to disease pathogenesis remains unclear.

Methods: LDNs were isolated from whole blood donations of clinically stable adult CF patients and from healthy donors.

Impact of ENaC downregulation in transgenic mice on the outcomes of acute lung injury induced by bleomycin.

New Findings: What is the central question of this study? How does the downregulation of ENaC, the major driving force for alveolar fluid clearance, impact acute lung injury outcomes induced by bleomycin, featuring alveolar damage, as observed during ARDS exudative phase? What is the main finding and its importance? ENaC downregulation in αENaC(-/-)Tg+ mice did not elicit a substantial worsening impact on the main bleomycin outcomes. In ARDS patients, both ENaC alteration and alveolar damage are observed. Thus, novel therapeutic avenues, favouring alveolar integrity restauration, in addition to lung oedema resolution capacity, mainly driven by ENaC, would be essential.

YKL-40 as a clinical biomarker in adult patients with CF: Implications of a CHI3L1 single nucleotide polymorphism in disease severity.

Background: YKL-40 (chitinase 3-like 1 gene; CHI3L1) is an inflammatory marker that is increased in the blood of patients with inflammatory diseases, including cystic fibrosis (CF). The objective of our study was to explore the relationship between circulating levels of YKL-40, selected CHI3L1 single nucleotide polymorphisms (SNPs) and the severity of CF disease.

Methods: A prospective cohort of 188 adult patients with CF was established in 2015.

Impact of Bacterial Toxins in the Lungs.

Bacterial toxins play a key role in the pathogenesis of lung disease. Based on their structural and functional properties, they employ various strategies to modulate lung barrier function and to impair host defense in order to promote infection. Although in general, these toxins target common cellular signaling pathways and host compartments, toxin- and cell-specific effects have also been reported.

Efficient Transcriptionally Controlled Plasmid Expression System for Investigation of the Stability of mRNA Transcripts in Primary Alveolar Epithelial Cells.

Studying posttranscriptional regulation is fundamental to understanding the modulation of a given messenger RNA (mRNA) and its impact on cell homeostasis and metabolism. Indeed, fluctuations in transcript expression could modify the translation efficiency and ultimately the cellular activity of a transcript. Several experimental approaches have been developed to investigate the half-life of mRNA although some of these methods have limitations that prevent the proper study of posttranscriptional modulation.

Dexamethasone fails to improve bleomycin-induced acute lung injury in mice.

Acute respiratory distress syndrome (ARDS) features an exudative phase characterized by alveolar damage, lung edema and exacerbated inflammatory response. Given their anti-inflammatory properties, the potential therapeutic effect of corticosteroids has been evaluated in ARDS clinical trials and experimental models of ALI. These studies produced contradictory results.

Effect of adrenalectomy on pulmonary edema resolution.

Purpose: The capacity of the lung to clear edema fluid has been shown to be one of the factors that can influence the prognosis of cardiogenic and noncardiogenic pulmonary edema. Active Na+ transport across the alveolar epithelium is the main driving force involved in this physiological process. Since endogenous catecholamines are known to activate the sodium-dependent mechanism of alveolar edema clearance, the objective of the present study was to explore if adrenalectomy, which prevents the release of endogenous catecholamines and other hormones, such as corticosterone, into circulation, would affect edema resolution in a model of lung injury induced by thiourea.

Post-Transcriptional Modulation of aENaC mRNA in Alveolar Epithelial Cells: Involvement of its 3' Untranslated Region.

Background/aims: The epithelial sodium channel (ENaC) expressed in alveolar epithelial cells plays a major role in lung liquid clearance at birth and lung edema resorption in adulthood. We showed previously that αENaC mRNA expression is downregulated in part via posttranscriptional regulation of mRNA stability. In the present work, the role of the αENaC 3' untranslated region (3'UTR) in the regulation of mRNA stability was studied further.

Glucose tolerance in Canadian and French cystic fibrosis adult patients.

Cystic fibrosis (CF)-related diabetes is associated with increased mortality. We analysed the clinical and glycemic profiles of two cohorts of patients treated according to the same guidelines in France and Canada. To investigate incidence differences in phenotypic and glucose abnormalities and to explore the evolution over a 4-year follow-up period, two cohorts of 224 Canadian and 147 French adult CF patients (≥18 years) without treated CF-related diabetes (CFRD) were followed over a 4 year period.

The effects of cycled inhaled aztreonam on the cystic fibrosis (CF) lung microbiome.

Background: To improve clinical outcomes, cystic fibrosis (CF) patients with chronic Pseudomonas aeruginosa infections are prescribed inhaled anti-pseudomonal antibiotics. Although, a diverse microbial community exists within CF airways, little is known about how the CF microbiota influences patient outcomes. We hypothesized that organisms within the CF microbiota are affected by inhaled-antibiotics and baseline microbiome may be used to predict therapeutic response.

Alveolar liquid clearance in lung injury: Evaluation of the impairment of the β-adrenergic agonist response in an ischemia-reperfusion lung injury model.

While alveolar liquid clearance (ALC) mediated by the β-adrenergic receptor (β-AR) plays an important role in lung edema resolution in certain models of lung injury, in more severe lung injury models, this response might disappear. Indeed, we have shown that in an ischemia-reperfusion-induced lung injury model, β-agonists do not enhance ALC. The objective of this study was to determine if downregulation of the β-AR could explain the lack of response to β-agonists in this lung injury model.

Loss of barrier integrity in alveolar epithelial cells downregulates ENaC expression and activity via Ca and TRPV4 activation.

The epithelial Na channel (ENaC) plays an essential role in lung physiology by modulating the amount of liquid lining the respiratory epithelium. Here, we tested the effect of breaking alveolar epithelial cell barrier integrity on ENaC expression and function. We found that either mechanical wounding by scratching the monolayer or disruption of tight junction with EDTA induced a ~ 50% decrease of α,β and γENaC mRNA expression and an 80% reduction of ENaC short-circuit current (I) at 6 h.

CFTR Deletion Confers Mitochondrial Dysfunction and Disrupts Lipid Homeostasis in Intestinal Epithelial Cells.

Background: Cystic Fibrosis (CF) is a genetic disease in which the intestine exhibits oxidative and inflammatory markers. As mitochondria are the central source and the main target of reactive oxygen species, we hypothesized that cystic fibrosis transmembrane conductance regulator (CFTR) defect leads to the disruption of cellular lipid homeostasis, which contributes to mitochondrial dysfunction.

Methods: Mitochondrial functions and lipid metabolism were investigated in Caco-2/15 cells with CFTR knockout (CFTR) engineered by the zinc finger nuclease technique.

DNA Methylation Regulates RGS2-induced S100A12 Expression in Airway Epithelial Cells.

RGS2 is a key modulator of stress in human airway epithelial cells, especially of hyperresponsiveness and mucin hypersecretion, both of which are features of cystic fibrosis (CF). Because its expression can be modulated through the DNA methylation pathway, we hypothesize that RGS2 is downregulated by DNA hypermethylation in CF airway epithelial cells. This downregulation would then lead to an enhanced inflammatory response.

Neutrophils as a Potential Source of Chitinase-3-like Protein 1 in Cystic Fibrosis.

The chitinase-3-like protein 1, also known as YKL-40, is an inflammatory marker increased in blood of patients with cystic fibrosis (CF). Systemic levels of YKL-40 are increased in dysglycemic patients with CF. Our objective is to determine if YKL-40 is expressed and released by CF neutrophils.

Adrenal Insufficiency in Cystic Fibrosis: A Rare Phenomenon?

Background: The prevalence of adrenal insufficiency (AI) in cystic fibrosis (CF) is unknown. The frequent use of glucocorticoids (inhaled or systemic) may induce the long-term suppression of the hypothalamic-pituitary-adrenal axis.

Methods: We reviewed the results of adrenocorticotropic hormone (ACTH) stimulation tests done over a 10-year period to evaluate adrenal function in 69 CF patients of the CHUM CF clinic.

S100A8/A9 and sRAGE kinetic after polytrauma; an explorative observational study.

Background: Following tissue injury after trauma, the activation of innate immune pathways results in systemic inflammation, organ failure and an increased risk of infections. The objective of this study was to characterize the kinetics of the S100A8/S100A9 complex, a new-recognized alarmin, as well as its soluble receptor sRAGE, over time after trauma as potential early biomarkers of the risk of organ damage.

Methods: We collected comprehensive data from consenting patients admitted to an ICU following severe trauma.

Proprotein Convertase Subtilisin/Kexin type 9 affects insulin but not lipid metabolism in cystic fibrosis.

Purpose: Cystic Fibrosis (CF) is the most common genetic disorder and, with improved survival, glucose abnormalities have emerged as a major comorbidity. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a regulator of plasma LDL-cholesterol homeostasis, is associated with lipid and glucose metabolism in healthy individuals. Here we report on the link between PCSK9 and markers of metabolism in CF.

A clinical tool to calculate post-transplant survival using pre-transplant clinical characteristics in adults with cystic fibrosis.

Background: We previously identified factors associated with a greater risk of death post-transplant. The purpose of this study was to develop a clinical tool to estimate the risk of death after transplant based on pre-transplant variables.

Methods: We utilized the Canadian CF registry to develop a nomogram that incorporates pre-transplant clinical measures to assess post-lung transplant survival.