[Natural history of COPD: evolution of concepts]. / Histoire naturelle de la BPCO : évolution des concepts.

NATURAL HISTORY OF COPD: EVOLUTION OF CONCEPTS. Chronic obstructive pulmonary disease (COPD) is a common chronic respiratory disease responsible for significant morbidity and mortality. The natural history of this disease is complex. The first cause is tobacco smoke exposure, followed by exposure to biomass smoke and occupational exposure to inhaled toxic substances. Genetic predisposing factors are known as the alpha-1-antitrypsin deficiency. The involvement of respiratory events in childhood in the genesis of the disease is also increasingly described. The decline of the different respiratory trajectories can be accelerated in COPD. The phenotypes of this disease also have a role in the evolution of respiratory function over time and their descriptions can modulate the therapeutic management in this disease.

HISTOIRE NATURELLE DE LA BPCO: ÉVOLUTION DES CONCEPTS. La bronchopneumopathie chronique obstructive (BPCO) est une maladie respiratoire chronique fréquente et responsable d'une morbi-mortalité importante. La compréhension de l'histoire naturelle de cette pathologie a évolué ces dernières années. La première cause de BPCO est le tabagisme, suivi de l'exposition à la fumée de biomasse et de l'exposition professionnelle à des toxiques inhalés. Des facteurs de prédisposition génétique sont connus, comme le déficit en alpha-1-antitrypsine. L'implication d'événements respiratoires au cours de l'enfance dans la genèse de la maladie est également de plus en plus décrite. Le déclin des différentes trajectoires de la fonction respiratoire peut être accéléré en cas de BPCO. Les phénotypes de cette maladie jouent aussi un rôle dans l'évolution de la fonction respiratoire au cours du temps et leur description peut moduler la prise en charge thérapeutique de cette maladie.

Combined effects of smoking and HIV infection on the occurrence of aging-related manifestations.

Both HIV-1 infection and smoking may contribute to the development of ageing-related manifestations affecting the prognosis of people living with HIV, but it is unclear whether HIV and smoking exert their effects independently or interact by potentiating each other. We conducted a cross-sectional study in 192 people living with HIV aged- and gender-matched with 192 HIV-uninfected controls, assessing the relative effect of HIV-1/smoking status on lung function (FEV1), bone mineral density (BMD), appendicular skeletal muscle mass index (ASMI), aortic pulse-wave velocity (PWV), insulin resistance (HOMA-IR) and renal function. In both unadjusted and adjusted analyses, FEV1, BMD and ASMI significantly differed according to smoking/HIV status, with the worst parameters found in HIV-1 infected patients currently smoking, and BMD and ASMI decreased to a lesser extent in HIV-1 infected patients formerly smoking (> 10 pack-years). Values in people living with HIV with < 10 pack-years exposure were of similar magnitude to those from controls. Regarding PWV, HOMA-R and eGFR, no significant differences were found, with the exception of eGFR values which were globally lower in HIV-1 infected patients. In conclusion HIV infection and smoking acted synergistically and were associated with a wasting phenotype combining muscle mass and bone mineral reduction.Clinical Trial Registration (registrar, website, and registration number), where applicable: CPP 10-023, 09-027, 10-034.

Complex urban atmosphere alters alveolar stem cells niche properties and drives lung fibrosis.

There is growing evidence suggesting that urban pollution has adverse effects on lung health. However, how urban pollution affects alveolar mesenchymal and epithelial stem cell niches remains unknown. This study aimed to determine how complex representative urban atmospheres alter alveolar stem cell niche properties. Mice were placed in an innovative chamber realistically simulating the atmosphere of a megalopolis, or "clean air," for 7 days. Lungs were collected, and fibroblasts and epithelial cells (EpCAM+) were isolated. Proliferative capacities of fibroblasts were tested by population doubling levels (PDL), and microarray analyses were performed. Fibroblasts and EpCAM+ cells from exposed, nonexposed, or naive mice were cocultured in organoid assays to assess the stem cell properties. Collagen deposition (Sirius red), lipofibroblasts (ADRP, COL1A1), myofibroblasts (αSMA), alveolar type 2 cells (AT2, SFTPC+), and alveolar differentiation intermediate cell [ADI, keratin-8-positive (KRT8+)/claudin-4-positive (CLDN4+)] markers were quantified in the lungs. Fibroblasts obtained from mice exposed to urban atmosphere had lower PDL and survival and produced fewer and smaller organoids. Microarray analysis showed a decrease of adipogenesis and an increase of genes associated with fibrosis, suggesting a lipofibroblast to myofibroblast transition. Collagen deposition and myofibroblast number increased in the lungs of urban atmosphere-exposed mice. AT2 number was reduced and associated with an increase in ADI cells KRT8+/CLDN4+. Furthermore, EpCAM+ cells from exposed mice also produced fewer and smaller organoids. In conclusion, urban atmosphere alters alveolar mesenchymal stem cell niche properties by inducing a lipofibroblast to myofibroblast shift. It also results in alveolar epithelial dysfunction and a fibrotic-like phenotype.NEW & NOTEWORTHY Urban pollution is known to have major adverse effects on lung health. To assess the effect of pollution on alveolar regeneration, we exposed adult mice to a simulated high-pollution urban atmosphere, using an innovative CESAM simulation chamber (Multiphase Atmospheric Experimental Simulation Chamber, https://cesam.cnrs.fr/). We demonstrated that urban atmosphere alters alveolar mesenchymal stem cell niche properties by inducing a lipofibroblast to myofibroblast shift and induces alveolar epithelial dysfunction.

pH-responsive nanoparticles based on POEOMA-b-PDPA block copolymers for RNA encapsulation, protection and cell delivery.

The use of gene-based products, such as DNA or RNA, is increasingly being explored for various innovative therapies. However, the success of these strategies is highly dependent on the effective delivery of these biomolecules to target cells. Therefore, the development of pH-responsive nanoparticles comprises the creation of intelligent delivery systems with high therapeutic efficiency. In this work, the pH-responsiveness of the poly(2-(diisopropylamino)ethyl methacrylate)) (PDPA) block was investigated for the encapsulation and delivery of small RNAs (sRNA) to cancer cells. The pH responsiveness was dependent on the protonation profile of the tertiary amines of PDPA, which directly affected the electrostatic interactions established with RNA. Thus, block copolymers based on poly(oligo(ethylene oxide) methyl ether methacrylate) (POEOMA) and PDPA, POEOMA-b-PDPA, were synthesized by supplemental activator and reducing agent atom transfer radical polymerization (SARA ATRP). The structure of the block copolymers was characterized by size exclusion chromatography and 1H NMR spectroscopy. The copolymers allowed effective complexation of model sRNAs and a pre-miRNA with efficiencies of about 89 % and 91 %, respectively. The characterization by dynamic light scattering revealed that these systems had sizes between 76 and 1375 nm. It was also found that the morphology of the polyplexes depended on the pH, since the preparation at a pH lower than the pKa of the copolymers resulted in spherical but polydisperse particles, while higher pH values resulted in nanoparticles with more homogeneous size, but altered morphology. Moreover, due to pH-responsiveness, it was achieved the release of RNA at pH higher than the pKa of the copolymers, while maintaining its integrity. The polyplexes also showed a high potential to protect RNA from RNases. The transfection of a lung cancer model (A549) and fibroblast cell lines showed that these polyplexes did not cause cell toxicity. In addition, the polyplexes enabled the effective transfection of the A549 cell line with pre-miRNA-29b and miRNA-29b, resulting in a decrease of expression levels of the target DNMT3B gene by approximately 51 % and 47 %, respectively. Overall, the POEOMA-b-PDPA copolymers proved to be a promising strategy for developing responsive delivery systems, that can play a critical role in some diseases, such as cancer, where pH varies between the intra and extracellular environments.

Growth of home respiratory equipment from 2006 to 2019 and cost control by health policies.

BACKGROUND: Home respiratory equipment (HRE) designed for the management of chronic respiratory failure includes oxygen therapy (O2), noninvasive ventilation (NIV) and mechanical insufflation-exsufflation (MI-E). The growth of the number of patients treated by HRE, the prevalence and the associated costs in France have not been determined. METHODS: The French open access national health insurance aggregated data was used to estimate the evolution of theses parameters from 2006 to 2019. RESULTS: The number of patients treated by HRE increased by 117% between 2006 and 2019, reaching a total of 245,896 patients (367/100,000). Prescriptions for O2, NIV, and MI-E increased by 88%, 189% and 162%, respectively. In 2019, 139,323 patients received long-term home O2 alone (208/100,000) with a 13% decrease for liquid O2 compared to a 44% increase for O2 concentrator. The number of patients treated by portable oxygen concentrator increased by 509% over the last 5 years. In 2019, 96,126 patients received NIV (144/100,000) and 97% of these patients were treated by NIV for less than 12 h/day. A total of 9,158 patients were treated by MI-E in 2019 (13.6/100,000). Despite the global increase in the number of patients, health costs decreased from 9% to 8% of total medical device spending in 2019 due to adjustment of health policies, such as a reduction of reimbursement rates. CONCLUSION: Our results highlighted the high rate of HRE prescription, but with cost control as a result of adapted health policies.

Identification of factors impairing exercise capacity after severe COVID-19 pulmonary infection: a 3-month follow-up of prospective COVulnerability cohort.

BACKGROUND: Patient hospitalized for coronavirus disease 2019 (COVID-19) pulmonary infection can have sequelae such as impaired exercise capacity. We aimed to determine the frequency of long-term exercise capacity limitation in survivors of severe COVID-19 pulmonary infection and the factors associated with this limitation. METHODS: Patients with severe COVID-19 pulmonary infection were enrolled 3 months after hospital discharge in COVulnerability, a prospective cohort. They underwent cardiopulmonary exercise testing, pulmonary function test, echocardiography, and skeletal muscle mass evaluation. RESULTS: Among 105 patients included, 35% had a reduced exercise capacity (VO2peak < 80% of predicted). Compared to patients with a normal exercise capacity, patients with reduced exercise capacity were more often men (89.2% vs. 67.6%, p = 0.015), with diabetes (45.9% vs. 17.6%, p = 0.002) and renal dysfunction (21.6% vs. 17.6%, p = 0.006), but did not differ in terms of initial acute disease severity. An altered exercise capacity was associated with an impaired respiratory function as assessed by a decrease in forced vital capacity (p < 0.0001), FEV1 (p < 0.0001), total lung capacity (p < 0.0001) and DLCO (p = 0.015). Moreover, we uncovered a decrease of muscular mass index and grip test in the reduced exercise capacity group (p = 0.001 and p = 0.047 respectively), whilst 38.9% of patients with low exercise capacity had a sarcopenia, compared to 10.9% in those with normal exercise capacity (p = 0.001). Myocardial function was normal with similar systolic and diastolic parameters between groups whilst reduced exercise capacity was associated with a slightly shorter pulmonary acceleration time, despite no pulmonary hypertension. CONCLUSION: Three months after a severe COVID-19 pulmonary infection, more than one third of patients had an impairment of exercise capacity which was associated with a reduced pulmonary function, a reduced skeletal muscle mass and function but without any significant impairment in cardiac function.

mRNA, a Revolution in Biomedicine.

The perspective of using messenger RNA (mRNA) as a therapeutic molecule first faced some uncertainties due to concerns about its instability and the feasibility of large-scale production. Today, given technological advances and deeper biomolecular knowledge, these issues have started to be addressed and some strategies are being exploited to overcome the limitations. Thus, the potential of mRNA has become increasingly recognized for the development of new innovative therapeutics, envisioning its application in immunotherapy, regenerative medicine, vaccination, and gene editing. Nonetheless, to fully potentiate mRNA therapeutic application, its efficient production, stabilization and delivery into the target cells are required. In recent years, intensive research has been carried out in this field in order to bring new and effective solutions towards the stabilization and delivery of mRNA. Presently, the therapeutic potential of mRNA is undoubtedly recognized, which was greatly reinforced by the results achieved in the battle against the COVID-19 pandemic, but there are still some issues that need to be improved, which are critically discussed in this review.

New RNA-Based Breakthroughs in Alzheimer's Disease Diagnosis and Therapeutics.

Dementia is described as the fifth leading cause of death worldwide and Alzheimer's disease (AD) is recognized as the most common, causing a huge impact on health costs and quality of patients' lives. The main hallmarks that are commonly associated with the pathologic process are amyloid deposition, pathologic Tau phosphorylation and neurodegeneration. It is still unclear how these events are linked to the disease progression, due to the complex pathologic mechanisms. Nevertheless, several hypotheses have been proposed for a better understanding of AD. The AD diagnosis is performed by using a combination of several tools to detect ß-amyloid peptide (Aß) deposits and modifications in cognitive performance, sometimes being expensive and invasive. In the treatment field, there is still an absence of effective treatments to delay or stop the progression of the disease, with most of the approved drugs used to relieve symptoms, and all of them with significant adverse side effects. Considering all limitations, the need to establish new and more effective diagnostic and therapeutic strategies becomes clear. This review aims not only to describe the disease and its impact but also to collect the currently available diagnostic and therapeutic strategies, highlighting new promising RNA-based strategies for AD.

Feasibility of a Hypoxic Challenge Test Under Noninvasive Ventilation Versus Oxygen in Neuromuscular Patients with Chronic Respiratory Insufficiency.

Ribeiro Baptista, Bruno, Morgane Faure, Gimbada Benny Mwenge, Capucine Morelot-Panzini, Christian Straus, Thomas Similowski, and Jésus Gonzalez-Bermejo. Feasibility of a hypoxic challenge test under noninvasive ventilation versus oxygen in neuromuscular patients with chronic respiratory insufficiency. High Alt Med Biol. 22:346-350, 2021. Background: The British Thoracic Society recommendations suggest that all patients with an oxygen saturation (SpO2) <85% during a hypoxic challenge test (HCT) should receive supplemental oxygen during air travel. However, neuromuscular patients already using ventilatory support are a specific population and noninvasive ventilation (NIV) during a flight could be an alternative to oxygen for hypoxemia correction, through the augmentation of ventilation. Methods: We conducted a comparative, observational study of neuromuscular patients with chronic respiratory failure, requiring nocturnal mechanical ventilation, who were planning to take a flight. HCT was performed with a ventilated canopy placed over the patient's head or the patient's home ventilator. The positive threshold value chosen for the HCT was <90% SpO2. Results: HCTs were performed on 13 adults with neuromuscular diseases using their home ventilator. Among them, 11 had a positive HCT. For all patients with a positive test, hypoxemia was corrected (SpO2 to >90%) by oxygen therapy (+9 [6-12]%, p = 0.0029). Patient's home ventilator also significantly increased the SpO2 by 8 [7-12]% (p = 0.016). Correction of SpO2 during the HCT was not different between oxygen and NIV. NIV was associated with a significant decrease in pressure, end tidal, carbon dioxide (PetCO2) (-10 [-16 to -7.5] mmHg, p = 0.04). Conclusions: The performance of an adapted HCT in home-ventilated patients with a neuromuscular pathology may be useful in a personalized treatment plan for air travel. NIV can be a new alternative to oxygen therapy for neuromuscular patients planning to take a flight.

Beclin-1 increases with obstructive sleep apnea severity.

Obstructive sleep apnea is a common chronic disorder that leads to chronic intermittent hypoxia described as an important factor contributing to the pathogenesis of OSA-related comorbidities. Besides, recent data suggest that intermittent hypoxia can induce adaptative cardiovascular pathways inducing a relative resistance to ischemic insults. Adaptative pathways induced by hypoxia could implicate autophagic processes and Beclin-1, one of the first mammalian autophagy effectors. Thus, activation of autophagy could protect against cardiovascular events in patients with OSA and could be considered as biomarker of a better prognosis.

Targeting p16INK4a Promotes Lipofibroblasts and Alveolar Regeneration after Early-Life Injury.

Rationale: Promoting endogenous pulmonary regeneration is crucial after damage to restore normal lungs and prevent the onset of chronic adult lung diseases.Objectives: To investigate whether the cell-cycle inhibitor p16INK4a limits lung regeneration after newborn bronchopulmonary dysplasia (BPD), a condition characterized by the arrest of alveolar development, leading to adult sequelae.Methods: We exposed p16INK4a-/- and p16INK4aATTAC (apoptosis through targeted activation of caspase 8) transgenic mice to postnatal hyperoxia, followed by pneumonectomy of the p16INK4a-/- mice. We measured p16INK4a in blood mononuclear cells of preterm newborns, 7- to 15-year-old survivors of BPD, and the lungs of patients with BPD.Measurements and Main Results: p16INK4a concentrations increased in lung fibroblasts after hyperoxia-induced BPD in mice and persisted into adulthood. p16INK4a deficiency did not protect against hyperoxic lesions in newborn pups but promoted restoration of the lung architecture by adulthood. Curative clearance of p16INK4a-positive cells once hyperoxic lung lesions were established restored normal lungs by adulthood. p16INK4a deficiency increased neutral lipid synthesis and promoted lipofibroblast and alveolar type 2 (AT2) cell development within the stem-cell niche. Besides, lipofibroblasts support self-renewal of AT2 cells into alveolospheres. Induction with a PPARγ (peroxisome proliferator-activated receptor γ) agonist after hyperoxia also increased lipofibroblast and AT2 cell numbers and restored alveolar architecture in hyperoxia-exposed mice. After pneumonectomy, p16INK4a deficiency again led to an increase in lipofibroblast and AT2 cell numbers in the contralateral lung. Finally, we observed p16INK4a mRNA overexpression in the blood and lungs of preterm newborns, which persisted in the blood of older survivors of BPD.Conclusions: These data demonstrate the potential of targeting p16INK4a and promoting lipofibroblast development to stimulate alveolar regeneration from childhood to adulthood.

Overexpression of Spock2 in mice leads to altered lung alveolar development and worsens lesions induced by hyperoxia.

SPARC/osteonectin, cwcv and kazal-like domains proteoglycan 2 (SPOCK2) was previously associated with genetic susceptibility to bronchopulmonary dysplasia in a French population of very preterm neonates. Its expression increases during lung development and is increased after exposure of rat pups to hyperoxia compared with controls bred in room air. To further investigate the role of SPOCK2 during lung development, we designed two mouse models, one that uses a specific anti-Spock2 antibody and one that reproduces the hyperoxia-induced Spock2 expression with a transgenic mouse model resulting in a conditional and lung-targeted overexpression of Spock2. When mice were bred under hyperoxic conditions, treatment with anti-Spock2 antibodies significantly improved alveolarization. Lung overexpression of Spock2 altered alveolar development in pups bred in room air and worsened hyperoxia-induced lesions. Neither treatment with anti-Spock2 antibody nor overexpression of Spock2 was associated with abnormal activation of matrix metalloproteinase-2. These two models did not alter the expression of known players in alveolar development. This study brings strong arguments for the deleterious role of SPOCK2 on lung alveolar development especially after lung injury, suggesting its role in bronchopulmonary dysplasia susceptibility. These effects are not mediated by a deregulation in metalloproteases activity and in expression of factors essential to normal alveolarization. The balance between types 1 and 2 epithelial alveolar cells may be involved.

Pulmonary arterial hypertension in patient treated for multiple sclerosis with 4-aminopyridine.

4-Aminopyridine (4-AP) is a recent treatment indicated to improve walking in patient with multiple sclerosis. We report the first case of pulmonary arterial hypertension (PAH) that we attribute to the use of 4-AP. A 64-year-old woman with multiple sclerosis presented with dyspnea. After excluding other secondary causes of pulmonary hypertension, a diagnosis of severe PAH due to 4-AP was made based on right heart catheterization. History revealed that the dyspnea began with the initiation of 4-AP. After discontinuation of 4-AP therapy and initiation of ambrisentan and tadalafil, dyspnea and pulmonary arterial pressure have improved significantly and one specific PAH treatment was stopped. 4-AP is an outward rectifying potassium channel blocker with a vasoconstrictor effect in animal's pulmonary artery. According to the chronological sequence of events, the lack of other etiology, and its pharmacological plausibility, 4-AP is highly suspected to have induced our patient's PAH.

The normal radiological anteroposterior alignment of the lower limb in children.

INTRODUCTION: The development of reconstructive surgery of the lower limbs aimed at multilevel correction demands a precise knowledge of the physiological variations in general radiological parameters of the lower limbs in children of various age groups. It is crucial in systemic skeletal diseases, when deformities affect limbs and the surgeon does not have an intact limb as a reference. The aim of this retrospective study was to establish the normal radiological values of lower limb parameters used in the surgical correction of deformities in children of various age groups. MATERIAL AND METHODS: Teleradiographs of the lower limbs taken in children with unilateral congenital or posttraumatic deformity were retrospectively reviewed. Weight-bearing full-length anteroposterior radiographs of the entire lower extremities were taken in a standing position. The study involved 215 extremities of 208 children (93 girls and 115 boys); the ages ranged from 2 years 1 month to 15 years 11 months old. Key variables included the anatomic medial proximal femoral angle (aMPFA), anatomic lateral distal femoral angle (aLDFA), anatomic medial proximal tibial angle (aMPTA), anatomic lateral distal tibial angle (aLDTA), mechanical axis deviation (MAD), the angle formed by the femoral anatomical axis and the mechanical axis of the lower limb. RESULTS: The means and dynamics of variations, standard deviations (SD) and 95% confidence intervals of each parameter were calculated for each age and gender group. Simple regression analysis was performed to determine the relationship between the patient's age and the magnitude of aMPFA, aLDFA, aMPTA and aLDTA. Simple regression analysis showed a significant inverse correlation between patient age and the magnitude of aMPFA: the correlation coefficient was -0.77. A statistically significant inverse correlation between the MAD and the angle between the anatomic femoral axis and mechanical limb axis was found: the correlation coefficient was -0.53. CONCLUSION: In general, the received values were concordant to results of other studies. It concerned the MAD, aLDFA, aMPTA and angle between the mechanical limb axis and anatomic femoral axis. This is the first chronological evaluation of aMPFA and aLDTA from a relavively large series of patients. These normative data should be taken into consideration when evaluating lower limb alignment in children or applied in practice for planning and evaluation of the quality of surgical correction of complex deformities.

Improved multiplex PCR method for the rapid detection of beta-lactamase genes in Escherichia coli of animal origin.

We developed 2 variants, A and B, of a multiplex polymerase chain reaction method for detecting the beta-lactam resistance genes bla(TEM), bla(SHV), and bla(OXA) in 122 uropathogenic Escherichia coli animal strains. Method B yielded 98% specificity and 100% sensitivity, and method A yielded 100% and 89%, respectively. Variant B was more accurate (99%) than A (94%).