Aspects diagnostiques et thérapeutiques des malformations pulmonaires congénitales symptomatiques de l’enfant au Mali

Symptomatic congenital pulmonary malformations (CPM) in child are rare. The diagnosis is based on clinical, radiological and histopathological confrontation. The aim of this study is to derterminate the diagnostic, therapeutic and evolutionary profile of CPM in a poor ressources country. This was a retrospective study over a period of 8 years (from January 2012 to March 2020), including 13 cases treated for CPM in the thoracic surgery department of a teaching hospital in Mali. Among patients, we found 5 cases of congenital lobar emphysema (38.8%), 4 cases of pulmoary cyst (30.8%), 3 cases of cystic adenomatoid malformation of the lung (23%) and 1 case of pulmonary sequestration(7,7%). The sex ratio was 2,2. All patients were symptomatic with an average age of 8,5 months. The symptoms were dominated by respiratory infection (38,4%), dyspnea (30,8%), dyspnea with cyanosis(7,7), dyspnea with thoracic pain (7,7%), respiratory distress (7,7%) and hemoptysis (7,7%). The chest X-ray has allowed to orient the diagnosis in most cases and the thoracic scan set it in 100% of the cases. All the patients underwent surgery by thoracotomy. Lobectomy was done for 53,8 % followed by cystectomy in 30,8%, segmentectomy (7,7%) and pneumonectomy (7,7%) of patients. Histopathological examination confirmed the diagnosis of malformation in all cases. The postoperative outcome was uneventful for all the patients. Clinical manifestations evoks the diagnosis of symptomatic CPM, the chest X-ray allowed to orient it and the thoracic scan set it in all cases. The treatment is mainly surgical. Keywords: Pulmonary malformation, diagnosis, treatment, child, Mali

Entropy-driven binding of opioid peptides induces a large domain motion in human dipeptidyl peptidase III

Opioid peptides are involved in various essential physiological processes, most notably nociception. Dipeptidyl peptidase III (DPP III) is one of the most important enkephalin-degrading enzymes associated with the mammalian pain modulatory system. Here we describe the X-ray structures of human DPP III and its complex with the opioid peptide tynorphin, which rationalize the enzyme's substrate specificity and reveal an exceptionally large domain motion upon ligand binding. Microcalorimetric analyses point at an entropy-dominated process, with the release of water molecules from the binding cleft (“entropy reservoir”) as the major thermodynamic driving force. Our results provide the basis for the design of specific inhibitors that enable the elucidation of the exact role of DPP III and the exploration of its potential as a target of pain intervention strategies

A genomic screen for activators of the antioxidant response element

The antioxidant response element (ARE) is a cis-acting regulatory enhancer element found in the 5′ flanking region of many phase II detoxification enzymes. Up-regulation of ARE-dependent target genes is known to have neuroprotective effects; yet, the mechanism of activation is largely unknown. By screening an arrayed collection of ≈15,000 full-length expression cDNAs in the human neuroblastoma cell line IMR-32 with an ARE-luciferase reporter, we have identified several cDNAs not previously associated with ARE activation. A subset of cDNAs, encoding sequestosome 1 (SQSTM1) and dipeptidylpeptidase 3 (DPP3), activated the ARE in primary mouse-derived cortical neurons. Overexpression of SQSTM1 and DPP3 in IMR-32 cells stimulated NF-E2-related factor 2 (NRF2) nuclear translocation and led to increased levels of NAD(P)H:quinone oxidoreductase 1, a protein which is transcriptionally regulated by the ARE. When transfected into IMR-32 neuroblastoma cells that were depleted of transcription factor NRF2 by RNA interference, SQSTM1 and DPP3 were unable to activate the ARE or induce NAD(P)H:quinone oxidoreductase 1 expression, indicating that the ARE activation upon ectopic expression of these cDNAs is mediated by NRF2. Studies with pharmacological inhibitors indicated that 1-phosphatidylinositol 3-kinase and protein kinase C signaling are essential for activity. Overexpression of these cDNAs conferred partial resistance to hydrogen peroxide or rotenone-induced toxicity, consistent with the induction of antioxidant and phase II detoxification enzymes, which can protect from oxidative stress. This work and other such studies may provide mechanisms for activating the ARE in the absence of general oxidative stress and a yet-unexploited therapeutic approach to degenerative diseases and aging