The metabolism of the orexin-1 selective receptor antagonist nivasorexant.

Nivasorexant was the first orexin-1 selective receptor antagonist entering clinical development. Despite encouraging preclinical evidence in animal models, a proof-of-concept trial in binge-eating patients recently failed to demonstrate its clinical utility in this population.Across species, nivasorexant clearance was driven by metabolism along seven distinct pathways, five of which were hydroxylation reactions in various locations of the molecule.

Proteinase 3 Interferes With C1q-Mediated Clearance of Apoptotic Cells.

Proteinase 3 (PR3) is the autoantigen in granulomatosis with polyangiitis, an autoimmune necrotizing vasculitis associated with anti-neutrophil cytoplasmic antibodies (ANCAs). Moreover, PR3 is a serine protease whose membrane expression can potentiate inflammatory diseases such as ANCA-associated vasculitis and rheumatoid arthritis. During apoptosis, PR3 is co-externalized with phosphatidylserine (PS) and is known to modulate the clearance of apoptotic cells through a calreticulin (CRT)-dependent mechanism.

Proteinase 3, the autoantigen in granulomatosis with polyangiitis, associates with calreticulin on apoptotic neutrophils, impairs macrophage phagocytosis, and promotes inflammation.

Proteinase 3 (PR3) is the target of anti-neutrophil cytoplasm Abs in granulomatosis with polyangiitis, a form of systemic vasculitis. Upon neutrophil apoptosis, PR3 is coexternalized with phosphatidylserine and impaired macrophage phagocytosis. Calreticulin (CRT), a protein involved in apoptotic cell recognition, was found to be a new PR3 partner coexpressed with PR3 on the neutrophil plasma membrane during apoptosis, but not after degranulation.

Effects of cellular, chemical, and pharmacological chaperones on the rescue of a trafficking-defective mutant of the ATP-binding cassette transporter proteins ABCB1/ABCB4.

The ATP-binding cassette transporter ABCB4 is a phosphatidylcholine translocator specifically expressed at the bile canalicular membrane in hepatocytes, highly homologous to the multidrug transporter ABCB1. Variations in the ABCB4 gene sequence cause progressive familial intrahepatic cholestasis type 3. We have shown previously that the I541F mutation, when reproduced either in ABCB1 or in ABCB4, led to retention in the endoplasmic reticulum (ER)/Golgi.

Molecular analysis of the membrane insertion domain of proteinase 3, the Wegener's autoantigen, in RBL cells: implication for its pathogenic activity.

PR3, also called myeloblastin, is a neutrophil serine protease that promotes myeloid cell proliferation by cleaving the cyclin-dependent kinase inhibitor p21(cip1/waf1). In addition, it is the target of ANCA in GPA, a necrotizing vasculitis. Anti-PR3 ANCA binding to membrane-expressed PR3 triggers neutrophil activation, potentiating vascular inflammation.

Coronin-1 is associated with neutrophil survival and is cleaved during apoptosis: potential implication in neutrophils from cystic fibrosis patients.

Because neutrophil apoptosis plays a key role in resolving inflammation, identification of proteins regulating neutrophil survival should provide new strategies to modulate inflammation. Using a proteomic approach, coronin-1 was identified as a cytosolic protein cleaved during neutrophil apoptosis. Coronin-1 is an actin-binding protein that can associate with phagosomes and NADPH oxidase, but its involvement in apoptosis was currently unknown.

[Superior mesenteric artery syndrome].

The superior mesenteric artery syndrome (SMAS) is a rare complication of spine surgery. A series of four patients who experienced a SMAS after surgery for either post-traumatic quadriplegia, paraplegia or scoliosis is reported. SMAS is a condition in which the third portion of the duodenum is squeezed between the superior mesenteric artery anteriorly, and the aorta and vertebral column posteriorly.

[Quality of blood salvaged in orthopedic surgery by washing swabs].

Objective: To establish the feasibility and safety of recuperating blood absorbed by swabs used during orthopaedic surgery.

Study Design: Open, prospective study.

Patients: Included were children undergoing potentially haemorrhagic orthopaedic surgery for whom intraoperative blood salvage seemed possible.

Biochemical assessment of nutritional status in patients with chronic obstructive pulmonary disease and acute respiratory failure on admission to an intensive care unit.

Although chronic obstructive pulmonary disease (COPD) is associated with weight loss and malnutrition, there is a paucity of relevant data on COPD patients with acute respiratory failure (ARF). We studied 30 consecutive patients on the day of admission to our intensive care unit for ARF. In addition to a clinical work-up, the following biochemical parameters were determined: markers of nutritional status (albumin - ALB, transferrin - TRF, transthyretin - TTR, retinol binding protein - RBP, fibronectin), inflammation (C-reactive protein - CRP, alpha(1) glycoprotein acid - alpha(1)GPA) and catabolism (plasma phenylalanine - PHE, urinary 3-methylhistidine - 3-MH).

Skin versus hub cultures to predict colonization and infection of central venous catheter in intensive care patients.

Central venous catheters (CVC) are an important source of nosocomial infection in intensive care units. The unnecessary removal of CVC suspected to be infected can probably be minimized. In order to test the accuracy of non-invasive methods for predicting catheter colonization, we prospectively compared the results of 50 consecutive CVC tip cultures, with cultures of the CVC hub and the skin at the insertion site.

[Enteral nutrition in patients with chronic obstructive bronchopathy treated by artificial ventilation. Effect of conventional feeding on anthropometric and biochemical parameters].

The influence of conventional gastric tube feeding on anthropometric and biochemical parameters was studied prospectively during 12 months in 14 patients with chronic obstructive lung disease put on mechanical ventilation for respiratory failure. The anthropometric parameters were: body weight, tricipital skin fold, brachial and brachial muscle circumferences. The biochemical parameters included albumin, transferrin, retinol binding protein, transthyretin, acid alpha-1-glycoprotein, C-reactive protein, fibronectin and amino acids in blood, and 3-methylhistidine in urine.

Prospective evaluation of self-extubations in a medical intensive care unit.

Objective: To evaluate the incidence, associated factors and gravity of self-extubations.

Design: Prospective study about all patients intubated over an 8 month period.

Setting: A medical intensive care unit of a University Hospital.

[Acidoketosis in a chronic alcoholic woman].

A 37-year-old chronic alcoholic female was admitted with epigastric pain, complete anorexia, vomiting and diarrhoea. She was dehydrated, and had polypnoea. Laboratory investigations revealed severe metabolic acidosis (pH 7.

[Inhibitors of factor VIIIc and pregnancy. Review of the literature].

Circulating anticoagulants directed against factor VIII coagulant activity are very rarely encountered. Eighteen per cent of them have been described in the peripartum period of primiparae aged 28 years on average. The clinical signs are the same as those of constitutional haemophilia, but they differ in frequency.

[Lung diseases complicating acute poisoning with psychotropic drugs].

474 patients admitted in ICU between 1976 and 1981 were retrospectively analysed. Pneumonia (P) was assessed by condensation on chest X ray. P developed in 14,3%.