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951.
Irene Martínez-Martínez Adriana Ordó?ez José Navarro-Fernández ángel Pérez-Lara Ricardo Gutiérrez-Gallego Rafael Giraldo Constantino Martínez Esther Llop Vicente Vicente Javier Corral 《Haematologica》2010,95(8):1358-1365
Background
Identification of mutations in the SERPINC1 gene has revealed different mechanisms responsible for antithrombin deficiency. Deletions and nonsense mutations associate with type I deficiency. Certain missense mutations cause type II deficiency by affecting the heparin binding site or the reactive center loop, while others result in type I deficiency by intracellular retention or RNA instability.Design and Methods
We studied the molecular, biochemical, proteomic and glycomic characterization of a new natural mutant (K241E) that may be classified as pleiotropic.Results
The mutation caused a significant decrease in the anticoagulant activity mainly due to a reduced heparin affinity and a modification of the electrostatic potential that might explain the impaired ability of the mutant protein to form complexes with the target protease in the absence of heparin. Mass spectrometry and glycomic analyses confirmed an increased molecular weight of 800 Da in the mutant protein possibly due to core-fucosylation, provoking the loss of heparin affinity. Additionally, carriers of this mutation also have a minor mutant isoform that still followed normal glycosylation, retaining similar heparin affinity to wild-type α-antithrombin, and certain anticoagulant activity, which may explain the milder thrombotic risk of patients carrying this mutation. Similar results were observed using recombinant K241E antithrombin molecules.Conclusions
Our data suggest a new mechanism involved in antithrombin type II deficiency by indirectly affecting the glycosylation of a natural variant. Additional studies are required to confirm this hypothesis. 相似文献952.
953.
Sonu I Lin MV Blonski W Lichtenstein GR 《Gastroenterology Clinics of North America》2010,39(3):559-599
Mesalamine has been the first-line of therapy in patients with inflammatory bowel disease (IBD) since the 1960s. This article serves as a review of the different 5-aminosalicylic acid compounds, release formulations, use and dosing in the treatment of IBD, in particular ulcerative colitis. 相似文献
954.
955.
María Chaparro Almudena Barbero Leticia Martín Carlos Esteban Laura Espinosa Felipe De La Morena Argeme Sánchez Irene Martín Cecilio Santander Ricardo Moreno‐Otero Javier P Gisbert 《Journal of gastroenterology and hepatology》2010,25(9):1525-1529
Background and Aim: To validate an early discharge policy in patients admitted with upper gastrointestinal bleeding (UGIB) due to ulcers. Methods: Patients with gastroduodenal ulcer or erosive gastritis/duodenitis were included in a previous study aiming to develop a practice guideline for early discharge of patients with UGIB. Variables associated with unfavorable evolution were analyzed in order to identify patients with low‐risk of re‐bleeding. After that, a one‐year prospective analysis of all UGIB episodes was carried out. Results: A total of 341 patients were identified in the retrospective study. Variables associated with unfavorable evolution were: systolic blood pressure ≤ 100 mmHg, heart rate ≥ 100 bpm, and a Forrest endoscopic classification of severe. 10% of patients were immediately discharged; however, if predictive variables obtained in the multivariate analysis had been used, hospitalization could have been prevented in 34% of patients. A total of 77 patients were included in the prospective analysis. Although only 19.5% of patients were immediately discharged without complications, 29 patients (37.7%) were theoretically suitable for early discharge. Conclusions: Patients with UGIB who have clean‐based ulcers and are stable on admission can be safely discharged immediately after endoscopy. Implementation of the clinical practice guideline safely reduced hospital admission for those patients. 相似文献
956.
957.
Constant advances in gene mapping technology have allowed research to focus from rare monogenic disorders on common complex diseases involving multiple susceptibility genes-environment interactions. Gestational diabetes mellitus (GDM) is a heterogeneous pathogenic condition affecting 2-5% of all pregnant women during pregnancy. GDM is considered to result when genetic predisposition is triggered by increased insulin resistance during pregnancy leading to what seems to be one of the primary characteristics of GDM, the pancreatic b-cell impairment. Genetic predisposition to GDM has been suggested given the occurrence of the disease within family members. Furthermore, GDM is reported to be often present in women with maturity onset diabetes of the young (MODY) gene mutations. In addition, candidate susceptibility gene variants have been suggested to increase the risk of GDM. These genes include glucokinase (GCK), HLA antigens, insulin receptor (INSR), insulin-like growth factor-2 (IGF2), HNF4A, insulin gene (INS-VNTR), plasminogen activator inhibitor 1 (PAI-1), potassium inwardly rectifying channel subfamily J, member 11 (KCNJ11), hepatocyte nuclear factor-4a (HNF4A). Identification of the possible underlying genetic factors of GDM would eventually enrich our knowledge on the pathophysiologic mechanism of the disease and contribute to the individualization of both prevention and treatment of complications for the mother and fetus. However, so far, little is known about the genetic basis of GDM and its potential clinical significance. This review focuses on possible gestational diabetes mellitus susceptibility genes and their association with the disease incidence and severity as well as the pregnancy outcome and the response to treatment. 相似文献
958.
Antolino-Lobo I Meulenbelt J Molendijk J Nijmeijer SM Scherpenisse P van den Berg M van Duursen MB 《Toxicology》2011,289(2-3):175-184
MDMA (3,4-methylenedioxymethamphetamine) metabolism is a major cause of MDMA-mediated hepatotoxicity. In this study the effects of MDMA and its metabolites on the glutathione system were evaluated. Glutathione (GSH/GSSG) levels and gene expression of glutamate cysteine ligase catalytic subunit (GCLC), glutathione-S-transferase (GST) and pregnane X receptor (PXR) were compared in the immortalized human liver epithelial cell line THLE-Neo lacking phase I metabolism and primary rat hepatocytes expressing both phase I and II metabolism. Furthermore, we evaluated the potential protective effects of two antioxidants, N-acetyl-cysteine (NAC) and sulforaphane (SFN) in these cell systems. In THLE-Neo cells, the MDMA metabolite 3,4-dihydroxymetamphetamine (HHMA) significantly decreased cell viability and depleted GSH levels, resulting in an increased expression of GCLC and GST up to 3.4- and 2.2-fold, respectively. In primary rat hepatocytes, cell viability or GSH levels were not significantly affected upon MDMA exposure. GCLC expression levels where not significantly altered either, although GST expression was increased 2.3-fold. NAC counteracted MDMA-induced cytotoxicity and restored GSH levels. Phase II enzyme expression was also reverted. Conversely, SFN increased MDMA-induced cytotoxicity and GSH depletion, while GCLC and GST expression were significantly induced. In addition, PXR expression decreased after HHMA and MDMA exposure, while co-exposure to SFN induced it up to 3.6- and 3.9-fold compared to vehicle-control in the THLE-Neo cells and rat hepatocytes, respectively. Taken together, these data indicate that HHMA is a major factor in the MDMA-mediated hepatotoxicity through interaction with the glutathione system. The results of our study show that for MDMA intoxication the treatment with an antioxidant such as NAC may counteract the potentially hepatotoxicity. However, SFN supplementation should be considered with care because of the indications of possible drug-drug interactions. 相似文献
959.
960.
Peptidoglycan activation of the proPO-system without a peptidoglycan receptor protein (PGRP)? 总被引:1,自引:0,他引:1
Haipeng Liu Chenglin Wu Yasuyuki MatsudaShun-ichiro Kawabata Bok Luel LeeKenneth Söderhäll Irene Söderhäll 《Developmental and comparative immunology》2011,35(1):51-61
Recognition of microbial polysaccharide by pattern recognition receptors triggers the prophenoloxidase (proPO) cascade, resulting in melanin synthesis and its deposition on the surface of invading pathogens. Several masquerade-like proteins and serine proteinase homologues have been shown to be involved in the proPO activation in insects. In this study, a novel serine proteinase homologue, Pl-SPH2, was found and isolated as a 30 kDa protein from hemocytes of the freshwater crayfish, Pacifastacus leniusculus, by its binding property to a partially lysozyme digested or TCA-treated insoluble Lysine (Lys)-type peptidoglycan (PGN) and soluble polymeric Lys-type PGN. Two other proteins, the Pl-SPH1 and lipopolysaccharide- and β-1,3-glucan-binding protein (LGBP) were also found in the several different PGN-binding assays. However no PGRP homologue was detected. Neither was any putative PGRP found after searching available crustacean sequence databases. If RNA interference of Pl-SPH2, Pl-SPH1 or LGBP in the crayfish hematopoietic tissue cell culture was performed, it resulted in lower PO activity following activation of the proPO-system by soluble Lys-type PGN. Taken together, we report for the first time that Lys-type PGN is a trigger of proPO-system activation in a crustacean and that two Pl-SPHs are involved in this activation possibly by forming a complex with LGBP and without a PGRP. 相似文献