Mucosal bromodomain-containing protein 4 mediates aeroallergen-induced inflammation and remodeling

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放射性核素介入治疗脑瘤的初步观察

目的　探讨放射性核素3 2 P或198Au介入治疗恶性脑瘤的方法和疗效。方法　介入方法A是术间将放射性核素均匀撒布于残腔壁上 ,B是术中残腔内放置Omaya囊 ,再注入放射性核素 ,3 2 P治疗 7例 ,198Au治疗 1例。结果　症状改善、平稳 ,无严重并发症 ,生存期延长。结论　放射性核素介入治疗脑瘤值得推广应用。     

溴泰君(W198)在大鼠和比格狗体内的药代动力学

目的研究溴泰君(W198)在大鼠和比格狗的药代动力学。方法采用HPLC紫外检测方法测定大鼠及比格狗注射W198后血清药物浓度。结果大鼠iv W198 10,20和40 mg·kg^-1 3个剂量的T_1/2β分别为6.60,7.36和6.77 h,AUC_0-24h分别为3.797,7.371和15.192 mg·h·L^-1,V_d分别为7.14,4.33和4.13 L·kg^-1,CL分别为2.83,2.60和2.71 L·(kg·h)^-1。大鼠im W198 20 mg·kg^-1后T_1/2β为11.61 h,AUC_0-24h为4.191 mg·h·L^-1,im的生物利用度为56.9%。比格狗iv W198 5 mg·kg^-1,T_1/2β为11.72 h,AUC_0-24h为12.646 mg·h·L^-1,V_d为0.70 L·kg^-1,CL为0.46 L·(kg·h)^-1。W198与人血浆蛋白的结合率平均为78.0%。结论W198 im的T_1/2β比iv的略长,其生物利用度为56.9%。在10～40 mg·kg^-1剂量内的吸收呈现一级动力学特征。     

Structural and functional characterization of myotoxin I, a Lys49 phospholipase A2 homologue from the venom of the snake Bothrops atrox.

A new myotoxin was isolated from the venom of Bothrops atrox from Colombia. B. atrox myotoxin I is a homodimer, with a subunit molecular mass of 13,826, and a pI of 8.9. Its complete nucleotide sequence was obtained by cDNA cloning, indicating a mature product of 122 residues that belongs to the family of Lys49 phospholipase A(2) (PLA(2)) homologues, a subgroup of catalytically inactive proteins within the group IIA. Accordingly, the toxin was devoid of phospholipase and anticoagulant activities, in vitro. In mice, it induced conspicuous local myonecrosis, edema, and a systemic interleukin-6 response. In vitro, it was cytolytic upon myoblasts, and weakly bactericidal. The toxin showed highest homology with other Lys49 PLA(2)s, both in its primary and three-dimensional modeled structure, although with an evident difference in the C-terminal region. Unlike Lys49 proteins of American crotalids having 121 residues, this toxin presents an insertion (Asn) between positions 118 and 119. Despite several substitutions within the C-terminal region 115-129 between B. atrox myotoxin I and B. asper myotoxin II, antibodies against synthetic peptide 115-129 of the latter were strongly cross-reactive to the former, indicating the antigenic conservation of this site, known to be critical for the membrane-damaging activities of Lys49 myotoxins.     

Morphology of chronic lymphocytic leukemia and its relationship to survival

The morphology of lymphocytes in blood and bone marrow from patients with chronic lymphocytic leukemia was studied; blood lymphocyte morphology was related to survival. Three primary morphologic groups emerged. Group I was characterized by small to medium-sized lymphocytes with narrow rims of cytoplasm and coarsely clumped nuclear chromatin. In group II the predominant lymphocytes were large with abundant cytoplasm. Group III was characterized by a heterogeneous population of lymphocytes with characteristics of both groups I and II. Clinical features of the patients were studied, and B and T typing of the lymphocytes was done. The median survival in group I was 26+ months; In group II 46+ months; and in group III 50+ months. Our data are at variance with previous reports and suggest that survival in patients with large lymphocytes Is longer than in those with small lymphocytes.     

Assay discrepancy in mild haemophilia A due to a factor VIII missense mutation (Asn694Ile) in a large Danish family

Factor VIII gene analysis in a large consanguinous Danish family comprising 24 affected males and four homozygously affected females revealed an Asn694Ile mutation within the A2 domain. The factor VIII gene mutation led to a mild haemophilia A phenotype with factor VIII function displaying discordance between one-stage clotting and chromogenic two-stage assays. In one-stage assays, values ranged from 0.05 to 0.30 IU/ml (males) and from 0.19 to 0.29 IU/ml (homozygous affected females), whereas the chromogenic two-stage assay produced values of around only 50% of the one-stage result [0. 02-0.12 IU/ml (males); 0.06-0.10 IU/ml (females)]. The differences are suggested to be caused by the effect of the mutation on the active cleaved form of the factor (F)VIII protein. As the original amino acid (Asn) is conserved in all known FVIII A2 sequences, but not in ceruloplasmin, we suggest that Asn694 is involved in an A2-specific functional role. Examination of a homology model of the A domains predicts that the Asn694Ile mutation (i) results in the loss of two potential hydrogen-bonding interactions and (ii) hampers the integration of the bulky side-chain of Ile into the A2 domain core, probably causing an altered stability and/or folding of the protein. Interestingly, the disease in this Danish family was originally proposed to be von Willebrand-Jürgens disease. However, the current study rules out the co-existence of either von Willebrand's disease or the presence of the Normandy variant of von Willebrand factor (type 2N).     

Phenotypic characterization and predictive analysis of p.Asp47Asn LDL receptor mutation associated with Familial Hypercholesterolemia in a Chilean population

BackgroundFamilial hypercholesterolemia (FH) is an inherited disorder mainly caused by mutations in the LDL receptor (LDL-R) and characterized by elevation of low-density lipoprotein cholesterol (LDL-C) levels and premature cardiovascular disease.ObjectiveIn this study, we evaluated the clinical phenotype of the p.Asp47Asn, described as an uncertain pathogenic variant, and its effect on the structure of LDL-R and ligand interactions with apolipoproteins.Methods27 children and adolescents with suspected FH diagnosis were recruited from a pediatric endocrinology outpatient clinic. Blood samples were collected after 12 h fasting for lipid profile analysis. DNA sequencing was performed for six FH-related genes by Ion Torrent PGM platform and copy number variation by MLPA. For index cases, a familial cascade screening was done restricted to the same mutation found in the index case. In silico analysis were developed to evaluate the binding capacity of LDL-R to apolipoproteins B100 and E.ResultsLipid profile in children and adolescents demonstrated higher LDL-C levels in p.Asp47Asn carriers compared to the wild type genotype. In silico analysis predicted a reduction in the binding capacity of the ligand-binding modules LA1-2 of p.Asp47Asn LDL-R for ApoB100 and ApoE, which was not produced by local structural changes or folding defects but as a consequence of a decreased apparent affinity for both apolipoproteins.ConclusionThe clinical phenotype and the structural effects of p.Asp47Asn LDL-R mutation suggest that this variant associates to FH.     

Influence of Lys656Asn polymorphism of the leptin receptor gene on insulin resistance in nondiabetic obese patients

BACKGROUND: Alterations of the normal leptin receptor (LEPR) gene may be involved in the development of obesity. Leptin has been shown to be able to modulate insulin secretion. Different polymorphisms in the LEPR gene have been studied, albeit with unclear results. The polymorphism on codon 656 produces a change in charge, making this change possibly functional. OBJECTIVE: The objective of this study was to investigate the influence of Lys656Asn polymorphism in the LEPR gene on serum insulin, glucose values, and insulin resistance in the fasted state among obese men and women without diabetes mellitus. DESIGN: Two hundred thirty-three (body mass index, >30 kg/m(2)) nondiabetic obese patients were analyzed. Indirect calorimetry, tetrapolar electrical bioimpedance, blood pressure determination, serial assessment of nutritional intake with 3-day written food records, and biochemical analysis were performed. Statistical analysis was performed for Lys656/Asn656 and Asn656/Asn656 jointly as a mutant allelic group and for Lys656/Lys656 as a wild allelic group. RESULTS: The subjects' (67 males and 166 females) mean age and mean body mass index were 43.6+/-16.6 years and 35.3+/-5.6 kg/m(2), respectively. One hundred forty-three patients (61.9%) had the genotype Lys656/Lys656 (wild group), whereas 88 (38.1%) had either the genotype Lys656/Asn656 (n=81; 30.7%) or the genotype Asn656/Asn656 (n=7; 7.4%) (mutant group). Age and sex distribution were similar in both groups. No difference was detected between the mutant and wild allelic groups in anthropometric parameters and dietary intakes. Homeostasis model assessment (HOMA; 2.8+/-1.7 vs. 5.6+/-4.8; P<.05) and insulin (18.1+/-10.7 vs. 32.1+/-25 mUI/ml; P<.05) levels were higher in males with the genotypes Lys656/Asn656 and Asn656/Asn656 than in males with the genotype Lys656/Lys656. Leptin levels were higher in males with a mutant genotype than in males with a wild genotype (39.3+/-23 vs. 63.5+/-28 ng/ml; P<.05). CONCLUSION: The novel findings of our study are those of the association of the Lys656/Asn656 and Asn656/Asn656 genotypes with higher levels of insulin, HOMA, and leptin in males and the lack of such an association in females.     

A meta-analysis of xeroderma pigmentosum gene D Ls751Gln polymorphism and susceptibility to hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of most common malignant tumors worldwide, but with unclear mechanisms. Xeroderma pigmentosum gene D (XPD) is one important DNA damage repair gene and can be involved in protein mutation. Currently little has been known about XPD polymorphism and HCC susceptibility in Chinese people. This study used a meta-analysis approach to comprehensively investigate the correlation between XPD polymorphism and HCC susceptibility in Chinese population, based on previously published literatures. A computer retrieval system was used to collect all case-control studies about XPD Lys751Gln polymorphism and HCC susceptibility. Data in literatures were extracted for meta-analysis. After the primary screening, four independent studies, which were published in 3 English articles and one Chinese article, were recruited in this study. There were 1,717 samples included in all studies. Using Gln/Gln + Lys/Gln, Lys/Lys + Lys/Gln and Lys allels as the reference, HCC disease alleles including Lys/Lys, Gln/Gln and Gln had OR values (95% CI, I²) of 1.007 (0.657~4.672, 91%), 3.516 (0.220~20.661, 48%) and 3.225 (0.278~12.326, 84%), respectively. The polymorphism of XPD751 loci is closely correlated with primary HCC. Lys751Gln polymorphism of XPD gene can be used as one susceptibility factor for HCC.