Copy number variants in patients with short stature

Height is a highly heritable and classic polygenic trait. Recent genome-wide association studies (GWAS) have revealed that at least 180 genetic variants influence adult height. However, these variants explain only about 10% of the phenotypic variation in height. Genetic analysis of short individuals can lead to the discovery of novel rare gene defects with a large effect on growth. In an effort to identify novel genes associated with short stature, genome-wide analysis for copy number variants (CNVs), using single-nucleotide polymorphism arrays, in 162 patients (149 families) with short stature was performed. Segregation analysis was performed if possible, and genes in CNVs were compared with information from GWAS, gene expression in rodents'' growth plates and published information. CNVs were detected in 40 families. In six families, a known cause of short stature was found (SHOX deletion or duplication, IGF1R deletion), in two combined with a de novo potentially pathogenic CNV. Thirty-three families had one or more potentially pathogenic CNVs (n=40). In 24 of these families, segregation analysis could be performed, identifying three de novo CNVs and nine CNVs segregating with short stature. Four were located near loci associated with height in GWAS (ADAMTS17, TULP4, PRKG2/BMP3 and PAPPA). Besides six CNVs known to be causative for short stature, 40 CNVs with possible pathogenicity were identified. Segregation studies and bioinformatics analysis suggested various potential candidate genes.     

基于CYP3A4酶探讨灯盏花素对洛伐他汀的药动学的影响及机制

目的 探究灯盏花素与洛伐他汀联用对大鼠体内药动学的影响,从代谢酶的角度揭示灯盏花素对洛伐他汀药动学产生影响的机制。方法 采用探针药物法及RT-HPLC法测定咪达唑仑在肝微粒体孵育体系中的浓度,评价灯盏花素与洛伐他汀联用对CYP3A4酶活性的影响。通过RT-PCR反应来检测CYP3A4酶mRNA基因表达,采用Western blot法,从蛋白翻译水平上分析灯盏花素与洛伐他汀联用对大鼠肝脏CYP3A4蛋白表达的影响。结果 洛伐他汀与灯盏花素联合用药后,洛伐他汀在大鼠体内的血药浓度显著升高,从0.39 mg?L-1 上升到1.08 mg?L-1 ,清除率从3.36L?h-1?kg-1降低到1.08L?h-1?kg-1,药物半衰期从5.0h延长到6.2h,联合给药后洛伐他汀的AUC从2.42mg?L-1?h-1上升到4.22mg?L-1?h-1。洛伐他汀组与空白组比较CYP3A4酶活性均没有明显变化;灯盏花素组及灯盏花素联合洛伐他汀组与空白组比较发现均抑制CYP3A4酶活性;灯盏花素与灯盏花素联合洛伐他汀组CYP3A4酶mRNA 表达量均较空白组显著降低;CYP3A4酶蛋白含量结果表明,洛伐他汀组与灯盏花素联合洛伐他汀组与空白组比较CYP3A4酶蛋白含量均没有明显变化。结论 洛伐他汀与灯盏花素联用,灯盏花素通过抑制其基因转录水平抑制CYP3A4的活性,使大鼠体内药动学过程发生变化,洛伐他汀药物的代谢减慢。     

Making the “new American workplace” safe and healthy: A joint labor-management-researcher approach

The American workplace is now in the midst of the most significant change since the advent of mass production. Whether these changes will lead to improvements in worker health and safety is not clear. This paper describes an approach to intervention and research—participatory action research (PAR)—that has the potential to redesign work organizations to improve performance while also improving health and safety. In the PAR method, researchers, managers, workers, and unions collaborate in a process of data-guided problem solving intended both to improve the system's performance and to contribute to general scientific knowledge. A case study example illustrates the use of a PAR approach in an automobile parts facility where labor, management, and researchers jointly conducted a longitudinal project aimed at reducing the major sources of stress and enhancing employee well-being. Results from the 6 year project suggest that, properly implemented, PAR has the potential to both lead to improved intervention and contribute to theoretical advances in occupational safety and health. The PAR approach to intervention research is contrasted with the total quality approach (TQA), and some suggestions are made for improving PAR research designs. © 1996 Wiley-Liss, Inc.     

山奈酚通过抑制NLRP3炎症小体介导的脂肪组织炎症改善db/db小鼠胰岛素抵抗发生

目的：探讨山奈酚能否通过调控肥胖小鼠脂肪组织炎症改善胰岛素抵抗发生并研究作用机制。方法：db/m小鼠作为对照组,db/db雄性小鼠随机分为模型组、二甲双胍组(0.15 g·kg^-1·d^-1)和山奈酚组(50 mg·kg^-1·d^-1)。连续灌胃给药6周,每周记录小鼠体重,6周后进行葡萄糖耐量试验、胰岛素耐量试验、皮下和附睾白色脂肪组织质量测定;HE染色观察脂肪组织形态学变化,免疫组化法观察巨噬细胞向脂肪组织的浸润程度及巨噬细胞标志物F4/80的表达,实时荧光定量PCR检测TNF-α和IL-18以及Arg-1和IL-10的mRNA表达,蛋白质免疫印迹试验检测NLRP3、pro-caspase1、cle-caspase1和IL-1β表达。结果：与模型组相比,山奈酚能够显著抑制db/db小鼠脂肪质量增加,抑制脂肪细胞肥大。山奈酚组小鼠脂肪组织巨噬细胞浸润减少,TNF-α和IL-18 mRNA表达减少,Arg-1和IL-10 mRNA表达增加;山奈酚治疗能够抑制小鼠附睾脂肪组织NLRP3、caspase1以及...     

In vitro cartilage degradation by escherichia coli and staphylococcus aureus

Effects of Escherichia coli and Staphylococcus aureus on cartilage and chondrocytes in culture are reported. Under these conditions, bacterial effects on cartilage degradation and cell viability are measured in the absence of inflammation. E coli causes a 28% loss and S aureus an 83% loss of cartilage glycosaminoglycan within 48 hours. Collagen content is unchanged. Both bacterial species induce chondrocyte death in explants and in monolayers within 48 hours. Bacterial effects on glycosaminoglycans and cell viability do not result from depletion of nutrients from the culture medium. Serum in the culture media inhibits the bacterial effects on cartilage degradation but does not prevent cell death.     

Protective effects of intermittent hydrostatic pressure on osteoarthritic chondrocytes activated by bacterial endotoxin in vitro.

The role of continuous passive motion (CPM) in the management of septic arthritis and inflammatory arthritis remains of interest. CPM produces cyclic variations in intraarticular pressure that facilitates transport of fluid, nutrients, and solutes within and/or across the joint and stimulates chondrocyte metabolism. However, the precise mechanisms mediating the responses of chondrocytes to joint motion remain unclear. This study tested the hypothesis that dynamic mechanical loading counteracts effects of bacterial lipopolysaccharide (LPS), an inflammatory mediator, on chondrocyte metabolism. Intermittent hydrostatic pressure (IHP) (10 MPa for 4 h) was applied to human chondrocytes pretreated with LPS (1 microg/ml for 18 h). LPS activation of chondrocytes decreased mRNA signal levels of type II collagen by 67% and aggrecan by 56% and increased nitric oxide by 3.1-fold, monocyte chemotactic protein-1 mRNA signal levels by 6.5-fold, and matrix metalloproteinase-2 mRNA signal levels by 1.3-fold. Application of IHP to LPS-activated chondrocytes decreased nitric oxide synthase mRNA signal levels and nitric oxide levels in the culture medium. Exposure of LPS-activated chondrocytes to IHP upregulated type II collagen and aggrecan mRNA signal levels by 1.7-fold, relative to chondrocytes activated by LPS and maintained without loading. In addition, application of IHP decreased the upregulation in signal levels of monocyte chemotactic factor-1 and matrix metalloproteinase-2 following LPS activation by 45% and 15%, respectively. These data show that mechanical loading counteract effects of inflammatory agents, such as bacterial LPS, and suggest that postinfection sequelae are influenced by the presence or absence of joint loading.     

Liver transplantation in tyrosinaemia type 1: the dilemma of timing the operation

Four children with tyrosinaemia type 1 received liver transplants. The metabolic disorder was corrected and all four had normal liver function on an unrestricted diet. Two children, transplanted at age five and seven years, proved to have occult hepatocellular carcinoma and both subsequently developed pulmonary metastases. One child was well 32 months after removal of a single pulmonary metastasis but the other child died with multiple metastases. The two younger children, transplanted at age 19 and 21 months, were well 28 and 44 months after operation, one after a second liver transplant. Our experience confirms the high risk of hepatocellular carcinoma in this disease and the potential value of early liver transplantation.     

Quantitation of glycocalyx production in coagulase-negative Staphylococcus

The purpose of this study was to develop sensitive and accurate methods of quantitating bacterial glycocalyx. Coagulase-negative staphylococci were cultured in trypticase soy broth. Quantitation of slime production was evaluated using various methods of fixation and staining. The amount of dye associated with bacterial slime was assessed spectrophotometrically following solubilization of the dye-biofilm complex by 0.2 M NaOH at 85 degrees C for 1 h. Carnoy's solution was optimal for fixation of the slime, and toluidine blue staining was most reproducible. Fifteen strains of Staphylococcus epidermidis showed a gradation in biofilm production ranging from high, medium, to low that was strain stable. Irrespective of the technique used, high, medium, and low producers of bacterial slime remained in the same category and always showed significantly different optical density readings (p less than 0.05). In our experiments, solubilization of a toluidine blue-bacterial biofilm complex was a direct, simple, and efficient method for reproducibily quantitating glycocalyx. This method provides a useful means of rapid quantitation of biofilm production to assess its role in the infection process and in the response to antibiotic therapy.     

Access to private obstetrics/gynecology services under Medicaid

Improving pregnancy outcomes for low-income women has been a long-standing Medicaid objective, yet exceptionally low Medicaid participation rates for private practice obstetrician-gynecologists (OB-GYNs) suggest that access to maternity care may be particularly limited. Using a national sample of more than 2,800 office-based physicians, the authors analyzed the factors influencing the Medicaid participation decision of physicians in three specialties: OB-GYN, pediatrics, and general surgery. Regression results suggest that OB-GYNs are equally, or even more, sensitive to Medicaid reimbursement and program administration characteristics. Higher Medicaid fees definitely raise OB-GYN participation rates, for instance. OB-GYNs are also more willing to participate in those states where Medicaid programs are more generous in their eligibility requirements and where administrative red tape is less onerous.