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81.
Hermine A van Duyvenvoorde Julian C Lui Sarina G Kant Wilma Oostdijk Antoinet CJ Gijsbers Mari?tte JV Hoffer Marcel Karperien Marie JE Walenkamp Cees Noordam Paul G Voorhoeve Verónica Mericq Alberto M Pereira Hedi L Claahsen-van de Grinten Sandy A van Gool Martijn H Breuning Monique Losekoot Jeffrey Baron Claudia AL Ruivenkamp Jan M Wit 《European journal of human genetics : EJHG》2014,22(5):602-609
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. 相似文献
82.
83.
Lock J DE Bruin A Scholten M Joosten M Seesing FM Beishuizen A DE Goede-Bolder A Cnossen MH 《Haemophilia》2012,18(5):766-772
Summary. The Group Medical Appointment (GMA) is a novel consultation form in which patients undergo individual consultations in each other’s presence. To compare participants’ experiences with GMA and Individual Medical Appointments (IMA), the usual standard of care, our team recently implemented the GMA for children aged 0–18 years with haemophilia or von Willebrand’s disease. Participants’ experiences with GMA were measured using a standardized QUOTE‐questionnaire. Of 100 addressed families, 53 participated in GMA. Of these 53 families, 38 parents (72%) and 14 adolescents (82%) filled in the questionnaire about the GMA. Patients not on prophylaxis were defined as less experienced and patients on prophylaxis, as experienced. Although parents were satisfied with both GMA and IMA (median score 8.0 vs. 9.0 of 10), a significant difference was demonstrated between less experienced and experienced parents. After GMA, less experienced parents were significantly more satisfied (median score 8.0 vs. 5.0; P‐value 0.006), felt more social support (82% vs. 30%; P‐value 0.005) and reported additional learning effects with regard to disease and treatment (64% vs. 0%; P‐value <0.001) than experienced parents. None of the less experienced parents reported privacy problems during GMA compared with 40% of experienced parents. In adolescents an identical trend was reported. Sixty‐six per cent of parents would join a GMA in the future and 87% would recommend a GMA to others. The GMA is a valuable addition in haemophilia and von Willebrand care, especially for less experienced patients. It leads to improved satisfaction, social support and improved information. 相似文献
84.
Ana Gvozdenovic Matthias JE Arlt Carmen Campanile Patrick Brennecke Knut Husmann Yufei Li Walter Born Roman Muff Bruno Fuchs 《Journal of bone and mineral research》2013,28(4):838-847
Formation of metastases in the lungs is the major cause of death in patients suffering from osteosarcoma (OS). Metastases at presentation and poor response to preoperative chemotherapy are strong predictors for poor patient outcome. The elucidation of molecular markers that promote metastasis formation and/or chemoresistance is therefore of importance. CD44 is a plasma membrane glycoprotein that binds to the extracellular matrix component hyaluronan (HA) and has been shown to be involved in metastasis formation in a variety of other tumors. Here we investigated the role of CD44 expression on OS tumor formation and metastasis. High CD44 expression, evaluated with a tissue microarray including samples from 53 OS patients and stained with a pan‐CD44 antibody (Hermes3), showed a tendency (p < 0.08) to shortened overall survival. However, nonresponders and patients with lung metastases and high CD44 expression had significantly poorer prognosis than patients with low CD44 expression. Overexpression of the standard CD44 isoform (CD44s) and its HA‐binding defective mutant R41A in osteoblastic SaOS‐2 cells resulted in HA‐independent higher migration rates and increased chemoresistance, partially dependent on HA. In an orthotopic mouse model of OS, overexpression of CD44s in SaOS‐2 cells resulted in an HA‐dependent increased primary tumor formation and increased numbers of micrometastases and macrometastases in the lungs. In conclusion, although CD44 failed to be an independent predictor for patient outcome in this limited cohort of OS patients, increased CD44 expression was associated with even worse survival in patients with chemoresistance and with lung metastases. CD44‐associated chemoresistance was also observed in vitro, and increased formation of lung metastases was found in vivo in SCID mice. © 2013 American Society for Bone and Mineral Research. 相似文献
85.
ABSTRACTThis study explored the neurodevelopmental outcomes of toddlers whose mothers have eating disorder histories and the contribution of maternal eating and comorbid psychopathology to the children’s cognitive functioning. Twenty-nine mothers with prenatal eating disorders and their toddlers (18–42 months old) were compared to a case-control matched group of mothers with no eating psychopathology and their toddlers. Measures included current maternal eating and co-occurring psychopathology, and a developmental assessment of each child. The children of mothers with eating disorders showed delayed mental and psychomotor development. Severity of maternal eating disorder symptoms emerged as a significant predictor of child development, but other maternal psychopathology did not. Findings suggest that maternal eating disorder history may play a unique role in the development of neurodevelopmental functions in their children. 相似文献
86.
Izabel Almeida Alves Keli Jaqueline Staudt Fernando Olinto Carreño Graziela de Araujo Lock Carolina de Miranda Silva Stela Maris Kuze Rates Teresa Dalla Costa Bibiana Verlindo De Araujo 《Pharmaceutical research》2018,35(7):132
Purpose
The present work aimed to evaluate the influence of experimental meningitis caused by C. neoformans on total plasma and free brain concentrations of fluconazole (FLC) in Wistar rats.Method
The infection was induced by the administration of 100 μL of inoculum (1.105 CFU) through the tail vein. Free drug in the brain was assessed by microdialisys (μD). Blood and μD samples were collected at pre-determined time points up to 12 h after intravenous administration of FLC (20 mg/kg) to healthy and infected rats. The concentration-time profiles were analyzed by non-compartmental and population pharmacokinetics approaches.Results
A two-compartmental popPK model was able to simultaneously describe plasma and free drug concentrations in the brain for both groups investigated. Analysis of plasma and μD samples showed a better FLC distribution on the brain of infected than healthy animals (1.04?±?0.31 vs 0.69?±?0.14, respectively). The probability of target attainment was calculated by Monte Carlo simulations based on the developed popPK model for 125 mg/kg dose for rats and 400–2000 mg for humans.Conclusions
FLC showed a limited use in monotherapy to the treatment of criptoccocosis in rats and humans to value of MIC >8 μg/mL.87.
Bee C. Chen Shanti Balasubramaniam Ivan N. McGown J. Patrick O’Neill Gaik S. Chng Wee T. Keng Lock H. Ngu John A. Duley 《Brain & development》2014
Background: Lesch–Nyhan disease (LND) is a rare X-linked recessive neurogenetic disorder caused by deficiency of the purine salvage enzyme hypoxanthine phosphoribosyltransferase (HPRT, EC 2.4.2.8) which is responsible for recycling purine bases into purine nucleotides. Affected individuals have hyperuricemia leading to gout and urolithiasis, accompanied by a characteristic severe neurobehavioural phenotype with compulsive self-mutilation, extrapyramidal motor disturbances and cognitive impairment. Aim: For its theoretical therapeutic potential to replenish the brain purine nucleotide pool, oral supplementation with S-adenosylmethionine (SAMe) was trialed in 5 Malaysian children with LND, comprising 4 related Malay children from 2 families, including an LND girl, and a Chinese Malaysian boy. Results: Dramatic reductions of self-injury and aggressive behaviour, as well as a milder reduction of dystonia, were observed in all 5 patients. Other LND neurological symptoms did not improve during SAMe therapy. Discussion: Molecular mechanisms proposed for LND neuropathology include GTP depletion in the brain leading to impaired dopamine synthesis, dysfunction of G-protein-mediated signal transduction, and defective developmental programming of dopamine neurons. The improvement of our LND patients on SAMe, particularly the hallmark self-injurious behaviour, echoed clinical progress reported with another purine nucleotide depletion disorder, Arts Syndrome, but contrasted lack of benefit with the purine disorder adenylosuccinate lyase deficiency. This first report of a trial of SAMe therapy in LND children showed remarkably encouraging results that warrant larger studies. 相似文献
88.
Alethea Ramos Penelope JE Quintana Ming Ji 《Hawai'i Journal of Medicine & Public Health》2014,73(1):19-25
Recent studies have established that men are susceptible to cardiotoxicity from methylmercury exposure, which also poses risks to the pregnant woman. Hair samples were obtained and questionnaires for methylmercury exposure assessment were administered to 110 adults (57 men, 53 women) throughout O‘ahu, Hawai‘i during December 2010 to January 2011. Hair samples were analyzed for total mercury with a direct mercury analyzer. Men ≥ 46 years had a median of 2.0 µg/g, which was above the reference dose of 1 µg/g, as compared to younger men with a median 1.0 µg/g (P < 0.05). Hair concentrations from older women had a median of 1.2 µg/g of mercury compared to 0.6 µg/g for younger women. Additionally, 38% of women of childbearing age had a Hazard Index > 1.0. This indicates that both men and women were at risk for excessive methylmercury exposure. In the final regression model, male gender, age > 45 years, length of residency > 10 years in Hawai‘i, and fish consumption frequency > 1 meal per week were significant factors in increased hair mercury levels. Following safe fish consumption practices allows residents to reap health benefits of fish consumption without excessive toxicant exposure. 相似文献
89.
Stephen M.F. Jamieson Yongchuan Gu Donya Moradi Manesh Jad El-Hoss Duohui Jing Karen L. MacKenzie Christopher P. Guise Annika Foehrenbacher Susan M. Pullen Juliana Benito Jeffrey B. Smaill Adam V. Patterson Medhanie A. Mulaw Marina Konopleva Stefan K. Bohlander Richard B. Lock William R. Wilson 《Biochemical pharmacology》2014
Aldo-keto reductase 1C3 (AKR1C3, EC 1.1.1.188) metabolises steroid hormones, prostaglandins and xenobiotics, and activates the dinitrobenzamide mustard prodrug PR-104A by reducing it to hydroxylamine PR-104H. Here, we describe a functional assay for AKR1C3 in cells using the fluorogenic probe coumberone (a substrate for all AKR1C isoforms) in conjunction with a specific inhibitor of AKR1C3, the morpholylurea SN34037. We use this assay to evaluate AKR1C3 activity and PR-104A sensitivity in human leukaemia cells. SN34037-sensitive reduction of coumberone to fluorescent coumberol correlated with AKR1C3 protein expression by immunoblotting in a panel of seven diverse human leukaemia cell lines, and with SN34037-sensitive reduction of PR-104A to PR-104H. SN34037 inhibited aerobic cytotoxicity of PR-104A in high-AKR1C3 TF1 erythroleukaemia cells, but not in low-AKR1C3 Nalm6 pre-B cell acute lymphocytic leukaemia (B-ALL) cells, although variation in PR-104H sensitivity confounded the relationship between AKR1C3 activity and PR-104A sensitivity across the cell line panel. AKR1C3 mRNA expression showed wide variation between leukaemia patients, with consistently higher levels in T-ALL than B-ALL. In short term cultures from patient-derived paediatric ALL xenografts, PR-104A was more potent in T-ALL than B-ALL lines, and PR-104A cytotoxicity was significantly inhibited by SN34037 in T-ALL but not B-ALL. Overall, the results demonstrate that SN34037-sensitive coumberone reduction provides a rapid and specific assay for AKR1C3 activity in cells, with potential utility for identifying PR-104A-responsive leukaemias. However, variations in PR-104H sensitivity indicate the need for additional biomarkers for patient stratification. 相似文献
90.
Grigg AP; Roberts AW; Raunow H; Houghton S; Layton JE; Boyd AW; McGrath KM; Maher D 《Blood》1995,86(12):4437-4445
To define an optimal regimen for mobilizing and collecting peripheral blood progenitor cells (PBPC) for use in allogeneic transplantation, we evaluated the kinetics of mobilization by filgrastim (recombinant met- human granulocyte colony-stimulating factor [r-metHuG-CSF]) in normal volunteers. Filgrastim was injected subcutaneously for up to 10 days at a dose of 3 (n = 10), 5 (n = 5), or 10 micrograms/kg/d (n = 15). A subset of volunteers from each dose cohort underwent a 7L leukapheresis on study day 6 (after 5 days of filgrastim). Granulocyte-macrophage colony-forming cell (GM-CFC) numbers in the blood were maximal after 5 days of filgrastim; a broader peak was evident for CD34+ cells between days 4 and 6. The 95% confidence intervals (CI) for mean number of PBPC per milliliter of blood in the three dose cohorts overlapped on each study day. However, on the peak day, CD34+ cells were significantly higher in the 10 micrograms/kg/d cohort than in a pool of the 3 and 5 micrograms/kg/d cohorts. Mobilization was not significantly influenced by volunteer age or sex. Leukapheresis products obtained at the 10 micrograms/kg/d dose level contained a median GM-CFC number of 93 x 10(4)/kg (range, 50 x 10(4)/kg to 172 x 10(4)/kg). Collections from volunteers receiving lower doses of filgrastim contained a median GM- CFC number of 36 x 10(4)/kg (range, 5 x 10(4)/kg to 204 x 10(4)/kg). The measurement of CD34+ cells per milliliter of blood on the day of leukapheresis predicted the total yield of PBPC in the leukapheresis product (r = .87, P < .0001). Assuming a minimum GM-CFC requirement of 50 x 10(4)/kg (based on our experience with autologous PBPC transplantation), all seven leukapheresis products obtained at the 10 micrograms/kg/d dose level were potentially sufficient for allogeneic transplantation purposes. We conclude that in normal donors, filgrastim 10 micrograms/kg/d for 5 days with a single leukapheresis on the following day is a highly effective regimen for PBPC mobilization and collection. Further studies are required to determine whether PBPC collected with this regimen reliably produce rapid and sustained engraftment in allogeneic recipients. 相似文献