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991.
992.
Clinical and molecular characterization of 17q21.31 microdeletion syndrome in 14 French patients with mental retardation 总被引:1,自引:0,他引:1
Dubourg C Sanlaville D Doco-Fenzy M Le Caignec C Missirian C Jaillard S Schluth-Bolard C Landais E Boute O Philip N Toutain A David A Edery P Moncla A Martin-Coignard D Vincent-Delorme C Mortemousque I Duban-Bedu B Drunat S Beri M Mosser J Odent S David V Andrieux J 《European journal of medical genetics》2011,54(2):144-151
Chromosome 17q21.31 microdeletion was one of the first genomic disorders identified by chromosome microarrays. We report here the clinical and molecular characterization of a new series of 14 French patients with this microdeletion syndrome. The most frequent clinical features were hypotonia, developmental delay and facial dysmorphism, but scaphocephaly, prenatal ischemic infarction and perception deafness were also described. Genotyping of the parents showed that the parent from which the abnormality was inherited carried the H2 inversion polymorphism, confirming that the H2 allele is necessary, but not sufficient to generate the 17q21.31 microdeletion. Previously reported molecular analyses of patients with 17q21.31 microdeletion syndrome defined a 493 kb genomic fragment that was deleted in most patients after taking into account frequent copy number variations in normal controls, but the deleted interval was significantly smaller (205 kb) in one of our patients, encompassing only the MAPT, STH and KIAA1267 genes. As this patient presents the classical phenotype of 17q21.31 syndrome, these data make it possible to define a new minimal critical region of 160.8 kb, strengthening the evidence for involvement of the MAPT gene in this syndrome. 相似文献
993.
Clozel M 《Science translational medicine》2011,3(67):67cm2
To continue to improve life expectancy and quality of life, the discovery of innovative therapies should be among the prime goals of the life sciences. The large majority of the drugs that are discovered and successfully developed to the point of being used by patients come from the drug industry, but publications from this sector are rare among life sciences research publications. Publications in the field of pharmaceutical drug discovery should take into account the confidentiality inherent to the protection of the intellectual property rights of a discovery, but they are fundamentally important because they can enhance scientific knowledge, improve the care and safety of patients, provide information for prescribers, and educate the public about the pharmaceutical industry. 相似文献
994.
Barth M Bondoux M Luccarini JM Peyrou V Dodey P Pruneau D Massardier C Paquet JL 《Journal of medicinal chemistry》2012,55(6):2574-2584
The bradykinin (BK) B1 receptor is an attractive target for the treatment of chronic pain and inflammation. Starting from a dual B1 and B2 antagonist, novel antagonists were designed that display low-nanomolar affinity for human B1 receptor and selectivity over B2. Initially, potent imidazoline derivatives were studied, but these compounds suffered from low bioavailability. This issue could be overcome by the use of less basic amino derivatives leading to orally active compounds. 相似文献
995.
Mark E. Schmidt Peter de Boer Randolph Andrews Martine Neyens Stefaan Rossenu Demiana William Falteos Erik Mannaert 《Psychopharmacology》2012,224(4):549-557
Rationale
JNJ-37822681 is a highly selective, fast dissociating dopamine D2-receptor antagonist being developed for the treatment of schizophrenia. A single dose [11C]raclopride positron emission tomography (PET) imaging study had yielded an estimated clinical dose range. Receptor occupancy at steady state was explored to test the validity of the single-dose estimates during chronic treatment.Objectives
The aims of this study are to characterize single and multiple dose pharmacokinetics and obtain striatal D2-receptor occupancies to predict doses for efficacy studies and assess the safety and tolerability of JNJ-37822681.Methods
An open-label single- and multiple-dose study with 10?mg JNJ-37822681 (twice daily for 13 doses) was performed in 12 healthy men. Twenty [11C]raclopride PET scans (up to 60?h after the last dose) from 11 subjects were used to estimate D2-receptor occupancy. A direct effect O max model was applied to explore the relationship between JNJ-37822681 plasma concentration and striatal D2-receptor occupancy.Results
Steady state was reached after 4?C5?days of twice daily dosing. JNJ-37822681 plasma concentrations of 3.17 to 63.0?ng/mL resulted in D2 occupancies of 0?% to 62?%. The concentration leading to 50?% occupancy was 18.5?ng/mL (coefficient of variation 3.9?%) after single dose and 26.0?ng/mL (8.2?%) at steady state. JNJ-37822681 was well tolerated.Conclusions
Receptor occupancy after single dose and at steady state differed for JNJ-37822681 and the robustness of the estimates at steady state will be tested in phase 2 studies. Dose predictions indicated that 10, 20, and 30?mg JNJ-37822681 twice daily could be suitable for these studies. 相似文献996.
997.
Céline René Damien Paulet Emmanuelle Girodon Catherine Costa Guy Lalau Julie Leclerc Fa?za Cabet-Bey Thierry Bienvenu Martine Blayau Albert Iron Hervé Mittre Delphine Feldmann Caroline Guittard Mireille Claustres Marie des Georges 《European journal of human genetics : EJHG》2011,19(1):36-42
Among the 1700 mutations reported in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, a missense mutation, p.Ser1235Arg, is a relatively frequent finding. To clarify its clinical significance, we collected data from 104 subjects heterozygous for the mutation p.Ser1235Arg from the French CF network, addressed for various indications including classical CF, atypical phenotypes or carrier screening in subjects with or without a family history. Among them, 26 patients (5 having CF, 10 CBAVD (congenital bilateral absence of the vas deferens) and 11 with CF-like symptoms) and 14 healthy subjects were compound heterozygous for a second CFTR mutation. An exhaustive CFTR gene analysis identified a second mutation in cis of p.Ser1235Arg in all CF patients and in 81.8% CBAVD patients. Moreover, epidemiological data from >2100 individuals found a higher frequency of p.Ser1235Arg in the general population than in CF or CBAVD patients. These data, added to the fact that in silico analysis and functional assays suggest a benign nature of this substitution, give several lines of evidence against an association of p.Ser1235Arg with CF or CBAVD. 相似文献
998.
999.
1000.
Aabye MG Ravn P Johansen IS Eugen-Olsen J Ruhwald M 《Clinical and Vaccine Immunology : CVI》2011,18(7):1150-1156
A rarely challenged dogma in cell-mediated immune (CMI) assays is the incubation temperature, 37°C. Fever augments proinflammatory immune responses in vivo, and the aim of this study was to explore whether incubation at fever-range temperature could increase antigen-specific biomarker responses. We compared CMI responses following incubation of whole blood at 37°C and 39°C. Whole blood was obtained from (i) 34 healthy subjects whose blood was incubated with TB10.4 antigen, present in the Mycobacterium bovis bacillus Calmette-Guérin vaccine and many environmental mycobacteria; (ii) 8 TB patients and 8 controls incubated with Mycobacterium tuberculosis-specific antigens in the QuantiFERON-TB Gold test (QFT-IT); and (iii) from both groups incubated with a T cell mitogen. T cell responses (gamma interferon [IFN-γ]) and responses from antigen-presenting cells (IFN-γ-induced protein 10 [IP-10]) were determined. We further evaluated the effect of adding interleukin-7 (IL-7) and blocking IL-10 during incubation. In TB patients, IFN-γ and IP-10 levels were increased 4.1- and 3.4-fold, respectively, at 39°C incubation (P < 0.001). Similar results were seen after mitogen stimulation. In subjects responding to TB10.4, the effects were less pronounced and significant only for IP-10. Incubation at 39°C increased IP-10 and IFN-γ responsiveness to both antigens and mitogen in persons with baseline or initial low responses. Adding IL-7 and blocking IL-10 augmented the effects in synergy with fever-range temperature. Incubation at fever-range temperature vividly increases CMI responsiveness to antigen stimulation in vitro in tuberculosis patients and may increase the sensitivity of CMI assays. 相似文献