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71.
Heterotaxy and complex structural heart defects in a mutant mouse model of primary ciliary dyskinesia 下载免费PDF全文
Tan SY Rosenthal J Zhao XQ Francis RJ Chatterjee B Sabol SL Linask KL Bracero L Connelly PS Daniels MP Yu Q Omran H Leatherbury L Lo CW 《The Journal of clinical investigation》2007,117(12):3742-3752
Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder associated with ciliary defects and situs inversus totalis, the complete mirror image reversal of internal organ situs (positioning). A variable incidence of heterotaxy, or irregular organ situs, also has been reported in PCD patients, but it is not known whether this is elicited by the PCD-causing genetic lesion. We studied a mouse model of PCD with a recessive mutation in Dnahc5, a dynein gene commonly mutated in PCD. Analysis of homozygous mutant embryos from 18 litters yielded 25% with normal organ situs, 35% with situs inversus totalis, and 40% with heterotaxy. Embryos with heterotaxy had complex structural heart defects that included discordant atrioventricular and ventricular outflow situs and atrial/pulmonary isomerisms. Variable combinations of a distinct set of cardiovascular anomalies were observed, including superior-inferior ventricles, great artery alignment defects, and interrupted inferior vena cava with azygos continuation. The surprisingly high incidence of heterotaxy led us to evaluate the diagnosis of PCD. PCD was confirmed by EM, which revealed missing outer dynein arms in the respiratory cilia. Ciliary dyskinesia was observed by videomicroscopy. These findings show that Dnahc5 is required for the specification of left-right asymmetry and suggest that the PCD-causing Dnahc5 mutation may also be associated with heterotaxy. 相似文献
72.
A sterically stabilized immunolipoplex for systemic administration of a therapeutic gene 总被引:5,自引:0,他引:5
Yu W Pirollo KF Rait A Yu B Xiang LM Huang WQ Zhou Q Ertem G Chang EH 《Gene therapy》2004,11(19):1434-1440
A sterically stabilized immunolipoplex (TsPLP), containing an antitransferrin receptor single-chain antibody fragment (TfRscFv)-PEG molecule, has been developed to specifically and efficiently deliver a therapeutic gene to tumor cells. A postcoating preparation strategy was employed in which a DNA/lipid complex (lipoplex) was formed first and then sequentially conjugated with PEG and TfRscFv. The complex prepared by this method was shown to be superior in ability to deliver genes to tumor cells than when prepared by a common precoating strategy, in which DNA is mixed with TfRscFv-PEG conjugated liposome. Using prostate cancer cell line DU145, a comparison was made between the in vitro and in vivo gene delivery efficiencies of four complexes, Lipoplex (LP), PEG-Lipoplex (PLP), TfRscFv-PEG-Lipoplex (TsPLP) and our standard TfRscFv-Lipoplex (TsLP). In vitro, the order of transfection efficiency was TsLP>LP approximately TsPLP>PLP. However, in vivo the order of transfection efficiency, after systemic administration via the tail vein, was TsPLP>TsLP>LP or PLP with TsPLP-mediated exogenous gene expression in tumor being two-fold higher than when mediated by TsLP. This suggests that the in vitro transfection efficiency of TsPLP was not indicative of its in vivo efficiency. In addition, it was found that the level of exogenous gene expression in the tumor mediated by TsPLP was higher than that mediated by TsLP and did not decrease over the time. More importantly, high exogenous gene expression in tumor, but low expression in liver, was observed after an i.v. delivery of TsPLP carrying either the GFP reporter gene or the p53 gene, indicating that tumor preferential targeting was maintained by this complex in the presence of PEG. These findings show that incorporation of PEG into our targeted lipoplex results in a more efficient delivery of the complex to the tumor cells, possibly by inhibiting the first pass clearance observed with non-PEG containing liposomes. Therefore, these data demonstrate that TsPLP is a improvement over our previously established tumor targeted gene delivery complex for systemic gene therapy of cancer. 相似文献
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74.
乳胶凝集试验快速诊断新生儿B群链球菌败血症 总被引:3,自引:0,他引:3
目的:探讨乳胶凝集试验在诊断新生儿B群链球菌(GBS)败血症中的作用。方法:174例疑有败血症的新生儿生后即作外耳道、脐部拭子培养及涂片镜检,胃液培养和血培养,并均采用乳胶凝集试验检测患儿尿中的GBS抗原。根据是否有GBS败血症将患儿分成两组:GBS败血症组(18例)及无GBS败血症组(156例)。将两组乳胶凝集试验结果作比较。结果:GBS败血症组有16例乳胶凝集试验阳性;无GBS败血症组有3例阳性。乳胶凝集试验对GBS败血症的诊断敏感性为88.9%,特异性为98.1%,假阳性率为1.9%。结论:乳胶凝集试验对新生儿GBS败血症的诊断具有重要意义,该方法敏感性和特异性均高,且简便、快速,值得推广应用。 相似文献
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76.
Bryden AM Kilgore KL Lind BB Yu DT 《Archives of physical medicine and rehabilitation》2004,85(11):1880-1885
OBJECTIVE: To determine whether the existence of elbow flexion contractures in persons with C5 or C6 tetraplegia is related to a lack of residual voluntary triceps function and triceps denervation (ie, lower motoneuron damage). DESIGN: A retrospective study of impairment data from 74 arms to identify the incidence of elbow flexion contractures and the contributing factors toward this deformity. SETTING: Five spinal cord injury (SCI) rehabilitation centers in the United States, 1 in England, and 1 in Australia. PARTICIPANTS: Forty-three subjects with motor complete C5 or C6 traumatic SCI. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Active and passive elbow extension, triceps voluntary muscle strength, and triceps response to electric stimulation. RESULTS: Subjects with weak voluntary triceps had significantly fewer and less severe elbow flexion contractures than those with paralyzed triceps ( P =.024). Subjects with completely denervated triceps (ie, no response to electric stimulation) had significantly more elbow flexion contractures than subjects with even a weak response to electric stimulation ( P =.003). Overall, 51% of the arms could not be passively extended to zero. Forty-six percent of the arms classified as C5 lacked full passive elbow extension, compared with 63% of the arms classified as C6 ( P =.302). CONCLUSIONS: A relationship has been found between elbow flexion contractures and lack of residual voluntary triceps and triceps denervation in subjects with C5 or C6 tetraplegia. There should be a greater awareness of the elbow flexion contractures that may develop as a result of this relationship. A better understanding of this deformity and its characteristics can lead to more effective clinical treatment and prevention strategies. 相似文献
77.
Yi SY Hong KS Lim HS Chung JY Oh DS Kim JR Jung HR Cho JY Yu KS Jang IJ Shin SG 《Clinical pharmacology and therapeutics》2004,76(5):418-427
BACKGROUND AND OBJECTIVES: There have been considerable disagreements regarding the influence of MDR1 (ABCB1) polymorphisms on the disposition of P-glycoprotein (P-gp) substrates. We speculated that the unknown function of the A allele of exon 21 G2677T/A (Ala893Ser/Thr) provides one of the reasons for the contradictory results. This study was performed to clarify the effects of major MDR1 gene polymorphisms, including a variant A allele in exon 21, on fexofenadine pharmacokinetics. METHODS: We investigated the occurrence of 3 high-frequency single-nucleotide polymorphisms (SNPs) in exons 12 (C1236T), 21 (G2677T/A), and 26 (C3435T) of the MDR1 gene in 232 healthy Koreans, using a polymerase chain reaction-restriction fragment length polymorphism method, and performed haplotype analysis on these 3 SNPs. A single oral dose of 180 mg fexofenadine hydrochloride was administered to 33 healthy Korean male volunteers, who were divided into 6 groups based on the MDR1 genotype for the G2677T/A polymorphism in exon 21 and the C3435T polymorphism in exon 26. RESULTS: A strong linkage disequilibrium was observed among the 3 SNPs. The frequencies of the 4 major haplotypes, 1236C-2677A-3435C, C-G-C, T-G-C, and T-T-T, were 16.4%, 18.6%, 21.6%, and 32.2%, respectively. Fexofenadine disposition varied considerably among the groups. In the 2677AA/3435CC genotype group (n=3), the values of area under the concentration-time curve from time 0 to 24 hours [AUC(0-24)] were significantly lower (P=.014) than those of the other 5 genotype groups (GG/CC, GT/CT, TT/TT, GA/CC, and TA/CT). As compared with the 2677GG/3435CC subjects, the AUC(0-24) values were 17% lower in the 2677AA/3435CC subjects and 47% higher in the 2677TT/3435TT subjects (GG/CC versus AA/CC versus TT/TT, 4017 +/- 1137 ng . h/mL versus 3315 +/- 958 ng . h/mL versus 5934 +/- 2,064 ng . h/mL; P=.018). By stratification for genotypes at position 3435, homozygous 3435TT subjects were found to have significantly higher AUC(0-24) (P=.024) and maximum plasma concentration (P=.040) values than CC subjects [AUC(0-24), 5934 +/- 2064 ng . h/mL versus 3998 +/- 1241 ng . h/mL; maximum plasma concentration, 958 +/- 408 ng/mL versus 673 +/- 242 ng/mL]. CONCLUSIONS: The plasma concentrations of fexofenadine after a single oral administration were lower in 2677AA/3435CC subjects than in subjects with the other 5 genotype combinations of the SNPs of G2677T/A and C3435T. These findings confirm the importance of analyzing MDR1 haplotypes and provide a plausible explanation for the conflicting results regarding the effect of MDR1 polymorphisms on the disposition of P-gp substrates. 相似文献
78.
Wang W Gao L Wang X Kang H Li Y Wang L Yu L 《Journal of immunotherapy (Hagerstown, Md. : 1997)》2011,34(4):353-361
Malignant lymphocytes are characterized by their low expression of poliovirus receptor (PVR), ligand for the activating natural killer (NK) cell receptors, which may explain their insensitivity toward NK cell-based therapeutic approaches. Here, we have studied the mechanism of this defective expression of PVR. We demonstrated that the characterization of NK-insensitive cell lines was of low expression of PVR in both mRNA and surface levels, and that PVR of RAJI cells able to resist NK cells has hypermethylated promoter-associated CpG islands. After treating with 5-azacytidine (5-AZA) (ie, hypomethylation agent) and suberoylanilide hydroxamic acid (SAHA) (ie, histone deacetylase inhibitor), respectively or simultaneously, the abnormal epigenetic status became partly reversed, and the mRNA and surface expression of PVR restored. The expression restoration of the gene enhanced susceptibility of RAJI cells to NK cells but, when the RAJI cells were incubated with the specific blocking antibody for PVR's receptor, the enhanced susceptibility would diminish. Patients with acute myeloid leukemia expressed higher PVR than patients with acute lymphoblastic leukemia in both mRNA and surface levels. Epigenetic modulation of hypermethylation and histone deacetylase is involved in repressing PVR expression in malignant lymphocytes resistant to NK cells. 相似文献
79.
Zablotny CM Nawoczenski DA Yu B 《Archives of physical medicine and rehabilitation》2003,84(11):1721-1725
OBJECTIVE: To compare the peak whole-body center of mass (COM) velocities and joint angular contributions in successful and unsuccessful sit-to-stand (STS) trials in a subject with traumatic brain injury (TBI). DESIGN: Single-case study. SETTING: Motion research laboratory. PARTICIPANT: A 24-year-old man who was 3.5 years post-TBI. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Peak horizontal and vertical velocities of the whole-body COM and peak angular velocities of the ankle, knee, hip, and shoulder joints. RESULTS: The peak whole-body COM vertical velocity was significantly lower in the unsuccessful STS trials. Angular velocities at the hip, knee, ankle, and shoulder joints in successful trials exceeded those in unsuccessful trials (P<.001). The subject's peak knee extension velocity was the single major predictor of the peak whole-body COM vertical velocity (r(2)=.90). Knee extension angular velocities greater than 3.25 radian/s were associated with successful STS trials. Knee extension angular velocities between 2.75 and 3.25 radian/s were associated with successful rising 50% of the time; the subject had no success in rising when velocities were less than 2.75 radian/s. CONCLUSIONS: For this subject, sit-back failures occurred in STS attempts characterized by peak whole-body COM vertical velocities that were lower than those generated in successful rising trials. These unsuccessful rising attempts were primarily the result of the subject's inability to generate sufficient knee extension angular velocity. 相似文献
80.