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11.
Quantitative evaluation of liver-specific promoters from retroviral vectors after in vivo transduction of hepatocytes 总被引:3,自引:1,他引:3
Hepatic gene therapy could be used to treat a number of inherited blood diseases such as hemophilia or thrombophilia. Although liver-directed retroviral transduction can result in long-term gene expression in vivo, the low level of protein production has limited its clinical application. We reasoned that the insertion of liver-specific promoters into retroviral vectors would increase gene expression in vivo. The 347- bp human alpha 1-antitrypsin (hAAT), the 810-bp murine albumin (mAIb), the 490-bp rat phosphoenolpyruvate carboxykinase (rPECK), and the 596- bp rat liver fatty acid binding protein promoters were inserted into a Moloney murine leukemia retroviral backbone containing the hAAT reporter gene. Vectors that produced appropriately sized RNA and hAAT protein in vitro were tested in vivo by transducing regenerating rat livers. Long-term serum expression of the hAAT reporter gene was normalized to retroviral transduction efficiency as determined by using a polymerase chain reaction-based assay of genomic DNA from transduced rat livers. The hAAT, mAIb, and rPEPCK promoters were, respectively, 35- , 8-, and 0.02-fold as strong as the previously studied constitutive Pol-II promoter. We conclude that the hAAT promoter resulted in the highest expression from a retroviral vector and may result in therapeutically significant expression of other clinically significant blood proteins. 相似文献
12.
13.
目的:观察海马区星形胶质细胞培养上清液能否在体外诱导人脂肪基质细胞向神经元样细胞分化。方法:实验于2004-10/2005-06在华北煤炭医学院中心实验室完成。在无菌条件下从Wistar乳鼠分离出海马组织,从分离的海马组织中获得星形胶质细胞,并收集其培养上清液。取外科手术获得的人腹部皮下脂肪组织进行人脂肪基质细胞的原代培养。30例患者均知情同意。取第3代人脂肪基质细胞接种到培养孔中,预先放置无菌盖玻片的24孔培养板,制备细胞爬片或者接种到培养瓶中,细胞生长达50%~60%融合时,去除培养液,换为海马区星形胶质细胞培养上清诱导液进行诱导,对照组培养液为无血清培养基。倒置相差显微镜下连续观察细胞生长情况和形态变化,应用免疫细胞化学、鉴定神经前体细胞的特异性标志神经巢蛋白、神经细胞的特异性标志神经元特异性烯醇化酶、微管联合蛋白2和神经胶质细胞的特异性标志胶质纤维酸性蛋白的表达。结果:①诱导培养第3天,部分人脂肪基质细胞开始变形,从原先的细长梭状细胞变成神经元样细胞,可见细胞伸出突起,多为双极或多极细胞。②刚分离接种的人脂肪基质细胞镜下呈圆形,悬浮状态,接种后24h内贴壁,并开始伸展,多呈梭形。1周后细胞融合成单层,排列出现方向性,但有少量圆形及卵圆形细胞混杂生长。③第4,5代人脂肪基质细胞在诱导48h后形态即开始发生变化,扁平的胞体较预诱导后逐渐回缩,向外伸出突起,72h后扁平的胞浆向胞核收缩,突起继续延长,以后随时间进展,具有典型神经细胞形态特点的细胞数量逐渐增多,形成双极或多极细胞。④免疫细胞化学检测人脂肪基质细胞诱导5d后发现有(10.5±3.7)%神经巢蛋白、(38.4±5.2)%胶质纤维酸性蛋白、(15.7±2.3)%神经元特异性烯醇化酶表达,未见微管联合蛋白2的表达。结论:海马区星形胶质细胞培养上清液可以在体外诱导人脂肪基质细胞向神经元样细胞方向分化。 相似文献
14.
Thrombosis in inflammatory bowel disease: clinical setting, procoagulant profile and factor V Leiden 总被引:7,自引:0,他引:7
Jackson LM; O'Gorman PJ; O'Connell J; Cronin CC; Cotter KP; Shanahan F 《QJM : monthly journal of the Association of Physicians》1997,90(3):183-188
Patients with inflammatory bowel disease have an increased frequency of
thromboembolism, and microvascular thrombosis has been proposed as a
contributory pathogenic factor. The mechanism of enhanced procoagulant
activity is not understood. We examined the clinical setting of
thromboembolic events in 52 patients with Crohn's disease or ulcerative
colitis, and assessed the procoagulant laboratory profile, including Factor
V Leiden, in a subset of 20 patients to identify procoagulant risk factors.
Patients who developed thrombosis tended to be young; 60% of thrombotic
events occurred in patients under 50 years. Multiple thromboembolic
episodes occurred in 13% and unusual sites of thrombosis (e.g.
intracardiac, cerebral, inominate veins) in 11%. No risk factor was
identifiable in 52% of cases and two-thirds of thromboses occurred in an
out-patient setting. The mortality rate was 8%. Evidence for inflammatory
disease activity was found in only 45% of patients with ulcerative colitis
at the time of the thromboembolic event, in contrast to 89% of those with
Crohn's disease. Assays for specific coagulation defects were negative in
all cases tested (protein S, C were normal in 17/17; anti-thrombin III,
anti-phospholipid antibodies and activated protein C resistance were
negative in 20/20, and only 1/20 patients was found to be heterozygous for
Factor V leiden. Thrombosis in inflammatory bowel disease is important
because it occurs in a young population, often in unusual sites, and has a
high mortality. The development of thrombosis is related to active
inflammatory disease in most patients with Crohn's disease but apparently
not in those with ulcerative colitis. Since approximately half of the
patients had no other identifiable risk factor, there remains a substantial
group of patients with IBD who develop thrombosis for unknown reasons.
相似文献
15.
Thalidomide attenuates nitric oxide-driven angiogenesis by interacting with soluble guanylyl cyclase
Syamantak Majumder Megha Rajaram Ajit Muley Himabindu S Reddy KP Tamilarasan Gopi Krishna Kolluru Swaraj Sinha Jamila H Siamwala Ravi Gupta R Ilavarasan S Venkataraman KC Sivakumar Sharmila Anishetty Pradeep G Kumar Suvro Chatterjee 《British journal of pharmacology》2009,158(7):1720-1734
Background and purpose:
Nitric oxide (NO) promotes angiogenesis by activating endothelial cells. Thalidomide arrests angiogenesis by interacting with the NO pathway, but its putative targets are not known. Here, we have attempted to identify these targets.Experimental approach:
Cell-based angiogenesis assays (wound healing of monolayers and tube formation in ECV304, EAhy926 and bovine arterial endothelial cells), along with ex vivo and in vivo angiogenesis assays, were used to explore interactions between thalidomide and NO. We also carried out in silico homology modelling and docking studies to elucidate possible molecular interactions of thalidomide and soluble guanylyl cyclase (sGC).Key results:
Thalidomide inhibited pro-angiogenic functions in endothelial cell cultures, whereas 8-bromo-cGMP, sildenafil (a phosphodiesterase inhibitor) or a NO donor [sodium nitroprusside (SNP)] increased these functions. The inhibitory effects of thalidomide were reversed by adding 8-bromo-cGMP or sildenafil, but not by SNP. Immunoassays showed a concentration-dependent decrease of cGMP in endothelial cells with thalidomide, without affecting the expression level of sGC protein. These results suggested that thalidomide inhibited the activity of sGC. Molecular modelling and docking experiments revealed that thalidomide could interact with the catalytic domain of sGC, which would explain the inhibitory effects of thalidomide on NO-dependent angiogenesis.Conclusion and implications:
Our results showed that thalidomide interacted with sGC, suppressing cGMP levels in endothelial cells, thus exerting its anti-angiogenic effects. These results could lead to the formulation of thalidomide-based drugs to curb angiogenesis by targeting sGC. 相似文献16.
Recent evidence describing a suboptimal clinical outcome in women with
hydrosalpinges who undergo in-vitro fertilization (IVF) and embryo transfer
suggests a potential deleterious effect of this fluid on in- utero embryo
development. Consequently, we evaluated in-vitro mouse embryo development
in the presence of hydrosalpingeal fluid (HF) collected from 10 infertile
women of reproductive age. Chemical analyses showed both similarities and
differences of these fluids to reported values for fluids collected from
non-diseased Fallopian tubes. The HF had a significant deleterious effect
upon mouse embryo cleavage and development to the expanded and hatched
blastocyst stage, although the effect was variable among patients. Dilution
of HF to 30% concentration with culture medium failed to negate this
effect. This argues against the effect resulting from a relative lack of
critical, supportive component(s) in the HF. Additionally, further
experiments performed with cultures under an oil overlay significantly
reduced the embryotoxicity of the HF. This evidence suggests there may be a
lipophilic factor that can impair embryo development. The relatively poor
IVF-embryo transfer success in women with proximally patent hydrosalpinges
may be explained, at least in part, by reflux of a lipophilic embryotoxic
factor(s) into the uterine cavity.
相似文献
17.
A randomized prospective comparison of oral versus intraperitoneal ofloxacin as the primary treatment of CAPD peritonitis 总被引:1,自引:0,他引:1
Ignatius KP CHENG SL LUI GX FANG PY CHAU SW CHENG Frances H CHIU TM CHAN WK LO BY CHOY CY LO 《Nephrology (Carlton, Vic.)》1997,3(6):431-435
Summary: Oral ofloxacin has been successfully used in our centres for the primary treatment of peritonitis complicating continous ambulatory peritoneal dialysis (CAPD). In view of the progressive rise in the resistance rate to ofloxacin among peritoneal bacterial isolates, a study was conducted to determine if oral ofloxacin remains a viable first line treatment for CAPD peritonitis in our centres and if the result can be improved by changing from an oral to an intraperitoneal (i.p.) route. In patients on three 2 L daily CAPD exchanges, ofloxacin given at the i.p. dosage of 200 mg loading followed by 25 mg/L of peritoneal dialysate achieved overnight trough peritoneal levels which are at least four times the minimal 90% inhibitory concentration (MIC90) of most bacterial pathogens without significant accumulation in the systemic circulation. This i.p. dosage was therefore chosen for the clinical study and the result was compared to that using ofloxacin given in the oral dosage of 400 mg loading followed by 300 mg once daily as maintenance. of all the recruited episodes, 35 were eligible for analysis. the overall primary cure rate including primary failures and relapses was 55.6% (10/18) in the oral treatment group and 70.6% (12/17) in the i.p. treatment group. the corresponding figures for gram positive bacterial (g +) infections were 36.4% and 50%, for gram negative bacterial (g -) infections were 66.7 and 80% and for culture negative infections were 75 and 80%. In culture positive cases, all treatment failures were due to resistant infections which were observed in 42.3% of all bacterial isolates, 47.1% of g + isolates and 33.3% of g - isolates. Due to the high background level of bacterial resistance among our CAPD population, ofloxacin monotherapy given either by the oral or the i.p. route can no longer be recommended for the primary treatment of CAPD peritonitis. 相似文献
18.
DM Tappin RPK Ford KP Nelson B Price PM Macey R Dove 《Acta paediatrica (Oslo, Norway : 1992)》1997,86(8):873-880
Abstract We tested the hypothesis that the febrile stress of routine vaccination would increase central apnoea in normal infants. Twenty-one normal infants had continuous overnight breathing and temperature recorded at home, before and after 58 routine vaccination episodes. Central apnoea, of at least 5 sec duration, was detected by computer algorithm and confirmed by human inspection. The longest recorded apnoea was 16 sec ( n = 1) during 3629 h of sleep. Overnight rectal temperature increased after vaccination (median 0.52°C, 95% CI 0.40, 0.65). Apnoea density reduced on 46/53 vaccination nights (median -29%, 95% CI -20, -37) followed by an increase on subsequent nights (median +10%, 95% CI +1%, +21%). Overall, apnoea density was similar during the 3 nights preceding and 4 nights following vaccination (median +1%, 95% CI +9,-6). The febrile stress of routine vaccination did not increase central apnoea in normal infants. 相似文献
19.
20.
Detection of the Philadelphia chromosome in acute lymphoblastic leukemia by pulsed-field gel electrophoresis 总被引:1,自引:0,他引:1
The Philadelphia (Ph1) chromosome is an acquired abnormality in the malignant cells of 10% to 25% of patients with acute lymphoblastic leukemia (ALL). Unlike chronic myelogenous leukemia (CML), where the molecular detection of the Ph1 chromosome is relatively straightforward using conventional Southern hybridization analysis, the detection of the Ph1 chromosome in ALL is complicated by the existence of several molecular subtypes, and the fact that translocation breakpoints are dispersed over a large genomic area. To circumvent these difficulties, we investigated pulsed-field gel electrophoresis (PFGE) to determine if this method could be used directly on clinical samples to detect the Ph1 chromosome in ALL. We report that, in a study of seven patients with Ph1-positive ALL, we could easily detect the Ph1 using only a single PFGE analysis, regardless of the Ph1 subtype, and we could confirm that the translocations occur either within or very near the BCR gene in all seven. We conclude that PFGE is a useful technique for the detection of the Ph1 in ALL, which ultimately may find wide applicability in the detection of other chromosomal abnormalities in other malignancies. 相似文献