A comparison of the therapeutic efficacy and tolerability of etoricoxib and diclofenac in patients with osteoarthritis

OBJECTIVE: To evaluate and compare the efficacy and tolerability of etoricoxib and diclofenac in patients with osteoarthritis of the knee or hip. METHODS: In this 6-week double-blind, active comparator controlled, parallel-group study eligible osteoarthritis patients were randomised to receive either etoricoxib 60 mg once daily (n = 256) or diclofenac 50 mg three times daily (n = 260). The primary study endpoint was the Western Ontario McMaster osteoarthritis index (WOMAC) pain subscale. Other endpoints included were the WOMAC stiffness and physical function subscales, and the Patient's Global Assessment of Response to Therapy (PGART) questionnaire. Early efficacy was evaluated using WOMAC first question (pain walking on a flat surface) and PGART 4 h after the morning dose of each drug on days 1 and 2. Rescue medication (paracetamol) used was also recorded. The study was designed to show comparable efficacy between etoricoxib 60 mg once daily and diclofenac 50 mg three times daily with respect to the primary endpoint and was conducted outside the United States at 67 centres in 29 countries. RESULTS: Etoricoxib (60 mg once daily) was comparable in efficacy to diclofenac (150 mg daily) on all the above parameters. The one exception was in the assessment of early efficacy where etoricoxib demonstrated significantly greater benefit within 4 h of taking the first dose on the first day of therapy (p = 0.007) as evaluated by the percentage of patients with good or excellent (PGART) responses. The treatment effects of both drugs were similar by the time day 2 was reached and were sustained throughout the 6 weeks of therapy. Both treatments were generally well tolerated. CONCLUSIONS: Etoricoxib is clinically effective in the therapy of osteoarthritis providing a magnitude of effect comparable to that of the maximum recommended daily dose of diclofenac. The onset of clinical benefit with etoricoxib on day one is more rapid than that of diclofenac. Both drugs were generally well tolerated.     

Locked nailing of severely comminuted or segmental humeral fractures

Some comminuted or segmental humeral fractures have been well-treated by functional bracing, but some also have been reported to have a bad outcome. If surgery is required, unlocked nailing has the disadvantage of unstable fixation, and plating has the disadvantage of extensive soft tissue injury. In the current study, closed locked nailing was used to treat 23 Orthopaedic Trauma Association Type C humeral fractures (C1, five; C2, three; C3, 15). The patients were 12 men and 11 women with a mean age of 42.4 years. There were 16 closed fractures and four Type I, two Type II, and one Type IIIA open fractures. Eight fractures were in the proximal third, seven in the middle third, and eight in the distal third. With one nailing, 21 of 23 (91%) fractures achieved solid union in an average of 13.2 weeks. The two nonunions eventually united after another revision nailing and bone grafting. No patients had significant impairment of elbow function. Excellent or satisfactory shoulder function was obtained in 20 patients. Closed locked nailing showed reliable treatment results for severely comminuted or segmental humeral fractures. The keys to success include compression of the fractures, static locking, postoperative external support, and experienced surgical technique.     

Long-term liver allograft survival induced by combined treatment with rAAV-hCTLA4Ig gene transfer and low-dose FK506

BACKGROUND: Recombinant adeno-associated virus vector (rAAV) is a promising vehicle for gene delivery, but few reports have documented its application in solid organ transplantation. In a rat orthotopic liver transplantation model, we investigated the efficacy of rAAV-mediated human cytotoxic T-lymphocyte-associated antigen 4 and immunoglobulin G (hCTLA4Ig) gene transfer to induce long-term allograft survival. METHODS: Dark Agouti and Lewis rats were used as donors and recipients, respectively, in six experimental groups: (a) syngeneic control, (b) no treatment, (c) rAAV-green fluorescent protein, (d) rAAV-hCTLA4Ig, (e) low-dose FK506 for 7 days, and (f) rAAV-hCTLA4Ig and low-dose FK506 for 7 days. RESULTS: The liver allografts were rejected within 10 days when no treatment was given or rAAV-green fluorescent protein was delivered. rAAV-hCTLA4Ig transduction slightly prolonged the survival time to 11 days. Long-term survival was achieved using the combined treatment of rAAV-hCTLA4Ig and low-dose FK506, whereas grafts were rejected on day 33 in the low-dose FK506 group. A sustained hCTLA4 level in plasma was detected in the combined treatment group from day 5 to day 180. On postoperative day 5, combined treatment significantly decreased the interleukin-2 and interferon-gamma protein levels in the grafts and the number of infiltrating B, T, CD25+, CD4+, CD8+, and NK cells. CONCLUSIONS: This study shows that rAAV-hCTLA4Ig gene transfer combined with low-dose FK506 can achieve long-term liver allograft survival.     

喉鳞癌原发灶和切缘p53蛋白表达及其与术后放疗的关系

目的 分析喉鳞癌原发灶和病理学阴性切缘中p53蛋白表达与术后放疗的关系。方法 回顾性分析67例喉鳞癌的临床资料,采用免疫组化方法检测病理学阴性切缘和原发灶中p53蛋白表达情况。结果 切缘和原发灶中p53阳性率分别为19．4％(13／67)和50．7％(34／67)。在原发灶p53阳性组中,与术后未放疗者相比,术后放疗者的生存率较未放疗者高(P=0．0005),复发率比较低(P=0．002);而在原发灶p53阴性组中,术后放疗者的生存率、复发率与未放疗者差异无显著性(P=0．4096,P=0．175)。在切缘p53蛋白阳性组中,术后放疗者的生存率和复发率与未放疗者差异无显著性、(P=0．378l,P=1．0);在切缘p53蛋白阴性组中,术后放疗者的生存率和复发率与未放疗者差异无显著性(P=0．0743,P=0．248)。结论 对喉鳞癌原发灶p53蛋白阳性表达者进行术后放疗是有必要的,但病理学阴性、而p53蛋白阳性切缘暂不能作为术后放疗与否的依据。     

Radiation therapy depletes extrachromosomally amplified drug resistance genes and oncogenes from tumor cells via micronuclear capture of episomes and double minute chromosomes

PURPOSE: To determine if clinically relevant doses of ionizing radiation are capable of inducing extrachromosomal DNA loss in transformed human cell lines. MATERIALS AND METHODS: The multidrug-resistant (MDR) human epidermoid KB-C1 cell line and the human neuroendocrine colon carcinoma line COLO320, which contain extrachromosomally amplified MDR1 drug resistance genes and MYCC oncogenes, were irradiated with 2 Gy fractions up to a total dose of 28 Gy. To track the fate of extrachromosomally amplified genes, cells surviving radiation therapy and unirradiated control cells were analyzed by fluorescent in situ hybridization of chromosomes using MDR1 and MYCC-specific cosmid DNA probes. In addition, total DNA and protein isolated from irradiated and control cells was subjected to Southern and Western blotting procedures, respectively, to determine amplified gene copy number and protein expression levels. Dose-response assays to follow loss of function of the MDR1 gene from KB-C1 cells were also performed. RESULTS: A significant reduction in extrachromosomal DNA, amplified gene copy number, and expression was detected in surviving cells after relatively low doses of radiation. Entrapment of extrachromosomal DNA into micronuclei was a consistent feature of irradiated cells. CONCLUSIONS: Clinically relevant doses of radiation can deplete extrachromosomal DNA in viable human malignant cells and alter their phenotype. Depletion of extrachromosomally amplified genes from tumor cells occurs via entrapment in radiation-induced micronuclei.     

鼻咽癌放疗前、中、后SOD和MT的动态变化及其意义初探

背景与目的:超氧阴离子自由基()和羟自由基(OH·)在肿瘤放射治疗过程中起着重要作用,超氧化物歧化酶(superoxidedismutase,SOD)和金属硫蛋白(metallothionein,MT)是和OH·的主要清除酶。目前有关鼻咽癌(nasophary-ngealcarcinoma,NPC)与SOD和MT关系的研究报道极少。本研究旨在了解NPC放疗过程中患者血清SOD活性和肿瘤组织MT表达的动态变化及意义。方法:从2000年12月至2002年1月,分别采用黄嘌呤氧化酶法和免疫组化法检测46例NPC患者放疗前、中、后外周静脉血T-SOD活性及肿瘤组织MT表达的动态变化。取26例确诊未患癌症者作为正常检测对照。结果:32例患者完成了3次T-SOD动态检测,放疗前T-SOD活性为(83.9±19.6)UN/ml,明显低于正常对照的(96.8±23.6)UN/ml(P<0.05)。放疗前、中、后血清T-SOD活性变化:早期(Ⅰ期)患者分别为(77.6±19.1)UN/ml、(87.1±18.6)UN/ml和(96.3±31.6)UN/ml(P>0.05);晚期(Ⅳ期)为(80.1±15.0)UN/ml、(78.0±35.4)UN/ml和(110.6±72.0)UN/ml(P>0.05);放疗近期疗效达CR患者为(79.8±18.2)UN/ml、(87.2±31.7)UN/ml和(94.8±36.3)UN/ml(P>0.05);PR为(98.5±18.6)UN/ml、(62.9±35.3)UN/ml和(79.2±27.3)UN/ml(P>0.05)。其中,27例NPC患者完成了3次MT检测,放疗前NPC组织MT表达率为(39.8±     

As2O3对多发性骨髓瘤细胞的细胞毒作用的机制研究

背景与目的:多发性骨髓瘤(multiple myeloma,MM)是恶性浆细胞疾病,目前仍难以治愈;已有研究证明三氧化二砷(arsenic trioxide,As2O3)在体外能够抑制骨髓瘤细胞增殖并诱导其凋亡.本研究拟探讨As2O3对多发性骨髓瘤细胞的可能作用机制.方法:采用MTr法检测As2O3对5株骨髓瘤细胞U266、SKO-007、LP-1、HS-Sultan和KM3的抑制作用,求出其IC50,同时研究维生素K3(vitamine K3,VK3)、N-乙酰半胱氨酸(N-acetyl-cysteine,NAC)和还原型谷胱甘肽(glutathione,GSH)对As2O3的协同或拮抗作用;利用光学比色法测定不同浓度As2O3作用后的5株骨髓瘤细胞以及As2O3与VK3、NAC或外源性GSH共同作用后的U266细胞的GSH含量,对细胞GSH含量与IC50进行相关性分析.结果:As2O3对5株骨髓瘤细胞均有增殖抑制作用,但其敏感性不同,细胞内GSH含量与其IC50正相关(r=0.87,P＜0.05);氧化剂VK3与As2O3有明显协同作用,抗氧化剂NAC和GSH对As2O3具有拮抗作用.结论:As2O3可能是通过与细胞内的含巯基化合物结合,降低细胞内GSH含量,从而诱导骨髓瘤细胞凋亡.     

Sperm penetration of immature and maturing oocytes does not affect phosphorylation of mitogen-activated protein kinase in pigs

Pig oocytes cultured in vitro for 0, 25, 33 and 44 h were inseminated by frozen-thawed ejaculated sperm. At specified times after insemination, sperm penetration, cell cycle progression and mitogen-activated protein kinase (MAPK) phosphorylation were evaluated. It was shown that: (1) oocytes at various maturational stages could be penetrated by sperm; (2) sperm penetration did not affect meiotic cell cycle progression; (3) sperm penetration of germinal vesicle (GV) oocytes and maturing oocytes did not alter MAPK phosphorylation; and (4) when premetaphase I (pre-MI) and metaphase I (MI) oocytes, in which MAPK was activated, were fertilised, no evident MAPK dephosphorylation was detected as in metaphase II oocytes. The data suggest that sperm penetration before oocyte maturation does not affect MAPK phosphorylation and that the machinery inactivating MAPK upon fertilisation is not developed in maturing (pre-MI to MI) oocytes.     

Contraceptive methods used by young women in the township of Lomé (Togo)

Despite intensive development of reproductive health services among Togolese youth over the past ten years, contraceptive prevalence remains low, particularly among young women. To help understand the reasons for the low rate of use of reproductive health services by young women (adolescents and young adults) and to assess prevalence of their contraceptive use in Lomé. In a cross-sectional study in the five precincts of Lomé township from March 08, 1999, to April 17, 1999, approximately 500 adolescent girls and young women (aged 10-24 years) were interviewed according to a semi-structured questionnaire. The variables studied were: social and demographic characteristics; knowledge about family planning, including whether they had discussed sexual issues with their parents; conditions of contraceptive use (method used by the interviewee or her sexual partner, who made the decision, geographical and financial accessibility of the method); suggestions to improve contraceptive prevalence. Data were analysed with Epi-Info 6.3 and comparisons tested with the chi-square test (significance set at 5%). 63.6% (318 of 500) of the young women and female teenagers lived with a partner; 43.4% discussed some aspects of reproductive health with their parents, especially menstruation and STDs, including AIDS. Although 93.4% of the interviewees knew about condoms and 68.2% about the calendar (rhythm) method, few of them used these (respectively 33.6% and 31.8%). The interviewees decided about contraceptive use with their partners (37%) or alone (28%), and rarely asked their parents (1%). Contraceptives were obtained at a health facility by 3.8% of the subjects, and at the drugstore or market by 20.6%. The main reason for the low rates of use of health facilities (10.4%) and of medical contraceptive methods (11.2% of all contraceptive methods used) were: lack of means, information, and interest (in such facilities and methods), and finally, lack of sexual activity. The condom was essentially the only modern contraceptive method used. The main reason for the low rate of use of reproductive health services may be that apart from the condom, women and female teenagers rarely use modern contraceptive methods. Improving information about reproductive health, creating more "young friendly clinics", and developing peer educators might improve the contraceptive prevalence rate among young women in Togo.     

Iron-induced oxidative damage and apoptosis in cerebellar granule cells: attenuation by tetramethylpyrazine and ferulic acid

Tetramethylpyrazine and ferulic acid are two active ingredients of a Chinese herbal medicine Ligusticum wallichi Franchat. In the present investigation, iron-induced oxidative neuronal damage and the protective effects of tetramethylpyrazine and ferulic acid against this induction were studied in primary cultures of rat cerebellar granule cells. When neurons were treated with 200 microM of FeSO(4) for 1 h, lipid peroxidation in neurons increased time dependently, as measured with the thiobarbituric acid assay. Thirty-six hours after iron treatment, the cell viability decreased to 43.6% and the percentage of apoptotic cells increased to 50.6%. Transmission electron microscopic examination showed a disrupted nuclear envelope and condensed chromatin in iron-treated neurons. Analysis of DNA extracted from iron-treated cells by agarose gel electrophoresis showed the typical "ladder pattern", which indicated the formation of mono- and oligonucleosomes. After iron treatment, caspase 3 activity increased significantly, as measured in a fluoregenic assay. The results above suggested that iron treatment triggered oxidative stress and apoptosis in neurons. Western blot revealed that iron treatment up-regulated the apoptosis-related gene p53 as well as its effector gene p21(waf1/cip1). Pretreatment of the cells with 100 microM of tetramethylpyrazine or ferulic acid effectively decreased the activation of caspase 3 as well as the expression of p53 and p21(waf1/cip1), and attenuated iron-induced oxidative damage and apoptosis. The results suggest that tetramethylpyrazine and ferulic acid might be used as preventive agents against neuronal diseases associated with oxidative stress.