自由基代谢与精神分裂症临床症状和药物治疗的关系

目的：探讨自由基代谢与精神分裂症临床症状和药物治疗的关系。方法：是否治疗的慢性精神分裂症患者各４０例分别评定定阳性和阴性症状量表（ＰＡＮＳＳ）,并测定膜脂质过氧化物丙二醛（ＭＤＡ）含量、铜／锌超氧化物歧化酶（Ｇｕ－ＺｎＳＯＤ）和谷胱苷肽过氧化物酶（ＧＳＨ－Ｐｘ）活性。结果：与健康对照组相比,未治疗组患者ＭＤＡ含量和ＧＳＨ－Ｐｘ活性显著增加,治疗组患者无显著改变;而两组患者ＳＯＤ活性显著降低;未治疗     

精液叶酸、维生素B_(12)、活性氧水平与精子质量关系研究

目的 :　检测人精液叶酸、维生素 B12 ( VB12 ) ,及活性氧 ( ROS)的含量 ,探讨三者与精子质量的关系。方法 :　收集经证实配偶已怀孕的新加坡籍健康成年男性 1 76名的精液 ,根据WHO推荐方法检测精子质量各项指标 ,并测定精液叶酸和 VB12 含量及 ROS水平。结果 :　平均精液量、精子浓度和其活力都在正常范围内。而精子存活率 ( 73.0 6% )略低于 WHO标准 (≥ 75% ) ,形态异常的精子 ( 77.0 6% )高于 WHO标准 ( 70 % )。精液的叶酸含量与 ROS水平呈显著负相关 ( r=- 0 .2 5,P=0 .0 0 3) ;VB12 与 ROS呈负相关 ( r=- 0 .2 5,P=0 .0 0 2 ) ,与精子形态异常也呈负相关( r=- 0 .1 5,P=0 .0 4 8) ,但与精子浓度呈正相关 ( r=0 .31 ,P<0 .0 0 1 )。ROS与精子形态异常呈正相关 ( r=0 .2 5,P=0 .0 0 2 ) ,与精子活力也呈正相关 ( r=0 .1 9,P=0 .0 1 9)。结论 :　 VB12 对精子生成和维持精子正常功能是必需的 ,ROS水平与精子功能缺陷有关 ,VB12 和叶酸可能通过降低 ROS以维持精子的正常功能。     

吸氧对P300 潜伏期和振幅的影响

目的研究吸氧对听觉诱发电位P300 潜伏期和振幅的影响。方法健康男性志愿者27 例,根据随机数字表分为对照组(n=12)和实验组(n=15)。志愿者均佩戴面罩,对照组呼吸空气,实验组呼吸医用纯氧60 min。应用Oddball 双声刺激序列,记录志愿者吸氧前、吸氧20 min、吸氧50 min、吸氧后30 min 的闭眼脑电图,计算靶刺激P300 潜伏期和电位。结果对照组吸氧前、吸氧20 min、吸氧50 min 和吸氧后30 min,P300 潜伏期分别为(335.91±15.40) ms、(358.58±15.32) ms、(353.42±9.41) ms和(354.10±10.42) ms,P300 潜伏期明显延长(P<0.01);实验组吸氧前、吸氧后20 min、吸氧50 min 和吸氧后30 min,P300 潜伏期分别为(332.98±14.63) ms、(326.05±13.53) ms、(319.17±14.34) ms 和(318.50±13.87) ms,吸氧50 min 和吸氧后30 min 与吸氧前相比,P300潜伏期缩短(P<0.05)。吸氧20 min、吸氧50 min和吸氧后30 min时两组比较,实验组比对照组P300 潜伏期显明缩短(P<0.01)。对照组P300 振幅相对稳定(P<0.05);实验组振幅逐渐下降,吸氧后30 min为(2.41±0.64) μV,吸氧前为(5.49±0.89) μV,两者相比有显著性差异(P<0.05)。结论吸氧使听觉诱发电位P300 潜伏期缩短,振幅减小,而且随吸氧时间延长,这种趋势更明显。     

4-酰硫基-4-脱氧-4-去甲表鬼臼毒素衍生物的合成和抗肿瘤活性

为研究4’-去甲表鬼臼毒素的C_4位不同原子及不同取代基类型同活性之间的关系,寻找活性高、毒性低的抗肿瘤新药,合成了11个4-酰硫基-4-脱氧-4’-去甲表鬼臼毒素,衍生物并进行了抗肿瘤活性试验。4-巯基-4-脱氧-4’-去甲表鬼臼毒素和不同的羧酸在二乙氧基磷酰氰酯存在下得相应的硫酯。该类化合物在L1210白血病细胞和KB细胞的体外抑制试验中普遍表现出抑制活性。化合物10的活性与依托泊甙相当。其余活性比依托泊甙差。与相应的C_4位酰氨基的4’-去甲表鬼臼毒素衍生物相比,活性明显弱。提示氮取代的衍生物活性更好。     

4-S-(5-酰氨基-1,3,4-噻二唑-2-基)-4-脱氧-4′-去甲基表鬼臼毒素衍生物的合成与抗肿瘤活性

基于在4′-去甲基表鬼臼毒素母核C_4位上联结含有杂原子的芳香环取代基,以此考察其结构与活性关系的设想,设计并合成了10个标题化合物。体外L_(1210)白血病细胞与KB细胞生长抑制试验结果表明,这类化合物有较强的抗肿瘤活性。其中化合物SIPI-92-1772,1774,1775,1776,1777与1779的活性超过临床用药依托泊甙。其余化合物活性与依托泊甙相当或略低。     

Validation of Methods to Control for Immortal Time Bias in a Pharmacoepidemiologic Analysis of Renin–Angiotensin System Inhibitors in Type 2 Diabetes

Background

Pharmacoepidemiologic analysis can confirm whether drug efficacy in a randomized controlled trial (RCT) translates to effectiveness in real settings. We examined methods used to control for immortal time bias in an analysis of renin–angiotensin system (RAS) inhibitors as the reference cardioprotective drug.

Methods

We analyzed data from 3928 patients with type 2 diabetes who were recruited into the Hong Kong Diabetes Registry between 1996 and 2005 and followed up to July 30, 2005. Different Cox models were used to obtain hazard ratios (HRs) for cardiovascular disease (CVD) associated with RAS inhibitors. These HRs were then compared to the HR of 0.92 reported in a recent meta-analysis of RCTs.

Results

During a median follow-up period of 5.45 years, 7.23% (n = 284) patients developed CVD and 38.7% (n = 1519) were started on RAS inhibitors, with 39.1% of immortal time among the users. In multivariable analysis, time-dependent drug-exposure Cox models and Cox models that moved immortal time from users to nonusers both severely inflated the HR, and time-fixed models that included immortal time deflated the HR. Use of time-fixed Cox models that excluded immortal time resulted in a HR of only 0.89 (95% CI, 0.68–1.17) for CVD associated with RAS inhibitors, which is closer to the values reported in RCTs.

Conclusions

In pharmacoepidemiologic analysis, time-dependent drug exposure models and models that move immortal time from users to nonusers may introduce substantial bias in investigations of the effects of RAS inhibitors on CVD in type 2 diabetes.Key words: cardiovascular disease, immortal time bias, renin–angiotensin system inhibitors, time-dependent Cox model, cancer, type 2 diabetes     

Bioactivation of the cooked food mutagen N-hydroxy-2-amino-1-methyl-6- phenylimidazo[4,5-b]pyridine by estrogen sulfotransferase in cultured human mammary epithelial cells

Cooked food mutagens from fried meat and fish have recently been suggested to contribute to the etiology of breast cancer. Thus, the most prevalent of these compounds, i.e. 2-amino-1-methyl-6- phenylimidazo[4,5-b]pyridine, or rather its more mutagenic N- hydroxylated metabolite (N-OH-PhIP), forms DNA adducts in mammary cells, including human mammary epithelial (HME) cells. The objective of this study was to determine the involvement of estrogen sulfotransferase (EST), the only sulfotransferase identified in HME cells, in the further bioactivation of N-OH-PhIP. These studies were done in vitro using human recombinant EST and in intact HME cells. Human recombinant EST increased the covalent binding of [3H]N-OH-PhIP to calf thymus DNA approximately 3.5-fold in the presence of the sulfotransferase co-substrate 3'-phosphoadenosine-5'-phosphosulfate at each N-OH-PhIP concentration (1, 10 and 100 microM) (n = 6, P < 0.001). In contrast, EST did not catalyze the DNA binding of two other cooked food mutagens, N-hydroxy-2-amino-3-methylimidazo[4,5-f]quinoline and N- hydroxy-2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline, which are mainly hepatocarcinogens. Cultured HME cells displayed high EST activity, which could be completely inhibited by 1 microM estrone. When the cells were incubated with [3H]N-OH-PhIP, binding to native DNA occurred at 60- 240 pmol/mg DNA. This binding was inhibited to 55% of control by 1 microM estrone (P < 0.01, n = 8), suggesting that EST plays a significant role in carcinogen bioactivation in human breast tissue.      

Anti‐inflammatory effects of exendin‐4, a glucagon‐like peptide‐1 analog,on human peripheral lymphocytes in patients with type 2 diabetes

Aims/Introduction

Type 2 diabetes is characterized by dysregulation of immunity, oxidative stress and reduced incretin effects. Experimental studies suggest that glucagon‐like peptide (GLP‐1) might have immunomodulating effects. We hypothesize that GLP‐1 receptor agonist, exendin‐4, might reduce inflammatory response in type 2 diabetes.

Materials and Methods

Using peripheral blood mononuclear cells (PBMC) sampled from 10 type 2 diabetes and 10 sex‐ and age‐matched control subjects and supernatants from PBMC culture, the expression of phospho‐mitogen activated protein kinase (MAPK) signaling pathways in CD4+ T helper lymphocytes and monocytes was analyzed using flow cytometry. Cytokines/chemokines and superoxide anion before and after treatment with exendin‐4 were measured by cytometric bead array and chemiluminesence assay, respectively.

Results

Compared with control subjects, PBMC from type 2 diabetes patients showed activated MAPK (P38, c‐Jun NH2‐terminal protein kinase and extracellular signal‐regulated kinase) signaling pathway, elevated superoxide anion, increased pro‐inflammatory cytokines (tumor necrosis factor‐α, interleukin‐1β, interleukin‐6) and chemokines (CCL5/regulated on activation normal T‐cell expressed and secreted and CXCL10/interferon‐γ‐induced protein 10). These changes were attenuated by exendin‐4, possibly through the suppression of p38 MAPK.

Conclusions

These results suggest that exendin‐4 might downregulate pro‐inflammatory responses and reduce oxidative stress by suppressing MAPK signaling pathways in type 2 diabetes.     

Ganciclovir Treatment for Cytomegalovirus Infection in Immunocompromised Patients With Renal Disease

The safety and efficacy of a 10-day course of ganciclovir therapywas assessed in 17 consecutive patients with proven cytomegalovirusinfection. The patients were receiving immunosuppressive therapyfor a variety of non-malignant renal conditions, including renaltransplantation (seven patients), small vessel vasculitis (sixpatients), systemic lupus erythematosus (three patients) andGoodpasture's disease (one patient). Fifteen patients were pyrexialat the time of their cytomegalovirus infection. Twelve patientshad pneumonitis manifesting as a pulmonary parenchymal infiltrateor a reduction in gas transfer. Fourteen patients had a significantlymphopenia (lymphocyte count <1x10⁹/l), nine were leucopenic(white cell count <3.5xtimes 10⁹/l) and nine had abnormalliver biochemistry. One patient had an infection of the ileumand one an infection of the larynx. All these disease manifestationsresponded completely to a single course of ganciclovir therapy.There were no clinical relapses and no side effects were observed. Ganciclovir is a safe and effective therapy when administeredearly in the course of cytomegalovirus infection in immunosuppressedpatients with renal impairment.