卷烟烟气中木犀草素和黄芩苷混合物对呼吸系统作用的研究

目的研究卷烟烟气中木犀草素和黄芩苷对呼吸系统的作用。方法将木犀草素和黄芩苷混合物加入卷烟制成特制卷烟,以动物吸烟机使混合物通过烟气接触动物呼吸系统。采用小鼠氨水引咳法制作咳嗽模型;以小鼠酚红排泄法评价气道分泌液量;以豚鼠整体动物药物引喘法评价对支气管痉挛的作用;并进行木犀草素和黄芩苷混合物经消化道给药和特制卷烟的急性毒性试验。结果与对照卷烟比较,特制卷烟可明显减少咳嗽,增加气道分泌液量,减轻动物呼吸道刺激。结论特制卷烟中木犀草素和黄芩苷能降低卷烟的呼吸系统危害性。     

The kinetics of transcriptomic changes induced by cigarette smoke in rat lungs reveals a specific program of defense, inflammation, and circadian clock gene expression.

Gene expression profiling in animal models exposed to cigarette mainstream smoke (CS) shapes up as a promising tool for investigating the molecular mechanisms involved in the onset and development of CS-related disease and may aid in the identification of disease candidate genes. Here we report on differential gene expression in lungs of rats exposed for 2, 7, and 13 weeks to 300 and 600 microg total particulate matter/l CS with sacrifice 2, 6, or 20 h after the last exposure. Regarding antioxidant and xenobiotic-metabolizing (phase I/II) enzymes, a stereotypic, mostly transient, expression pattern of differentially expressed genes was observed after each exposure period. The expression patterns were generally dose dependent for antioxidant and phase II genes and not dose dependent for phase I genes at the CS concentrations tested. However, with increasing length of exposure, there was a distinct, mostly sustained and dose-sensitive, expression of genes implicated in innate and adaptive immune responses, clearly pointing to an emerging inflammatory response. Notably, this inflammatory response included the expression of lung disease-related genes not yet linked to CS exposure, such as galectin-3, arginase 1, and chitinase, as well as genes encoding proteolytic enzymes. Finally, our experiments also revealed a CS exposure-dependent shift in the cyclical expression of genes involved in controlling the circadian rhythm. Altogether, these results provide further insight into the molecular mechanisms of CS-dependent disease onset and development and thus may also be useful for defining CS-specific molecular biomarkers of disease.     

氯喹对烟雾吸入伤大鼠肺微血管通透性的影响

目的探讨氯喹对烟雾吸入伤大鼠肺微血管通透性的影响。方法健康Ｗｉｓｔａｒ大鼠随机分成正常对照组，吸入伤１，３，５，１２，２４ｈ组及氯喹治疗６ｈ和１２ｈ组。肺含水量用干湿重法测定，肺微血管通透性用１３１Ｉ－白蛋白渗出量表示，肺出血量用９９Ｔｃ标记的红细胞出量表示。结果烟雾吸入伤后肺水含量、１３１Ｉ－白蛋白渗出量明显增加，至伤后６ｈ达峰值（Ｐ＜０．０１），而肺内９９Ｔｃ红细胞出量以伤后１ｈ最明显，伤后２４ｈ仍明显高于正常对照组（Ｐ＜０．０１），氯喹治疗伤后６ｈ组，上述指标明显低于吸入伤６ｈ组（Ｐ＜０．０１）。结论氯喹可以明显降低烟雾吸入伤大鼠肺微血管通透性。     

羧甲司坦对香烟烟雾提取物诱导A549细胞炎性损伤的影响

目的：探讨羧甲司坦抑制香烟烟雾提取物（CSE）诱导A549细胞炎性损伤的作用。方法：传代培养人A549细胞并分为5组：对照组,CSE组,羧甲司坦低、中、高剂量组（予不同浓度羧甲司坦孵育和CSE诱导）。qRT-PCR、ELISA检测主要细胞因子的合成和释放,免疫蛋白印迹（Western-blot）、免疫荧光（IF）观察NF-κB及MAPK相关信号通路的活化情况。结果：以羧甲司坦预处理或后处理,均可降低CSE诱导的A549细胞的IL-6、IL-8和MIP-1β mRNA的表达;降低IL-6及IL-8的释放。羧甲司坦预处理可抑制p65入核。Western-blot结果显示,对照组,CSE组,羧甲司坦低、中、高剂量组的P-p65蛋白相对表达量分别为（0.17±0.05）、（0.90±0.19）、（0.68±0.15）、（0.64±0.12）和（0.57±0.13）,pERK1/2蛋白相对表达量分别为（0.30±0.10）、（1.25±0.33）、（1.01±0.19）、（0.89±0.22）和（0.81±0.18）,CSE组均明显高于对照组,羧甲司坦低、中、高剂量组均明显低于CSE组（P<0.05）。结论：羧甲司坦通过抑制NF-κB p65及ERK1/2 MAPK活化,发挥对CSE诱导的A549细胞炎性损伤的保护作用。     

Influence of methotrexate exposure on outcome in patients treated with MBVP chemotherapy for primary central nervous system lymphoma

AIMS

Although the standard treatment for primary central nervous system lymphoma (PCNSL) consists of three cycles of MBVP (methotrexate, BCNU, VP16, methylprednisolone) and radiotherapy, early failure of treatment may require modification of the treatment. However, our understanding of the outcome in such patients and of the factors involved in early failure of treatment is poor. In addition to known prognostic factors, we evaluated the influence of methotrexate (MTX) exposure on the response to MBVP chemotherapy in patients treated for PCNSL after the first two cycles.

METHODS

We retrospectively analyzed all patients with PCNSL treated with the MBVP regimen over the previous 10 years. Clinical, personal data and known prognostic factors were studied. The parameters of MTX exposure were estimated using a population pharmacokinetic approach with NONMEM. Objective response (OR), overall survival (OS) and failure-free survival (FFS) were evaluated in all patients.

RESULTS

Thirty-seven patients were studied. We observed lower FFS and OS (0.49 years) in patients who were not able to receive the planned treatment (group 1, n = 12) than in those who received three cycles (8.04 years) (group 2, n = 25). Known prognostic factors were comparable in both groups, but mean dose of MTX and mean AUC tended to be lower in patients who failed prematurely or showed no response after two cycles.

CONCLUSIONS

We found that patients who were early non-responders to MBVP chemotherapy had poor survival, without major influence of MTX exposure. It is thus probably unlikely that increasing the dose of MTX would improve outcome.     

烟草烟雾暴露结合基因工程小鼠在COPD药物靶点及机制研究的应用进展

慢性阻塞性肺疾病(pulmonary disease,chronic obstructive,COPD)是一种常见的呼吸系统疾病,严重威胁人类的生命和健康。COPD的形成与发展,决定于内在基因与外在环境因素的共同作用。烟草烟雾暴露结合基因工程小鼠模拟了特定基因在致病条件下的COPD的生物效应。该文查阅近年的研究文献,总结了上述方法在药物靶标、炎症及免疫机制研究的应用及其发现,概括了这种方法的研究流程。该文为COPD的发病机制和药物研究提供了参考。     

抗真菌药物联合治疗侵袭性真菌感染的研究进展

近些年,侵袭性真菌感染的发病率逐年增加。由于临床上单药治疗侵袭性真菌感染的效果欠佳,特别是耐药真菌的感染,可选择的药物极少,导致相关疾病的发病率和死亡率仍很高,故抗真菌药物的联合治疗得到了广大学者的青睐。总结了抗真菌药物联合治疗侵袭性真菌感染的机制,综述了针对中枢神经系统、肺部、血液系统、其他部位侵袭性真菌感染的联合用药情况,为临床合理使用抗菌药物提供参考依据。     

Effect of endosulfan pretreatment on organ weights and on pentobarbital hypnosis in rats

The effects of ebdosulfan on the weights of the liver, adrenal and ovary, on pentobarbital blood and brain levels and on sleeping time (ST) have been investigated in female rats after daily oral doses of 0, 1.0, 2.5 and 5.0 mg/kg for a period of 7 or 15 days. No significant change in body weight was observed. With higher doses (2.5–5.0 mg/kg) the liver weight was significantly increased, but ovary and adrenal weights did not increase. Endosulfan treatment shortened sleeping time, while induction time was significantly increased. The concentration of pentobarbital in the blood and brain of rats after 30 min and upon awakening indicated that there was a significant decrease at 30 min. No change at awakening was observed in endosulfan-treated rats as compared to controls. It is suggested that endosulfan may shorten the duration of pentobarbital-induced sleep, perhaps by induction of hepatic microsomal enzyme activity.     

The effect of hexachlorophene on the optic nerve and visual faculty in beagle dogs after prolonged dermal application

In a systemic tolerance study in Beagle dogs the effect of an ointment, containing 1, 3 or 10% hexachlorophene (HCP), applied dermally, on the optic system over a period of 12 weeks was investigated.Besides an irreversible loss of visual faculty during treatment with 3 and 10% HCP, a permanent mydriasis, peripapillary exudations and other alterations of the ocular fundus were observed at the same dose levels, suggesting that HCP has a strong affinity to the optic nervous system in dogs without clear-cut correlations to HCP plasma levels.     

The Effect of Coarse Ambient Particulate Matter on First,Second, and Overall Hospital Admissions for Respiratory Disease Among the Elderly

Abstract

The objective of this article is to examine differences in the effect of ambient particulate matter on first, second, and overall hospital admissions for respiratory disease among the elderly. We studied 8989 adults 65 yr of age or older living in the greater Vancouver area who were admitted to hospital for any acute respiratory disease (ICD-9 codes 460–519) between June 1, 1995, and March 31, 1999. Time-series analysis was used to evaluate the association between respiratory admissions and daily measures of particulate matter (PM₁₀, PM_2.5, and PM_{10 ? 2.5}) in urban air, after adjustment for gaseous copollutants (CO, O₃, NO₂, and SO₂) and meteorological variables. Repeated admissions for respiratory disease were common among the elderly. Approximately 30% of the subjects were readmitted to hospital after the first admission; 9% had more than 2 admissions for respiratory disease during the 4-yr study period. PM_{10 ? 2.5} was significantly associated with the second and overall admissions for respiratory disease, but not with the first admission. The adjusted relative risks for an increment of 4.2 μ g/m³ in -day average PM_{10 ? 2.5} concentrations were 1.03 (95% confidence interval: 0.98–1.09) for the first admission, 1.22 (1.10–1.36) for the second admission, and 1.06 (1.02, 1.11) for overall admissions. There was no significant association between PM_2.5 and hospital admissions for respiratory disease among the elderly. Our data suggest that (1) people with a history of respiratory admissions are at a higher risk of respiratory disease in relation to particulate air pollution in urban areas, (2) analyses based on overall rather than repeated hospital admissions lead to lower estimates of the risk of respiratory disease associated with particulate air pollution, and (3) PM_{10 ? 2.5} has a larger effect on respiratory admissions than PM_2.5.     

美蓝对电刺激毁脑脊髓大鼠交感神经诱发的后肢缩血管反应的影响

用含10/μmol·L~(-1)的美蓝及同浓度的血红蛋白营养液恒速灌流,使高频(16Hz)电刺激毁脑脊髓大鼠交感神经诱发的后肢血管灌流压升高作用明显增强,但对低频电刺激作用无明显影响.1μmol·L~(-1)乙酰胆碱显著抑制各频率电刺激引起的灌流压增高,提示血管内皮可能通过释放血管内皮舒张国子来缓解过度刺激肾上腺素能神经引起的缩血管反应。     

脑中抗坏血酸的功能及神经递质对其的调节

目的综述抗环血酸在中枢神经系统中的功能以及神经递质对其的调节作用。方法查阅近年来国内外公开发表的有关研究论文 ,按功能和调节作用分类汇总。结果研究成果表明 ,抗环血酸在中枢不仅表现为抗氧化作用 ,还对神经递质、酶类及神经肽等物质起到调节作用 ,并且共浓度、释放以及功能受到中枢神经递质的调节。结论抗环血酸在中枢神经系统中的功能复发杂而重要 ,并受到多种节作用     

Central and peripheral tissue distribution of diclofenac after subcutaneous injection in the rat

Nonsteroidal anti-inflammatory drugs (NSAIDs) are viewed as peripherally acting analgesics; however, evidence is accruing that they also act centrally. To help clarify the regional actions of diclofenac, we studied its plasma and tissue concentrations after subcutaneous injection in a model of acute pain, the rat tail ischaemia-reperfusion acute hyperalgesia model. After antinociceptive doses (20 and 40 mg kg^-1), diclofenac plasma C _max occurred at 20 min and neither plasma or tissue concentrations were affected by application of the pain model. Brain, spinal cord, heart, skeletal muscle, (injured) tail cartilaginous tissue, stomach and fat had similar distribution coefficients (0.05-0.2). Distribution coefficients for liver (0.5-1.4) and kidney (0.3-0.5) increased with time, presumably reflecting their roles in the elimination of diclofenac. Subcutaneous injection was found a pharmacokinetically reliable method for administering diclofenac for antinociception studies in the rat. The finding that CNS and peripheral tissue distribution coefficients of diclofenac were similar provides indirect support for a potential central action of NSAIDs.     

MRI对原发性中枢神经系统淋巴瘤的诊断价值探讨

目的探讨磁共振成像(MRI)对原发性中枢神经系统淋巴瘤(PCNSL)的诊断价值。方法 50例疑似原发性中枢神经系统淋巴瘤患者,随机分为对照组与研究组,各25例。对照组患者接受CT检查,研究组患者接受MRI检查。分析所有患者的手术病理结果;对比两组患者对病灶的检测准确率。结果 50例患者均接受手术病理确诊,对照组患者中有64个病灶,边界清晰的38个,边界较为清晰的19个,边界模糊不清的7个;所有病灶均未出现出血以及钙化,仅有18个病灶周围未见水肿;研究组患者中有73个病灶,边界清晰的43个,边界较为清晰的21个,边界模糊不清的9个;所有病灶均未出现出血以及钙化,仅有20个病灶周围未见水肿。研究组患者的病灶、边界清晰、边界较为清晰、病灶周围未见水肿的检测准确率分别为95.89%、95.35%、95.24%、95.00%,均高于对照组的73.44%、78.95%、63.16%、55.56%,差异有统计学意义(P<0.05);研究组边界模糊不清的检测准确率为100.00%,与对照组的71.43%比较,差异无统计学意义(P>0.05)。结论原发性中枢神经系统淋巴瘤采用进行MRI诊断,结合患者的个体情况,可对于确诊原发性中枢神经系统淋巴瘤有一定的提示作用,同时MRI还能探查到患者的病灶具体情况,为患者临床治疗方案提供参考依据,该诊断方式值得推广。     

不同时间睡眠剥夺对健康男性注意力的影响及莫达非尼的干预作用

目的：观察不同时间睡眠剥夺对健康青年男性注意力的影响以及新型中枢兴奋剂莫达非尼的干预作用。方法：采用自身交叉设计,10名健康青年男性先后进行3次睡眠剥夺,第1次不服药（剥夺组）,后2次睡眠剥夺中被试者交叉服用莫达非尼和安慰剂,其中服用莫达非尼的被试者归入莫达非尼组,服用安慰剂的被试者归入安慰剂组。药物在1次睡眠剥夺中分先后2次服用（分别于睡眠剥夺14h和27h服用）,每次服药后3h进行持续性注意力任务（CPT）、选择性注意力（Stroop试验）测试,剥夺组也在同样时间点进行测试,即每次睡眠剥夺进行2次测试,分别称第Ⅰ、Ⅱ次测试。结果：在2项注意力测试中,剥夺组的成绩均低于安慰剂组和莫达非尼组,剥夺组第Ⅱ次的注意能力明显低于第Ⅰ次。安慰剂组和莫达非尼组在第Ⅰ次测试中无明显差异,第Ⅱ次测试中莫达非尼组的注意能力明显高于安慰剂组。结论：莫达非尼能明显改善睡眠剥夺后受损的注意力,受损程度越严重,莫达非尼的改善作用越显著。     

Effects of acrylamide given during gestation on dopamine receptor binding in rat pups

Acrylamide (20 $\text{mg}\text{kg}$) was administered by gavage to time-pregnant Fischer 344 rats daily from day 7 to day 16 of gestation. Acrylamide did not affect the number, size, or body weights of litters obtained but did decrease the [³H]spiroperidol binding in striatal membranes of 2-week-old pups. This effect could not be seen at 3 weeks of age. Scatchard analysis showed that acrylamide changed the affinity as well as the number of dopamine receptor sites. There were no signs of maternal toxicity in dosed mothers as evaluated by their body weights or general appearance.     

Neurotoxic Effects of Disulfiram on Autonomic Nervous System in Rat

Abstract: Two groups of male Wistar rats weighing about 140 (WI) and 200 g (WII) and a group of Sprague-Dawley (S.D.) rats (140 g) received oral disulfiram 220–580 mg/kg (DSF) daily for one or three weeks. Isolated ilea of both control and treated rats showed similar responses to acetylcholine, but the responses to 5-hydroxytryptamine (5-HT) were decreased after one and three weeks’treatment in the WI and SD rats. Pretreatment with reserpine intensified this effect in treated WI rats. A distinct decrease in the histochemical reactivity for the acetylcholinesterase and the non-specific cholinesterase was observed in the nerve plexuses of the gut wall indicating a DSF-induced nerve damage. Autonomic (cholinergic) nerves seemed thus to be affected by DSF. The two rats strains studied did not differ in their responses to 5-HT.     

万古霉素和利奈唑胺治疗儿童中枢神经系统感染研究进展

儿童发生中枢神经系统感染时,尤其是多重耐药革兰氏阳性菌株感染时,万古霉素常常作为一线选择药物。糖肽类在正常脑脊液（cerebrospinal fluid,CSF）中药物浓度低,而在脑膜炎症时,万古霉素透入血脑屏障的药物增多,但CSF/血浆的AUC比值个体差异很大,常常导致治疗失败。利奈唑胺常用于治疗严重的革兰氏阳性菌株中枢神经系统感染,其在CSF中药物浓度与血浆中游离的药物浓度接近,透入血脑屏障基本不受脑膜炎症的影响。但利奈唑胺未批准用于中枢神经系统感染。因此,评估万古霉素和利奈唑胺治疗儿童多重耐药革兰氏阳性菌中枢神经系统感染的临床效果和不良反应仍然是重要的研究方面。     

Preliminary studies on the validity of in vitro measurement of drug toxicity using HeLa cells III. Lethal action to man of 43 drugs related to the HeLa cell toxicity of the lethal drug concentrations

The human lethal plasma concentrations of 46 drugs were divided by their IC50 for HeLa cells in vitro to make up a series of cytotoxic quotients (CQL_v). CQL_v was then compared with the recorded lethal action to man of 43 of the drugs. While the 7 drugs with the lowest CQL_v values produce a non-cytotoxic interference with neuro-transmission, most of the remaining 36 drugs have a known local or systemic cytotoxicity to man. A majority of the 36 drugs induces a non-specific central nervous system (CNS)-depression at lethal dosage, intermingled with function loss from organs outside CNS in proportion to decreasing drug accumulation in CNS cells and increasing CQL_v. The remaining drugs which do not penetrate CNS cells and at lethal dosage induce a widespread injury and function loss of tissues outside the CNS, have a CQL_v near unity. Non-specific CNS-depression may thus be the primary human reaction to lethal systemic drug cytotoxicity, while wide-spread drug injury to various tissues outside CNS — conventionally considered to be cytotoxic in origin — may be the obligatory human reaction to drugs that do not penetrate cells well. The present findings indicate a relevance to human toxicity of the HeLa toxicity for most drugs.