多巴胺受体在大鼠结肠黏膜下神经丛的表达和细胞分布

目的多巴胺(dopamine,DA)与其受体结合调节肠道动力、黏膜分泌及屏障等,黏膜下神经元参与DA对黏膜的生理调节,但其受体的具体分布尚不明了。通过检测DA受体在大鼠结肠黏膜下层的蛋白和mRNA表达及细胞分布,为DA调节大鼠结肠病理生理机制提供依据。方法用RT-PCR和Western blotting方法定性测定DA受体在大鼠结肠黏膜下层的mRNA和蛋白的表达;免疫荧光双染色后在激光共聚焦显微镜下观察DA受体在黏膜下血管活性肠肽(vasoactive intestinal peptide,VIP)能和胆碱能神经元上的分布。结果在大鼠结肠黏膜下层,DA受体D_1、D_2、D_5的mRNA及蛋白均有表达;在黏膜下神经丛VIP能阳性的神经元中有大量分布,其中D_1阳性的神经元占58.94%±2.245%,D_2阳性神经元占52.03%±9.384%,D_5阳性神经元占86.21%±2.902%,且D_5阳性神经元数量显著高于D_1和D_2;在黏膜下神经丛胆碱能阳性的神经元广泛表达DA受体,其中D_1阳性神经元占87.75%±7.307%,D_2阳性神经元占88.50%±8.761%,D_5阳性神经元占89.25%±10.75%。结论 DA受体在大鼠结肠黏膜下层有D_1、D_2及D_5的表达,且在VIP能及胆碱能神经元上均有分布,其中D_5受体在VIP能神经元上的分布显著高于D_1及D_2受体。本研究可为深入探讨DA调节结肠黏膜生理及病理机制提供形态学依据。     

β_2肾上腺能受体与黏蛋白2在大鼠结肠黏膜的共存

目的探究去甲肾上腺素对大鼠结肠黏液分泌的影响以及肾上腺能β受体在大鼠结肠黏膜的分布。方法采用酶联免疫吸附测定法检测去甲肾上腺素(norepinephrine,NE)对结肠黏液分泌的影响;用免疫荧光组织化学方法观察黏蛋白2(mucin2,MUC2)及β肾上腺能受体在结肠黏膜的分布;实时定量PCR方法检测β肾上腺能受体在大肠结肠黏膜的表达;同时采用阿利新蓝/过碘酸雪夫染色方法检测黏液细胞在结肠黏膜的分布;使用激光共聚焦显微镜观察β2肾上腺能受体与MUC2在结肠黏液细胞的共存。结果去甲肾上腺素可刺激大鼠远端结肠黏膜的黏液释放增加,比对照组增加约247%。免疫荧光组织化学结果显示β1和β3肾上腺能受体在结肠黏膜有弱表达,β2肾上腺能受体为高表达。β1和β2肾上腺能受体mRNA表达相对量与免疫荧光组织化学一致。黏蛋白MUC2主要表达在结肠隐窝的黏液细胞内,且与β2肾上腺能受体有共存。结论β2肾上腺能受体与MUC2在结肠黏液细胞共存;去甲肾上腺素可促进结肠黏液分泌。     

大鼠纹状体脑片多巴胺和谷氨酸的相互作用及其对乳酸脱氢酶释放的影响

目的　研究多巴胺 (DA)、谷氨酸 (Glu)及其受体拮抗剂对大鼠纹状体脑片乳酸脱氢酶 (LDH)释放的影响 ,以探讨DA和Glu相互作用及其机制。方法　以大鼠纹状体脑片孵育作为体外研究模型 ,用比色法测定LDH的活性。结果　DA和Glu均能增加纹状体脑片LDH的释放 ,且呈剂量依赖性 ,在较低浓度 ( 10 μmol·L-1)时 ,两者对LDH的释放有协同作用。MK - 80 1(NMDA受体拮抗剂 )可拮抗DA诱导的LDH的释放 ;DAD2 受体拮抗剂spiperone ,而不是D1受体拮抗剂SCH2 3 3 90 ,也能显著降低Glu对LDH释放的影响。结论　DA和Glu均对纹状体产生细胞毒性 ,这种作用至少部分是通过受体介导的 ,DA和Glu的相互作用对纹状体神经元的损伤有重要影响     

多巴胺与免疫反应调节的研究进展

 神经递质多巴胺(dopamine,DA)是联接神经和免疫的重要分子。白细胞能合成和转运DA,几乎所有的免疫细胞亚群都表达DA受体,DA与其受体结合,通过自分泌/旁分泌方式调节免疫细胞的活化、增殖和细胞因子分泌。在中枢神经系统和外周组织,DA主要通过D1和D2受体抑制或加强免疫效应细胞的功能。中枢神经系统退行性疾病表现出免疫功能失调,可能与免疫细胞上DA受体表达水平以及信号传导通路的变化相关。因此,选择性针对免疫细胞的DA受体激动剂或拮抗剂在治疗DA介导的免疫失调性疾病中可能发挥重要作用。本文就DA受体在免疫细胞上的表达、DA作为免疫调节分子的作用以及在免疫功能障碍相关疾病中的研究进展作一综述。     

DA1受体激动剂对大鼠离体肺动脉和肠动脉cAMP生成量的影响

目的 :对比分析多巴胺 1(DA1)受体激动剂非诺多泮 (FODA)对大鼠离体肺动脉和肠动脉cAMP含量的影响。方法 :采用放射免疫测定法 ,测定FODA对肺动脉和肠系膜动脉cAMP生成量的影响以及DA受体拮抗剂对FODA诱发肠动脉、肺动脉血管cAMP变化的影响。结果 :非诺多泮可剂量依赖性增加肠、肺动脉cAMP的生成量 ,肠动脉cAMP的生成量显著高于肺动脉cAMP的生成量。选择性多巴胺 1(DA1)受体阻断剂SCH2 3390能够阻断非诺多泮所引起的肺动脉和肠动脉cAMP生成量增加 ,多巴胺 2 (DA2 )受体阻断剂Domperidone则不影响非诺多泮的反应。结论 :大鼠肺动脉和肠动脉均存在有刺激腺苷酸环化酶 (AC)活性的DA1受体 ,但肺动脉DA1受体的位点数明显少于肠动脉DA1受体位点数 ,提示肺动脉DA1受体的生理反应弱于肠动脉。     

参苓白术散对溃疡性结肠炎脾虚湿困证大鼠结肠组织TLR2、MyD88、COX-2表达的影响

目的观察参苓白术散对溃疡性结肠炎脾虚湿困证大鼠结肠组织Toll样受体2(TLR2)、髓样分化因子88(MyD88)及环氧化酶-2(COX-2)表达的影响,探讨参苓白术散改善溃疡性结肠炎的作用机制。方法采用TNBS/乙醇灌肠结合环境与饮食干预法复制溃疡性结肠炎脾虚湿困证大鼠模型。按照随机数字表将大鼠分为正常组、模型组、参苓白术散组(15.6 g/kg)、参苓白术散(15.6 g/kg)+TLR2激动剂(50μg/只)组、参苓白术散(15.6 g/kg)+TLR2拮抗剂组(0.121 2μg/g),每组12只,连续给药14 d。ELISA法检测血清肿瘤坏死因子-α(TNF-α)、白细胞介素6(IL-6)及白细胞介素1β(IL-1β)水平,免疫组织化学法和Western blot法测定结肠组织中TLR2、MyD88、COX-2蛋白表达,Real-time PCR法检测结肠组织TLR2、MyD88、COX-2 mRNA表达。结果模型组大鼠血清TNF-α、IL-6及IL-1β水平均升高(P<0.05),结肠组织TLR2、MyD88、COX-2蛋白和mRNA表达增强(P<0.01);与模型组比较,参苓白术散组和参苓白术散+TLR2拮抗剂组大鼠血清TNF-α、IL-6及IL-1β水平均下降,结肠组织TLR2、MyD88、COX-2蛋白和mRNA表达下调(P<0.01)。与参苓白术散组比较,参苓白术散+TLR2拮抗剂组大鼠血清TNF-α、IL-6及IL-1β水平,结肠组织TLR2、MyD88、COX-2蛋白和mRNA表达差异无统计学意义(P>0.05);参苓白术散+TLR2激动剂组大鼠血清TNF-α、IL-6及IL-1β水平,结肠组织TLR2、MyD88、COX-2蛋白和mRNA表达均高于参苓白术散组(P<0.01)。结论参苓白术散可下调溃疡性结肠炎脾虚湿困证大鼠结肠组织TLR2、MyD88、COX-2表达,降低炎性因子的释放;参苓白术散通过负性调控TLR2/MyD88信号通路,减轻肠道炎症反应,可能是其治疗溃疡性结肠炎的重要机制之一。     

大豆苷原(DA)对成骨细胞雌激素受体(ER)和过氧化物酶体增殖物激活受体γ(PPARγ)表达的调节作用及其受雌激素的影响(英文)

目的研究大豆苷原(daidzein,DA)对成骨细胞雌激素受体(estrogen receptor,ER)和过氧化物酶体增殖物激活受体γ(peroxisome proliferator-activated receptorγ,PPARγ)表达的调节作用,并观察雌激素对这种调节的影响。方法小鼠成骨细胞MC3T3-E1体外低血清(α-MEM,含2%FBS)培养,分别用0.1和10μmol/L的DA处理,采用实时定量PCR或Western blot分析细胞ERα、ERβ和PPARγ的表达变化。加入浓度均为0.1μmol/L的ER拮抗剂ICI182780或PPARγ拮抗剂GW9662,观察ER和PPARγ在DA调节中的作用。为观察雌激素的影响,采用无血清培养,在10nmol/L 17β-雌二醇(E2)条件下研究DA对细胞受体表达的作用。结果 DA抑制体外培养成骨细胞ER表达,而刺激其PPARγ表达。0.1和10μmol/L的DA分别下调ERα蛋白水平44%和38%(P<0.05),下调ERβ蛋白水平50%(P<0.05)和31%(P<0.05),上调PPARγ74%和78%(P<0.05)。ICI182780可阻断DA对ERα转录水平的抑制作用,DA对成骨细胞ERβmRNA水平的下调无统计学意义(P=0.087 4);GW9662可阻断DA对PPARγ表达的上调作用,提示成骨细胞ER和PPARγ参与自身表达调节。在10nmol/L 17β-雌二醇条件下,DA对无血清培养的成骨细胞ERα转录水平的抑制作用由28.0%～29.6%(P<0.05)增强至74.0%～82.8%(P<0.01),其对ERβ表达的抑制作用也明显增强,而对PPARγ的上调作用几乎丧失。结论 DA可通过调节ERs和PPARγ等受体表达间接影响成骨细胞的药物反应,雌激素可明显影响DA的受体调节作用。DA对细胞受体表达的调节作用可能是其对成骨细胞时间相关双相调节的重要机制之一。     

大豆苷原（DA）对成骨细胞雌激素受体（ER）和过氧化物酶体增殖物激活受体γ（PPARγ）

 目的 研究大豆苷原(daidzein,DA)对成骨细胞雌激素受体(estrogen receptor,ER)和过氧化物酶体增殖物激活受体γ (peroxisome proliferator-activated receptor γ,PPARγ)表达的调节作用,并观察雌激素对这种调节的影响。方法 小鼠成骨细胞MC3T3-E1体外低血清(α-MEM,含2% FBS)培养,分别用0.1和10 μmol/L的DA处理,采用实时定量PCR或Western blot分析细胞ERα、ERβ和PPARγ的表达变化。加入浓度均为0.1 μmol/L的ER拮抗剂ICI182780或PPARγ拮抗剂GW9662,观察ER和PPARγ在DA调节中的作用。为观察雌激素的影响,采用无血清培养,在10 nmol/L 17β-雌二醇(E2)条件下研究DA对细胞受体表达的作用。结果 DA抑制体外培养成骨细胞ER表达,而刺激其PPARγ表达。0.1和10 μmol/L的DA分别下调ERα 蛋白水平44%和38% (P<0.05),下调ERβ蛋白水平50%(P<0.05)和31% (P<0.05),上调PPARγ 74%和78% (P<0.05)。 ICI182780可阻断DA对ERα转录水平的抑制作用,DA对成骨细胞ERβ mRNA水平的下调无统计学意义(P=0.087 4);GW9662可阻断DA对PPARγ表达的上调作用,提示成骨细胞ER和PPARγ参与自身表达调节。在10 nmol/L 17β-雌二醇条件下,DA对无血清培养的成骨细胞ERα转录水平的抑制作用由28.0%～29.6%(P<0.05)增强至74.0%～82.8%(P<0.01),其对ERβ表达的抑制作用也明显增强,而对PPARγ的上调作用几乎丧失。结论 DA可通过调节ERs和PPARγ等受体表达间接影响成骨细胞的药物反应,雌激素可明显影响DA的受体调节作用。DA对细胞受体表达的调节作用可能是其对成骨细胞时间相关双相调节的重要机制之一。     

犬冠状动脉和脑动脉多巴胺受体亚型对比研究

目的 :对比分析犬冠状动脉和脑动脉多巴胺 (DA)受体亚型类别与反应特性。方法 :利用离体血管微量生物反应检测技术 ,测定多巴胺 1(DA1)受体激动剂非诺多泮 (Fenoldopam ,FODA)和多巴胺 2 (DA2 )受体激动剂propy lbutyl dopamine(PBDA)对冠状动脉和脑动脉血管环的舒张反应。结果 :①冠状动脉和脑动脉均有DA1受体分布 ,但其分布密度存在明显差别 ;②脑动脉内既有DA1受体又有DA2 受体分布 ;③用 6 羟多巴胺 (6 OHDA)处理后的实验进一步证实脑动脉存在有DA2 受体。结论 :冠状动脉和脑动脉DA受体亚型存在明显的异质性 ,阐明这种异质性将有助于了解多巴胺受体对冠脉循环和脑循环的不同生理反应。     

帕金森鼠结肠黏膜炎性反应与多巴胺和5-羟色胺受体表达

目的 主要观察多巴胺（dopamine,DA）和5-羟色胺（serotonin,5-HT）受体在结肠黏膜的分布,6-羟多巴（6-hydroxydopamine,6-OHDA）大鼠结肠黏膜通透性和炎性反应因子的改变以及DA和5-HT含量及其受体的表达变化,初步探讨DA与5-HT在结肠黏膜保护中的可能作用。方法 双侧黑质内注射6-OHDA制作帕金森病（Parkinson's disease,PD）大鼠模型。通过免疫荧光染色和Western blotting法对模型进行鉴定,利用高效液相色谱-电化学检测法检测DA和5-HT的含量,通过实时定量PCR和Western blotting法检测DA和5-HT受体的表达。结果 6-OHDA大鼠黑质中酪氨酸羟化酶蛋白表达水平明显降低（对照组：0.335±0.073,模型组：0.132±0.028,P<0.05）,粪便含水量显著减少（对照组：0.119%±0.005%,模型组：0.062%±0.006%,P<0.01）,转棒停留时间明显缩短［对照组（35.330±3.148） s,模型组（24.000±1.424） s,P<0.01］,表明造模成功。结肠黏膜电阻降低［对照组（73.750±4.024）Ω/cm²,模型组（53.400±6.282）Ω/cm²,P<0.05］,异硫氰酸荧光素（fluorescein isothiocyanate,FITC）-葡聚糖透过量显著升高［60 min时,对照组：（18.860±1.856）μg/L,模型组：（37.000±4.457）μg/L,P<0.05］,炎性反应因子肿瘤坏死因子（tumor necrosis factor-α,TNF-α）明显增加［对照组：（269.10±18.00） ng/g,模型组：（340.40±21.52） ng/g,P<0.05］,提示6-OHDA大鼠结肠黏膜存在炎性反应。进一步发现6-OHDA大鼠结肠黏膜中DA受体D₁（对照组：0.728±0.132,模型组：0.272±0.067,P<0.01）和D₅（对照组：0.721±0.036,模型组：0.543±0.051,P<0.05）的蛋白表达水平明显降低,5-HT₃的表达虽有升高趋势,差异无统计学意义（P<0.01）。而DA与5-HT含量,以及D₂和5-HT₄的表达水平均无明显变化。结论 6-OHDA大鼠结肠黏膜中DA受体D₁和D₅的表达明显降低,黏膜通透性与炎性反应因子TNF-α升高,提示6-OHDA大鼠结肠黏膜存在有炎性反应。     

HEK293细胞内源性电压门控钾离子通道电生理学特性研究

目的探讨人胚胎肾细胞(HEK293细胞)内源性电压门控钾通道的电生理特性,避免HEK293细胞上内源性离子通道对外源性离子通道表达时的干扰。方法利用全细胞膜片钳技术分析了HEK293细胞内源性电压门控钾通道的电生理特性。结果在HEK293细胞上去极化电压从-80 mV开始可触发1个外向电流。在+100 mV时电流为(422.78±68.87)pA,电流密度为(21.91±3.20)pA/pF。钾通道阻断剂四乙胺(tetraethylammonium,TEA)、4-氨基吡啶(4-aminopyri-dine,4-AP),在将细胞外液钾浓度由4 mmol/L提高到40 mmol/L时,对外向电流有影响。结论正常培养的HEK293细胞本身有内源性的钾通道。该外向电流可能包括了IK、IK1、IKur和Ito。     

Intensity and Amount of Physical Activity in Relation to Insulin Sensitivity: The Insulin Resistance Atherosclerosis Study

Context.— Exercise training is associated with improved insulin sensitivity (S_I), but the potential impact of habitual, nonvigorous activity is uncertain. Objective.— To determine whether habitual, nonvigorous physical activity, as well as vigorous and overall activity, is associated with better S_I. Design.— A multicultural epidemiologic study. Setting.— The Insulin Resistance Atherosclerosis Study, conducted in Oakland, Calif; Los Angeles, Calif; the San Luis Valley, Colo; and San Antonio, Tex. Participants.— A total of 1467 men and women of African American, Hispanic, and non-Hispanic white ethnicity, aged 40 to 69 years, with glucose tolerance ranging from normal to mild non–insulin-dependent diabetes mellitus. Main Outcome Measure.— Insulin sensitivity as measured by an intravenous glucose tolerance test. Results.— The mean S_I for individuals who participated in vigorous activity 5 or more times per week was 1.59 min^-1·µU^-1·mL^-1·10^-4 (95% confidence interval [CI], 1.39-1.79) compared with 0.90 (95% CI, 0.83-0.97) for those who rarely or never participated in vigorous activity, after adjusting for potential confounders (P<.001). When habitual physical activity (estimated energy expenditure [EEE]) was assessed by 1-year recall of activities, the correlation coefficient between S_I and total EEE was 0.14 (P<.001). After adjustment for confounders, vigorous and nonvigorous levels of EEE (metabolic equivalent levels 6.0 and <6.0, respectively) were each positively and independently associated with S_I (P.01 for each). The association was attenuated after adjustment for the potential mediators, body mass index (a measure of weight in kilograms divided by the square of the height in meters), and waist-to-hip ratio. Results were similar for subgroups of sex, ethnicity, and diabetes. Conclusions.— Increased participation in nonvigorous as well as overall and vigorous physical activity was associated with significantly higher S_I. These findings lend further support to current public health recommendations for increased moderate-intensity physical activity on most days.      

体外培养视网膜神经元电压门控钾离子通道特性的研究

目的探讨体外培养不同时期新生小牛视网膜神经元电压门控钾离子通道的特性。方法分别取培养2、4、6周的视网膜神经元,进行全细胞膜片钳记录,并进行统计学分析。结果去极化刺激可诱导3组细胞产生IK电流,各组检出率差异无统计学意义(P>0.05);随培养时间延长,IK电流平均峰值增高(P<0.05)。超极化刺激可诱导培养6周的部分细胞产生内向整流钾电流。结论体外培养新生小牛视网膜神经元表达不同电压门控钾电流。某些神经元的电生理学特性在不同培养阶段发生变化。     

Supplemental perioperative oxygen and the risk of surgical wound infection: a randomized controlled trial

Context  Supplemental perioperative oxygen has been variously reported to halve or double the risk of surgical wound infection. Objective  To test the hypothesis that supplemental oxygen reduces infection risk in patients following colorectal surgery. Design, Setting, and Patients  A double-blind, randomized controlled trial of 300 patients aged 18 to 80 years who underwent elective colorectal surgery in 14 Spanish hospitals from March 1, 2003, to October 31, 2004. Wound infections were diagnosed by blinded investigators using Centers for Disease Control and Prevention criteria. Baseline patient characteristics, anesthetic treatment, and potential confounding factors were recorded. Interventions  Patients were randomly assigned to either 30% or 80% fraction of inspired oxygen (FIO₂) intraoperatively and for 6 hours after surgery. Anesthetic treatment and antibiotic administration were standardized. Main Outcome Measures  Any surgical site infection (SSI); secondary outcomes included return of bowel function and ability to tolerate solid food, ambulation, suture removal, and duration of hospitalization. Results  A total of 143 patients received 30% perioperative oxygen and 148 received 80% perioperative oxygen. Surgical site infection occurred in 35 patients (24.4%) administered 30% FIO₂ and in 22 patients (14.9%) administered 80% FIO₂ (P=.04). The risk of SSI was 39% lower in the 80% FIO₂ group (relative risk [RR], 0.61; 95% confidence interval [CI], 0.38-0.98) vs the 30% FIO₂ group. After adjustment for important covariates, the RR of infection in patients administered supplemental oxygen was 0.46 (95% CI, 0.22-0.95; P = .04). None of the secondary outcomes varied significantly between the 2 treatment groups. Conclusions  Patients receiving supplemental inspired oxygen had a significant reduction in the risk of wound infection. Supplemental oxygen appears to be an effective intervention to reduce SSI in patients undergoing colon or rectal surgery. Trial Registration  ClinicalTrials.gov Identifier: NCT00235456      

Respiration during snow burial using an artificial air pocket

Context  Asphyxia is the most common cause of death after avalanche burial. A device that allows a person to breathe air contained in snow by diverting expired carbon dioxide (CO₂) away from a 500-cm³ artificial inspiratory air pocket may improve chances of survival in avalanche burial. Objective  To determine the duration of adequate oxygenation and ventilation during burial in dense snow while breathing with vs without the artificial air pocket device. Design  Field study of physiologic respiratory measures during snow burial with and without the device from December 1998 to March 1999. Study burials were terminated at the subject's request, when oxygen saturation as measured by pulse oximetry (SpO₂) dropped to less than 84%, or after 60 minutes elapsed. Setting  Mountainous outdoor site at 2385 m elevation, with an average barometric pressure of 573 mm Hg. Participants  Six male and 2 female volunteers (mean age, 34.6 years; range, 28-39 years). Main Outcome Measures  Burial time, SpO₂, partial pressure of end-tidal CO₂ (ETCO₂), partial pressure of inspiratory CO₂(PICO₂), respiratory rate, and heart rate at baseline (in open atmosphere) and during snow burial while breathing with the device and without the device but with a 500-cm³ air pocket in the snow. Results  Mean burial time was 58 minutes (range, 45-60 minutes) with the device and 10 minutes (range, 5-14 minutes) without it (P=.001). A mean baseline SpO₂ of 96% (range, 90%-99%) decreased to 90% (range, 77%-96%) in those buried with the device (P=.01) and to 84% (range, 79%-92%) in the control burials (P=.02). Only 1 subject buried with the device, but 6 control subjects buried without the device, decreased SpO₂ to less than 88% (P=.005). A mean baseline ETCO₂ of 32 mm Hg (range, 27-38 mm Hg) increased to 45 mm Hg (range, 32-53 mm Hg) in the burials with the device (P=.02) and to 54 mm Hg (range, 44-63 mm Hg) in the control burials (P=.02). A mean baseline PICO₂ of 2 mm Hg (range, 0-3 mm Hg) increased to 32 mm Hg (range, 20-44 mm Hg) in the burials with the device (P=.01) and to 44 mm Hg (range, 37-50 mm Hg) in the control burials (P=.02). Respiratory and heart rates did not change in burials with the device but significantly increased in control burials. Conclusions  In our study, although hypercapnia developed, breathing with the device during snow burial considerably extended duration of adequate oxygenation compared with breathing with an air pocket in the snow. Further study will be needed to determine whether the device improves survival during avalanche burial.      

Surgical site infection and the routine use of perioperative hyperoxia in a general surgical population: a randomized controlled trial

Context  Surgical site infection (SSI) in the general surgical population is a significant public health issue. The use of a high fractional inspired concentration of oxygen (FIO₂) during the perioperative period has been reported to be of benefit in selected patients, but its role as a routine intervention has not been investigated. Objective  To determine whether the routine use of high FIO₂ during the perioperative period alters the incidence of SSI in a general surgical population. Design, Setting, and Patients  Double-blind, randomized controlled trial conducted between September 2001 and May 2003 at a large university hospital in metropolitan New York City of 165 patients undergoing major intra-abdominal surgical procedures under general anesthesia. Interventions  Patients were randomly assigned to receive either 80% oxygen (FIO₂ of 0.80) or 35% oxygen (FIO₂ of 0.35) during surgery and for the first 2 hours after surgery. Main Outcome Measures  Presence of clinically significant SSI in the first 14 days after surgery, as determined by clinical assessment, a management change, and at least 3 prospectively defined objective criteria. Results  The study groups were closely matched in a large number of clinical variables. The overall incidence of SSI was 18.1%. In an intention-to-treat analysis, the incidence of infection was significantly higher in the group receiving FIO₂ of 0.80 than in the group with FIO₂ of 0.35 (25.0% vs 11.3%; P = .02). FIO₂ remained a significant predictor of SSI (P = .03) in multivariate regression analysis. Patients who developed SSI had a significantly longer length of hospitalization after surgery (mean [SD], 13.3 [9.9] vs 6.0 [4.2] days; P<.001). Conclusions  The routine use of high perioperative FIO₂ in a general surgical population does not reduce the overall incidence of SSI and may have predominantly deleterious effects. General surgical patients should continue to receive oxygen with cardiorespiratory physiology as the principal determinant.      

磷酸鞘胺醇受体在四氯化碳引起的肝纤维化小鼠肝脏的表达

目的研究四氯化碳(CCl4)引起的肝纤维化小鼠肝组织中的磷酸鞘胺醇(sphingosine 1-phosphate,S1P)受体1、2、3(S1P1-3)mRNA和蛋白含量的变化。方法制备小鼠CCl4肝纤维化模型,采用实时荧光定量聚合酶链反应方法测定小鼠肝组织S1P1-3mRNA表达情况;采用免疫印记(Western blotting)方法测定小鼠肝组织S1P1-3蛋白表达情况。结果CCl4诱导小鼠肝纤维化2周或4周后,与对照组相比,小鼠肝组织的S1P1mRNA的表达差异无统计学意义,而S1P2、S1P3mRNA的表达显著上调(P<0.05);与之相对应,S1P1的蛋白表达差异无统计学意义,而S1P2、S1P3的蛋白表达明显增加(P<0.05)。结论在CCl4引起的小鼠肝纤维化形成过程中,S1P、S1P在mRNA和蛋白水平均显著上调,表明S1P相关受体在肝纤维化发生过程中起重要作用。     

Human Cardiovascular and Metabolic Response to Acute, Severe Isovolemic Anemia

Context.— Although concern over the risks of red blood cell transfusion has resulted in several practice guidelines for transfusion, lack of data regarding the physiological effects of anemia in humans has caused uncertainty regarding the blood hemoglobin (Hb) concentration requiring treatment. Objective.— To test the hypothesis that acute isovolemic reduction of blood Hb concentration to 50 g/L in healthy resting humans would produce inadequate cardiovascular compensation and result in tissue hypoxia secondary to inadequate oxygen transport. Design.— Before and after interventional study. Setting.— Academic tertiary care medical center. Participants.— Conscious healthy patients (n=11) prior to anesthesia and surgery and volunteers not undergoing surgery (n=21). Interventions.— Aliquots of blood (450-900 mL) were removed to reduce blood Hb concentration from 131 (2) g/L to 50 (1) g/L [mean (SE)]. Isovolemia was maintained with 5% human albumin and/or autologous plasma. Cardiovascular parameters, arterial and mixed venous oxygen content, oxyhemoglobin saturation, and arterial blood lactate were measured before and after removal of each aliquot of blood. Electrocardiogram and, in a subset, Holter monitor were monitored continuously. Main Outcome Measures.— "Critical" oxygen delivery (TO₂) as assessed by oxygen consumption (O₂), plasma lactate concentration, and ST changes on electrocardiogram. Results.— Acute, isovolemic reduction of Hb concentration decreased systemic vascular resistance and TO₂ and increased heart rate, stroke volume, and cardiac index (each P<.001). We did not find evidence of inadequate oxygenation: O₂ increased slightly from a mean (SD) of 3.07 (0.44) mL of oxygen per kilogram per minute (mL O₂·kg^-1·min^-1) to 3.42 (0.54) Ml O₂·kg^-1·min^-1 (P<.001) and plasma lactate concentration did not change (0.81 [0.11] mmol/L to 0.62 [0.19] mmol/L;P=.09). Two subjects developed significant ST changes on Holter monitor: one apparently related to body position or activity, the other to an increase in heart rate (at an Hb concentration of 46-53 g/L); both occurred in young women and resolved without sequelae. Conclusions.— Acute isovolemic reduction of blood Hb concentration to 50 g/L in conscious healthy resting humans does not produce evidence of inadequate systemic TO₂, as assessed by lack of change of O₂ and plasma lactate concentration. Analysis of Holter readings suggests that at this Hb concentration in this resting healthy population, myocardial ischemia would occur infrequently.      

Effects of Raloxifene on Serum Lipids and Coagulation Factors in Healthy Postmenopausal Women

Context.— Raloxifene is a selective estrogen receptor modulator that has estrogen-agonistic effects on bone and estrogen-antagonistic effects on breast and uterus. Objective.— To identify the effects of raloxifene on markers of cardiovascular risk in postmenopausal women, and to compare them with those induced by hormone replacement therapy (HRT). Design.— Double-blind, randomized, parallel trial. Setting.— Eight sites in the United States. Participants.— 390 healthy postmenopausal women recruited by advertisement. Intervention.— Participants were randomized to receive 1 of 4 treatments: raloxifene, 60 mg/d; raloxifene, 120 mg/d; HRT (conjugated equine estrogen, 0.625 mg/d, and medroxyprogesterone acetate, 2.5 mg/d); or placebo. Main Outcome Measures.— Change and percent change from baseline of lipid levels and coagulation parameters after 3 months and 6 months of treatment. Results.— At the last visit completed, compared with placebo, both dosages of raloxifene significantly lowered low-density lipoprotein cholesterol (LDL-C) by 12% (P<.001), similar to the 14% reduction with HRT (P<.001). Both dosages of raloxifene significantly lowered lipoprotein(a) by 7% to 8% (P<.001), less than the 19% decrease with HRT (P<.001). Raloxifene increased high-density lipoprotein-2 cholesterol (HDL₂-C) by 15% to 17% (P<.05), less than the 33% increase with HRT (P<.001). Raloxifene did not significantly change high-density lipoprotein cholesterol (HDL-C), triglycerides, or plasminogen activator inhibitor-1 (PAI-1); whereas HRT increased HDL-C by 11% and triglycerides by 20%, and decreased PAI-1 by 29% (for all, P< .001). Raloxifene significantly lowered fibrinogen by 12% to 14% (P<.001), unlike HRT, which had no effect. Neither treatment changed fibrinopeptide A or prothrombin fragment 1 and 2. Conclusions.— Raloxifene favorably alters biochemical markers of cardiovascular risk by decreasing LDL-C, fibrinogen, and lipoprotein(a), and by increasing HDL₂-C without raising triglycerides. In contrast to HRT, raloxifene had no effect on HDL-C and PAI-1, and a lesser effect on HDL₂-C and lipoprotein(a). Further clinical trials are necessary to determine whether these favorable biochemical effects are associated with protection against cardiovascular disease.      

Effect of Prolonged Methylprednisolone Therapy in Unresolving Acute Respiratory Distress Syndrome: A Randomized Controlled Trial

Context.— No pharmacological therapeutic protocol has been found effective in modifying the clinical course of acute respiratory distress syndrome (ARDS) and mortality remains greater than 50%. Objective.— To determine the effects of prolonged methylprednisolone therapy on lung function and mortality in patients with unresolving ARDS. Design.— Randomized, double-blind, placebo-controlled trial. Setting.— Medical intensive care units of 4 medical centers. Participants.— Twenty-four patients with severe ARDS who had failed to improve lung injury score (LIS) by the seventh day of respiratory failure. Interventions.— Sixteen patients received methylprednisolone and 8 received placebo. Methylprednisolone dose was initially 2 mg/kg per day and the duration of treatment was 32 days. Four patients whose LIS failed to improve by at least 1 point after 10 days of treatment were blindly crossed over to the alternative treatment. Main Outcome Measures.— Primary outcome measures were improvement in lung function and mortality. Secondary outcome measures were improvement in multiple organ dysfunction syndrome (MODS) and development of nosocomial infections. Results.— Physiological characteristics at the onset of ARDS were similar in both groups. At study entry (day 9 [SD, 3] of ARDS), the 2 groups had similar LIS, ratios of PaO₂ to fraction of inspired oxygen (FIO₂), and MODS scores. Changes observed by study day 10 for methylprednisolone vs placebo were as follows: reduced LIS (mean [SEM], 1.7 [0.1] vs 3.0 [0.2]; P<.001); improved ratio of PaO₂ to FIO₂ (mean [SEM], 262 [19] vs 148 [35]; P<.001); decreased MODS score (mean [SEM], 0.7 [0.2] vs 1.8 [0.3]; P<.001); and successful extubation (7 vs 0; P=.05). For the treatment group vs the placebo group, mortality associated with the intensive care unit was 0 (0%) of 16 vs 5 (62%) of 8 (P=.002) and hospital-associated mortality was 2 (12%) of 16 vs 5 (62%) of 8 (P=.03). The rate of infections per day of treatment was similar in both groups, and pneumonia was frequently detected in the absence of fever. Conclusions.— In this study, prolonged administration of methylprednisolone in patients with unresolving ARDS was associated with improvement in lung injury and MODS scores and reduced mortality.