• 【辛伐他汀对脂多糖诱导的肝脏微血管功能障碍的啮齿动物的影响。】 复制标题 收藏 收藏
    DOI:10.1002/hep.26127 复制DOI
    作者列表:La Mura V,Pasarín M,Meireles CZ,Miquel R,Rodríguez-Vilarrupla A,Hide D,Gracia-Sancho J,García-Pagán JC,Bosch J,Abraldes JG
    BACKGROUND & AIMS: UNLABELLED:Endothelial dysfunction drives vascular derangement and organ failure associated with sepsis. However, the consequences of sepsis on liver sinusoidal endothelial function are largely unknown. Statins might improve microvascular dysfunction in sepsis. The present study explores liver vascular abnormalities and the effects of statins in a rat model of endotoxemia. For this purpose, lipopolysaccharide (LPS) or saline was given to: (1) rats treated with placebo; (2) rats treated with simvastatin (25 mg/kg, orally), given at 3 and 23 hours after LPS/saline challenge; (3) rats treated with simvastatin (25 mg/kg/24 h, orally) from 3 days before LPS/saline injection. Livers were isolated and perfused and sinusoidal endothelial function was explored by testing the vasodilation of the liver circulation to increasing concentrations of acetylcholine. The phosphorylated endothelial nitric oxide synthase (PeNOS)/endothelial nitric oxide synthase (eNOS) ratio was measured as a marker of eNOS activation. LPS administration induced an increase in baseline portal perfusion pressure and a decrease in vasodilation to acetylcholine (sinusoidal endothelial dysfunction). This was associated with reduced eNOS phosphorylation and liver inflammation. Simvastatin after LPS challenge did not prevent the increase in baseline portal perfusion pressure, but attenuated the development of sinusoidal endothelial dysfunction. Treatment with simvastatin from 3 days before LPS prevented the increase in baseline perfusion pressure and totally normalized the vasodilating response of the liver vasculature to acetylcholine and reduced liver inflammation. Both protocols of treatment restored a physiologic PeNOS/eNOS ratio. CONCLUSION:LPS administration induces intrahepatic endothelial dysfunction that might be prevented by simvastatin, suggesting that statins might have potential for liver protection during endotoxemia.
    背景与目标: 未加标签:内皮功能障碍可导致败血症相关的血管紊乱和器官衰竭。然而,败血症对肝窦窦内皮功能的影响在很大程度上尚不清楚。他汀类药物可能会改善败血症中的微血管功能障碍。本研究探讨了内毒素血症大鼠模型中的肝血管异常和他汀类药物的作用。为此,将脂多糖(LPS)或盐水给予以下动物:(1)用安慰剂治疗的大鼠; (2)在LPS /盐水刺激后3和23小时给予辛伐他汀(25mg / kg,口服)治疗的大鼠; (3)从LPS /盐水注射前3天开始,用辛伐他汀(25 mg / kg / 24 h,口服)治疗的大鼠。分离并灌注肝脏,并通​​过测试肝循环的血管舒张作用以增加乙酰胆碱的浓度来探索正弦内皮功能。测量磷酸化内皮一氧化氮合酶(PeNOS)/内皮一氧化氮合酶(eNOS)的比率作为eNOS活化的标志。 LPS给药引起基线门静脉灌注压力增加,乙酰胆碱(正弦血管内皮功能障碍)的血管舒张减少。这与减少的eNOS磷酸化和肝脏炎症有关。 LPS刺激后的辛伐他汀不能阻止基线门静脉灌注压力的升高,但可以减轻正弦血管内皮功能障碍的发展。 LPS前3天开始用辛伐他汀治疗可防止基线灌注压力增加,并使肝血管对乙酰胆碱的血管舒张反应完全正常化,并减轻肝脏炎症。两种治疗方案均恢复了生理性PeNOS / eNOS比率。
    结论:LPS给药可引起辛伐他汀可预防肝内内皮功能障碍,这表明他汀类药物可能在内毒素血症期间具有保护肝脏的潜能。
  • 【染料木黄酮的长期给药可改善自发性高血压大鼠的内皮功能障碍:参与eNOS,小窝蛋白和钙调蛋白的表达以及NADPH氧化酶的活性。】 复制标题 收藏 收藏
    DOI:10.1042/CS20060185 复制DOI
    作者列表:Vera R,Sánchez M,Galisteo M,Villar IC,Jimenez R,Zarzuelo A,Pérez-Vizcaíno F,Duarte J
    BACKGROUND & AIMS: :The soya-derived phytoestrogen genistein has been suggested to be protective in cardiovascular diseases. In the present study, we have analysed whether chronic oral genistein might influence endothelial function in male SHRs (spontaneously hypertensive rats) via ERs (oestrogen receptors), changes in eNOS (endothelial NO synthase) activity and vascular O(2)(-) (superoxide) production. Rats (23-weeks old) were divided into the following groups: WKY (Wistar-Kyoto)-vehicle, SHR-vehicle, WKY-genistein (10 mg.kg(-1) of body weight.day(-1)); SHR-genistein; SHR-genistein-faslodex (ICI 182780; 2.5 mg.kg(-1) of body weight.day(-1)). Vascular expression of eNOS, caveolin-1 and calmodulin-1 were analysed by Western blotting, eNOS activity by conversion of [(3)H]arginine into L-[(3)H]citrulline and O(2)(-) production by chemoluminescence of lucigenin. In SHRs, after 5 weeks of treatment, genistein reduced systolic blood pressure and enhanced endothelium-dependent aortic relaxation to acetylcholine, but had no effect on the vasodilator responses to sodium nitroprusside. Compared with WKY rats, SHRs had up-regulated eNOS and down-regulated caveolin-1 and calmodulin-1 expression, increased NADPH-induced O(2)(-) production, but reduced eNOS activity. Genistein increased aortic calmodulin-1 protein abundance and eNOS activity, and reduced NADPH-induced O(2)(-) production in SHRs. The pure ERalpha and ERbeta antagonist faslodex did not modify any of the changes induced by genistein in SHRs, suggesting that these effects are unrelated to ER stimulation. In conclusion, genistein reduced the elevated blood pressure and endothelial dysfunction in SHRs. This latter effect appears to be related to increased eNOS activity associated with increased calmodulin-1 expression and decreased O(2)(-) generation.
    背景与目标: 大豆来源的植物雌激素染料木黄酮已被建议在心血管疾病中具有保护作用。在本研究中,我们分析了慢性口服染料木黄酮是否可能通过ER(雌激素受体),eNOS(内皮型NO合酶)活性和血管O(2)(-)(超氧化物)生产。将大鼠(23周龄)分为以下几组:WKY(Wistar-Kyoto)车辆,SHR车辆,WKY-染料木黄酮(10 mg.kg(-1)体重.day(-1)); SHR-染料木黄酮; SHR-genistein-faslodex(ICI 182780; 2.5 mg.kg(-1)体重.day(-1))。通过蛋白质印迹分析eNOS,caveolin-1和钙调蛋白-1的血管表达,通过将[(3)H]精氨酸转化为L-[(3H)]瓜氨酸和通过生成O(2)(-)来分析eNOS活性。发光素的化学发光。在SHR中,经过5周的治疗,金雀异黄素降低了收缩压,增强了内皮依赖性的主动脉对乙酰胆碱的舒张作用,但对血管扩张剂对硝普钠的反应没有影响。与WKY大鼠相比,SHRs上调了eNOS,下调了Caveolin-1和calmodulin-1的表达,增加了NADPH诱导的O(2)(-)的产生,但降低了eNOS的活性。金雀异黄素增加主动脉钙调蛋白1蛋白的丰度和eNOS的活性,并减少NADPH诱导SHRs中的O(2)(-)生产。单纯的ERalpha和ERbeta拮抗剂faslodex并未改变染料木黄酮在SHRs中诱导的任何变化,表明这些作用与ER刺激无关。总之,金雀异黄素减轻了SHRs的血压升高和内皮功能障碍。后者的作用似乎与增加的钙调蛋白-1表达和减少的O(2)(-)生成有关的eNOS活性有关。
  • 【甲状腺功能异常调节大鼠的糖调节机制。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Chakrabarti S,Guria S,Samanta I,Das M
    BACKGROUND & AIMS: :The role of the thyroid gland in glucose homeostasis remains incompletely understood. To get a better insight hypo-and hyperthyroid conditions were experimentally induced in rat and found severe defects in glucose homeostasis. While blood glucose level returned to normal level after 2.5 hr of oral glucose challenge in control rats the blood glucose level remained high even after 24 hr of glucose load in both hypo- and hyperthyroid rats. These experimentally manipulated rats displayed higher levels of liver glycogen (10.45-22.8-fold) and serum glutamic pyruvic transaminase (1.48-9.8-fold). Liver histology of hyperthyroid treated rats revealed hepatotoxicity. From the results it can be concluded that thyroid gland plays an important role in glucose homeostasis.
    背景与目标: :甲状腺在葡萄糖稳态中的作用仍未完全了解。为了更好地了解大鼠的甲状腺功能低下和甲状腺功能亢进症,并发现其体内葡萄糖稳态严重缺陷。在对照组大鼠口服葡萄糖2.5小时后血糖水平恢复到正常水平时,即使在甲状腺功能减退和甲状腺功能亢进的大鼠中,即使在葡萄糖加载24小时后,血糖水平仍保持较高水平。这些实验操作的大鼠显示出较高水平的肝糖原(10.45-22.8倍)和血清谷氨酸丙酮酸转氨酶(1.48-9.8倍)。甲亢治疗大鼠的肝脏组织学显示肝毒性。从结果可以得出结论,甲状腺在葡萄糖稳态中起重要作用。
  • 【短暂的右心室压力超负荷后,右心室功能障碍持续存在。】 复制标题 收藏 收藏
    DOI:10.1016/s0008-6363(97)00038-2 复制DOI
    作者列表:Greyson C,Xu Y,Cohen J,Schwartz GG
    BACKGROUND & AIMS: OBJECTIVE:Acute pulmonary hypertension may cause right ventricular (RV) contractile failure. While it has been assumed that restoration of normal loading conditions after acute pulmonary hypertension is sufficient for complete recovery of RV function, this has not been rigorously examined. The purpose of this study was to test the hypothesis that acute RV pressure overload produces RV contractile dysfunction that persists following restoration of control loading conditions. METHODS:We subjected 18 autonomically-blocked, chloralose-anesthetized, open-chest pigs to 1 h of pulmonary artery constriction to increase RV systolic pressure from 35 +/- 1 to 55 +/- 1 mmHg, followed by 2 h of measurements after pulmonary artery constriction release. We determined regional RV free wall function from pressure-segment length loops and preload recruitable stroke work relations, and global RV function from stroke work vs. end-diastolic pressure relations. RESULTS:As expected, RV free wall systolic shortening diminished during pulmonary artery constriction, but the endo/epi blood flow ratio, lactate uptake, and coronary venous pH were not significantly changed. Following release of pulmonary artery constriction, RV systolic and diastolic pressure returned to control values. Nonetheless, contractile dysfunction persisted, with depressed RV free wall systolic shortening (70 +/- 22% of control), RV regional external work (59 +/- 11% of control at control end-diastolic length), and global RV stroke work (56 +/- 14% of control at control end-diastolic pressure). Depressed regional work was due to a parallel, rightward shift of the preload recruitable stroke work relation. Five pigs identically instrumented but not subjected to pulmonary artery constriction showed no significant over 3 h. CONCLUSIONS:Acute pulmonary hypertension causes RV contractile dysfunction that persists at least 2 h after restoration of control loading conditions. Contractile dysfunction is not attributable to RV ischemia during pressure overload.
    背景与目标: 目的:急性肺动脉高压可能导致右心室(RV)收缩衰竭。尽管已经假定急性肺动脉高压后恢复正常负荷状态足以使RV功能完全恢复,但尚未对此进行严格检查。本研究的目的是检验以下假设:急性RV压力超负荷会导致RV收缩功能障碍,并在控制负荷条件恢复后持续存在。
    方法:我们对18头经氯醛糖麻醉的自闭式开胸猪进行了1小时的肺动脉收缩,以将RV收缩压从35 /-1增加到55 /-1 mmHg,然后在肺动脉进行2小时的测量收缩释放。我们从压力段长度环和预负荷可招募的卒中功关系中确定了区域RV无壁功能,并从卒中功与舒张末期压力关系中确定了整体RV功能。
    结果:正如预期的那样,在肺动脉收缩期间右室游离壁收缩期缩短减少,但是内/外血流量比,乳酸摄取和冠状静脉pH没有明显变化。释放肺动脉收缩后,RV收缩压和舒张压恢复至控制值。然而,收缩功能障碍持续存在,右室游离壁收缩期缩短(控制区的70 /-22%),右室局部外部工作(在控制舒张末期的控制区为59 /-11%)和整体右室卒中工作持续存在(56)在对照舒张末期压力下为对照的14%)。较低的区域工作量是由于预载可招募中风工作关系的平行,向右移动。五只相同仪器但未经历肺动脉收缩的猪在3 h内无明显变化。
    结论:急性肺动脉高压导致右室收缩功能障碍,在控制负荷恢复后至少持续2 h。压力超负荷期间收缩功能障碍不归因于RV缺血。
  • 【奥沙利铂在肝功能受损的成年癌症患者中的剂量递增和药理研究:美国国家癌症研究所器官功能障碍工作组的一项研究。】 复制标题 收藏 收藏
    DOI:10.1158/1078-0432.CCR-06-2385 复制DOI
    作者列表:Synold TW,Takimoto CH,Doroshow JH,Gandara D,Mani S,Remick SC,Mulkerin DL,Hamilton A,Sharma S,Ramanathan RK,Lenz HJ,Graham M,Longmate J,Kaufman BM,Ivy P,National Cancer Institute Organ Dysfunction Working Group.
    BACKGROUND & AIMS: PURPOSE:To determine the toxicities, pharmacokinetics, and maximally tolerated doses of oxaliplatin in patients with hepatic impairment and to develop formal guidelines for oxaliplatin dosing in this patient population. EXPERIMENTAL DESIGN:Sixty adult cancer patients with variable hepatic function received i.v. oxaliplatin ranging from 60 to 130 mg/m(2) every 3 weeks. Patients were stratified by levels of total bilirubin, aspartate aminotransferase (AST), and alkaline phosphatase (AP) into five cohorts based on the degree of hepatic dysfunction: control group A [bilirubin, AST, and AP < or = upper limit of normal (ULN)], mild dysfunction group B (bilirubin < or = ULN, ULN < AST < or = 2.5 x ULN, or ULN < AP < or = 5 x ULN), moderate dysfunction group C (ULN < bilirubin < or = 3.0 mg/dL, AST > 2.5 x ULN, or AP > 5 x ULN), severe dysfunction group D (bilirubin > 3.0 mg/dL, any AST, and any AP), and liver transplantation group E (any bilirubin, any AST, and any AP). Doses were escalated in cohorts of three patients, and urine and plasma ultrafiltrates were assayed for platinum concentrations. RESULTS:Dose escalation of single-agent oxaliplatin to 130 mg/m(2) was well tolerated in all cohorts. Platinum clearance did not correlate with any liver function test. Two of 56 assessable patients with a diagnosis of laryngeal carcinoma and cervical adenocarcinoma experienced partial responses lasting 3 and 5.5 months. CONCLUSIONS:Oxaliplatin at 130 mg/m(2) every 3 weeks was well tolerated in all patients with impaired liver function. Dose reductions of single-agent oxaliplatin are not indicated in patients with hepatic dysfunction.
    背景与目标: 目的:确定奥沙利铂在肝功能不全患者中的毒性,药代动力学和最大耐受剂量,并为该患者人群制定奥沙利铂剂量的正式指南。
    实验设计:60例肝功能可变的成年癌症患者接受了静脉内注射。奥沙利铂每3周从60到130 mg / m(2)不等。根据肝功能障碍的程度将患者按总胆红素,天冬氨酸转氨酶(AST)和碱性磷酸酶(AP)的水平分为五个队列:对照组A [胆红素,AST和AP <或=正常上限( ULN)],轻度功能障碍B组(胆红素<或= ULN,ULN 2.5 x ULN或AP> 5 x ULN),严重功能障碍D组(胆红素> 3.0 mg / dL,任何AST和任何AP)和肝移植E组(任何胆红素,任何AST和任何AP)。在三名患者的队列中增加剂量,并测定尿液和血浆超滤液的铂浓度。
    结果:在所有队列中,单药奥沙利铂的剂量递增都可耐受130 mg / m(2)。铂清除率与任何肝功能检查均不相关。在56例可诊断为喉癌和宫颈腺癌的可评估患者中,有2例的局部反应持续了3个月和5.5个月。
    结论:在所有肝功能受损的患者中,每3周服用130 mg / m(2)的奥沙利铂具有良好的耐受性。肝功能不全的患者未提示降低单药奥沙利铂的剂量。
  • 【糖尿病引起的脑血管功能障碍:聚(ADP-核糖)聚合酶的作用。】 复制标题 收藏 收藏
    DOI:10.1016/j.mvr.2006.08.001 复制DOI
    作者列表:Arrick DM,Sharpe GM,Sun H,Mayhan WG
    BACKGROUND & AIMS: :Our goal was to identify the role of poly(ADP-ribose) polymerase (PARP) in cerebrovascular dysfunction in Type 1 diabetes mellitus (T1D). In a first series of studies, rats were assigned to nondiabetic and diabetic (streptozotocin; 50 mg/kg IP) groups. Two to three months after injection of streptozotocin, we examine in vivo responses of pial arterioles to nitric oxide synthase (NOS)-dependent (adenosine diphosphate (ADP), acetylcholine and histamine) and -independent (nitroglycerin) agonists. After the initial examination of reactivity to the agonists, we treated pial arterioles acutely with an inhibitor of PARP (PJ-34; 1 microM), and then we again examined responses to the agonists. In a second series of studies, we examine superoxide production (lucigenin chemiluminescence) by parietal cortex tissue in nondiabetic and diabetic rats. We found that dilation of pial arterioles in response to ADP, acetylcholine and histamine, but not to nitroglycerin, was impaired in diabetic compared to nondiabetic rats. In addition, although PJ-34 did not alter responses in nondiabetic rats, PJ-34 alleviated T1D-induced impairment of NOS-dependent vasodilation. We also found that basal production of superoxide was increased in diabetic compared to nondiabetic rats and that PJ-34 decreased this basal production of superoxide. Our findings suggest that T1D impairs NOS-dependent reactivity of cerebral arterioles by a mechanism that appears to be related to the formation of superoxide via activation of PARP.
    背景与目标: :我们的目标是确定聚(ADP-核糖)聚合酶(PARP)在1型糖尿病(T1D)的脑血管功能障碍中的作用。在第一个系列研究中,将大鼠分为非糖尿病和糖尿病(链脲佐菌素; 50 mg / kg IP)组。注射链脲佐菌素后两到三个月,我们检查了小动脉对一氧化氮合酶(NOS)依赖性(二磷酸腺苷(ADP),乙酰胆碱和组胺)和非依赖性(硝酸甘油)激动剂的体内反应。初步检查与激动剂的反应性后,我们用PARP抑制剂(PJ-34; 1 microM)急性治疗了小动脉,然后再次检查了对激动剂的反应。在第二系列研究中,我们检查了非糖尿病和糖尿病大鼠顶叶皮质组织的超氧化物生成(荧光素化学发光)。我们发现,与非糖尿病大鼠相比,糖尿病患者对ADP,乙酰胆碱和组胺(而非对硝酸甘油)响应的小动脉小动脉扩张受到损害。此外,尽管PJ-34不会改变非糖尿病大鼠的反应,但PJ-34减轻了T1D诱导的NOS依赖性血管舒张功能受损。我们还发现,与非糖尿病大鼠相比,糖尿病患者的基础过氧化物含量增加,而PJ-34降低了基础过氧化物含量。我们的发现表明,T1D通过一种机制似乎削弱了NOS依赖性的脑小动脉反应性,该机制似乎与通过激活PARP形成超氧化物有关。
  • 【Th2分化对于由淋巴水肿引起的软组织纤维化和淋巴功能障碍是必需的。】 复制标题 收藏 收藏
    DOI:10.1096/fj.12-222695 复制DOI
    作者列表:Avraham T,Zampell JC,Yan A,Elhadad S,Weitman ES,Rockson SG,Bromberg J,Mehrara BJ
    BACKGROUND & AIMS: :Lymphedema is a dreaded complication of cancer treatment. However, despite the fact that >5 million Americans are affected by this disorder, the development of effective treatments is limited by the fact that the pathology of lymphedema remains unknown. The purpose of these studies was to determine the role of inflammatory responses in lymphedema pathology. Using mouse models of lymphedema, as well as clinical lymphedema specimens, we show that lymphatic stasis results in a CD4 T-cell inflammation and T-helper 2 (Th2) differentiation. Using mice deficient in T cells or CD4 cells, we show that this inflammatory response is necessary for the pathological changes of lymphedema, including fibrosis, adipose deposition, and lymphatic dysfunction. Further, we show that inhibition of Th2 differentiation using interleukin-4 (IL-4) or IL-13 blockade prevents initiation and progression of lymphedema by decreasing tissue fibrosis and significantly improving lymphatic function, independent of lymphangiogenic growth factors. We show that CD4 inflammation is a critical regulator of tissue fibrosis and lymphatic dysfunction in lymphedema and that inhibition of Th2 differentiation markedly improves lymphatic function independent of lymphangiogenic cytokine expression. Notably, preventing and/or reversing the development of pathological tissue changes that occur in lymphedema may be a viable treatment strategy for this disorder.
    背景与目标: :淋巴水肿是一种可怕的癌症治疗并发症。然而,尽管事实上有超过500万美国人受到这种疾病的影响,但淋巴水肿的病理学仍然未知,这限制了有效疗法的发展。这些研究的目的是确定炎症反应在淋巴水肿病理中的作用。使用小鼠模型的淋巴水肿,以及临床淋巴水肿标本,我们显示淋巴淤积导致CD4 T细胞炎症和T辅助2(Th2)分化。使用缺乏T细胞或CD4细胞的小鼠,我们表明这种炎症反应对于淋巴水肿的病理变化(包括纤维化,脂肪沉积和淋巴功能障碍)是必需的。此外,我们显示,使用白介素4(IL-4)或IL-13阻滞抑制Th2分化可通过减少组织纤维化并显着改善淋巴功能来防止淋巴水肿的发生和进展,而与淋巴管生成生长因子无关。我们显示,CD4炎症是淋巴水肿中组织纤维化和淋巴功能障碍的关键调节器,抑制Th2分化显着提高了淋巴功能,而与淋巴管生成细胞因子的表达无关。值得注意的是,预防和/或逆转在淋巴水肿中发生的病理组织改变的发展可能是该疾病的可行治疗策略。
  • 【泰国南部屋面纤维水泥工人的呼吸道症状和肺功能障碍模式。】 复制标题 收藏 收藏
    DOI:10.1539/joh.12-0122-oa 复制DOI
    作者列表:Thepaksorn P,Pongpanich S,Siriwong W,Chapman RS,Taneepanichskul S
    BACKGROUND & AIMS: OBJECTIVE:This study examined the associations between respiratory symptoms and patterns of pulmonary dysfunction of 115 male roofing cement workers compared with 134 unexposed subjects. METHODS:A cross-sectional study was conducted. Environmental samplings and spirometry measurements were also collected. RESULTS:The exposed workers had higher respiratory dust exposure levels (0.65 mg/m3) compared with the unexposed groups (0.32 mg/m3). The exposed group had significantly higher prevalence than the unexposed group for shortness of breath (OR=2.19). The exposed group also had higher but insignificant prevalence of chronic cough (OR=1.34), chest tightness (OR=1.64), and wheezing (OR=1.89). The ventilatory respiratory function values (FEV1 and FVC) were slightly lower for the exposed group. CONCLUSION:An association between higher cement dust levels and a decline in ventilatory function among roofing fiber cement workers suggests that the respiratory health of roofing cement workers should be protected through policies or work standards.
    背景与目标: 目的:本研究调查了115名男性屋面水泥工人与134名未暴露受试者的呼吸系统症状与肺功能障碍类型之间的关系。
    方法:进行横断面研究。还收集了环境采样和肺活量测定法。
    结果:暴露工人的呼吸粉尘暴露水平(0.65 mg / m3)高于未暴露组(0.32 mg / m3)。暴露组的呼吸困难患病率明显高于未暴露组(OR = 2.19)。暴露组的慢性咳嗽(OR = 1.34),胸闷(OR = 1.64)和喘息(OR = 1.89)的患病率也较高,但微不足道。暴露组的通气呼吸功能值(FEV1和FVC)略低。
    结论:屋面纤维水泥工人中较高的水泥粉尘含量与通风功能下降之间存在关联,这表明应通过政策或工作标准保护屋面水泥工人的呼吸健康。
  • 【左心室收缩功能不全患者小波变换模量最大值与心率的多重分形趋势波动分析的比较。】 复制标题 收藏 收藏
    DOI:10.1111/j.1542-474X.2008.00215.x 复制DOI
    作者列表:Galaska R,Makowiec D,Dudkowska A,Koprowski A,Chlebus K,Wdowczyk-Szulc J,Rynkiewicz A
    BACKGROUND & AIMS: BACKGROUND:In recent years the WTMM (wavelet transform modulus maxima) and MDFA (multifractal detrended fluctuation analysis) methods have become widely used techniques for the determination of nonlinear, multifractal heart rate (HR) dynamics. The purpose of our study was to compare multifractal parameters of heart rate calculated using both methods in a group of 90 patients with reduced left ventricular systolic function (rlvs group) and in a group of 39 healthy persons (nsr group). METHODS:For each subject from the rlvs group (LVEF < or =40%) and the nsr group, a 24-hour ECG Holter monitoring was performed. The width of the multifractal spectrum and global Hurst exponent were calculated by means of WTMM and MDFA methods for 5-hour daytime and nighttime subsets. RESULTS:The width of the multifractal spectrum was significantly lower and the Hurst exponent was significantly higher in rlvs group in comparison to nsr group both during diurnal activity and nocturnal rest according to MDFA and only during diurnal activity according to WTMM method. In both groups we observed significant differences of the multifractal spectrum width and the global Hurst exponent between the nighttime and daytime recordings. CONCLUSIONS:MDFA seems to be more sensitive as compared with WTMM method in differentiation between multifractal properties of the heart rate in healthy subjects and patients with left ventricular systolic dysfunction.
    背景与目标: 背景:近年来,WTMM(小波变换模极大值)和MDFA(多重分形趋势波动分析)方法已成为广泛用于确定非线性,多重分形心率(HR)动力学的技术。我们研究的目的是比较90例左室收缩功能降低的患者(rlvs组)和39例健康人的组(nsr组)使用两种方法计算的心率的多重分形参数。
    方法:对来自rlvs组(LVEF <或= 40%)和nsr组的每位受试者进行24小时ECG动态心电图监测。利用WTMM和MDFA方法,针对5小时的白天和夜间子集,计算了多重分形谱的宽度和整体赫斯特指数。
    结果:根据MDFA,rlvs组的昼夜活动和夜间休息时,多重分形谱的宽度明显小于nsr组,Hurst指数显着较高;仅根据WTMM方法,在昼间活动时,多重分形谱的宽度较nsr组高。在两组中,我们观察到夜间和白天记录之间的多重分形谱宽度和全局赫斯特指数存在显着差异。
    结论:与WTMM方法相比,MDFA在区分健康受试者和左室收缩功能不全患者的心率的多重分形特性方面似乎更为敏感。
  • 【自主神经功能紊乱,过敏和上呼吸道。】 复制标题 收藏 收藏
    DOI:10.1097/MOO.0b013e32826fbcc9 复制DOI
    作者列表:Loehrl TA
    BACKGROUND & AIMS: PURPOSE OF REVIEW:The autonomic nervous system has been implicated in the pathophysiology of chronic upper airway inflammatory disease for decades. We discuss the most recent literature with regard to autonomic nervous system dysfunction and chronic upper airway disease. RECENT FINDINGS:Recently, state of the art autonomic nervous system testing has demonstrated autonomic nervous system dysfunction in patients with chronic upper airway inflammatory disease. This dysfunction has been characterized as hypoadrenergic. SUMMARY:Autonomic nervous system dysfunction likely plays a role in chronic upper airway inflammatory disease. Further investigation may lead to a better understanding of the role of autonomic nervous system dysfunction in these disorders and, hence, opportunities for novel therapeutic modalities.
    背景与目标: 审查目的:数十年来,自主神经系统已被纳入慢性上呼吸道炎性疾病的病理生理中。我们讨论有关自主神经系统功能障碍和慢性上呼吸道疾病的最新文献。
    最近的发现:最近,最先进的自主神经系统测试已证明患有慢性上呼吸道炎性疾病的患者的自主神经系统功能异常。这种功能障碍的特征是肾上腺皮质功能低下。
    摘要:自主神经系统功能异常可能在慢性上呼吸道炎性疾病中起作用。进一步的研究可能会导致对这些疾病中自主神经系统功能障碍的作用有更好的了解,因此,有可能寻求新的治疗方法。
  • 【重新考虑使用国际勃起功能指数问卷来评估接受前列腺癌根治术患者的术前勃起功能状态。】 复制标题 收藏 收藏
    DOI:10.1111/j.1464-410X.2007.06898.x 复制DOI
    作者列表:Papadoukakis S,Kusche D,Stolzenburg JU,Truss MC
    BACKGROUND & AIMS: OBJECTIVE:To assess the use of the International Index of Erectile Function (IIEF), routinely used in patients being treated for localized prostate cancer, including potency-preserving, nerve-sparing radical prostatectomy (RP), as many patients complain that the results of the IIEF over 4 weeks before RP are not representative. PATIENTS AND METHODS:The study included 123 consecutive patients (mean age 64.6 years, range 52-78) who had endoscopic-extraperitoneal RP and who completed the IIEF. The interval between the diagnosis of the disease and surgery was >4 weeks in all. The patients completed the same questionnaire referring to the last 4 weeks before their prostate biopsy, as a modified index of their sexual status (IIEFm and EFm). RESULTS:The clinical stage of disease was cT1c (34.9%), cT2a (49.5%), cT2b (5.7%) and cT2c (9.9%) before RP. The mean IIEF score was 42.8 and the mean EF domain score was 16.9; the mean IIEFm was 54.9 and the EFm domain score was 23.7. All the differences were statistically significant (P < 0.001). CONCLUSION:The IIEF questionnaire scores are influenced by many factors. Depression after a diagnosis of cancer, and the prostate biopsy-related symptoms, e.g. prostatitis, perineal pain and haemospermia, might compromise the patients' well-being and libido, and thus affect the IIEF scores before RP. We therefore suggest using the IIEFm and EFm scores before prostate biopsy to assess the patients' sexual status before any treatment for localized prostate cancer.
    背景与目标: 目的:评估国际勃起功能指数(IIEF)的使用情况,该指数通常用于接受局部前列腺癌治疗的患者,包括保留效能,保留神经的根治性前列腺切除术(RP),因为许多患者抱怨RP之前4周内的IIEF不具有代表性。
    患者与方法:该研究纳入了123例内镜-腹膜外RP并完成IIEF的连续患者(平均年龄64.6岁,范围52-78)。疾病诊断与手术之间的间隔总计> 4周。患者在完成前列腺活检前的最后4周内填写了相同的问卷,作为其性状态的修正指标(IIEFm和EFm)。
    结果:RP前的临床分期为cT1c(34.9%),cT2a(49.5%),cT2b(5.7%)和cT2c(9.9%)。 IIEF平均得分为42.8,EF域平均得分为16.9;平均IIEFm为54.9,EFm域得分为23.7。所有差异均具有统计学意义(P <0.001)。
    结论:IIEF问卷的得分受许多因素影响。诊断出癌症后出现抑郁症,以及与前列腺活检相关的症状,例如前列腺炎,会阴痛和血精症可能会损害患者的健康和性欲,从而影响RP之前的IIEF评分。因此,我们建议在进行前列腺活检之前,先使用IIEFm和EFm评分来评估患者的性状况,然后再对局部前列腺癌进行任何治疗。
  • 【奈比洛尔的保护作用和逆转与高血压有关的糖尿病中的内皮功能障碍。】 复制标题 收藏 收藏
    DOI:10.1016/j.ejphar.2007.05.031 复制DOI
    作者列表:Georgescu A,Popov D,Dragan E,Dragomir E,Badila E
    BACKGROUND & AIMS: :This study aims to decipher the potential effects of nebivolol in prevention and/or regression of renal artery dysfunction in diabetes associated with hypertension. Renal arteries were isolated from 80 male mice divided into four experimental groups: (i) group D: diabetics, at 2 months since streptozotocin injection; (ii) group Din: mice that at the initiation of streptozotocin diabetes were treated with 10 mg/kg b.w./day nebivolol for 2 months, to test for the potential prevention of vascular dysfunction; (iii) group Dfin: mice that after 2 months of diabetes were treated daily with 10 mg/kg b.w./day nebivolol for additional 2 months, in order to follow the possible regression of the dysfunction, and (iv) controls (C), age-matched healthy animals. The following measurements were performed: arterial blood pressure, plasma glucose concentration, and the vascular reactivity of the renal arteries in response to noradrenaline (10(-4) M), acetylcholine (10(-4) M) and sodium nitroprusside (10(-4) M). To assess the molecular mechanisms involved in the reactivity of the renal artery, the contribution of mitogen-activated protein kinase (MAP kinase) pathway and of L-type voltage gated Ca(2+) channels (in the contractile response to noradrenaline), of nitric oxide (NO) and Ca(2+) activated K(+) channels (in the endothelium-dependent vasodilator response), and of cGMP (in the endothelium-independent vasodilator response) was examined by exposing the arteries to corresponding inhibitors, and by using myograph and patch-clamp techniques, immunoblotting and NO assays. Results showed that, group D was characterized by hyperglycemia (blood glucose concentration: 136.66 +/- 4.96 mg/dl, a value approximately 65% increased compared to group C) and hypertension (systolic blood pressure: 145.66 +/- 5.96 mm Hg, a value approximately 34% increased compared to group C). Compared to group D, group Din was characterized by diminished blood glucose concentration ( approximately 1.6 fold), reduced systolic and diastolic blood pressure ( approximately 1.3 fold) and heart rate ( approximately 1.6 fold), as well as by increased contractile response of the renal artery to noradrenaline ( approximately 1.84 fold) and of the impeded vasodilator response to acetylcholine ( approximately 1.81 fold) and sodium nitroprusside ( approximately 1.42 fold). Together, these effects demonstrate that administration of 10 mg/kg b.w./day nebivolol at the moment of diabetes induction has preventive effects, ameliorating diabetes dysfunctions. Compared to group D, group Dfin was characterized by diminished glucose concentration ( approximately 1.3 fold), reduced systolic and diastolic blood pressure and heart rate (both approximately 1.2 fold), and by augmentation of contractile response of the renal artery to noradrenaline ( approximately 1.62 fold) and of vasodilator response to acetylcholine ( approximately 1.13 fold) and sodium nitroprusside ( approximately 1.19 fold). These effects assess that administration of 10 mg/kg b.w./day nebivolol after 2 months of diabetes contributes to regression of diabetes-associated dysfunctionalies. Nebivolol influenced the molecular mechanisms involved in renal artery reactivity in diabetic and hypertensive mice: it increased the NO production and endothelial NO synthase (eNOS) protein expression, decreased the expression of proportional, variant protein in L-type calcium channels and Ca(2+) activated K(+) channels, and diminished the MAP kinase activity. The reported data suggest that nebivolol may offer additional vascular protection for treating diabetes associated with hypertension.
    背景与目标: :本研究旨在阐明奈必洛尔在与高血压相关的糖尿病中预防和/或预防肾动脉功能障碍的潜在作用。从80只雄性小鼠中分离肾动脉,将其分为四个实验组:(i)D组:糖尿病患者,注射链脲佐菌素后2个月; (ii)Din组:在链脲佐菌素糖尿病开始时,用10mg / kg b.w./天的奈必洛尔治疗小鼠2个月,以测试其潜在的预防血管功能障碍的能力; (iii)Dfin组:在糖尿病2个月后,每天接受10 mg / kg bw /天的奈必洛尔治疗的小鼠再持续2个月,以追踪功能障碍的可能消退;和(iv)对照组(C),年龄匹配的健康动物。进行了以下测量:动​​脉血压,血浆葡萄糖浓度和响应去甲肾上腺素(10(-4)M),乙酰胆碱(10(-4)M)和硝普钠(10(4 -4)M)。若要评估参与肾动脉反应的分子机制,有丝分裂原激活的蛋白激酶(MAP激酶)途径和L型电压门控的Ca(2)通道(对去甲肾上腺素的收缩反应),硝酸的贡献通过将动脉暴露于相应的抑制剂并通过使用肌电描记器来检查氧化物(NO)和Ca(2)激活的K()通道(在内皮依赖性血管舒张反应中)和cGMP(在内皮依赖性血管舒张反应中)和膜片钳技术,免疫印迹和NO分析。结果表明,D组的特征是高血糖症(血糖浓度:136.66 /-4.96 mg / dl,与C组相比,升高约65%)和高血压(收缩压:145.66 /-5.96 mm Hg,与C组相比,约增加了34%。与D组相比,Din组的特征在于血糖浓度降低(约1.6倍),收缩压和舒张压降低(约1.3倍)和心率(约1.6倍),以及肾脏的收缩反应增强动脉至去甲肾上腺素(约1.84倍),以及对乙酰胆碱(约1.81倍)和硝普钠(约1.42倍)的血管舒张反应受阻。这些作用加在一起表明在糖尿病诱发时给予10 mg / kg体重/天的奈必洛尔具有预防作用,可减轻糖尿病的机能障碍。与D组相比,Dfin组的特征是葡萄糖浓度降低(约1.3倍),收缩压和舒张压和心率降低(约1.2倍),以及肾动脉对去甲肾上腺素的收缩反应增强(约1.62)倍)和舒张剂对乙酰胆碱(约1.13倍)和硝普钠(约1.19倍)的反应。这些效果评估了糖尿病2个月后给予10 mg / kg b.w./天的奈比洛尔有助于糖尿病相关功能障碍的消退。奈必洛尔影响糖尿病和高血压小鼠肾动脉反应的分子机制:它增加了NO的产生和内皮NO合酶(eNOS)蛋白的表达,降低了L型钙通道和Ca(2)中比例蛋白,变异蛋白的表达。激活K()通道,并降低MAP激酶活性。报道的数据表明奈必洛尔可能为治疗高血压相关的糖尿病提供额外的血管保护作用。
  • 【与阿尔茨海默氏病相比,路易体痴呆患者更严重的功能障碍与锥体束外运动功能障碍有关。】 复制标题 收藏 收藏
    DOI:10.1097/01.JGP.0000216177.08010.f4 复制DOI
    作者列表:McKeith IG,Rowan E,Askew K,Naidu A,Allan L,Barnett N,Lett D,Mosimann UP,Burn D,O'Brien JT
    BACKGROUND & AIMS: OBJECTIVE:The objective of this study was to compare functional impairments in dementia with Lewy bodies (DLB) and Alzheimer disease (AD) and their relationship with motor and neuropsychiatric symptoms. METHODS:The authors conducted a cross-sectional study of 84 patients with DLB or AD in a secondary care setting. Patients were diagnosed according to published criteria for DLB and AD. The Bristol Activities of Daily Living Scale (BADLS) was used to assess functional impairments. Participants were also assessed using the Unified Parkinson's Disease Rating Scale (motor section), the Neuropsychiatric Inventory, and the Mini-Mental Status Examination. RESULTS:Patients with DLB were more functionally impaired and had more motor and neuropsychiatric difficulties than patients with AD with similar cognitive scores. In both AD and DLB, there were correlations between total BADLS scores and motor and neuropsychiatric deficits. There was more impairment in the mobility and self-care components of the BADLS in DLB than in AD, and in DLB, these were highly correlated with UPDRS score. In AD, orientation and instrumental BADLS components were most affected. CONCLUSION:The nature of functional disability differs between AD and DLB with additional impairments in mobility and self-care in DLB being mainly attributable to extrapyramidal motor symptoms. Consideration of these is important in assessment and management. Activities of daily living scales for use in this population should attribute the extent to which functional disabilities are related to cognitive, psychiatric, or motor dysfunction.
    背景与目标: 目的:本研究的目的是比较路易体(DLB)和阿尔茨海默氏病(AD)痴呆患者的功能障碍及其与运动和神经精神症状的关系。
    方法:作者进行了横断面研究,对84名患有DLB或AD的二级保健患者进行了研究。根据公布的DLB和AD标准诊断出患者。布里斯托尔日常生活活动量表(BADLS)用于评估功能障碍。还使用统一帕金森氏病评分量表(运动部分),神经精神病学量表和小精神状况检查对参与者进行了评估。
    结果:与认知评分相似的AD患者相比,DLB患者的功能障碍更严重,运动和神经精神障碍更大。在AD和DLB中,总BADLS评分与运动和神经精神病学缺陷之间存在相关性。与AD相比,DLB中BADLS的活动性和自我护理成分受损更多,而在DLB中,这些与UPDRS评分高度相关。在AD中,定向和工具BADLS组件受到的影响最大。
    结论:AD和DLB之间功能性残疾的性质不同,DLB的活动性和自我护理方面的其他损伤主要归因于锥体外系运动症状。在评估和管理中,考虑这些因素很重要。在该人群中使用的日常生活量表的活动应归因于功能障碍与认知,精神病或运动功能障碍相关的程度。
  • 【IV长春氟宁在患有肝功能异常的癌症患者中的I期和药代动力学研究。】 复制标题 收藏 收藏
    DOI:10.1007/s10637-012-9878-7 复制DOI
    作者列表:Delord JP,Ravaud A,Bennouna J,Fumoleau P,Favrel S,Pinel MC,Ferré P,Saliba F
    BACKGROUND & AIMS: :Vinflunine is a novel tubulin-targeted agent that is currently indicated as a monotherapy in bladder cancer patients. The recommended dose of 320 mg/m(2) is given as an intravenous infusion once every 3 weeks. Vinflunine is metabolized through CYP3A4 and mainly eliminated via the feces. A phase I trial was designed to explore the tolerability and pharmacokinetics of vinflunine in cancer patients with ranging degrees of liver dysfunction (LD). A sequential design was used for patient accrual, with the objective of determining the maximum tolerated dose (MTD) and the recommended dose (RD) of vinflunine in 3 groups of increasing LD levels. Vinflunine and its only active metabolite 4-O-deacetylvinflunine were quantified in serial whole blood samples. PK parameters were derived and compared between LD groups and with a reference PK database. Vinflunine and 4-O-deacetylvinflunine PK parameters were not affected in any of the explored LD levels. Geometric mean values for vinflunine total clearance were 47.8, 37.5 and 45.4 L/h in the 3 groups of increasing degrees of LD, as compared to 42.5 L/h in reference patients with no LD. No relationship was found between vinflunine clearance and the presence or absence of cirrhosis, nor was it found with the presence or absence of liver metastasis or with liver-related biochemical parameters. Based on the observed tolerability profile, the recommended doses of i.v. vinflunine are 320 mg/m(2), 250 mg/m(2) or 200 mg/m(2) for patients with increasing degrees of liver dysfunction.
    背景与目标: :长春氟宁是一种新型的微管蛋白靶向药物,目前被认为是膀胱癌患者的一种单一疗法。每3周一次静脉滴注,建议剂量为320 mg / m(2)。长春氟宁通过CYP3A4代谢,主要通过粪便消除。设计了一项I期试验,以研究长春氟宁在具有一定程度的肝功能不全(LD)的癌症患者中的耐受性和药代动力学。为了确定患者的累积量,采用了顺序设计,目的是确定3组LD水平升高的患者中长春氟宁的最大耐受剂量(MTD)和推荐剂量(RD)。在连续全血样品中对长春氟宁及其唯一的活性代谢物4-O-去乙酰长春氟宁进行了定量。得出PK参数,并在LD组之间与参考PK数据库进行比较。在任何探索的LD水平中,长春氟宁和4-O-去乙酰长春氟宁PK参数均不受影响。在3组LD升高程度较高的组中,长春氟宁总清除率的几何平均值为47.8、37.5和45.4 L / h,而没有LD的参考患者为42.5 L / h。在长春氟宁清除率与是否存在肝硬化之间未发现相关性,也未发现其与是否存在肝转移或与肝脏相关的生化参数有关。根据观察到的耐受性,推荐静脉注射剂量。对于肝功能异常程度增加的患者,长春氟宁为320 mg / m(2),250 mg / m(2)或200 mg / m(2)。
  • 【严重左心功能不全患者的冠脉血运重建。】 复制标题 收藏 收藏
    DOI:10.1016/j.athoracsur.2013.06.052 复制DOI
    作者列表:Nagendran J,Norris CM,Graham MM,Ross DB,Macarthur RG,Kieser TM,Maitland AM,Southern D,Meyer SR,APPROACH Investigators.
    BACKGROUND & AIMS: BACKGROUND:The efficacy of coronary artery bypass graft surgery (CABG) and percutaneous coronary intervention (PCI) in patients with coronary artery disease has been well defined by randomized controlled trials. However, patients with severe left ventricular dysfunction (ejection fraction <35%) were underrepresented in these trials, and management of these complex patients remains unclear. The purpose of this study was to compare the outcomes of patients with coronary artery disease and left ventricular dysfunction undergoing CABG versus PCI. METHODS:The Alberta Provincial Project for Outcome Assessment in Coronary Heart Disease (APPROACH), a clinical data collection and outcome monitoring initiative for the province of Alberta, Canada, was used to identify 2925 patients with coronary artery disease and left ventricular dysfunction undergoing CABG (n = 1,326) or PCI (n = 1,599) between 1995 and 2008. Patients were propensity matched to obtain comparable subgroups among left ventricular dysfunction patients. RESULTS:Cox proportional hazard analysis of the propensity-matched subgroups identified that CABG was significantly associated with lower rates of repeat revascularization and better survival compared with PCI at 1, 5, 10, and 15 years. Other significant independent predictors of poor long-term survival included age, renal failure, heart failure, diabetes mellitus, peripheral vascular disease, prior myocardial infarction, left main coronary artery disease, and prior CABG. CONCLUSIONS:For patients with coronary artery disease and left ventricular dysfunction, CABG was associated with lower rates of repeat revascularization and improved survival over PCI, after adjustment for baseline risk profile differences. Further research exploring the factors leading to use of a particular revascularization modality in this patient population is required.
    背景与目标: 背景:通过随机对照试验已经很好地定义了冠状动脉搭桥术(CABG)和经皮冠状动脉介入治疗(PCI)在冠心病患者中的疗效。但是,在这些试验中,严重左心功能不全(射血分数<35%)的患者代表性不足,对这些复杂患者的治疗仍不清楚。这项研究的目的是比较接受CABG与PCI的冠心病和左心功能不全患者的结局。
    方法:加拿大加拿大艾伯塔省的一项临床数据收集和结果监测计划-艾伯塔省冠心病结果评估项目(APPROACH)用于确定2925例冠状动脉疾病和左心功能不全的CABG患者(在1995年至2008年之间,n = 1,326)或PCI(n = 1,599)。患者的倾向性匹配,以在左心功能不全患者中获得可比的亚组。
    结果:倾向匹配亚组的Cox比例风险分析表明,与1、3.5、10、15和15年的PCI相比,CABG与较低的重复血运重建率和更好的生存率显着相关。长期生存不良的其他重要独立预测因素包括年龄,肾衰竭,心力衰竭,糖尿病,周围血管疾病,先前的心肌梗塞,左主冠状动脉疾病和先前的CABG。
    结论:对于患有冠心病和左心功能不全的患者,在调整基线风险谱差异后,CABG与较低的重复血运重建率和改善的PCI生存率相关。需要进一步研究探索导致在该患者人群中使用特定血运重建方式的因素。

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