• 【低能电子诱导的早期物理和化学事件引起的DNA损伤的计算模型。】 复制标题 收藏 收藏
    DOI:10.1080/095530097143798 复制DOI
    作者列表:Nikjoo H,O'Neill P,Goodhead DT,Terrissol M
    BACKGROUND & AIMS: Modelling and calculations are presented as a first step towards mechanistic interpretation and prediction of radiation effects based on the spectrum of initial DNA damage produced by low energy electrons (100 eV-4.5 keV) that can be compared with experimental information. Relative yields of single and clustered strand breaks are presented in terms of complexity and source of damage, either by direct energy deposition or by reaction of OH radicals, and dependence on the activation probability of OH radicals and the amount of energy required to give a single strand break (ssb). Data show that the majority of interactions in DNA do not lead to damage in the form of strand breaks and when they do occur, they are most frequently simple ssb. However, for double-strand breaks (dsb), a high proportion (approximately 30%) are of more complex forms, even without considering additional complexity from base damage. The greater contribution is from direct interactions in the DNA but reactions of OH radicals add substantially to this, both in terms of the total number of breaks and in increasing the complexity within a cluster. It has been shown that the lengths of damaged segments of DNA from individual electron tracks tend to be short, indicating that consequent deletion length (simply by loss of a fragment between nearby dsb) would be short, very seldom exceeding a few tens of base pairs.

    背景与目标: 建模和计算是迈向机理解释和辐射效应预测的第一步,该过程基于低能电子(100 eV-4.5 keV)产生的初始DNA损伤的光谱,可以与实验信息进行比较。单链和簇状链断裂的相对产量通过复杂性和破坏源(通过直接能量沉积或OH自由基的反应)以及OH自由基的活化概率和产生单原子所需的能量的数量来表示。断链(ssb)。数据表明,DNA中的大多数相互作用都不会以链断裂的形式导致损伤,并且当它们发生时,它们通常是简单的单链断裂。但是,对于双链断裂(dsb),即使不考虑基础损伤带来的额外复杂性,也有较高比例(约30%)具有更复杂的形式。更大的贡献来自于DNA中的直接相互作用,但是OH自由基的反应在断裂总数和增加簇内复杂性方面都大大增加了这一点。已经显示,来自单个电子迹线的DNA的受损片段的长度趋于较短,表明随后的缺失长度(仅由于附近dsb之间的片段的丢失)将较短,很少很少超过几十个碱基对。 。

  • 【从俄罗斯图拉地区的监狱犯人中分离出的结核分枝杆菌中,耐多药的LAM和北京家族菌株占优势。】 复制标题 收藏 收藏
    DOI:10.1099/jmm.0.46575-0 复制DOI
    作者列表:Ignatova A,Dubiley S,Stepanshina V,Shemyakin I
    BACKGROUND & AIMS: :The genotypic characteristics and drug susceptibility profiles of clinical isolates of Mycobacterium tuberculosis recovered from prison hospital patients in the Tula region (central Russia) during 2001 and 2002 are reported. The emergence of multi-drug-resistant tuberculosis (TB) poses a major health risk to the population, with economic implications for TB control. Prisons serve as a continuous source of TB transmission. The results showed that members of the LAM and Beijing families are major contributors to the epidemiological picture of TB in the population studied. The two families of strains accounted for most of the drug-resistant TB in the population. The genotypic characteristics of the M. tuberculosis predominant LAM strain that was responsible for 31 % of TB cases in this setting are presented.
    背景与目标: :报告了2001和2002年从图拉地区(俄罗斯中部)的监狱医院患者中回收的结核分枝杆菌临床分离株的基因型特征和药物敏感性分布。耐多药结核病(TB)的出现给人们带来了重大的健康风险,对结核病控制产生了经济影响。监狱是结核病传播的持续来源。结果表明,LAM和北京家庭的成员是所研究人群中结核病流行病学特征的主要贡献者。菌株的两个家族占人口中大多数耐药结核病的比例。呈现了结核分枝杆菌占主导地位的LAM菌株的基因型特征,该菌株在这种情况下占31%的结核病病例。
  • 【氯氮平在帕金森氏病中治疗左旋多巴引起的精神病的回顾性研究。】 复制标题 收藏 收藏
    DOI:10.1177/089198879701000205 复制DOI
    作者列表:Widman LP,Burke WJ,Pfeiffer RF,McArthur-Campbell D
    BACKGROUND & AIMS: Levodopa-induced psychosis can complicate the treatment of Parkinson's disease (PD). In this retrospective, uncontrolled report, we describe our experience treating PD-related psychosis with clozapine, emphasizing those patients treated for longer than 1 year. Twenty-seven patients were treated, 14 for longer than 1 year. Most patients showed a rapid improvement from baseline within 1 month using the Clinical Global Impression and Global Psychosis Rating Scores. Five patients discontinued the drug due to side effects, but only two patients reported side effects after 6 months of treatment. Clozapine appears to be effective in treating PD related psychotic symptoms while not interfering with motor function.

    背景与目标: 左旋多巴引起的精神病会使帕金森氏病(PD)的治疗复杂化。在这份回顾性的,不受控制的报告中,我们描述了用氯氮平治疗PD相关性精神病的经验,强调那些接受治疗超过1年的患者。治疗了27例患者,其中14例的病程超过1年。使用临床总体印象和总体精神病评分分数,大多数患者在1个月内显示出从基线开始的快速改善。有5名患者由于副作用而停药,但只有2名患者在治疗6个月后报告了副作用。氯氮平似乎可以有效治疗PD相关的精神病症状,同时又不影响运动功能。

  • 【肿瘤诱导的前哨淋巴结免疫调节。】 复制标题 收藏 收藏
    DOI:10.1038/nri1919 复制DOI
    作者列表:Cochran AJ,Huang RR,Lee J,Itakura E,Leong SP,Essner R
    BACKGROUND & AIMS: :Sentinel lymph nodes (SLNs), being the first nodes to receive lymph from a primary tumour and the preferential site of initial tumour metastases, are intensively exposed to the bioactive products of tumour cells and other associated cells. This makes them ideal for studies of the factors that determine selective tissue susceptibility to metastases. We postulate that tumour-induced immune modulation of SLNs facilitates lymph-node metastases by inhibiting the generation of tumour-specific cytotoxic T cells that are active against tumour cells of primary and metastatic melanomas. Immune modulation of the lymph nodes can be reversed by granulocyte/macrophage colony-stimulating factor (GM-CSF), a finding that has implications for the future therapy of lymph-node metastases.
    背景与目标: 前哨淋巴结(SLNs)作为第一个从原发性肿瘤接受淋巴结和初始肿瘤转移的优先部位的淋巴结,被强烈暴露于肿瘤细胞和其他相关细胞的生物活性产物。这使它们成为研究决定选择性组织对转移的敏感性的因素的理想选择。我们推测,肿瘤诱导的SLNs免疫调节通过抑制对原发性和转移性黑素瘤的肿瘤细胞有活性的肿瘤特异性细胞毒性T细胞的产生而促进淋巴结转移。粒细胞/巨噬细胞集落刺激因子(GM-CSF)可逆转淋巴结的免疫调节作用,这一发现对未来淋巴结转移的治疗具有重要意义。
  • 【碳酸磷灰石引起的关节炎:多关节炎病例的考虑因素。】 复制标题 收藏 收藏
    DOI:10.1038/ncprheum0174 复制DOI
    作者列表:Blair-Levy JM
    BACKGROUND & AIMS: BACKGROUND:A 79-year-old woman was referred for evaluation of her painful and swollen joints. She had a medical history of congestive heart failure, renal insufficiency and peptic ulcer disease. For the past 3 years she had experienced recurrent bouts of debilitating arthritis, lasting approximately 3-4 weeks at a time. The symptoms were most severe in the hands and knees, where the joints were warm, swollen and tender. During each flare-up, the patient was housebound and required therapeutic dosing of nonsteroidal anti-inflammatory drugs and codeine to control joint pain. INVESTIGATIONS:Physical examination, fine-detailed radiographs of the hands, standing radiographs of the knees, arthrocentesis including cell count and gram stain, compensated polarized light microscopy, alizarin-red staining, X-ray diffraction, scanning and transmission electron microscopy with energy dispersive spectrometry, electron microprobe analysis with energy dispersive spectrometry, Fourier transform infrared spectroscopy, and atomic force microscopy. DIAGNOSIS:Carbonated-substituted apatite arthropathy. MANAGEMENT:Both knees were aspirated and large volumes of a straw-colored synovial fluid was removed. The knees were injected with corticosteroid, resulting in excellent symptomatic response.
    背景与目标: 背景:一名79岁的妇女被要求评估她的关节疼痛和肿胀。她有充血性心力衰竭,肾功能不全和消化性溃疡病的病史。在过去的三年中,她经历了反复发作的衰弱性关节炎发作,一次持续约3-4周。症状最严重的地方是手和膝盖,那里的关节温暖,肿胀和触痛。在每次发作期间,该患者待在屋内,需要非甾体抗炎药和可待因的治疗剂量以控制关节痛。
    调查:体格检查,手部细微X线照片,膝盖站立X线照片,关节穿刺术(包括细胞计数和革兰氏染色),补偿偏振光显微镜,茜素红染色,X射线衍射,扫描和透射电子显微镜(能量分散)光谱分析,带能量色散光谱的电子显微探针分析,傅立叶变换红外光谱和原子力显微镜。
    诊断:碳取代磷灰石关节炎。
    处理:吸除两个膝盖,并去除大量稻草色滑液。膝关节注射皮质类固醇激素,可产生出色的症状反应。
  • 【药物见解:男性激素避孕的最新进展。】 复制标题 收藏 收藏
    DOI:10.1038/ncpendmet0069 复制DOI
    作者列表:Amory JK,Page ST,Bremner WJ
    BACKGROUND & AIMS: :As there are limitations to current methods of male contraception, research has been undertaken to develop hormonal contraceptives for men, analogous to the methods for women based on estrogen and progestogens. When testosterone is administered to a man, it functions as a contraceptive by suppressing the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary gland. Since these hormones are the main stimulatory signals for spermatogenesis, low levels of LH and FSH markedly impair sperm production. After 3-4 months of testosterone treatment, 60-70% of men no longer have sperm in their ejaculate, and most other men exhibit markedly diminished sperm counts. Male hormonal contraception is well tolerated, free of serious adverse side effects, and 95% effective in the prevention of pregnancy. Importantly, male hormonal contraception is reversible, with sperm counts usually recovering within 4 months of the discontinuation of hormone treatment. Because exogenous testosterone administration alone does not completely suppress sperm production in all men, researchers have combined testosterone with second agents, such as progestogens or gonadotropin-releasing-hormone antagonists, to further suppress secretion of LH and FSH and improve suppression of spermatogenesis. Recent trials have used combinations of long-acting injectable or implantable forms of testosterone with progestogens, which can be administered orally, by injection or by a long-acting implant. Such combinations suppress spermatogenesis to zero without severe side effects in 80-90% of men, with near-complete suppression in the remainder of individuals. One of these testosterone and progestogen combination regimens might soon bring the promise of male hormonal contraception to fruition.
    背景与目标: :由于目前男性避孕方法的局限性,已经进行了研究以开发男性荷尔蒙避孕药,类似于基于雌激素和孕激素的女性避孕方法。当男人服用睾丸激素时,它通过抑制垂体促黄体生成激素(LH)和促卵泡激素(FSH)的分泌而起避孕作用。由于这些激素是精子发生的主要刺激信号,因此低水平的LH和FSH明显损害了精子的产生。经过3-4个月的睾丸激素治疗后,60-70%的男性不再有精子射精,其他大多数男性的精子数量也明显减少。男性荷尔蒙避孕药耐受性好,没有严重的不良副作用,并且95%的预防怀孕有效。重要的是,男性荷尔蒙避孕是可逆的,在停止激素治疗后的4个月内,精子数量通常会恢复。由于单独使用外源性睾丸激素并不能完全抑制所有男性的精子产生,因此研究人员已将睾丸激素与第二种药物(如孕激素或促性腺激素释放激素拮抗剂)联合使用,以进一步抑制LH和FSH的分泌并改善对精子发生的抑制作用。最近的试验已将长效可注射或可植入形式的睾丸激素与孕激素结合使用,可以口服,注射或长效植入物给药。这样的组合在80-90%的男性中将精子发生抑制为零而没有严重的副作用,而在其余个体中则几乎完全被抑制。这些睾丸激素和孕激素联合治疗方案之一可能很快会带来雄激素避孕的希望。
  • 【体外药物活性和药代动力学在预测抗分枝杆菌疗法有效性中的价值:一项重要综述。】 复制标题 收藏 收藏
    DOI:10.1097/00000441-199706000-00008 复制DOI
    作者列表:Burman WJ
    BACKGROUND & AIMS: Marked increases in case rates of drug-resistant tuberculosis and nontuberculous mycobacterial infections have brought renewed urgency to the development of new treatment regimens for mycobacterial infections. Preclinical data, such as in vitro measures of drug activity and pharmacokinetics, are used in the design of new treatment regimens. This review surveys the extensive published clinical experience concerning the treatment of drug-susceptible tuberculosis to evaluate the use of these preclinical measures in predicting clinical outcomes of antimycobacterial therapy. In vitro measures of drug activity predict the potency of a drug to prevent the emergence of resistance to other antimycobacterial drugs but do not predict the sterilizing activity of a drug or the activity of drug combinations. In vitro measures of drug activity do not allow reliable predictions of the level at which an organism should be considered resistant. Assays of drug penetration in tissues and activity against intracellular bacilli add modestly to the predictive value of in vitro measures of drug activity but still do not predict sterilizing activity. In contrast, animal models of tuberculosis have predicted relative drug potency (including sterilizing activity), the efficacy of multidrug regimens, and the duration of therapy needed. Despite pharmacokinetic parameters that would suggest the need for multiple doses per day, all of the first-line antituberculous drugs are active when given as infrequently as twice weekly. It is difficult to predict the efficacy of therapy for an intracellular pathogen that has the capacity for dormancy. Better in vitro models are needed, particularly ones that predict sterilizing activity.

    背景与目标: 耐药结核病和非结核分枝杆菌感染的病例率显着增加,这为开发针对分枝杆菌感染的新治疗方案带来了新的紧迫性。临床前数据,例如药物活性和药代动力学的体外测量,用于设计新的治疗方案。这篇综述调查了有关药物敏感性肺结核治疗的广泛发表的临床经验,以评估这些临床前措施在预测抗分枝杆菌治疗的临床结果中的应用。药物活性的体外量度可以预测药物对其他抗分枝杆菌药物产生抗药性的能力,但不能预测药物的灭菌活性或药物组合的活性。药物活性的体外测量不能可靠地预测应将生物体视为抗药性的水平。药物在组织中的渗透和针对细胞内细菌的活性的测定适度地增加了药物活性体外测量的预测价值,但仍不能预测灭菌活性。相反,结核病的动物模型预测了相对的药效(包括杀菌活性),多种药物疗法的疗效以及所需的治疗时间。尽管药代动力学参数表明每天需要多剂量,但每隔一周两次不频繁使用时,所有一线抗结核药物均具有活性。难以预测具有休眠能力的细胞内病原体的治疗效果。需要更好的体外模型,尤其是预测杀菌活性的模型。

  • 【进入三级医院内科病房的患者不良药物反应的直接费用和临床方面】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Tribiño G,Maldonado C,Segura O,Díaz J
    BACKGROUND & AIMS: INTRODUCTION:Adverse drug reactions (ADRs) occur frequently in hospitals and increase costs of health care; however, few studies have quantified the clinical and economic impact of ADRs in Colombia. OBJECTIVES:These impacts were evaluated by calculating costs associated with ADRs in patients hospitalized in the internal medicine ward of a Level 3 hospital located in Bogotá, Colombia. In addition, salient clinical features of ADRs were identified and characterized. MATERIAL AND METHODS:Intensive follow-ups for a cohort of patients were conducted for a five month period in order to detect ADRs; different ways to classify them, according to literature, were considered as well. Information was collected using the INVIMA reporting format, and causal probability was evaluated with the Naranjo algorithm. Direct costs were calculated from the perspective of payer, based on the following costs: additional hospital stay, medications, paraclinical tests, additional procedures, patient displacement to intermediate or intensive care units, and other costs. RESULTS:Of 836 patients admitted to the service, 268 adverse drug reactions were detected in 208 patients (incidence proportion 25.1%, occurence rate 0.32). About the ADRs found, 74.3% were classified as probable, 92.5% were type A, and 81.3% were moderate. The body system most often affected was the circulatory system (33.9%). Drugs acting on the blood were most frequently those ones associated with adverse reactions (37.6%). The costs resulting from medical care of adverse drug reactions varied from COL dollar 93,633,422 (USD dollar 35,014.92) to COL dollar 122,155,406 (USD dollar 45,680.94), according to insurance type, during the study period. CONCLUSIONS:Adverse drug reactions have a significant negative health and financial impact on patient welfare. Because of the substantial resources required for their medical care and the significant proportion of preventable adverse reactions, active programs of institutional pharmacovigilance are highly recommended.
    背景与目标: 简介:药物不良反应(ADR)在医院中经常发生,并增加了医疗保健费用;但是,很少有研究能够量化ADR在哥伦比亚的临床和经济影响。
    目的:通过计算在哥伦比亚波哥大三级医院内科病房住院的患者与ADR相关的费用来评估这些影响。此外,ADR的显着临床特征已得到鉴定和表征。
    材料与方法:对一组患者进行了为期五个月的强化随访,以检测ADR。根据文献,还考虑了不同的分类方法。使用INVIMA报告格式收集信息,并使用Naranjo算法评估因果概率。直接费用是根据以下费用从付款人的角度计算的:额外的住院时间,药物,辅助临床检查,其他程序,将患者转移到中级或重症监护室以及其他费用。
    结果:836例入院患者中,208例患者发生了268例药物不良反应(发生率25.1%,发生率0.32)。关于发现的ADR,有74.3%被归为可能,A型为92.5%,中度为81.3%。受影响最严重的身体系统是循环系统(33.9%)。作用于血液的药物最常见于那些与不良反应有关的药物(37.6%)。根据保险类型,在研究期间,药物不良反应的医疗费用从93,633,422美元(35,014.92美元)到122,155,406美元(45,680.94美元)不等。
    结论:药物不良反应会对患者的健康产生重大的负面健康和财务影响。由于其医疗服务所需的大量资源以及可预防的不良反应的比例很大,因此强烈建议积极进行机构药物警戒计划。
  • 【蛋白激酶D2通过NF-κB介导未转化的人结肠上皮细胞中溶血磷脂酸诱导的白介素8的产生。】 复制标题 收藏 收藏
    DOI:10.1152/ajpcell.00308.2006 复制DOI
    作者列表:Chiu TT,Leung WY,Moyer MP,Strieter RM,Rozengurt E
    BACKGROUND & AIMS: :The signaling pathways mediating lysophosphatidic acid (LPA)-stimulated PKD(2) activation and the potential contribution of PKD(2) in regulating LPA-induced interleukin 8 (IL-8) secretion in nontransformed, human colonic epithelial NCM460 cells were examined. Treatment of serum-deprived NCM460 cells with LPA led to a rapid and striking activation of PKD(2), as measured by in vitro kinase assay and phosphorylation at the activation loop (Ser706/710) and autophosphorylation site (Ser876). PKD(2) activation induced by LPA was abrogated by preincubation with selective PKC inhibitors GF-I and Ro-31-8220 in a dose-dependent manner. These inhibitors did not have any direct inhibitory effect on PKD(2) activity. LPA induced a striking increase in IL-8 production and stimulated NF-kappaB activation, as measured by NF-kappaB-DNA binding, NF-kappaB-driven luciferase reporter activity, and IkappaBalpha phosphorylation. PKD(2) gene silencing utilizing small interfering RNAs targeting distinct PKD(2) sequences dramatically reduced LPA-stimulated NF-kappaB promoter activity and IL-8 production. PKD(2) activation is a novel early event in the biological action of LPA and mediates LPA-stimulated IL-8 secretion in NCM460 cells through a NF-kappaB-dependent pathway. Our results demonstrate, for the first time, the involvement of a member of the PKD family in the production of IL-8, a potent proinflammatory chemokine, by epithelial cells.
    背景与目标: :审查了介导溶血磷脂酸(LPA)刺激的PKD(2)激活和PKD(2)在调节LPA诱导的非转化型人结肠上皮NCM460细胞中LPA诱导的白介素8(IL-8)分泌中的潜在作用。用体外LPA处理血清缺乏的NCM460细胞会导致PKD(2)迅速而惊人的活化,这是通过体外激酶测定和活化环(Ser706 / 710)和自磷酸化位点(Ser876)的磷酸化来测量的。通过与选择性PKC抑制剂GF-1和Ro-31-8220呈剂量依赖性方式进行预孵育,可以消除LPA诱导的PKD(2)激活。这些抑制剂对PKD(2)活性没有任何直接的抑制作用。如通过NF-κB-DNA结合,NF-κB驱动的萤光素酶报道分子活性和IkappaBalpha磷酸化所测量,LPA诱导IL-8产量显着增加并刺激NF-κB活化。 PKD(2)基因沉默利用针对不同的PKD(2)序列的小干扰RNA,大大降低了LPA刺激的NF-κB启动子活性和IL-8的产生。 PKD(2)激活是LPA的生物学作用中的一个新的早期事件,并通过NF-κB依赖性途径介导LCM刺激NCM460细胞中IL-8的分泌。我们的结果首次证明,上皮细胞参与了PKD家族成员参与IL-8(一种有效的促炎趋化因子)的生产。
  • 【白细胞介素8在亨通巴尔通体诱导的血管生成中的自分泌作用。】 复制标题 收藏 收藏
    DOI:10.1128/IAI.00622-06 复制DOI
    作者列表:McCord AM,Resto-Ruiz SI,Anderson BE
    BACKGROUND & AIMS: :The gram-negative bacterium Bartonella henselae is capable of causing angiogenic lesions as a result of infection. Previously, it has been shown that B. henselae infection can result in production of the chemokine interleukin-8 (IL-8). In this study, we demonstrated that monocytes, endothelial cells, and hepatocytes produce IL-8 in response to B. henselae infection. We also investigated the role of IL-8 in B. henselae-induced endothelial cell proliferation and capillary tube formation. Both in vitro angiogenesis assays were IL-8 dependent. B. henselae-mediated inhibition of apoptosis, as indicated by gene expression of Bax and Bcl-2, was also shown to be IL-8 dependent in endothelial cells. Furthermore, infection of endothelial cells with B. henselae stimulated upregulation of the IL-8 chemokine receptor CXCR2. Infection of human endothelial cells by B. henselae resulting in IL-8 production likely plays a central role in the ability of this organism to cause angiogenesis during infection.
    背景与目标: 革兰氏阴性细菌汉氏巴尔通体(Bartonella henselae)能够由于感染而引起血管生成性病变。以前,已经证明,亨氏芽孢杆菌感染可以导致趋化因子白介素8(IL-8)的产生。在这项研究中,我们证明了单核细胞,内皮细胞和肝细胞对B. henselae感染产生IL-8。我们还研究了IL-8在B. henselae诱导的内皮细胞增殖和毛细管形成中的作用。两种体外血管生成测定都是IL-8依赖性的。如Bax和Bcl-2的基因表达所表明的,B。henselae介导的凋亡抑制在内皮细胞中也显示为IL-8依赖性。此外,用汉逊芽孢杆菌感染内皮细胞刺激了IL-8趋化因子受体CXCR2的上调。亨氏芽孢杆菌对人内皮细胞的感染导致IL-8的产生可能在该生物体在感染过程中引起血管生成的能力中起着核心作用。
  • 【儿茶酚胺诱导的痛觉感受器在交感神经中维持疼痛。】 复制标题 收藏 收藏
    影响因子 :
    发表时间:2007-02-01
    来源期刊:Pain
    DOI:10.1016/j.pain.2006.08.022 复制DOI
    作者列表:Jørum E,Ørstavik K,Schmidt R,Namer B,Carr RW,Kvarstein G,Hilliges M,Handwerker H,Torebjörk E,Schmelz M
    BACKGROUND & AIMS: :Sympathetically maintained pain could either be mediated by ephaptic interactions between sympathetic efferent and afferent nociceptive fibers or by catecholamine-induced activation of nociceptive nerve endings. We report here single fiber recordings from C nociceptors in a patient with sympathetically maintained pain, in whom sympathetic blockade had repeatedly eliminated the ongoing pain in both legs. We classified eight C-fibers as mechano-responsive and six as mechano-insensitive nociceptors according to their mechanical responsiveness and activity-dependent slowing of conduction velocity (latency increase of 0.5+/-1.1 vs. 7.1+/-2.0 ms for 20 pulses at 0.125 Hz). Two C-fibers were activated with a delay of several seconds following strong endogenous sympathetic bursts; they were also excited for about 3 min following the injection of norepinephrine (10 microl, 0.05%) into their innervation territory. In these two fibers, a prolonged activation by injection of low pH solution (phosphate buffer, pH 6.0, 10 microl) and sensitization of their heat response following prostaglandin E2 injection were recorded, evidencing their afferent nature. Moreover, their activity-dependent slowing was typical for mechano-insensitive nociceptors. We conclude that sensitized mechano-insensitive nociceptors can be activated by endogenously released catecholamines and thereby may contribute to sympathetically maintained pain. No evidence for ephaptic interaction between sympathetic efferent and nociceptive afferent fibers was found.
    背景与目标: :交感神经维持的疼痛可能由交感传入和传入的伤害性纤维之间的神经元相互作用或儿茶酚胺诱导的伤害性神经末梢的激活介导。我们在这里报告了在交感神经痛患者中,C伤害感受器的单纤维记录,在该患者中,交感神经阻滞反复消除了双腿持续的疼痛。根据它们的机械响应性和依赖于传导速度的活动性减慢,我们将8根C纤维归为机械响应性伤害感受器,将6根C纤维归类为对机械响应不敏感的伤害感受器(20脉冲在0.125时延迟时间为0.5 /-1.1与7.1 /-2.0 ms的增加)赫兹)。在强烈的内源性交感神经爆发后,几秒钟的延迟激活了两根C纤维。在将去甲肾上腺素(10微升,0.05%)注入其神经支配区域后,他们还兴奋了约3分钟。在这两根纤维中,记录了通过注射低pH溶液(磷酸盐缓冲液,pH 6.0,10微升)而延长的活化作用以及注射前列腺素E2后对其热响应的敏化,证明了它们的传入性质。此外,它们对机械不敏感的伤害感受器的活动依赖性减慢作用是典型的。我们得出结论,致敏的对机械不敏感的伤害感受器可以被内源性释放的儿茶酚胺激活,从而可能有助于交感神经维持性疼痛。没有发现交感传入纤维和伤害性传入纤维之间的神经元相互作用的证据。
  • 【透皮硝化甘油连续或间歇治疗对有意识的兔子起搏诱导的预处理的影响。】 复制标题 收藏 收藏
    DOI:10.1038/sj.bjp.0701163 复制DOI
    作者列表:Szilvassy Z,Ferdinandy P,Nagy I,Jakab I,Koltai M
    BACKGROUND & AIMS: :1. Tolerance to the hypotensive effect of nitroglycerin (NG) blocks preconditioning induced by rapid ventricular pacing (RVP) in rabbits. In the present work the effect of continuous versus intermittent treatment with transdermal nitroglycerin on the pacing-induced preconditioning phenomenon was studied in conscious rabbits. 2. RVP (500 beats min-1 over 5 min) increased left ventricular end-diastolic pressure (LVEDP) from baseline 4.1 +/- 0.9 to postpacing 13.8 +/- 2.9 mmHg (P < 0.001) with a right intraventricular ST-segment elevation of 1.25 +/- 0.13 mV, two indicators of myocardial ischaemia. These changes were significantly attenuated when the RVP period was preceded by a preconditioning pacing of the same rate and duration with an interpacing interval of 5 min. 3. Protection by preconditioning was abolished when the animals had been made tolerant to the vasodilator effect of 30 micrograms kg-1 NG by the application of transdermal NG (approx. 0.07 mg kg-1 h-1) over 7 days. Furthermore, transdermal NG per se attenuated both RVP-induced ST-segment elevation and LVEDP-increase over the 7 day period. 4. With intermittent transdermal NG treatment (12 h 'patch on' vs 'patch off'), neither development of vascular tolerance nor attenuation of the NG- or preconditioning-induced anti-ischaemic effects were observed. However, the severity of pacing-induced myocardial ischaemia was significantly increased during the 'patch off' periods. 5. In a second set of experiments, postpacing changes in cardiac cyclic GMP and cyclic AMP levels were determined by means of radioimmunoassay in chronically instrumented anaesthetized open-chest rabbits with the same NG-treatment protocols. Preconditioning reduced postpacing increase in cyclic AMP with an increase in cyclic GMP concentrations in hearts of the untreated animals and in those given patches intermittently during both 'patch on' and 'patch off' periods. However, the preconditioning effect on either cyclic nucleotide was blocked in the tolerant animals. 6. Transdermal NG increased resting levels of both cardiac cyclic nucleotides in the non-tolerant but not in the tolerant state. The postpacing increase in cyclic AMP content was inhibited by transdermal NG, independent of vascular tolerance development, whereas an cyclic GMP content was exclusively seen in the non-tolerant animals. 7. We conclude that the anti-ischaemic effect of NG is independent of the cyclic GMP mechanism in the tolerant state. While intermittent NG therapy prevents development of vascular tolerance and preserves preconditioning, the nitrate-free periods yield an increased susceptibility of the heart to ischaemic challenges.
    背景与目标: :1。耐硝酸甘油(NG)的降压作用可阻止兔快速心室起搏(RVP)诱导的预处理。在目前的工作中,在有意识的兔子中研究了经皮硝酸甘油连续或间歇治疗对起搏诱发的预适应现象的影响。 2. RVP(5分钟内每分钟5次搏动)使左心室舒张末期压力(LVEDP)从基线4.1 /-0.9增加到后起搏13.8 /-2.9 mmHg(P <0.001),并且右室ST段抬高。 1.25 /-0.13 mV,是心肌缺血的两个指标。当在RVP周期之前以5分钟的间隔间隔进行相同速度和持续时间的预适应性起搏后,这些变化会大大减弱。 3.当通过在7天内施用透皮NG(约0.07 mg kg-1 h-1)使动物耐受30微克kg-1 NG的血管舒张作用时,取消了通过预处理的保护。此外,在7天内,透皮NG本身减弱了RVP诱导的ST段升高和LVEDP升高。 4.间歇性经皮NG治疗(12小时“贴片”与“贴片”),既未观察到血管耐受性的发展,也未观察到NG或预处理引起的抗局部缺血作用的减弱。但是,起搏期间,起搏诱发的心肌缺血的严重程度显着增加。 5.在第二组实验中,通过放射免疫测定法在具有相同NG处理方案的经慢性麻醉的开胸兔中测定心脏循环GMP和循环AMP水平的起搏变化。预处理可以减少循环AMP的起搏后增加,同时在“贴片”和“贴片”期间间歇地给未治疗的动物的心脏和那些间歇给予贴片的动物增加心脏中的循环GMP浓度。然而,在耐受性动物中,对任一环状核苷酸的预处理作用均被阻断。 6.经皮NG增加了非耐受性但非耐受性状态下两个心脏环状核苷酸的静息水平。循环AMP含量的起搏后增加受透皮NG抑制,与血管耐受性的发展无关,而环状GMP含量仅在非耐受性动物中可见。 7.我们得出结论,在耐受状态下,NG的抗缺血作用与循环GMP机制无关。间歇性NG治疗可防止血管耐受性发展并保留预处理,而无硝酸盐治疗期则增加了心脏对缺血性疾病的敏感性。
  • 【P物质氨基末端代谢产物在P物质引起的小鼠脱敏中的作用。】 复制标题 收藏 收藏
    DOI:10.1016/0306-4522(90)90003-3 复制DOI
    作者列表:Igwe OJ,Sun X,Larson AA
    BACKGROUND & AIMS: :Intrathecal injection of mice with substance P or its C-terminal fragments evokes a well documented behavioral syndrome characterized by caudally-directed biting and scratching. We have previously shown that repeated injections of substance P result in naloxone-sensitive desensitization to this substance P-induced behavior, possibly through interactions of N-terminal fragments of substance P with mu opiate binding sites. The present investigation tests the hypothesis that substance P metabolites play a role in the development of desensitization to substance P by using the biting and scratching behavioral paradigm. While substance P-induced behaviors are produced by as little as 1 pmol of substance P, repeated injections of 7.5 pmol at 60-s intervals was found to be the minimum dose capable of causing desensitization. The C-terminal peptides, substance P3-11 and substance P5-11, elicited substance P-like behaviors, but repeated injection of these compounds did not result in desensitization to this behavior. In contrast to C-terminal fragments, intrathecal injection of N-terminal fragments, (substance P1-4, substance P1-7 and substance P1-9), did not elicit any overt substance P-like behaviors when administered alone, but when co-administered with substance P, decreased the magnitude of substance P-induced behaviors in a dose-related fashion. Various peptidase inhibitors significantly inhibited the catabolism of co-administered substance P. Co-administration of substance P with peptidase inhibitors enhanced and prolonged the substance P-induced behavioral episode, but also prevented the development of substance P-induced desensitization. Together these results support the hypothesis that the accumulation of endogenously generated N-terminal metabolites of substance P mediate desensitization to substance P-induced behaviors in the spinal cord. Substance P metabolism may therefore decrease ongoing substance P activity both by the hydrolysis of the C-terminal portion of substance P as well as by the production of N-terminal metabolites that are capable of inhibiting the effects of substance P.
    背景与目标: 鞘内注射P物质或其C端片段会引起行为异常综合征,其特征是尾巴定向咬伤和抓挠。先前我们已经表明,重复注射P物质可能导致纳洛酮对P物质诱导的行为敏感,这可能是由于P物质的N末端片段与阿片结合位点的相互作用所致。本研究检验了以下假设,即物质P代谢产物通过使用咬和抓挠行为范式在对物质P脱敏的发展中起作用。虽然物质P诱导的行为仅由1 pmol的物质P产生,但发现以60秒的间隔重复注射7.5 pmol是能够引起脱敏的最小剂量。 C末端肽(物质P3-11和物质P5-11)引起了物质P样的行为,但是重复注射这些化合物不会导致对该行为的脱敏。与C末端片段相反,鞘内注射N末端片段(物质P1-4,物质P1-7和物质P1-9)在单独给药时不会引起任何明显的类似P的行为,但在共同给药时与物质P一起给药,以剂量相关的方式降低了物质P诱导的行为的幅度。各种肽酶抑制剂可显着抑制物质P共同给药的分解代谢。物质P与肽酶抑制剂的共同给药增强并延长了物质P引起的行为发作,但也阻止了物质P引起的脱敏。这些结果共同支持以下假设:内源性生成的P物质的N末端代谢产物的积累介导了对P物质诱导的脊髓行为的脱敏。因此,P物质的代谢可能会通过P物质C末端部分的水解以及产生能够抑制P物质作用的N末端代谢产物而降低正在进行的P物质活动。
  • 【吸毒规则:古代世界中的葡萄酒和罂粟衍生物。六。罂粟是食物和毒品的来源。】 复制标题 收藏 收藏
    DOI:10.3109/10826089709039375 复制DOI
    作者列表:Nencini P
    BACKGROUND & AIMS: :Poppies were widely used during antiquity as a source of food, therapeutics, and poisons. It is likely that the alimentary value of poppy seeds was known in the Neolithic age, and there is some evidence that the neuropsychopharmacological effects of poppy juice were exploited during the Minoan civilization in the eastern Mediterranean basin. The Minoan civilization dates the attribution to poppies of symbolic meanings connected with rites of agricultural fertility. The persistence throughout antiquity of this symbolism is testified by literary and iconographic evidence of the attribution of poppies to goddesses of fertility, such as Demeter, Aphrodite, and Ceres.
    背景与目标: :在古代,罂粟被广泛用作食物,治疗剂和毒药的来源。罂粟种子的营养价值很可能是在新石器时代就已经知道的,并且有一些证据表明,罂粟汁的神经心理药理作用是在地中海东部的米诺斯文明期间被利用的。米诺斯文明可追溯到象征意义的罂粟的归属,这些象征意义与农业生育的仪式有关。这种象征主义在整个上古时代的持久性通过文学和肖像学证据证明,罂粟归因于狄特耳特,阿芙罗狄蒂和谷神星等生育女神。
  • 【抗坏血酸对维生素E缺乏大鼠离体肾上腺细胞中ACTH诱导的环AMP形成和类固醇生成的影响。】 复制标题 收藏 收藏
    DOI:10.1016/0304-4165(75)90255-x 复制DOI
    作者列表:Nathans AH,Kitabchi AE
    BACKGROUND & AIMS: :Isolated adrenal cells from Vitamin E-deficient and control rats were prepared by a trypsin digestion method. Cyclic adenosine 3',5'-monophosphate (cyclic AMP) formation was studied in response to adrenocorticotropin (ACTH) in the presence and absence of ascorbate by measuring the conversion of prelabeled adenosine 5'-triphosphate [14C]ATP to cyclic [14C]AMP. Ascorbate (0.5 mM) inhibited ACTH-induced cyclic [14C]AMP formation in adrenal cells isolated from Vitamin E-deficient rats but had no effect in the control cells. The inhibitory effect of ascorbate on ACTH-induced cyclic AMP formation in Vitamin E-deficient rats decreased as the concentration of ACTH increased. In Vitamin E-deficient rats ascorbate inhibited ACTH-induced cyclic [14C]AMP formation after 30 min of incubation. There was no further significant accumulation of cyclic [14C]AMP at 60 min or 120 min although in the absence of ascorbate cyclic [14C]AMP continued to be formed. The in vitro addition of alpha-tocopherol reduced the inhibition of ACTH-induced cyclic [14C]AMP formation by ascorbate in Vitamin E-deficient rats. These studies suggest that alpha-tocopherol and ascorbate may affect ACTH-induced cyclic AMP formation through interaction with the membrane-bound enzyme adenylate cyclase.
    背景与目标: :通过胰蛋白酶消化方法,从维生素E缺乏和对照大鼠中分离出肾上腺细胞。通过测量预先标记的5'-三磷酸腺苷[14C] ATP向环状[14C]的转化,研究了存在和不存在抗坏血酸时对肾上腺皮质激素(ACTH)的响应,研究了环状腺苷3',5'-单磷酸(环状AMP)的形成AMP。抗坏血酸(0.5 mM)抑制ACTH诱导的从维生素E缺乏症大鼠分离的肾上腺细胞中环[14C] AMP的形成,但对对照细胞没有作用。随着ACTH浓度的增加,抗坏血酸对ACTH诱导的维生素E缺乏症大鼠环AMP形成的抑制作用降低。在维生素E缺乏的大鼠中,孵育30分钟后,抗坏血酸会抑制ACTH诱导的环状[14C] AMP的形成。尽管在不存在抗坏血酸盐的情况下仍继续形成环状[14C] AMP,但在60分钟或120分钟时没有进一步显着的环状[14C] AMP蓄积。在维生素E缺乏的大鼠中,体外添加α-生育酚可降低抗坏血酸对ACTH诱导的环[14C] AMP形成的抑制作用。这些研究表明,α-生育酚和抗坏血酸可能通过与膜结合酶腺苷酸环化酶相互作用而影响ACTH诱导的环AMP的形成。

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