BACKGROUND & AIMS: :A 43-year-old man developed a skin eruption characterized by 'macules with blisters' typical to Stevens-Johnson syndrome, as well as erosions of the lips and buccal mucosa, 2 weeks after he had started treatment with lamotrigine. He had a fever (39.6 degrees C), elevated liver enzymes and atypical lymphocytes in the peripheral blood. This undoubtedly reflects a case of Stevens-Johnson syndrome induced by lamotrigine, but it can also fulfill the criteria of anticonvulsant hypersensitivity syndrome or drug rash with eosinophilia and systemic signs. A case that precisely fits the definition of two syndromes that have different characteristics, different treatments and different prognoses indicates that there is a flaw in the classification.

背景与目标： ：开始使用拉莫三嗪治疗2周后，一名43岁的男子出现了以史蒂文斯-约翰逊综合症为特征的“具有水泡的斑疹”以及嘴唇和颊粘膜糜烂的皮肤疹。他发烧（39.6摄氏度），外周血肝酶和非典型淋巴细胞增多。这无疑反映了拉莫三嗪引起的史蒂文斯-约翰逊综合症，但它也可以满足抗惊厥超敏综合症或嗜酸性粒细胞增多和全身性症状的皮疹的标准。一个病例恰好符合两种具有不同特征，不同治疗方法和不同预后的综合症的定义，表明该分类存在缺陷。

BACKGROUND & AIMS: In parkinsonism, glutamate pathways within the basal ganglia become overactive, leading to the suggestion that glutamate antagonists might possess antiparkinsonian qualities. This report examines the motor properties of antagonists of NMDA and AMPA-type glutamate receptors, as well as some inhibitors of glutamate release, in animal models of idiopathic Parkinson's disease. High affinity NMDA open-channel blockers (e.g. MK 801, phencyclidine), are highly potent antagonists with inconsistent antiakinetic and strong myorelaxant activity. Other compounds are better tolerated and are capable of relieving immobility and muscular rigidity by themselves (e.g. 1-aminoadamantanes, polyamine site antagonists, kappa agonists, riluzole). Yet others do not restore movements alone (e.g. dextromethorphan, ketamine), but may interact with and strengthen the antiparkinsonian action of L-DOPA (e.g. competitive NMDA and AMPA antagonists, lamotrigine). They may do this by potentiating dopaminergic behaviours mediated by D1 or D2 receptors, or by some other mechanism.

背景与目标： 在帕金森病中，基底神经节内的谷氨酸途径变得过度活跃，从而提示谷氨酸拮抗剂可能具有抗帕金森病的特性。该报告检查了特发性帕金森氏病动物模型中NMDA和AMPA型谷氨酸受体的拮抗剂的运动特性，以及谷氨酸释放的某些抑制剂。高亲和力NMDA开放通道阻滞剂（例如MK 801，苯环利定）是高效抗药，具有抗运动活性不一致和强肌松活性。其他化合物具有更好的耐受性，并能自行缓解不动和肌肉僵硬（例如1-氨基金刚烷，多胺位点拮抗剂，κ激动剂，利鲁唑）。还有一些人不能单独恢复运动（例如右美沙芬，氯胺酮），而是可以与L-DOPA相互作用并增强其抗帕金森病作用（例如竞争性NMDA和AMPA拮抗剂，拉莫三嗪）。他们可以通过增强D1或D2受体或其他某种机制介导的多巴胺能行为来做到这一点。

BACKGROUND & AIMS: Interleukin-1 alpha (IL-1 alpha) induces cell motility in a variety of benign cell types and in some but not all malignant cell lines in vitro. This study characterizes the IL-1 alpha-induced motility of an aggressive human melanoma cell line that expresses both type I and type II IL-1 receptors. We tested the effect of monoclonal antibodies including function-blocking moAbs against the type I and type II IL-1 receptors on melanoma cell motility to determine which receptor is involved in signal transduction of IL-1 alpha-induced melanoma cell motility. IL-1 alpha significantly increases MM-RU melanoma cell migration in a dose-dependent manner using modified Boyden chamber assays at concentrations 10 to 100 times less than concentrations that significantly inhibit cell growth. Computer-assisted time-lapse image analysis reveals that the motility is inhibited in a dose-dependent manner by neutralizing antibodies against IL-1 alpha. Function-blocking monoclonal antibodies against either type I or type II IL-1 receptors show a significant inhibition of cytokine-induced enhanced cell migration. When both the anti-IL-1 receptor antibodies are added together, the motility-response is completely blocked to control levels. Taken together the data indicate that the IL-1 alpha-induced motility of MM-RU melanoma cells is mediated through both type I and type II IL-1 receptors. The significant inhibition of motility by neutralizing IL-1 alpha or blocking either one or both of the IL-1 receptors indicates an integration of IL-1-induced signals in the induction of melanoma cell migration.

背景与目标： 白细胞介素-1（IL-1 alpha）在多种良性细胞类型中以及某些但不是全部恶性细胞系中诱导细胞运动。这项研究的特点是表达I型和II型IL-1受体的侵略性人黑素瘤细胞系的IL-1α诱导的运动。我们测试了包括针对I型和II型IL-1受体的功能阻断性单抗的单克隆抗体对黑素瘤细胞运动的影响，以确定哪个受体参与了IL-1α诱导的黑素瘤细胞运动的信号转导。 IL-1α使用改良的Boyden室测定法以剂量依赖性方式显着增加MM-RU黑色素瘤细胞迁移，其浓度比明显抑制细胞生长的浓度低10至100倍。计算机辅助的延时图像分析表明，通过中和针对IL-1α的抗体，可以以剂量依赖性的方式抑制运动性。针对I型或II型IL-1受体的功能阻断性单克隆抗体显示出对细胞因子诱导的细胞迁移增强的显着抑制作用。当两种抗IL-1受体抗体一起添加时，运动反应完全被阻断至对照水平。数据合计表明，IL-1α诱导的MM-RU黑色素瘤细胞的运动是通过I型和II型IL-1受体介导的。通过中和IL-1α或阻断任何一个IL-1受体或两个IL-1受体来显着抑制运动性，这表明在黑素瘤细胞迁移的诱导中整合了IL-1诱导的信号。

BACKGROUND & AIMS: :Oral tolerance, an important feature of the mucosal immune system, appears to protect against immune-mediated disease by blunting production of systemic IgG and IgM antibody directed toward immunogens chronically present at mucosal surfaces. In this study, we explored the role of oral tolerance and mucosal immunoregulation in an experimental model of IgA nephropathy (IgAN), an important form of nephritis in humans. Cyclophosphamide and estradiol were used to inhibit the expression of oral tolerance, which otherwise develops after chronic oral presentation of Ag. BALB/c mice given drinking water containing 0.1% bovine gamma globulin (BGG) continuously for 14 wk were randomly assigned to groups given either 2 mg of cyclophosphamide i.p., 2 mg of estradiol s.c. or both drugs. Groups of control mice received neither BGG nor drugs. In three separate experiments, a low percentage of saline-treated orally immunized mice had microscopic hematuria (0 to 20%), as did nonimmunized controls (0 to 20%). However, 58 to 83% of mice given estradiol and/or cyclophosphamide at appropriate times developed significant hematuria. If drugs were given at suboptimal times, only 25 to 56% of mice developed hematuria. Drug-treated immunized mice also had more serum IgG and IgM anti-BGG antibodies than control and saline groups. Immunofluorescence showed significantly more glomerular deposits of IgG, IgM, and C3 in drug-treated immunized mice compared to saline-treated immunized and normal untreated control mice. Hematuria and glomerular deposits of IgG, IgM, and C3 paralleled serum IgG and IgM antibody. All immunized mice showed significant mesangial IgA and BGG deposits and there were no differences in such deposits between saline- and drug-treated immunized mice. We suggest that blunting of oral tolerance with promotion of systemic IgG and IgM antibody production leads to nephritis in chronically orally immunized mice and that glomerular immune complexes containing IgG and/or IgM promote complement deposition and hematuria in IgAN. Analogous defects in oral (or more generally mucosal) tolerance could play a role in the genesis of symptomatic human IgAN.

背景与目标： ：口腔耐受是粘膜免疫系统的一个重要特征，它似乎通过减弱针对长期存在于粘膜表面的免疫原的全身性IgG和IgM抗体的产生，来保护自身免受免疫介导的疾病的侵害。在这项研究中，我们探讨了口服耐受性和粘膜免疫调节在IgA肾病（IgAN）实验模型中的作用，IgA肾病是人类肾炎的一种重要形式。环磷酰胺和雌二醇被用来抑制口腔耐受的表达，否则这种耐受会在长期口服银后产生。连续14周连续喝含0.1％牛γ-球蛋白（BGG）的饮用水的BALB / c小鼠被随机分为两组，分别给予2 mg环磷酰胺i.p.，2 mg雌二醇s.c.或同时使用这两种药物。对照组小鼠既不接受BGG也不接受药物。在三个独立的实验中，经盐水处理的口服免疫小鼠中，有低百分比的患者有镜下血尿（0％至20％），而未免疫的对照小鼠则为0％至20％。但是，在适当的时间接受雌二醇和/或环磷酰胺的小鼠中有58％至83％出现了明显的血尿。如果在次佳的时间服用药物，则只有25％到56％的小鼠会出现血尿。药物治疗的免疫小鼠也比对照组和生理盐水组具有更多的血清IgG和IgM抗BGG抗体。与用盐水处理的免疫和正常未处理的对照小鼠相比，免疫荧光显示在药物处理的免疫小鼠中IgG，IgM和C3的肾小球沉积明显更多。血尿和IgG，IgM和C3的肾小球沉积物与血清IgG和IgM抗体平行。所有免疫的小鼠均表现出明显的肾小球系膜IgA和BGG沉积物，盐水和药物处理的免疫小鼠之间的沉积物无差异。我们建议通过口服全身免疫的小鼠促进全身性IgG和IgM抗体产生的口服耐受性减退会导致肾炎，而含有IgG和/或IgM的肾小球免疫复合物会促进IgAN中的补体沉积和血尿。口腔（或更常见的粘膜）耐受性的类似缺陷可能在有症状的人类IgAN的发生中起作用。

BACKGROUND & AIMS: :We have proposed a transdermal biolistic method to accelerate a powder formulation of drugs to penetrate human skin for the treatment of a range of diseases. One of the key issues for designing and evaluating transdermal biolistic system is ensuing that the powder drugs are delivered into the skin with a controllable velocity range and spatial distribution. The aerodynamics of supersonic nozzles and performance of the delivery system were initially studied, mainly analytically and experimentally. In this paper, computational fluid dynamics is utilized to characterize two existing prototype devices, in order to further investigate the transient gas and particle dynamics in their supersonic nozzles. To validate the implemented numerical approach, calculated pressure histories, two-dimensional flow structures and particle velocity distributions are made and compared with the reported experimental measurements. The key features of gas dynamics, gas-particle interaction and performance of the prototype transdermal biolistics are discussed and interpreted.

背景与目标： ：我们提出了一种透皮生物弹射法，以加速药物粉末制剂渗透人体皮肤，从而治疗多种疾病。设计和评估透皮生物弹药系统的关键问题之一是确保将粉末药物以可控制的速度范围和空间分布传递到皮肤中。最初主要是通过分析和实验研究超音速喷嘴的空气动力学和输送系统的性能。在本文中，利用计算流体动力学来表征两个现有的原型设备，以进一步研究其超音速喷嘴中的瞬态气体和粒子动力学。为了验证已实施的数值方法，计算了压力历史，二维流动结构和颗粒速度分布，并将其与报告的实验测量结果进行了比较。讨论并解释了气体动力学，气体-颗粒相互作用和原型透皮生物弹性能的关键特征。

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。 。

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。

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。

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。

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。

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。

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。

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。

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。

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。