• 【核苷 (酸) 类似物治疗对慢性乙型肝炎患者肝癌发生的影响: 倾向评分分析。】 复制标题 收藏 收藏
    DOI:10.1016/j.jhep.2012.10.025 复制DOI
    作者列表:Kumada T,Toyoda H,Tada T,Kiriyama S,Tanikawa M,Hisanaga Y,Kanamori A,Niinomi T,Yasuda S,Andou Y,Yamamoto K,Tanaka J
    BACKGROUND & AIMS: BACKGROUND & AIMS:Some patients with chronic hepatitis B virus (HBV) infection progress to hepatocellular carcinoma (HCC). However, the long-term effect of nucleos(t)ide analogue (NA) therapy on progression to HCC is unclear. METHODS:Therefore, we compared chronic hepatitis B patients who received NA therapy to those who did not, using a propensity analysis. RESULTS:Of 785 consecutive HBV carriers between 1998 and 2008, 117 patients who received NA therapy and 117 patients who did not, were selected by eligibility criteria and propensity score matching. Factors associated with the development of HCC were analyzed. In the follow-up period, HCC developed in 57 of 234 patients (24.4%). Factors significantly associated with the incidence of HCC, as determined by Cox proportional hazards models, include higher age (hazard ratio, 4.36 [95% confidence interval, 1.33-14.29], p=0.015), NA treatment (0.28 [0.13-0.62], p=0.002), basal core promoter (BCP) mutations (12.74 [1.74-93.11], p=0.012), high HBV core-related antigen (HBcrAg) (2.77 [1.07-7.17], p=0.036), and high gamma glutamyl transpeptidase levels (2.76 [1.49-5.12], p=0.001). CONCLUSIONS:NA therapy reduced the risk of HCC compared with untreated controls. Higher serum levels of HBcrAg and BCP mutations are associated with progression to HCC, independent of NA therapy.
    背景与目标:
  • 【MDMA (± 3,4-亚甲二氧基甲基苯丙胺) 辅助心理治疗治疗耐药性慢性创伤后应激障碍 (PTSD) 的随机对照试验研究。】 复制标题 收藏 收藏
    DOI:10.1177/0269881112464827 复制DOI
    作者列表:Oehen P,Traber R,Widmer V,Schnyder U
    BACKGROUND & AIMS: :Psychiatrists and psychotherapists in the US (1970s to 1985) and Switzerland (1988-1993) used MDMA legally as a prescription drug, to enhance the effectiveness of psychotherapy. Early reports suggest that it is useful in treating trauma-related disorders. Recently, the first completed pilot study of MDMA-assisted psychotherapy for PTSD yielded encouraging results. Designed to test the safety and efficacy of MDMA-assisted psychotherapy in patients with treatment-resistant PTSD; our randomized, double-blind, active-placebo controlled trial enrolled 12 patients for treatment with either low-dose (25 mg, plus 12.5 mg supplemental dose) or full-dose MDMA (125 mg, plus 62.5 mg supplemental dose). MDMA was administered during three experimental sessions, interspersed with weekly non-drug-based psychotherapy sessions. Outcome measures used were the Clinician-Administered PTSD Scale (CAPS) and the Posttraumatic Diagnostic Scale (PDS). Patients were assessed at baseline, three weeks after the second and third MDMA session (end of treatment), and at the 2-month and 1-year follow-ups. We found that MDMA-assisted psychotherapy can be safely administered in a clinical setting. No drug-related serious adverse events occurred. We did not see statistically significant reductions in CAPS scores (p = 0.066), although there was clinically and statistically significant self-reported (PDS) improvement (p = 0.014). CAPS scores improved further at the 1-year follow-up. In addition, three MDMA sessions were more effective than two (p = 0.016).
    背景与目标: : 美国 (20世纪70年代1985年) 和瑞士 (1988-1993) 的精神科医生和心理治疗师合法使用MDMA作为处方药,以提高心理治疗的有效性。早期报告表明,它在治疗创伤相关疾病中很有用。最近,第一个完成的MDMA辅助心理治疗PTSD的初步研究取得了令人鼓舞的结果。旨在测试MDMA辅助心理治疗在治疗耐药的PTSD患者中的安全性和有效性; 我们的随机,双盲,活性安慰剂对照试验招募了12名患者接受低剂量 (25 mg,加12.5 mg补充剂量) 或全剂量MDMA (125 mg,加62.5 mg补充剂量)。MDMA在三个实验课程中进行,并散布在每周的非基于药物的心理治疗课程中。使用的结果指标是临床医生管理的PTSD量表 (CAPS) 和创伤后诊断量表 (PDS)。在基线,第二次和第三次MDMA疗程 (治疗结束) 后三周以及2个月和1年随访时对患者进行评估。我们发现MDMA辅助心理治疗可以在临床环境中安全施用。未发生与药物相关的严重不良事件。尽管有临床和统计学上显着的自我报告 (PDS) 改善 (p = 0.066),但我们没有看到CAPS评分的统计学显着降低 (p = 0.014)。在1年的随访中,CAPS评分进一步提高。此外,三个MDMA会话比两个更有效 (p = 0.016)。
  • 【肺肺泡上皮II型细胞长期暴露于烟草特异性致癌物NNK导致恶性转化: 一种新的体外肺癌发生模型。】 复制标题 收藏 收藏
    DOI:10.1002/mc.21987 复制DOI
    作者列表:Mennecier G,Torres LN,Cogliati B,Sanches DS,Mori CM,Latorre AO,Chaible LM,Mackowiak II,Nagamine MK,Da Silva TC,Fukumasu H,Dagli ML
    BACKGROUND & AIMS: :Lung cancer is the leading cause of cancer-related mortality in both men and women throughout the world. This disease is strongly associated with tobacco smoking. The aim of this manuscript was to establish an in vitro model that mimics the chronic exposures of alveolar epithelial type II cells to the tobacco-specific nitrosamine carcinogen, NNK. Immortalized non-neoplastic alveolar epithelial cells type II, (E10 cells), from BALB/c mice were exposed to low concentration of NNK (100 pM) during 5, 10, 15, and 20 cycles of 48 h. NNK-transformed cells showed an increase of proliferation rate and motility. Moreover, these cells underwent epithelial-to-mesenchymal transition (EMT). Increased migratory capacity and EMT were correlated to the time of exposure to NNK. NNK-transformed cells were tested for their growth and metastatic capacity in vivo. Subcutaneous injection of cells exposed to NNK for 20 cycles (E10-NNK20 clone) into BALB/c mice led to the formation of subcutaneous tumors that arose after 40 ± 17 d in all animals, which died 95 ± 18 d after cell inoculation, with lymph nodes and lung metastasis. The morphological characteristics of tumors were compatible with metastatic undifferentiated carcinoma. Cells exposed to NNK for 5-10 cycles did not display metastatic capacity, while those exposed for 15 cycles displayed low capacity. Our results show that prolonged exposures to NNK led the cells to increasingly acquire malignant properties. The cellular model presented in this study is suitable for studying the molecular events involved in the different stages of malignant transformation.
    背景与目标: : 肺癌是全世界男性和女性癌症相关死亡率的主要原因。这种疾病与吸烟密切相关。本手稿的目的是建立一个体外模型,该模型模拟肺泡上皮II型细胞对烟草特异性亚硝胺致癌物NNK的慢性暴露。来自BALB/c小鼠的永生化的非肿瘤性II型肺泡上皮细胞 (E10细胞) 在48  h的5、10、15和20个周期中暴露于低浓度的NNK (100  pM)。NNK转化的细胞显示出增殖速率和运动能力的增加。此外,这些细胞经历了上皮-间质转化 (EMT)。迁移能力和EMT的增加与NNK暴露时间相关。测试NNK转化的细胞在体内的生长和转移能力。在BALB/c小鼠中皮下注射暴露于NNK 20个周期的细胞 (E10-NNK20克隆) 导致所有动物皮下肿瘤的形成,该肿瘤在40  ±   17 d后出现,在细胞接种后95  ±   18 d死亡,并伴有淋巴结和肺转移。肿瘤的形态特征与转移性未分化癌相容。暴露于NNK 5-10个周期的细胞未显示转移能力,而暴露于15个周期的细胞显示低容量。我们的结果表明,长时间暴露于NNK导致细胞越来越多地获得恶性特性。本研究中提出的细胞模型适用于研究恶性转化不同阶段涉及的分子事件。
  • 【以慢性护理为重点的医疗体系的途径: 来自西班牙的证据。】 复制标题 收藏 收藏
    DOI:10.1016/j.healthpol.2012.09.014 复制DOI
    作者列表:García-Goñi M,Hernández-Quevedo C,Nuño-Solinís R,Paolucci F
    BACKGROUND & AIMS: :Increasing healthcare expenditure is a matter of concern in many countries, particularly in relation to the underlying drivers of such escalation that include ageing, medical innovation, and changes in the burden of disease, such as the growing prevalence of chronic diseases. Most healthcare systems in developed countries have been designed to 'cure' acute episodes, rather than to 'manage' chronic conditions, and therefore they are not suitably or efficiently organized to respond to the changing needs and preferences of users. New models of chronic care provision have been developed to respond to the changing burden of disease and there is already considerable practical experience in several different countries showing their advantages but also the difficulties associated with their implementation. In this paper, we focus on the Spanish experience in terms of policy changes and pilot studies focused on testing the feasibility of moving towards chronic care models. In particular, we discuss a framework that identifies and analyses ten key prerequisites to achieving high performing chronic care-based healthcare systems and apply it to the current Spanish National Health System (NHS). We find that the design of the Spanish NHS already meets some of these pre-requisites. However, other features are still in their early stages of development or are being applied only in limited geographical and clinical contexts. We outline the policies that are being implemented and the pathway that the Spanish NHS is taking to address the crucial challenge of the transition towards an optimal health system focused on chronic care. Given the current evidence and trends, we expect that the pathway for developing a chronicity strategy being followed by the Spanish NHS will significantly transform its current healthcare delivery model in the next few years.
    背景与目标: : 在许多国家,医疗保健支出的增加是一个令人关注的问题,特别是在这种升级的潜在驱动因素方面,包括老龄化、医疗创新和疾病负担的变化,例如慢性病的日益流行。发达国家的大多数医疗保健系统旨在 “治愈” 急性发作,而不是 “管理” 慢性病,因此它们没有适当或有效地组织起来以应对用户不断变化的需求和偏好。已经开发了新的长期护理模式,以应对不断变化的疾病负担,几个不同国家已经有相当多的实践经验,显示了它们的优势,但也显示了与实施相关的困难。在本文中,我们着重于西班牙在政策变化方面的经验,并着重于测试转向慢性病模式的可行性的试点研究。特别是,我们讨论了一个框架,该框架确定并分析了实现高性能的基于慢性护理的医疗保健系统的十个关键先决条件,并将其应用于当前的西班牙国家卫生系统 (NHS)。我们发现西班牙NHS的设计已经满足了其中一些先决条件。但是,其他功能仍处于开发的早期阶段,或者仅在有限的地理和临床环境中应用。我们概述了正在实施的政策以及西班牙NHS为应对向以长期护理为重点的最佳卫生系统过渡的关键挑战而采取的途径。鉴于目前的证据和趋势,我们预计西班牙NHS遵循的制定慢性病策略的途径将在未来几年内显着改变其当前的医疗保健模式。
  • 【T细胞缺失骨髓移植后慢性粒细胞性白血病患者嵌合和白血病复发的细胞遗传学分析。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Offit K,Burns JP,Cunningham I,Jhanwar SC,Black P,Kernan NA,O'Reilly RJ,Chaganti RS
    BACKGROUND & AIMS: :Serial cytogenetic studies were performed on 64 patients with chronic myelogenous leukemia (CML) after T cell-depleted allogeneic bone marrow transplantation (BMT). Forty patients with CML in chronic phase (CP) received cytoreduction followed by BMT with HLA-matched T cell-depleted allogeneic marrow. The remaining 24 patients were transplanted in second chronic, accelerated, or blastic phase, or received T cell-depleted grafts with a dose of T cells added back. The Y chromosome and autosomal heteromorphisms were used to distinguish between donor and host cells. Mixed hematopoietic chimerism (presence of donor and host cells) was identified in 90% of patients in first CP. The Philadelphia (Ph) chromosome reappeared in 16 of the 40 first CP CML patients. As expected, patients who had detectable Ph chromosome positive cells at any time during the posttransplant period had a high likelihood of subsequent clinical relapse. Transient disappearance of the Ph positive clone was rarely observed, and was followed by reappearance of the Ph chromosome or clinical relapse. A subset of engrafted patients with greater than 25% host cells within 3 months post-BMT had a significantly shorter survival time free of cytogenetic or clinical relapse compared with other patients. In patients who had received donor T cells added to the T cell-depleted graft, there was a higher proportion of complete chimerism. Clonal progression of Ph positive as well as negative cells was observed and may be the result of radiation induced breakage. Serial cytogenetic studies of patients post-BMT can provide useful information regarding the biologic and clinical behavior of CML.
    背景与目标: : 在T细胞耗尽的同种异体骨髓移植 (BMT) 后,对64例慢性粒细胞性白血病 (CML) 患者进行了系列细胞遗传学研究。40例慢性期 (CP) 的CML患者接受了细胞减灭,然后接受了HLA匹配的T细胞耗尽的同种异体骨髓的BMT。其余24例患者被移植到第二个慢性,加速或母细胞期,或接受T细胞耗尽的移植物,并加回一定剂量的T细胞。Y染色体和常染色体异形被用来区分供体细胞和宿主细胞。在第一个CP的90% 患者中鉴定出混合的造血嵌合体 (供体和宿主细胞的存在)。费城染色体重新出现在40例第一批CP CML患者中的16例中。如预期的那样,在移植后的任何时候都具有可检测到的Ph染色体阳性细胞的患者随后临床复发的可能性很高。很少观察到Ph阳性克隆的瞬时消失,随后出现Ph染色体或临床复发。与其他患者相比,BMT后3个月内移植的宿主细胞大于25% 的患者亚群的无细胞遗传学或临床复发的生存时间明显更短。在接受T细胞耗尽移植物中添加了供体T细胞的患者中,完全嵌合的比例更高。观察到Ph阳性细胞和阴性细胞的克隆进程,这可能是辐射引起的破坏的结果。BMT后患者的一系列细胞遗传学研究可以提供有关CML生物学和临床行为的有用信息。
  • 【维生素d减少左心室肥厚和慢性肾脏疾病患者的左心房体积。】 复制标题 收藏 收藏
    DOI:10.1016/j.ahj.2012.09.018 复制DOI
    作者列表:
    BACKGROUND & AIMS: BACKGROUND:Left atrial enlargement, a sensitive integrator of left ventricular diastolic function, is associated with increased cardiovascular morbidity and mortality. Vitamin D is linked to lower cardiovascular morbidity, possibly modifying cardiac structure and function; however, firm evidence is lacking. We assessed the effect of an activated vitamin D analog on left atrial volume index (LAVi) in a post hoc analysis of the PRIMO trial (clinicaltrials.gov: NCT00497146). METHODS AND RESULTS:One hundred ninety-six patients with chronic kidney disease (estimated glomerular filtration rate 15-60 mL/min per 1.73 m(2)), mild to moderate left ventricular hypertrophy, and preserved ejection fraction were randomly assigned to 2 μg of oral paricalcitol or matching placebo for 48 weeks. Two-dimensional echocardiography was obtained at baseline and at 24 and 48 weeks after initiation of therapy. Over the study period, there was a significant decrease in LAVi (-2.79 mL/m(2), 95% CI -4.00 to -1.59 mL/m(2)) in the paricalcitol group compared with the placebo group (-0.70 mL/m(2) [95% CI -1.93 to 0.53 mL/m(2)], P = .002). Paricalcitol also attenuated the rise in levels of brain natriuretic peptide (10.8% in paricalcitol vs 21.3% in placebo, P = .02). For the entire population, the change in brain natriuretic peptide correlated with change in LAVi (r = 0.17, P = .03). CONCLUSIONS:Forty-eight weeks of therapy with an active vitamin D analog reduces LAVi and attenuates the rise of BNP. In a population where only few therapies alter cardiovascular related morbidity and mortality, these post hoc results warrant further confirmation.
    背景与目标:
  • 【慢性纳曲酮治疗可增加离散脑区域中前脑啡肽和前激肽mRNA的表达。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Tempel A,Kessler JA,Zukin RS
    BACKGROUND & AIMS: :Long-term blockade of brain opioid receptors by the opiate antagonist naltrexone increases methionine-enkephalin content in the striatum and nucleus accumbens (Tempel et al., 1984). To determine whether these changes in peptide levels reflect increased peptide synthesis, we examined preproenkephalin mRNA content in discrete brain regions of control (placebo-treated) and chronic naltrexone-treated animals by Northern analysis. Chronic naltrexone treatment (8 d) led to an approximately 12-fold increase in the striatal content of preproenkephalin mRNA relative to that of control animals. In contrast, no statistically significant change was observed in striatal mRNA for cyclophilin (1B15) or actin. Small increases in preproenkephalin mRNA content occurred in the hippocampus (+40%) and hypothalamus (+19%). No significant changes occurred in the frontal cortex. Increases in levels of the mRNA were seen as early as 24 hr after antagonist treatment. In contrast, changes in opioid receptor density required 3-4 d to reach half-maximal up-regulation after chronic antagonist treatment. Recent evidence has suggested that substance P is regulated by opioid peptides. To determine whether substance P synthesis is altered by chronic antagonist treatment, the mRNA corresponding to the precursor for substance P was examined using a probe for exon-7 of the preprotachykinin gene. Preprotachykinin mRNA content in the striatum was increased 6-fold after chronic antagonist treatment relative to that of control animals. Substance P content was increased 3-fold after chronic antagonist treatment. These data suggest that chronic blockade of brain opioid receptors leads to the increased synthesis of both enkephalin and substance P in the striatum and that these changes are relatively specific.(ABSTRACT TRUNCATED AT 250 WORDS)
    背景与目标: 鸦片拮抗剂纳曲酮对脑阿片受体的长期阻断增加纹状体和伏隔核中的蛋氨酸-脑啡肽含量 (Tempel等,1984)。为了确定肽水平的这些变化是否反映了肽合成的增加,我们通过Northern分析检查了对照组 (安慰剂治疗) 和慢性纳曲酮治疗动物的离散大脑区域中的前脑啡肽mRNA含量。与对照动物相比,慢性纳曲酮治疗 (8 d) 导致前脑啡肽前mRNA的纹状体含量增加了约12倍。相反,亲环蛋白 (1B15) 或肌动蛋白的纹状体mRNA未观察到统计学上的显着变化。前脑啡肽mRNA含量在海马 (+ 40%) 和下丘脑 (+ 19%) 中出现少量增加。额叶皮层无明显变化。早在拮抗剂治疗后24小时,就可以看到mRNA水平的升高。相比之下,慢性拮抗剂治疗后,阿片受体密度的变化需要3-4 d才能达到一半的最大上调。最近的证据表明,p物质受阿片肽调节。为了确定是否通过慢性拮抗剂治疗改变了p物质的合成,使用用于exon-7预速激肽基因的探针检查了对应于p物质前体的mRNA。与对照动物相比,慢性拮抗剂治疗后,纹状体中的促前激肽mRNA含量增加了6倍。慢性拮抗剂治疗后,p物质含量增加了3倍。这些数据表明,大脑阿片受体的慢性阻断导致纹状体中脑啡肽和p物质的合成增加,并且这些变化是相对特定的。(摘要截短于250字)
  • 【CD11c在慢性淋巴细胞白血病中的表达与并发症和生存有关。】 复制标题 收藏 收藏
    DOI:10.1111/ijlh.12695 复制DOI
    作者列表:Umit EG,Baysal M,Durmus Y,Demir AM
    BACKGROUND & AIMS: INTRODUCTION:Chronic lymphocytic leukemia (CLL) is a disorder of mature but dysfunctional monoclonal B cells. Microenvironment, antigenic stimulation and genetical mutations are demonstrated in etiopathogenesis. We aimed to evaluate the expression of CD11c in patients with CLL and its possible clinical significance. METHODS:Data of 259 patients with CLL between 2010 and 2016 in Trakya University Faculty of Medicine, including age at diagnosis, sex, whole blood count, stage, percentage of CLL cells in bone marrow, line of treatments, development of Richter's transformation and secondary tumors, autoimmune complications, IgG level, prognostic cytogenetic analysis, and length of survival were recorded from files. RESULTS:151 patients were male (58.3%) and 108 were male (41.7%). Mean age was 70 (21-92) years. CD11c was observed to be positive (>%20) in 103 patients (39.8%). Development of Richter's transformation, secondary tumors and ITP was significantly frequent in patients with CD11c positivity (P values .000, .003, .000 respectively). Also, IgG levels were significantly lower in this group (P = .000). Hemoglobin level, RAI stage and bone marrow CLL infiltration percentage were statistically related with CD11c (P values .036, .037, .000 respectively). Finally, CD11c was statistically related (in positive group 70 months, negative group 79 months, P = .001). CONCLUSION:CD11c, expressed not only in Hairy cell leukemia but also in dendritic cells, macrophages and monocytes is a differentiation marker for inflammation. Prolonged inflammation in the microenvironment of CLL cells may cause a susceptibility to autoimmune disorders and secondary tumors in CLL, in this way, an increase in mortality.
    背景与目标:
  • 【慢性边缘牙周炎患者牙髓变化的微观方面。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Caraivan O,Manolea H,Corlan Puşcu D,Fronie A,Bunget A,Mogoantă L
    BACKGROUND & AIMS: :Chronic periodontitis is one of the most frequent and severe diseases involving the tooth. Untreated, they can lead to tooth loss. Our study involved 67 patients with chronic marginal periodontitis who underwent tooth extraction, of which 29 had moderate periodontal lesions and 38 severe periodontal lesions. The microscopic study of the dental pulp revealed significant changes in all patients. In patients with moderate periodontitis the pulp tissue was found to be the site of an enhanced process of collagenous fibrosis associated with a moderate inflammatory infiltrate, dystrophic mineralization, reduced blood vascularization and arteriolosclerosis. The dental pulp of patients with severe periodontitis showed an abundant chronic inflammatory infiltrate associated with pulpal necrosis, vascular congestion, microhemorrhages, dentin demineralization and odontoblast impairment.
    背景与目标: : 慢性牙周炎是涉及牙齿的最常见和最严重的疾病之一。如果不治疗,它们会导致牙齿脱落。我们的研究涉及67例接受拔牙的慢性边缘牙周炎患者,其中29例患有中度牙周病变,38例患有严重牙周病变。牙髓的显微镜研究显示,所有患者均发生了显着变化。在中度牙周炎患者中,发现牙髓组织是胶原性纤维化过程增强的部位,与中度炎症浸润,营养不良矿化,血液血管化减少和动脉硬化相关。严重牙周炎患者的牙髓显示出大量的慢性炎症浸润,与牙髓坏死,血管充血,微出血,牙本质脱矿质和成牙本质损伤有关。
  • 【日本慢性丙型肝炎病毒的治疗: 治疗和指南的最新进展。】 复制标题 收藏 收藏
    DOI:10.1007/s00535-012-0714-9 复制DOI
    作者列表:Chayama K,Hayes CN,Ohishi W,Kawakami Y
    BACKGROUND & AIMS: :Hepatitis C virus (HCV) infection is a serious health problem leading to cirrhosis, liver failure and hepatocellular carcinoma. The recent introduction of telaprevir, which was approved in November 2011, in combination with peg-interferon and ribavirin is expected to markedly improve the eradication rate of the virus. However, side effects of triple therapy may be severe. In a phase three III clinical trial, 2250 mg of telaprevir, which is the same dosage used in clinical trials in Western countries, was given to Japanese patients. As this dosage is considered to be relatively high for Japanese patients, who typically have lower weight than patients in Western countries, reduction of telaprevir is recommended in the 2012 revision of the guidelines established by the Study Group for the Standardization of Treatment of Viral Hepatitis Including Cirrhosis published by the Ministry of Health, Labour and Welfare of Japan. Other protease inhibitors with fewer side effects are now in clinical trials in Japan. Alternatively, treatment of patients with combination of direct acting antivirals without interferon has been reported. In this review we summarize current treatment options in Japan and discuss how we treat patients with chronic HCV infection.
    背景与目标: 丙型肝炎病毒 (HCV) 感染是导致肝硬化,肝衰竭和肝细胞癌的严重健康问题。最近在2011年11月获得批准的telaprevir与peg-干扰素和利巴韦林联合使用,有望显着提高病毒的根除率。然而,三联疗法的副作用可能很严重。在一项三期临床试验中,向日本患者提供了2250毫克的telaprevir,与西方国家的临床试验中使用的剂量相同。由于这一剂量被认为是相对较高的日本患者,他们的体重通常低于西方国家的患者,建议减少telaprevir在2012修订的指南建立的标准化治疗病毒性肝炎包括肝硬化卫生部出版,日本的劳动和福利。其他副作用较少的蛋白酶抑制剂目前正在日本进行临床试验。或者,已经报道了使用无干扰素的直接作用抗病毒药物联合治疗的患者。在这篇综述中,我们总结了日本目前的治疗选择,并讨论了我们如何治疗慢性HCV感染患者。
  • 【染料木黄酮的慢性给药可改善自发性高血压大鼠的内皮功能障碍: eNOS,caveolin和钙调蛋白表达以及NADPH氧化酶活性的参与。】 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: : 大豆衍生的植物雌激素染料木黄酮被认为对心血管疾病具有保护作用。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ERs (雌激素受体),eNOS (内皮NO合酶) 活性的变化和血管O(2)(-) 影响雄性shr (自发性高血压大鼠) 的内皮功能 (超氧化物) 产生。将大鼠 (23周龄) 分为以下组: WKY (Wistar-Kyoto)-载体,SHR-载体,WKY-染料木黄酮 (10 mg.kg(-1) 体重)。天 (-1)); SHR-染料木黄酮; SHR-genistein-faslodex (ICI 182780; 体重2.5 mg.kg(-1) 天 (-1))。通过蛋白质印迹法分析eNOS,caveolin-1和calmodulin-1的血管表达,通过将 [(3)H] 精氨酸转化为L-[(3)H] 瓜氨酸和通过荧光素的化学发光产生O(2)(-) 的eNOS活性。在shr中,治疗5周后,金雀异黄素降低了收缩压,增强了内皮依赖性主动脉对乙酰胆碱的舒张作用,但对硝普钠的血管舒张反应没有影响。与WKY大鼠相比,SHRs上调了eNOS,下调了caveolin-1和calmodulin-1表达,增加了NADPH诱导的O(2)(-) 产生,但降低了eNOS活性。染料木黄酮增加了主动脉calmodulin-1蛋白丰度和eNOS活性,并降低了NADPH诱导的shr中O(2)(-) 的产生。纯的ERalpha和ERbeta拮抗剂faslodex没有改变由染料木黄酮在shr中诱导的任何变化,提示这些作用与ER刺激无关。总之,染料木黄酮降低了shr的血压升高和内皮功能障碍。后一种作用似乎与与calmodulin-1表达增加和O(2)(-) 生成减少相关的eNOS活性增加有关。
  • 【Fen1突变导致自身免疫,慢性炎症和癌症。】 复制标题 收藏 收藏
    DOI:10.1038/nm1599 复制DOI
    作者列表:Zheng L,Dai H,Zhou M,Li M,Singh P,Qiu J,Tsark W,Huang Q,Kernstine K,Zhang X,Lin D,Shen B
    BACKGROUND & AIMS: :Functional deficiency of the FEN1 gene has been suggested to cause genomic instability and cancer predisposition. We have identified a group of FEN1 mutations in human cancer specimens. Most of these mutations abrogated two of three nuclease activities of flap endonuclease 1 (FEN1). To demonstrate the etiological significance of these somatic mutations, we inbred a mouse line harboring the E160D mutation representing mutations identified in human cancers. Selective elimination of nuclease activities led to frequent spontaneous mutations and accumulation of incompletely digested DNA fragments in apoptotic cells. The mutant mice were predisposed to autoimmunity, chronic inflammation and cancers. The mutator phenotype results in the initiation of cancer, whereas chronic inflammation promotes the cancer progression. The current work exemplifies the approach of studying the mechanisms of individual polymorphisms and somatic mutations in cancer development, and may serve as a reference in developing new therapeutic regimens through the suppression of inflammatory responses.
    背景与目标: : FEN1基因的功能缺陷已被认为会导致基因组不稳定性和癌症易感性。我们已经在人类癌症标本中鉴定出一组FEN1突变。这些突变中的大多数消除了皮瓣内切核酸酶1 (FEN1) 的三个核酸酶活性中的两个。为了证明这些体细胞突变的病因学意义,我们自交了一个小鼠品系,该品系包含代表人类癌症中鉴定出的突变的E160D突变。核酸酶活性的选择性消除导致凋亡细胞中频繁的自发突变和不完全消化的DNA片段的积累。突变小鼠易患自身免疫,慢性炎症和癌症。突变表型会导致癌症的发生,而慢性炎症会促进癌症的发展。当前的工作举例说明了研究个体多态性和体细胞突变在癌症发展中的机制的方法,并且可以作为通过抑制炎症反应开发新的治疗方案的参考。
  • 【在高胰岛素血症,胰岛素抵抗和高血压大鼠中,用米贝拉地慢性T型Ca2通道阻断。】 复制标题 收藏 收藏
    DOI:10.1016/s0008-6363(97)00032-1 复制DOI
    作者列表:Verma S,Bhanot S,Hicke A,McNeill JH
    BACKGROUND & AIMS: OBJECTIVES:To determine the effects of calcium antagonists on hyperinsulinemia, hypertriglyceridemia and hypertension, we examined the long-term effects of a new calcium channel blocker, mibefradil, on plasma insulin levels, plasma triglyceride levels and systolic blood pressure in insulin-resistant and hyperinsulinemic fructose-hypertensive (FH) rats. To this aim, both prevention and reversal protocols were employed.

    METHODS:Prevention study: Male Sprague-Dawley rats were procured at 6 weeks of age and were divided into: control (C, n = 6), control-treated (CT, n = 5), fructose (F, n = 7) and fructose-treated (FT, n = 6). Baseline measurements of plasma glucose, insulin and systolic blood pressure were conducted in all groups. At week 7, chronic mibefradil treatment (30 mg/kg/day, orally for 6 weeks) was initiated in the CT and FT groups. At week 8, the rats in the F and FT groups were started on a 66% fructose diet to induce hyperinsulinemia and hypertension. Weekly measurements of plasma insulin, plasma triglycerides and systolic blood pressure were conducted for the following 4 weeks. Reversal protocol: In a separate study, 8-week-treated FH rats and their age-matched controls were used to examine the effects of mibefradil on reversing fructose-induced hyperinsulinemia and hypertension.

    RESULTS:The F group exhibited hyperinsulinemia (3.2 +/- 0.1 vs. C 2.3 +/- 0.07 ng/ml, P < 0.05), hypertension (148 +/- 3 vs. C 121 +/- 1 mmHg, P < 0.002) and elevated triglyceride levels (5.4 +/- 0.8 vs. C 1.6 +/- 0.3 mM, P < 0.05). Chronic mibefradil treatment prevented the development of hyperinsulinemia (1.6 +/- 0.08 ng/ml, P < 0.004 vs. F) and hypertension (123 +/- 1 mmHg. P < 0.001 vs. F) and attenuated the development of hypertriglyceridemia. In the reversal study, mibefradil treatment reversed the development of hyperinsulinemia, hypertriglyceridemia and elevated BP in FH rats. Treatment did not affect the plasma glucose levels in any group (prevention or reversal).

    CONCLUSIONS:Long-term treatment with the calcium antagonist, mibefradil, both prevents and reverses the development of hyperinsulinemia, hypertriglyceridemia and hypertension in FH rats. These data indicate beneficial effects of mibefradil on carbohydrate and lipid metabolism in hyperinsulinemic and insulin-resistant states.

    背景与目标: 目的 : 为了确定钙拮抗剂对高胰岛素血症,高甘油三酯血症和高血压的影响,我们检查了新型钙通道阻滞剂mibefradil对血浆胰岛素水平的长期影响,胰岛素抵抗和高胰岛素性果糖高血压 (FH) 大鼠的血浆甘油三酸酯水平和收缩压。为此,采用了预防和逆转方案。
    方法 : 预防研究: 雄性Sprague-Dawley大鼠在6周龄时被购买,并分为: 对照组 (C,n = 6),对照处理 (CT,n = 5),果糖 (F,n = 7) 和果糖处理 (FT,n = 6)。所有组均进行了血糖,胰岛素和收缩压的基线测量。在第7周时,CT和FT组开始了慢性mibefradil治疗 (30 mg/kg/天,口服6周)。在第8周,F和FT组的大鼠开始66% 果糖饮食以诱导高胰岛素血症和高血压。在接下来的4周内,每周测量血浆胰岛素,血浆甘油三酸酯和收缩压。逆转方案: 在一项单独的研究中,使用8周治疗的FH大鼠及其年龄匹配的对照组来检查米贝拉地对逆转果糖诱导的高胰岛素血症和高血压的作用。
    结果 : F组表现为高胰岛素血症 (3.2 +/- 0.1 vs. C 2.3 +/- 0.07 ng/ml,P <0.05),高血压 (148 +/- 3 vs. C 121 +/- 1 mmHg,P <0.002) 和甘油三酯水平升高 (5.4 +/- 0.8 vs. C 1.6 +/- 0.3 mM,P <0.05)。慢性米贝拉地尔治疗可防止高胰岛素血症 (1.6 +/- 0.08 ng/ml,P <0.004 vs. F) 和高血压 (123 +/- 1 mmHg。P <0.001 vs. F) 的发展,并减轻高甘油三酯血症的发展。在逆转研究中,米贝拉地尔治疗逆转了FH大鼠高胰岛素血症,高甘油三酯血症和BP升高的发展。治疗不会影响任何组的血浆葡萄糖水平 (预防或逆转)。
    结论 : 钙拮抗剂mibefradil的长期治疗都可以预防和逆转FH大鼠的高胰岛素血症,高甘油三酯血症和高血压。这些数据表明mibefradil在高胰岛素血症和胰岛素抵抗状态下对碳水化合物和脂质代谢的有益作用。
  • 【进入LORD试验的慢性肾脏病患者的饮食摄入量: 根据漏报进行调整。】 复制标题 收藏 收藏
    DOI:10.1053/j.jrn.2007.04.004 复制DOI
    作者列表:Fassett RG,Robertson IK,Geraghty DP,Ball MJ,Coombes JS
    BACKGROUND & AIMS: OBJECTIVE:The study objective was to determine the dietary intake of patients with chronic kidney disease before and after filtering for suspected underreporters and to investigate the impact of underreporting on the interpretation of diet data. DESIGN:This was a cross-sectional study. SETTING:The study included outpatients from hospitals and clinics in Northern Tasmania, Australia. PATIENTS:Data from 113 patients enrolled in the Lipid Lowering and Onset of Renal Disease trial were used in this study. Patients with serum creatinine greater than 120 mmol/L were included, and those taking lipid-lowering medication were excluded. METHODS:Patients completed a 4-day self-report diet diary, and FoodWorks software was used to determine their daily intake of energy, macronutrients, and specific micronutrients. Diet diaries were assessed for likely underreporting using the Goldberg cutoff approach with a ratio of energy intake to estimated resting energy expenditure of 1.27. Nutrient intakes were compared with current National Kidney Foundation's Kidney Disease Outcomes Quality Initiative guidelines, World Health Organization recommendations, recommended daily allowances, and daily values adjusted for energy intake. RESULTS:Demographics of the patients were as follows: male/female, 71/42; age (mean +/- standard deviation), 60 +/- 15 years; body mass index, 28.6 +/- 6.0 kg/m(2), and serum creatinine, 223.4 +/- 110.0 mmol/L. According to the criteria, 80 patients (70.8%) were underreporting their energy intake. Underreporters were more likely to be female and younger, and have a higher body mass index and elevated serum creatinine. In all patients, daily energy intake (89.6 +/- 32.4 kJ/kg) was lower than recommended (125-145 kJ/kg); however, this was not the case for valid reporters (128.3 +/- 23.7 kJ/kg). Protein intake was higher (0.9 +/- 0.3 g/kg) than recommended (0.75 g/kg) in all patients and even higher (1.2 +/- 0.3 g/kg) in valid reporters. Mean calcium, zinc, and dietary fiber intakes were all below recommendations in all patients, but these differences were not apparent in valid reporters. CONCLUSION:Interpreting self-report diet diary data from patients with chronic kidney disease without attempting to exclude underreporters will lead to erroneous conclusions, especially in respect to energy, protein, dietary fiber, calcium, and zinc intakes.
    背景与目标:
  • 【在患有透析的慢性肾脏病患者中实施铁管理临床实践指南。】 复制标题 收藏 收藏
    DOI:10.5694/j.1326-5377.2006.tb00584.x 复制DOI
    作者列表:Irving MJ,Craig JC,Gallagher M,McDonald S,Polkinghorne KR,Walker RG,Roger SD
    BACKGROUND & AIMS: OBJECTIVE:To evaluate the outcomes of and barriers to implementing standard guidelines (Caring for Australasians with renal impairment [CARI]), using iron management in patients having dialysis as an example. DESIGN AND SETTING:On-site review of iron management processes at six Australian dialysis units varying in size and locality. Patients' iron indices and haemoglobin levels were obtained from the Australian and New Zealand Dialysis and Transplant Registry. PARTICIPANTS:Patients with chronic kidney disease who were dependent on dialysis. MAIN OUTCOME MEASURES:Processes for assessing indices of iron stores and iron supplementation; comparison with target indices in the CARI guidelines. RESULTS:There was considerable variability among the units in achievement of haemoglobin and iron targets, with 25%-32% of patients achieving haemoglobin targets of 110-120 g/L, 30%-68% achieving ferritin targets of 300-800 microg/L, and 65%-73% achieving transferrin saturation targets of 20%-50%. Implementation barriers included lack of knowledge, lack of awareness of or trust in the CARI guideline, inability to implement the guideline, and inability to agree on a uniform unit protocol. Factors associated with achieving the CARI guideline targets included nurse-driven iron management protocols, use of an iron management decision aid, fewer nephrologists per dialysis unit, and a "proactive" (actively keeping iron levels within target range) rather than "reactive" (only reacting if iron levels are out of the range) protocol. CONCLUSIONS:Variability in achievement of iron targets, despite the availability of a clinical practice guideline, may be explained by variability in processes of care for achieving and maintaining adequate iron parameters.
    背景与目标:

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