• 【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:
  • 【通过竞争性聚合酶链反应监测干扰素 α 治疗慢性粒细胞性白血病 (CML) 患者的效率。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Hochhaus A,Lin F,Reiter A,Skladny H,Hehlmann R,Goldman JM,Cross NC
    BACKGROUND & AIMS: Interferon alpha (IFN-alpha) induces cytogenetic responses of variable degree in patients with CML. We sought to establish the relationship between BCR-ABL transcript numbers measured by competitive two-step reverse transcription polymerase chain reaction (RT-PCR) and cytogenetic status in CML patients treated with IFN-alpha. All 398 samples from 163 patients investigated by RT-PCR were positive for BCR-ABL transcripts. In order to standardize results for variability in RNA and cDNA quality, we quantified total ABL transcripts in each sample as internal control. The BCR-ABL/ABL ratios correlated with the cytogenetic results. Quantitative nested PCR allowed the detection of residual BCR-ABL transcripts in all complete cytogenetic responders on IFN-alpha. We conclude that competitive PCR with internal controls is a reliable method for monitoring patients on IFN-alpha and reduces the need for repeated marrow investigations.

    背景与目标: 干扰素 α (IFN-α) 诱导CML患者不同程度的细胞遗传学反应。我们试图建立通过竞争性两步逆转录聚合酶链反应 (rt-pcr) 测量的bcr-abl转录数与接受IFN-α 治疗的CML患者的细胞遗传学状态之间的关系。通过rt-pcr调查的来自163名患者的所有398样品的bcr-abl转录物均为阳性。为了标准化RNA和cDNA质量变异性的结果,我们将每个样品中的总ABL转录本量化为内部对照。Bcr-abl/ABL比值与细胞遗传学结果相关。定量巢式PCR可以检测到IFN-α 上所有完整的细胞遗传学反应中的残留BCR-ABL转录本。我们得出的结论是,带有内部对照的竞争性PCR是一种可靠的方法,用于监测患者的IFN-α,并减少了重复进行骨髓检查的需要。
  • 【供体嵌合症是慢性粒细胞性白血病骨髓移植后无病生存的有力指标。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Gardiner N,Lawler M,O'Riordan J,De'Arce M,McCann SR
    BACKGROUND & AIMS: Although Chronic Myeloid Leukaemia (CML) can be treated successfully with allogeneic bone marrow transplantation (BMT), leukaemia relapse remains a significant clinical problem. Molecular monitoring of the post transplant marrow can be useful in predicting relapse particularly in CML patients where the Philadelphia chromosome or its molecular counterpart, the BCR-ABL fusion messenger RNA can be used as a leukaemia specific marker of minimal residual disease (MRD). We have investigated chimaerism (using polymerase chain reaction of short tandem repeat sequences (STR-PCR)) and MRD status (using reverse transcriptase PCR of the BCR-ABL fusion mRNA) in a serial fashion in 18 patients who were in clinical and haematological remission post allogeneic BMT for chronic phase CML. Eleven patients exhibited complete donor chimaerism with no evidence of minimal residual disease. Five patients had transient or low level stable MC. Late MC and MRD was observed in two patients who relapsed > 6 years after T cell depleted BMT for CML. Thus STR-PCR is an appropriate screening test in the post transplant setting for CML patients, but those patients exhibiting mixed haemopoietic chimaerism should also be monitored using a leukaemia specific sensitive molecular assay.

    背景与目标: 尽管同种异体骨髓移植 (BMT) 可以成功治疗慢性粒细胞白血病 (CML),但白血病复发仍然是一个重要的临床问题。移植后骨髓的分子监测可用于预测复发,特别是在费城染色体或其分子对应物的CML患者中,bcr-abl融合信使RNA可用作最小残留疾病 (MRD) 的白血病特异性标志物。我们已经连续研究了18例临床和血液学患者的嵌合体 (使用短串联重复序列的聚合酶链反应 (str-pcr)) 和MRD状态 (使用bcr-abl融合mRNA的逆转录酶PCR) 慢性期CML的同种异体BMT后缓解。11例患者表现出完全的供体嵌合体,没有最小残留疾病的证据。5例患者有短暂或低水平稳定的MC。在两名T细胞耗尽CML BMT后复发> 6年的患者中观察到晚期MC和MRD。因此,在CML患者的移植后环境中,STR-PCR是一种适当的筛查测试,但是那些表现出混合造血嵌合体的患者也应使用白血病特异性敏感分子测定法进行监测。
  • 【慢性丙型肝炎肝内T细胞的表型和功能状态。】 复制标题 收藏 收藏
    DOI:10.1086/507681 复制DOI
    作者列表:Wang J,Holmes TH,de Guevara LL,Cheung R,Wright TL,He XS,Greenberg HB
    BACKGROUND & AIMS: :Polychromatic flow-cytometric assays were used to analyze paired intrahepatic and peripheral lymphocyte samples from 37 patients with chronic hepatitis C. Compared with peripheral cells, intrahepatic T cells were selectively enriched with CD45RO+ memory T cells but had a lower percentage of CD4+ T cells expressing the differentiation markers CD27 and CD28. The percentage of intrahepatic CD45RO+ and CD28+ T cells correlated with the degree of liver inflammation, which suggests that memory T cells at relatively early stages of differentiation are directly involved in liver inflammation. Despite their memory phenotype, intrahepatic T cells were defective in proliferation capability, produced less interferon- gamma in response to stimulation by T cell receptor, and contained less perforin but expressed higher levels of Fas and Fas ligand, compared with their counterparts in peripheral blood. The distinct characteristics of intrahepatic T cells suggest that they play an important role in the immunopathogenesis of chronic hepatitis C.
    背景与目标: : 使用多色流式细胞仪分析来自37例慢性丙型肝炎患者的成对的肝内和外周血淋巴细胞样本。与外周细胞相比,肝内T细胞选择性富集CD45RO记忆T细胞,但表达分化标记CD27和cd28的CD4 T细胞百分比较低。肝内CD45RO和CD28 T细胞的百分比与肝脏炎症程度相关,这表明处于分化相对早期的记忆T细胞直接参与了肝脏炎症。尽管肝内T细胞具有记忆表型,但其增殖能力存在缺陷,对T细胞受体的刺激产生的干扰素 γ 较少,并且穿孔素较少,但表达的Fas和Fas配体水平较高。血液。肝内T细胞的独特特征表明它们在慢性丙型肝炎的免疫发病中起重要作用。
  • 【小鼠flt3配体在小鼠中的慢性表达导致循环白细胞水平升高和与脾脏纤维化相关的异常细胞浸润。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Juan TS,McNiece IK,Van G,Lacey D,Hartley C,McElroy P,Sun Y,Argento J,Hill D,Yan XQ,Fletcher FA
    BACKGROUND & AIMS: :The effect of chronic expression of flt3 ligand (FL) on in vivo hematopoiesis was studied. Retroviral vector-mediated gene transfer was used in a mouse model of bone marrow transplantation to enforce expression of mouse FL cDNA in hematopoietic tissues. As early as 2 weeks posttransplantation, peripheral blood white blood cell counts in FL-overexpressing recipients were significantly elevated compared with controls. With the exception of eosinophils, all nucleated cell lineages studied were similarly affected in these animals. Experimental animals also exhibited severe anemia and progressive loss of marrow-derived erythropoiesis. All of the FL-overexpressing animals, but none of the controls, died between 10 and 13 weeks posttransplantation. Upon histological examination, severe splenomegaly was noted, with progressive fibrosis and infiltration by abnormal lymphoreticular cells. Abnormal cell infiltration also occurred in other organ systems, including bone marrow and liver. In situ immunocytochemistry on liver sections showed that the cellular infiltrate was CD3+/NLDC145+/CD11c+, but B220- and F4/80-, suggestive of a mixed infiltrate of dendritic cells and activated T lymphocytes. Infiltration of splenic blood vessel perivascular spaces resulted in vascular compression and eventual occlusion, leading to splenic necrosis consistent with infarction. These results show that FL can affect both myeloid and lymphoid cell lineages in vivo and further demonstrate the potential toxicity of in vivo treatment with FL.
    背景与目标: : 研究了flt3配体 (FL) 的慢性表达对体内造血的影响。逆转录病毒载体介导的基因转移被用于骨髓移植的小鼠模型中,以增强小鼠FL cDNA在造血组织中的表达。移植后2周,与对照组相比,FL过表达受体的外周血白细胞计数明显升高。除嗜酸性粒细胞外,所有研究的有核细胞谱系在这些动物中都受到类似的影响。实验动物还表现出严重的贫血和骨髓来源的红细胞生成的进行性丧失。所有FL过表达的动物,但没有对照组,在移植后10到13周死亡。经组织学检查,发现严重的脾肿大,进行性纤维化和异常的淋巴网状细胞浸润。异常细胞浸润也发生在其他器官系统,包括骨髓和肝脏。肝脏切片上的原位免疫细胞化学显示细胞浸润为CD3/NLDC145/CD11c,但B220-和F4/80-提示树突状细胞和活化的T淋巴细胞混合浸润。脾血管周围空间的浸润导致血管受压并最终阻塞,导致脾脏坏死与梗塞一致。这些结果表明,FL可以在体内影响髓样和淋巴样细胞谱系,并进一步证明了FL在体内治疗的潜在毒性。

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