Enhanced liver regeneration in rats treated with 15-deoxyspergualin alone and in combination with FK 506

The effects of 15-deoxyspergualin (DSG) alone and in combination with FK 506 (FK) on liver regeneration after 2/3 hepatectomy was studied. The administration of 5 mg/kg DSG increased the liver weight as a percentage of the body weight (RLW) in the 5 days following the hepatectomy. This enhanced regeneration was not affected if interleukin(IL)-2 was also given. The combination of 1 mg/kg DSG and 0.05 mg/kg FK induced the highest values for RLW. The amounts of food and water intake increased in the DSG and FK combined group. Blood chemistry indicated that the combined administration of DSG and FK could reduce side-effects more effectively than separate administration. These observation led us to conclude that DSG has a stimulating potency in liver regeneration by means of direct supression of T cell activation, and there is a synergistic effect on regeneration by DSG and FK.     

Ethanol Self-Administration in Deprived Rats: Effects of Ro15-4513 Alone, and in Combination with Flumazenil (Ro15-1788)

Previous work in our laboratory demonstrated that Ro15-4513, a partial inverse benzodiazepine agonist, decreases self-administration of ethanol (ETOH) in rats maintained on a two-bottle regmine of a saccharin ethanol solution (ES) and water over a 35-day consumption period. The present study extended the consumption period to 60 days and examined the effects of Ro15-4513 (2.5 mg/kg), flumazenil (Ro15-1788) (8.0 mg/kg), and Ro15-4513 in combination with Ro15-1788 on the time course of ETOH self-administration. High initial intake of ES observed during the first 4 weeks declined significantly over subsequent weeks. Ro15-4513 pretreatment, however, resulted in significant reduction of ES, while significantly preventing the "normal" reduction of consumption as was observed under control conditions. The antagonistic actions of Ro15-4513 were blocked/attenuated by the benzodiazepine receptor antagonist, Ro15-1788, independent of whether consumption of the ES was low or high. Both Ro15-4513 and Ro15-1788 affected water intake differentially compared with vehicle-injected controls. The results suggest that GABA-benzodiazepine mechanisms may be important in altering chronic ETOH drinking patterns depending upon experience with ETOH, tolerance, or learning.     

Serum and muscle interleukin-15 levels decrease in aging mice: Correlation with declines in soluble interleukin-15 receptor alpha expression

Interleukin-15 (IL-15) is a skeletal muscle-derived cytokine with favorable effects on muscle mass and body composition. Modulation of IL-15 levels has been suggested as a treatment for sarcopenia and age-associated increases in adiposity. However, it is unclear whether IL-15 levels change during aging, as measurement of IL-15 at physiological concentrations in mice has been technically difficult, and translational regulation of IL-15 is complex. Moreover, the IL-15 receptor alpha (IL-15Rα) can comprise part of a membrane-associated receptor complex, or appear as a soluble form which stabilizes IL-15 and facilitates IL-15 secretion. Here, we report measurement of physiological levels of murine IL-15, and determine that muscle and serum IL-15 levels decline progressively with age. However, expression of IL-15 mRNA and membrane-associated subunits of the IL-15 receptor did not change with age in muscle. Expression of soluble IL-15Rα (sIL-15Rα) mRNA declined 5-fold with age, and serum IL-15 levels correlated highly with muscle sIL-15 mRNA expression, suggesting declines in sIL-15Rα expression lead to decreased circulating IL-15 levels during aging. These findings complement studies which described several single-nucleotide polymorphisms in the human IL-15Rα gene which impact muscularity and adiposity, and provide a technical basis for further investigation of IL-15 and the sIL-15Rα in determining body composition in aging mice, as a model for humans.     

Donor Cell-Derived Chronic Myeloproliferative Disease with t(7;11)(p15;p15) after Cord Blood Transplantation in a Patient with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

We report a case of donor cell-derived chronic myeloproliferative disease with t(7;11)(p15;p15) occurring after cord blood transplantation (CBT). A 41-year-old man developed precursor B-cell acute lymphoblastic leukemia with a karyotype of 46, XY, t(9;22)(q34;q11) and inv(9)(p11;q13), for which he received CBT from a sex-mismatched donor at the first complete remission of the leukemia. Five months after CBT, gradual neutrophilia of unknown origin developed following the myeloid reconstitution after CBT. Karyotyping of bone marrow cells at 9 months after CBT showed 46, XX, t(7;11)(p15;p15) in 17/20 dividing cells, but neither Philadelphia chromosome (Ph) nor inv(9)(p11;q13) was present. This is the first report of chronic myeloproliferative disease with t(7;11)(p15;p15) that developed in donor cells after CBT. The donor was well-developed and healthy, at least at the time of follow-up, half a year after the birth.     

瘦素在大鼠非酒精性脂肪性肝病中的作用

目的探讨瘦素与非酒精性脂肪性肝病（NAFLD）肝脂肪变性程度和炎症活动度的关系。方法40只SD大鼠随机分为4组：正常对照组、非酒精性脂肪肝模型：A组（高脂喂养8周）、B组（高脂喂养12周）、C组（高脂喂养16周）。测定各组血清瘦素、白介素10（IL-10）、白介素12（IL-12）、白介素15（IL-15）;评价各组大鼠肝脂变程度和炎症活动度积分水平。结果模型组脂肪变性明显,炎症活动度记分均显著高于正常对照组（P〈0.01）,模型C组炎症活动度记分水平显著高于模型A、B组（P〈0.01）。模型组瘦素水平均显著高于正常对照组（P〈0.01）,模型B组瘦素水平显著高于模型A组（P〈0.01）。模型C组IL-10水平显著低于模型A、B组及正常对照组（P〈0.01）;模型C组IL-12水平显著高于模型A、B组及正常对照组（P〈0.01）;模型C组IL-15水平与模型A、B组有显著差异（P〈0.05）。瘦素与NAFLD肝脂肪变性程度有相关性（R2=0.378,P〈0.05）;IL-10、IL-12、IL-15与NAFLD炎症活动度相关（R2=0.551,P〈0.01）。结论本实验初步认为,瘦素可能是影响NAFLD肝脂肪变性程度的重要因素;IL-10、IL-12、IL-15对NAFLD炎症活动可能有一定影响。     

血浆生长分化因子-15水平检测对左心衰竭的临床意义

目的:通过检测生长分化因子-15(GDF-15)血浆水平来探讨其与左侧心力衰竭(心衰)的关系,并与脑钠肽(BNP)比较其在左心衰诊断中的价值。方法:入选左心衰患者110例和正常人36例。ELISA检测血浆GDF-15水平。结果:左心衰组血浆GDF-15水平较对照组明显升高[2 368.65(1 493.96,3 859.89)ng/L∶1 090.80(892.59,1 749.35)ng/L,P<0.01],且随着NYHA程度的加重而增加。相关分析显示,GDF-15分别与NYHA分级(r=0.567,P=0.00)、左室舒张末径(r=0.209,P=0.030)、左室射血分数(r=-0.226,P=0.019)、BNP(r=0.223,P=0.020)有相关性。多元线性回归分析中,仅有NYHA分级(标化的相关系数B=0.576,P=0.000)与GDF-15密切相关。ROC曲线分析表明,GDF-15与BNP均可用于诊断慢性心衰。结论:GDF-15是良好心衰标志物,可作为辅助诊断左心衰的指标。     

Eoxins are proinflammatory arachidonic acid metabolites produced via the 15-lipoxygenase-1 pathway in human eosinophils and mast cells

Human eosinophils contain abundant amounts of 15-lipoxygenase (LO)-1. The biological role of 15-LO-1 in humans, however, is unclear. Incubation of eosinophils with arachidonic acid led to formation of a product with a UV absorbance maximum at 282 nm and shorter retention time than leukotriene (LT)C4 in reverse-phase HPLC. Analysis with positive-ion electrospray tandem MS identified this eosinophil metabolite as 14,15-LTC4. This metabolite could be metabolized to 14,15-LTD4 and 14,15-LTE4 in eosinophils. Because eosinophils are such an abundant source of these metabolites and to avoid confusion with 5-LO-derived LTs, we suggest the names eoxin (EX)C4, -D4, and -E4 instead of 14,15-LTC4, -D4, and -E4, respectively. Cord blood-derived mast cells and surgically removed nasal polyps from allergic subjects also produced EXC4. Incubation of eosinophils with arachidonic acid favored the production of EXC4, whereas challenge with calcium ionophore led to exclusive formation of LTC4. Eosinophils produced EXC4 after challenge with the proinflammatory agents LTC4, prostaglandin D2, and IL-5, demonstrating that EXC4 can be synthesized from the endogenous pool of arachidonic acid. EXs induced increased permeability of endothelial cell monolayer in vitro, indicating that EXs can modulate and enhance vascular permeability, a hallmark of inflammation. In this model system, EXs were 100 times more potent than histamine and almost as potent as LTC4 and LTD4. Taken together, this article describes the formation of proinflammatory EXs, in particular in human eosinophils but also in human mast cells and nasal polyps.     

Association of serum growth differentiation factor-15 levels with the risks of death and vascular events in patients with ischemic stroke: The role of diabetes

Background and aimsResearchers have not determined whether the association between growth differentiation factor-15 (GDF-15) levels and stroke outcomes is modified by the diabetes status. We aimed to evaluate the prognostic value of GDF-15 among patients with ischemic stroke stratified by diabetes.Methods and resultsA total of 3001 patients with ischemic stroke were selected from the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS) and included in this study. The primary outcome was a composite outcome of death and vascular events at 3 months after acute ischemic stroke. An elevated GDF-15 level was significantly associated with the primary outcome in patients with diabetes but not in those without diabetes (p_interaction = 0.038). The multivariate-adjusted hazard ratio (95% confidence intervals) for the primary outcome was 3.33 (1.07–10.35) when 2 extreme tertiles were compared, and a linear association between GDF-15 levels and the primary outcome was observed in patients with diabetes (p for linearity = 0.046). The addition of serum GDF-15 to conventional risk factors improved the risk prediction for the primary outcome in patients with diabetes (net reclassification improvement: 31.98%, p = 0.043; integrated discrimination index: 0.85%, p = 0.034) but not in those without diabetes.ConclusionsA modifying effect of the diabetes status on the association between serum GDF-15 levels and ischemic stroke prognosis was observed. Elevated serum GDF-15 levels were associated with the primary outcome within 3 months after ischemic stroke in patients with diabetes, suggesting that GDF-15 may be an important prognostic factor for ischemic stroke in patients with diabetes.     

一个新的保护心脏TGF-β超家族成员——GDF15

GDF15基因是TGF-β超家族成员之一,具有抗肿瘤、抗器官损伤等多种功能。最新文献报道,GDF15基因抑制心肌肥厚,对缺血／缺血再灌注中的心脏损伤亦有保护作用,是一个新的心脏保护因子。本文就GDF15基因在多种心血管疾病中的功能及其相关的信号通路做一综述。     

IL-15对人γδT细胞杀伤结核杆菌感染THP-1细胞的影响

目的建立结核杆菌(Mtb)感染单核细胞THP-1细胞系模型;用流式细胞术检测人γδT细胞对Mtb感染THP-1细胞的细胞毒活性;并观察IL-15对人γδT细胞杀伤Mtb感染THP-1细胞的细胞毒活性的影响。方法 Mtb以10∶1的比例感染佛波醇酯(PMA)分化的THP-1细胞,建立Mtb感染细胞模型。人外周血单个核细胞用Mtb耐热性低分子多肽类抗原刺激优势扩增γδT细胞,作为效应细胞用于细胞毒活性实验。用羧基荧光素二醋酸盐琥珀酰亚胺酯(CFSE)标记Mtb感染THP-1细胞,作为靶细胞。效应细胞和靶细胞以不同比例孵育4 h,用碘化丙啶(PI)染色后在流式细胞仪上检测,CSFE和PI双阳性细胞为被杀伤靶细胞。IL-15作用于γδT细胞24 h后,再检测γδT细胞对Mtb感染THP-1细胞的细胞毒活性。结果人γδT细胞与Mtb感染THP-1细胞以1∶1至50∶1的比例作用4 h后,人γδT细胞对结核杆菌感染的THP-1细胞的细胞毒活性从22.5%增加至80.7%;而γδT细胞与未感染Mtb的THP-1细胞的细胞毒活性为16.1%至47.2%。IL-15作用γδT细胞后的细胞毒活性(64.06%)与对照组(46.81%)相比明显增加(P0.05)。结论人γδT细胞对Mtb感染THP-1细胞的杀伤活性明显高于对未感染Mtb的THP-1细胞的作用,杀伤活性随效靶比的增加而增加。IL-15可以增强人γδT细胞对Mtb感染巨噬细胞的细胞毒活性。     

子宫内膜癌中p15及MDM2蛋白表达

目的 采用流式细胞术并结合免疫组化法检测p15蛋白和MDM2蛋白在正常子宫内膜、良、恶性子宫内膜肿物组织中表达,研究其与原发性妇科恶性肿瘤的关系及三者在原发性妇科恶性肿瘤表达的相关关系.方法 采用石蜡切片,提取各个实验组的单细胞悬液,利用流式细胞术并结合免疫组织化学链霉素抗生物素蛋白-过氧化酶结合法,分别检测子宫系列病变组织p15、MDM2表达情况.结果 从子宫肌瘤到子宫内膜癌,p15的表达量有明显进行性增高(P<0.01).而p15过度表达时(FI>1.30)5年生存率很低.两组生存率比较有显著性差异(P<0.01);MDM2的表达在子宫内膜样癌为48.28% 、非子宫内膜样癌为41.5%,都明显低于功能性子宫出血诊断性刮宫标本的60.2%(P<0.01).结论 p15、MDM2蛋白表达异常可成为子宫内膜癌危险性评估、子宫内膜癌早期诊断及预后和复发判定的新途径.     

白介素-15与支气管哮喘

白介素 15属TH1相关性细胞因子 ,与IL 2共用β和γ链 ,有许多相似生物活性。促进T细胞、B细胞、单核 /巨噬细胞等多种细胞的增殖、分化和分泌各种细胞因子 ,参与哮喘气道炎症的形成。研究IL 15在哮喘中的作用 ,有利于进一步阐述哮喘的发病机制。     

Central role of interleukin-15 in human immunodeficiency virus (HIV)-infected patients with visceral leishmaniasis

To evaluate clinical and immunological parameters, interleukin (IL)-15 production and outcome of patients with visceral leishmaniasis (VL), including HIV positive patients, we analyzed 48 cases of VL. Clinical manifestations and response to therapy were similar in VL/HIV- and VL/HIV+ patients. However, relapses were more frequent in patients with HIV infection. Low levels of IL-15 concentrations were found in HIV+ patients without VL. These levels were comparable to concentrations obtained in healthy donors. We found a relationship between response to therapy and IL-15 levels. We found increased levels of IL-15 in VL/HIV- and VL/HIV+ patients with clinical and parasitological response to therapy. Our data demonstrate that VL in HIV-infected patients occurs in subjects with severe immunodeficiency and presents high rate of relapses. Low levels of IL-15 in illness patients and restored production in cured persons suggest that this cytokine could play a central role in immune responses during Leishmania/HIV co-infection.     

Additive anti-atherogenic effect of thromboxane receptor antagonism with 12/15lipoxygenase gene disruption in apolipoprotein E-deficient mice

Previous studies in mouse models showed that 12/15lipoxygenase (12/15LO) gene disruption diminishes atherosclerosis. Pharmacologic suppression of thromboxane (Tx) A₂ biosynthesis or blockade of its receptor also reduces the development of the disease in the same models. We tested the hypothesis that simultaneous genetic absence of 12/15LO with TxA₂ receptor blockade might result in an additive anti-atherogenic effect.Apolipoprotein E (apoE)-deficient mice and apoE-deficient mice lacking 12/15LO were maintained on normal chow diet, or chow supplemented with BM-573, a selective TxA₂ receptor antagonist, for 12 weeks. Urinary TxA₂ and prostacyclin metabolites, isoprostaneF_2α-III and atherosclerotic aortic lesions were assessed.12/15LO gene disruption resulted in significantly reduced atherosclerotic lesion areas and decreased urinary isoprostaneF_2α-III in apoE-deficient mice. TxA₂ receptor antagonism alone also afforded a significant reduction in atherosclerosis in apoE-deficient mice. However, thromboxane receptor blockade resulted in an additive and more potent anti-inflammatory and anti-atherogenic effect when administered to apoE-deficient mice lacking 12/15LO.These results suggest that the 12/15LO- and TxA₂ receptor-mediated pro-atherogenic effects are two distinct pathways and represent two separate therapeutic targets for a better anti-atherogenic strategy.     

不同剂量比索洛尔治疗心力衰竭的效果

目的探讨不同剂量比索洛尔（康可）对心力衰竭（简称心衰）的治疗效果，促进β受体阻滞剂在心衰治疗中的应用。方法106例心衰患者随机分为康可2．5mg／d（A组）和康可5～7．5mg／d治疗组（B组），观察主要事件和指标的变化。结果康可5～7．5mg／d治疗组较康可2．5mg／d组，心衰恶化及再住院显著减少，NYHA心功能和EF显著改善，对血压和心率控制更理想。结论大剂量比索洛尔能更好地保护心脏，应积极使用β受体阻滞剂治疗心衰。     

生长分化因子-15与正常高值血压者左室重构的相关性分析

目的 对比观察生长分化因子-15 （GDF-15）在理想血压、正常高值血压人群中的浓度变化及其与部分左室重构指标的相关性.方法 以2011年10月～2013年3月在我院体检中心参加体检的200例正常高值血压者为研究对象,以同期体检的100例理想血压者作为对照,应用彩色多普勒超声测定左心室质量指数（LVMI）,抽取空腹静脉血测定GDF-15以及其它生化指标.并用Pearson相关性分析正常高值血压者的血清GDF-15与其它指标的相关性.结果 正常高值血压组收缩压、舒张压、GDF-15、LVMI明显高于理想血压组,两组比较差异有统计学意义（P＜0.01或0.05）.正常高值血压组GDF-15与收缩压（r=0.412,P＜0.01）、舒张压（r=0.263,P＜0.01）、LVMI（r =0.520,P＜0.01）呈正相关.结论 GDF-15在正常高值血压人群中浓度即开始升高,可能与其左室重构具有一定的相关性.     

急性冠状动脉综合征患者生长分化因子-15水平与冠状动脉病变程度及预后的关系

目的 探讨急性冠状动脉综合征（acute coronary syndrome，ACS）患者生长分化因子-15（GDF-15）水平与冠状动脉SYNTAX积分及患者预后的关系。方法 检测147例ACS患者血清GDF-15水平，并依其将ACS分为高水平组（>1800 μmol/L）31例，中水平组（1200~1800 μmol/L）46例，低水平组（<1200 μmol/L）70例。据冠状动脉造影结果计算SYNTAX积分。分析GDF-15在ACS中的作用及其与SYNTAX积分的相关性。结果 ACS患者GDF-15水平明显升高（1266.79±589.36）ng/L，Logistic回归分析显示：众多研究变量中仅GDF-15及SYNTAX 积分显著影响ACS患者预后（GDF-15：Wals=9.75,P<0.05；SYNTAX 积分：Wals=3.51，P<0.05），差异有统计学意义。进一步的相关性检验发现，GDF-15水平与SYNTAX 积分具有直线相关性，呈中等程度正相关（r=0.54，P=0.00）。结论 ACS患者GDF-15明显升高，其水平与冠状动脉SYNTAX积分具有相关性，可能预测ACS患者冠状动脉病变程度及预后。     

Predictors of Mortality in Home-Dwelling Patients with Cardiovascular Disease Aged 75 and Older

OBJECTIVES: To compare the predictive value of biomarkers commonly measured in older patients with cardiovascular disease (CVD) with an indicator of cognitive function.
DESIGN: Prospective cohort study.
SETTING: Helsinki, Finland.
PARTICIPANTS: Three hundred ninety-eight home-dwelling older persons (261 women, mean age 80) with stable CVD and without a diagnosis of clinical dementia.
MEASUREMENTS: Simple laboratory and clinical measurements (including the Mini Mental State Examination (MMSE, maximum score 30 points) and New York Heart Association (NYHA) classification) were used to predict mortality. A MMSE score between 18 and 24 points was considered to indicate cognitive impairment.
RESULTS: At baseline, median MMSE score was 27 (interquartile range 25–28), with 59 individuals having a score below 24 points. During a mean follow-up of 6.0 years, 129 participants died. In the fully adjusted Cox proportional hazards model, low MMSE score was the strongest predictor of mortality, with a relative hazard of 2.38 (95% confidence interval=1.52–3.74; P <.001). Of the various clinical and laboratory variables, only creatinine, C-reactive protein, and history of congestive heart failure were significant independent predictors, whereas conventional risk factors were not.
CONCLUSION: Only a few clinical variables independently predicted 6-year mortality in older home-living patients with CVD. The strongest predictor was impaired cognitive function assessed using MMSE.