雷公藤甲素对胶原诱导关节炎大鼠滑膜血管新生的调节作用

目的 观察雷公藤甲素(TP)对血管新生的影响,探讨TP治疗关节炎的作用机制.方法 建立胶原诱导关节炎(CIA)大鼠模型,常规苏木素-伊红(HE)染色,测量关节体积,计算关节炎指数和病理积分,分别检测滑膜和血清中血管内皮生长因子(VEGF)、碱性成纤维细胞生长因子(bFGF)和内皮抑素(endostatin)的蛋白表达,并通过CD34给滑膜血管密度计数(MVD).结果 CIA大鼠滑膜和血清中VEGF、bFGF及滑膜MVD明显高于正常组(X2分别为65.3、31.6,q=9.2,三者P＜0.01),endostatin的表达与正常组差异无统计学意义(X2=0.8,P＞0.05).TP治疗后,滑膜和血清中VEGF、bFGF、滑膜MVD均下降(X2分别为19.7、6.0,q=6.5,三者P＜0.01),而endostatin表达却升高(X2=3.9,P＜O.05),甲氨蝶呤(MTX)则主要以endostatin表达升高为主(X2=17.9,P＜0.01).结论 生长因子的表达失衡可能在关节炎的形成及发展过程中起重要作用,TP能够调整生长因子的失衡状态而发挥治疗作用.     

鼠血管内皮生长因子及其抗体对内皮细胞增生影响的研究

目的 研究探讨血管内皮生长因子（VEGF）及其抗体对内皮细胞增生的影响。方法 采用体外培养人脐静脉内皮细胞（HUVEC）,用^3H－TaR掺入检测技术分别检测鼠血管内皮生长因子（mVEGF）及其抗体和Ⅱ型胶原诱导的关节炎（CIA）小鼠关节组织提取液对HUVEC增生影响。结果 抗VEGF中和抗体抑制在mVEGF刺激下引起的HUVEC增生及在CIA小鼠关节组织提取液作用下引起的HUVEC增生,抑制率分别为72．2％和69．9％。结论 mVEGF特异性作用于血管内皮增生;CIA形成的早期关节组织内可能产生大量的VEGF,并以较强的生物活性形式存在,能被抗VEGF中和抗体抑制。     

缺氧诱导因子-1α血管内皮生长因子在胶原诱导性关节炎滑膜中的表达及其与血管生成的关系

目的 探讨缺氧诱导因子(HIF)-1α和血管内皮生长因子(VEGF)在类风湿关节炎(RA)血管生成中的作用.方法 建立大鼠胶原诱导性关节炎(CIA)模型,采用苏木素-伊红(HE)染色评估滑膜病理血管生成、SP法免疫组织化学染色检测HIF-1α和VEGF的表达,动态观察HIF-1α表达与VEGF表达及血管生成之间的关系.结果 CIA大鼠滑膜HIF-1α及VEGF表达增加,且随发病时间的延长而逐渐增加,两者均与滑膜病理血管生成评分呈显著正相关,同时滑膜衬里层和衬里下层HIF-1α表达又与相应部位的VEGF表达呈显著正相关.结论 HIF-1α可能参与上调VEGF表达促进血管生成,从而在RA关节破坏中起一定作用.     

VEGF与TGF-β1在胶原诱导的RA大鼠滑膜组织中的表达及意义

目的探讨血管内皮生长因子（VEGF）和转化生长因子（TGF）-β1在类风湿关节炎（RA）发病中的作用,为RA的靶点治疗提供依据。方法采用皮下多点注射牛Ⅱ型胶原方法对18只Wistar大鼠建立RA模型（实验组）,同时选择10只Wistar大鼠皮下注射等量生理盐水作对照组,实验28d处死大鼠、收集滑膜组织,用免疫组化法检测两组VEGF蛋白与TGF-β1蛋白表达,RT—PCR技术检测VEGF mRNA、TGF-β1 mRNA水平。结果VEGF蛋白及TGF-β1蛋白阳性染色均主要位于滑膜衬里层和滑膜下层的滑膜细胞及血管内皮细胞,实验组滑膜VEGF、TGF-β1蛋白及mRNA表达均显著高于对照组（P均〈0．01）;VEGF mRNA与TGF-β1 mRNA表达呈正相关,r=0．481（P〈0．05）。结论VEGF和TGF-β1在RA滑膜增生、浸润及关节破坏中起协同作用,以两者为靶点的药物有望为RA治疗提供新思路。     

实验性关节炎大鼠血浆肿瘤坏死因子-α和滑膜血管内皮生长因子表达相关性分析

目的　同步观察实验性关节炎大鼠不同时间点的血浆肿瘤坏死因子 α (TNF α)含量与滑膜内皮生长因子 (VEGF)表达变化 ,探讨TNF α和VEGF在类风湿关节炎 (RA)发病机制中的作用及其相关性。方法　采用Ⅱ型胶原与完全福氏佐剂诱导SD大鼠实验性关节炎 (CIA)模型 ,同步检测CIA大鼠不同时间点的血浆TNF α含量和滑膜组织VEGF的表达水平 ,并同时观察其发病时间与滑膜新生血管形成、关节炎指数积分以及TNF α和VEGF之间关系。用直线相关分析法分析TNF α与VEGF之间的关系 ,用等级相关分析法分析关节炎指数积分与VEGF及TNF α之间的关系。结果　随着CIA发病时间的延长 ,滑膜新生血管逐渐增多 ,滑膜增厚 ,关节炎指数积分逐渐增加 ,TNF α含量和VEGF水平也随之升高 ;其关节炎指数积分与VEGF表达水平呈正相关关系 (r =0 5 35、P <0 0 5 ) ,与TNF α含量虽有相关增高趋势 ,但差异无显著性 (r =0 371 ,P >0 0 5 )。血浆TNF α含量与VEGF表达水平呈显著正相关关系 (r =0 893,P <0 0 1 )。结论　TNF α与VEGF在RA炎症反应 ,滑膜新生血管形成的细胞因子网络中起重要作用 ,二者可能具有互相影响 ,相互促进 ,充当恶性网络循环的调控作用 ;是介导RA发生和发展以及骨质侵蚀、致残的众多因子中的关键因子。     

血管内皮生长因子在大鼠实验性关节炎模型中表达的动态观察

目的：观察血管内皮生长因子（VEGF）在大鼠实验性关节炎模型中的表达，探讨VEGF在类风湿关节炎（RA）发病机制中的作用。方法：30只雄性Wistar大鼠采用皮下注射Ⅱ型胶原的方法诱导实验性关节炎模型，并随机分为6组，每组5只。致敏1、2、3、4、5、6周后分别将各组动物处死，采用免疫组织化学方法对组织中表达的VEGF进行观察，并采用计算机图像分析的方法对各时期VEGF的表达量进行定量分析。结果：大鼠在接受胶原致敏后2周左右发病，滑膜组织中的VEGF蛋白的分泌与炎症发展密切相关。结论：VEGF参与了实验性关节炎滑膜血管翳的形成过程，在RA的发病机制中具有重要意义。     

血管内皮生长因子在Ⅱ型胶原诱导的关节炎小鼠关节组织中的表达

目的 研究血管生成因子－血管内皮生长因子（VEGF）在Ⅱ型胶原诱导的关节炎（CIA）形成期的表达及功能。方法 于DBA／1J小鼠皮下注射Ⅱ型胶原制作关节炎模型并进行关节指数评价。用酶联免疫吸附法（ELISA）及免疫组织化学技术，检测关节组织内VEGF和vWF含量，以及通过RT－PCR，Southern blotting技术检测VEGF mRNA表达。结果 VEGF与vWF呈平行变化关系，均在关节炎发生后第4天达到最高，并与血管新生程度、关节炎严重程度呈正相关。VEGF mRNA在关节组织内表达形式为279、304bp。结论 VEGF在关节炎形成早期起着重要作用，影响着实验诱导关节炎血管新生及进展。     

缺氧诱导因子-1α及血管内皮生长因子在Ⅱ型胶原诱导性关节炎模型中的致病作用

目的 探讨低氧诱导因子-1α(HIF-1α)及血管内皮生长因子(VEGF)在Ⅱ型胶原诱导性关节炎(CIA)模型中的致病作用.方法 选用50只SD大鼠(雌雄各半),建立CIA模型,分别于造模第21、28、35、42天取踝关节作HE染色及HIF-1α免疫组化染色,分析其在CIA中与关节炎活动指标,滑膜病理学评分之间的关系.结果 CIA大鼠关节滑膜层和滑膜下层均表达HIF-1α,第21天阳性表达量最高,随病程进展,表达逐渐下降,与滑膜病理学评分、滑膜增生评分及血管生成评分呈显著正相关.结论 HIF-1α在RA致病机制中发挥关键作用,可能是重要的治疗靶点.     

低氧诱导因子-1α在大鼠胶原诱导性关节炎中的表达及与血管生成的关系

目的制备牛Ⅱ型胶原诱导性大鼠关节炎(CIA)模型,探讨低氧诱导因子-1α(HIF-1α)、血管内皮生长因子(VEGF)在类风湿关节炎(RA)组织中的动态表达及其相关性作用。方法 50只SD大鼠,随机分为对照组与模型组。建立CIA模型,动态观察各项关节炎活动指标,于造模21、28、35、42d取踝关节行HE染色及HIF-1α、VEGF免疫组化染色,分析两者在CIA中的相关性及与关节炎活动指标、滑膜病理学评分之间的关系。结果 CIA大鼠关节滑膜层和滑膜下层均表达HIF-1α、VEGF,第21天阳性表达量最高,随病程进展,表达逐渐下降,与滑膜病理学评分、滑膜增生评分及血管生成评分呈显著正相关,与炎症浸润评分无明显相关。结论Ⅱ型胶原可成功诱导大鼠关节炎模型。HIF-1α、VEGF在RA组织中的表达,与炎症严重程度呈明显正相关。HIF-1α可能通过调控一系列下游靶基因,如VEGF等,促进滑膜增生及血管生成,影响RA的发生、发展。     

VEGF、Ang-2形成中的作用在Graves病血管形成中的作用

采用S—P免疫组织化学法检测35例Graves病患者甲状腺组织切除标本（观察组）和11例甲状腺良性腺瘤患者的正常甲状腺组织（对照组）中血管内皮生长因子（VEGF）、促血管生成素-2（Ang-2）蛋白的表达和CD34标记的微血管密度（MVD），并分析其相关性。结果 观察组VEGF、Ang-2的表达程度明显高于对照组（P均〈0．05）;观察组VEGF蛋白表达与Ang-2蛋白表达呈显著正相关（r=0.351，P〈0．05）．二者的表达程度与MVD亦均呈显著正相关（r分别为0．723、0．675，P均〈0．01）。提示VEGF、Ang-2表达在Graves病甲状腺血管形成中起重要作用。     

Regulation of fetal growth: consequences and impact of being born small

The first trimester of pregnancy is the time during which organogenesis takes place and tissue patterns and organ systems are established. In the second trimester the fetus undergoes major cellular adaptation and an increase in body size, and in the third trimester organ systems mature ready for extrauterine life. In addition, during that very last period of intrauterine life there is a significant increase in body weight. In contrast to the postnatal endocrine control of growth, where the principal hormones directly influencing growth are growth hormone (GH) and the insulin-like growth factors (IGFs) via the GH-IGF axis, fetal growth throughout gestation is constrained by maternal factors and placental function and is coordinated by growth factors. In general, growth disorders only become apparent postnatally, but they may well be related to fetal life. Thus, fetal growth always needs to be considered in the overall picture of human growth as well as in its metabolic development.     

IGF-1、IGFBP-3在儿童生长激素缺乏症诊断和疗效判断中的应用

目的探讨胰岛素样生长因子1(IGF-1)及其结合蛋白3(IGFBP-3)在儿童生长激素缺乏症(GHD)诊断及疗效判断中的价值。方法68例GHD患儿予以国产0.1 IU/(kg.d)r-hGH治疗12个月,于治疗前及治疗后3、6、12个月分别测定身高、体重、骨龄及血清IGF-1、IGFBP-3,并与60例正常儿童进行对照。结果GHD患儿血清IGF-1和IGFBP-3水平明显低于正常对照组(P均<0.01);r-hGH治疗后身高增长速度明显加快,血清IGF-1、IGFBP-3水平显著升高;治疗前血清IGF-1与治疗6、12个月时的生长速度(GV6,GV12)呈负相关(r=-0.72-、0.78,P均<0.01);治疗3个月时IGFBP-3水平变化与GV6、GV12呈正相关(r=0.82、0.80,P均<0.01)。结论IGF-1、IGFBP-3可用于儿童GHD的诊断及疗效预测。     

Serum levels of growth hormone-binding protein and insulin-like growth factor I in children and adolescents with Type 1 (insulin-dependent) diabetes mellitus

Summary Serum levels of insulin-like growth factor I are reduced in patients with Type 1 (insulin-dependent) diabetes mellitus. To evaluate the role of the hepatic growth hormone receptor in the decreased serum concentrations of insulin-like growth factor I, serum levels of the high affinity growth hormone-binding protein, which is qualitatively and quantitatively related to the hepatic growth hormone receptor, and of insulin-like growth factor I were measured in 70 children and adolescents with Type 1 diabetes and 105 healthy control children. Analysis of variance revealed a significant negative effect of Type 1 diabetes on serum levels of the growth hormone-binding protein and of insulin-like growth factor I. In the diabetic patients, serum levels of the growth hormone-binding protein were positively related to body mass index and to insulin dose per kg body weight, and were not influenced by pubertal stage, gender, or plasma levels of haemoglobin A_1c. Serum levels of insulin-like growth factor I increased during early puberty reaching peak levels at midpuberty and decreasing thereafter. No relationship was found between serum levels of growth hormone-binding protein and of insulin-like growth factor I. Our data suggest that decreased liver somatogenic receptor levels, as reflected by the concentrations of circulating growth hormone-binding protein, play a minor role in the suppressed concentrations of circulating insulin-like growth factor I. Post-growth hormone receptor defects or changes in the insulin-like growth factor binding proteins probably contribute more to the lower serum levels of insulin-like growth factor I.     

Intestinal hormones and growth factors： Effects on the small intestine

There are various hormones and growth factors which may modify the intestinal absorption of nutrients, and which might thereby be useful in a therapeutic setting, such as in persons with short bowel syndrome. In part I, we focus first on insulin-like growth factors, epidermal and transferring growth factors, thyroid hormones and glucocorticosteroids. Part Ⅱ will detail the effects of glucagon-like peptide （GLP）-2 on intestinal absorption and adaptation, and the potential for an additive effect of GLP2 plus steroids.     

妊娠妇女不同时期口服碘油对婴幼儿智力及身高体重的影响

为探讨妊娠妇女口服碘油对预防婴幼儿碘缺乏病的确切效果，对４０２名婴幼儿进行调查，结果发现：妊娠前及妊娠各期口服碘油的母亲子代智力异常发生率，与未服碘油对照组有显著性差异（Ｐ＜０．０１）。各组间身高、体重和血清激素水平无显著性差异。同时发现，在妊娠早期的３个月内口服碘油对于其子代智力发育的促进作用较小，其智力发育异常的比例为２．５３％，大于妊娠中、后期的１．３７％，但小于对照组的５．８０％。     

Therapeutic aspects of growth hormone and insulin-like growth factor-I treatment on visceral fat and insulin sensitivity in adults

Growth hormone (GH) is generally considered to exert anti-insulin actions, whereas insulin-like growth factor I (IGF-I) has insulin-like properties. Paradoxically, GH deficient adults and those with acromegaly are both predisposed to insulin resistance, but one cannot extrapolate from these pathological conditions to determine the normal metabolic roles of GH and IGF-I on glucose homeostasis. High doses of GH treatment have major effects on lipolysis, which plays a crucial role in promoting its anti-insulin effects, whereas IGF-I acts as an insulin sensitizer that does not exert any direct effect on lipolysis or lipogenesis. Under physiological conditions, the insulin-sensitizing effect of IGF-I is only evident after feeding when the bioavailability of circulating IGF-I is increased. In contrast, many studies in GH deficient adults have consistently shown that GH replacement improves the body composition profile although these studies differ considerably in terms of age, the presence or absence of multiple pituitary hormone deficiency, and whether GH deficiency was childhood or adult-onset. However, the improvement in body composition does not necessarily translate into improvements in insulin sensitivity presumably due to the anti-insulin effects of high doses of GH therapy. More recently, we have found that a very low dose GH therapy (0.1 mg/day) improved insulin sensitivity without affecting body composition in GH-deficient adults and in subjects with metabolic syndrome, and we postulate that these effects are mediated by its ability to increase free 'bioavailable' IGF-I without the induction of lipolysis. These results raise the possibility that this low GH dose may play a role in preventing the decline of beta-cell function and the development of type 2 diabetes in these "high risk" subjects.     

Controversies in the Definition and Treatment of Idiopathic Short Stature (ISS)

The term idiopathic short stature (ISS) refers to short children with no identifiable disorder of the growth hormone (GH)/insulin like growth factor (IGF) axis and no other endocrine, genetic or organ system disorder. This heterogeneous group of short children without GH deficiency (GHD) includes children with constitutional delay of growth and puberty, familial short stature, or both, as well as those with subtle cartilage and bone dysplasias. In rare cases, ISS is due to IGF molecular abnormalities. In this review we tackle the major challenges in the definition and treatment of ISS.