BACKGROUND & AIMS: INTRODUCTION:Frequent use of modern imaging methods (such as ultrasound, CT and MRI) results in high incidence of accidentally discovered adrenal mass. Adrenal incidentalomas are accidentally discovered adrenal tumors by imaging methods without any prior suspicion of adrenal disease. Some studies have shown decreased insulin sensitivity in patients with adrenal incidentaloma. OBJECTIVE:The objective of our study was to assess the insulin sensitivity in patients with adrenal incidentalom a. METHOD:A total of 22 patients with accidentally discovered adrenal mass confirmed by CT/MRI were evaluated in our study. Average age was 53.31 +/- 26.5 years and average BMI 25.84 +/- 3.65 kg/m2. Control group consisted of 33 healthy subjects. Insulin sensitivity was assessed by short ITT (insulin tolerance test). Blood samples were taken before, 3, 6, 9, 12, 15, 20 and 30 minutes after i.v. bolus of regular insulin (0.05 IU/kg BW). Glycemia was determined by glucose oxidase method. Statistical analysis was done by ANCOVA, using BMI as covariate. RESULTS:Our results showed significantly lower insulin sensitivity in patients with adrenal incidentalomas comparing to the control group (4.95 +/- 0.58 vs. 6.62 +/- 0.47, p=0.015). CONCLUSION:Our patients with adrenal incidentalomas manifested lower insulin sensitivity what suggested further follow up and assessment of insulin sensitivity during endocrine evaluation of these patients.

背景与目标： 简介：频繁使用现代成像方法（例如超声，CT和MRI）会导致意外发现的肾上腺肿块的发生率很高。肾上腺偶发瘤是通过影像学方法意外发现的肾上腺肿瘤，而没有任何先前怀疑的肾上腺疾病。一些研究表明，肾上腺偶发瘤患者的胰岛素敏感性降低。
目的：本研究的目的是评估肾上腺偶然性a患者的胰岛素敏感性。
方法：本研究共评估22例经CT / MRI确诊的意外发现肾上腺肿块的患者。平均年龄为53.31 /-26.5岁，平均BMI为25.84 /-3.65 kg / m2。对照组由33名健康受试者组成。胰岛素敏感性通过短期ITT（胰岛素耐受性测试）进行评估。在静脉内注射之前，3、6、9、12、15、20和30分钟之前采集血样。大剂量普通胰岛素（0.05 IU / kg体重）。血糖测定采用葡萄糖氧化酶法。由ANCOVA使用BMI作为协变量进行统计分析。
结果：我们的结果显示，肾上腺偶发瘤患者的胰岛素敏感性明显低于对照组（4.95 /-0.58 vs. 6.62 /-0.47，p = 0.015）。
结论：我们的肾上腺偶发瘤患者表现出较低的胰岛素敏感性，这提示对这些患者进行内分泌评估时需要进一步随访和评估胰岛素敏感性。

BACKGROUND & AIMS: :The extracellular calcium-sensing receptor (CaR) is usually associated with systemic Ca(2+) homeostasis, but the CaR is also expressed in many other tissues, including pancreatic islets of Langerhans. In the present study, we have used human islets and an insulin-secreting cell line (MIN6) to investigate the effects of CaR activation using the calcimimetic R-568, a CaR agonist that activates the CaR at physiological concentrations of extracellular Ca(2+). CaR activation initiated a marked but transient insulin secretory response from both human islets and MIN6 cells at a sub-stimulatory concentration of glucose, and further enhanced glucose-induced insulin secretion. CaR-induced insulin secretion was reduced by inhibitors of phospholipase C or calcium-calmodulin-dependent kinases, but not by a protein kinase C inhibitor. CaR activation was also associated with an activation of p42/44 mitogen-activated protein kinases (MAPK), and CaR-induced insulin secretion was reduced by an inhibitor of p42/44 MAPK activation. We suggest that the beta-cell CaR is activated by divalent cations co-released with insulin, and that this may be an important mechanism of intra-islet communication between beta-cells.

背景与目标： ：细胞外钙敏感受体（CaR）通常与全身性Ca（2）稳态相关，但该CaR在许多其他组织中也表达，包括Langerhans的胰岛。在本研究中，我们已经使用人类胰岛和胰岛素分泌细胞系（MIN6）来研究使用拟钙剂R-568（CaR激动剂在生理浓度的细胞外Ca（2）激活CaR的CaR激活）的作用。 。 CaR激活在葡萄糖的亚刺激浓度下启动了来自人胰岛和MIN6细胞的显着但短暂的胰岛素分泌反应，并进一步增强了葡萄糖诱导的胰岛素分泌。 CaR诱导的胰岛素分泌通过磷脂酶C或钙钙调蛋白依赖性激酶的抑制剂降低，但不通过蛋白激酶C抑制剂降低。 CaR激活还与p42 / 44丝裂原激活的蛋白激酶（MAPK）激活相关，并且CaR诱导的胰岛素分泌被p42 / 44 MAPK激活的抑制剂减少。我们建议β细胞CaR被与胰岛素共释放的二价阳离子激活，这可能是β细胞之间胰岛内通讯的重要机制。

BACKGROUND & AIMS: BACKGROUND:Clopidogrel is a widely used antithrombotic agent that inhibits the platelet P2Y(12) adenosine diphosphate (ADP) receptor. There is increasing interest in 'clopidogrel resistance'. OBJECTIVES:To determine whether 'clopidogrel resistance' is accounted for by a pre-existent variability in platelet response to ADP. METHODS:Platelet response to 20 microm ADP was analyzed by four independent whole blood flow cytometric assays: platelet surface activated GPIIb-IIIa, platelet surface P-selectin, monocyte-platelet aggregates and neutrophil-platelet aggregates. In 25 consecutive, non-aspirin-treated healthy subjects, we studied platelet response before and after clopidogrel administration. In addition, we studied the platelet response in 613 consecutive aspirinated patients with or without coronary artery disease (CAD, as determined by angiography) who had or had not been treated with clopidogrel. In these patients, we tested for homogeneity of variance across all durations of clopidogrel exposure and severity of CAD by estimating the 'goodness of fit' of two independent models. RESULTS:In the healthy subjects, pre-clopidogrel response to ADP predicted post-clopidogrel response to ADP. In the patients, clopidogrel, as expected, inhibited the platelet response to ADP. However, irrespective of the duration of clopidogrel administration, the severity of CAD, and the dose of aspirin, clopidogrel did not increase the variance in the platelet response to ADP in any of the four assays of platelet response. CONCLUSIONS:These studies provide evidence that 'clopidogrel resistance' is accounted for by a pre-existent variability in platelet response to ADP and this variability is not increased by clopidogrel administration.

背景与目标： 背景：氯吡格雷是一种广泛使用的抗血栓药，可抑制血小板P2Y（12）二磷酸腺苷（ADP）受体。人们对“氯吡格雷抵抗”的兴趣日益浓厚。
目的：要确定“氯吡格雷抵抗”是否由血小板对ADP的反应中先前存在的变异性引起。
方法：通过四个独立的全血流式细胞术分析血小板对20微米ADP的反应：血小板表面活化的GPIIb-IIIa，血小板表面P-选择素，单核细胞-血小板聚集体和中性白细胞-血小板聚集体。在连续25次非阿司匹林治疗的健康受试者中，我们研究了氯吡格雷给药前后的血小板反应。此外，我们研究了613名连续接受或未接受氯吡格雷治疗的有或没有冠状动脉疾病（CAD，通过血管造影术确定）的吸气患者的血小板反应。在这些患者中，我们通过评估两个独立模型的“拟合优度”，测试了氯吡格雷暴露的所有持续时间和CAD严重性的方差同质性。
结果：在健康受试者中，氯吡格雷对ADP的反应可预测氯吡格雷对ADP的反应。如预期的那样，在患者中，氯吡格雷抑制了血小板对ADP的反应。但是，不管使用氯吡格雷的持续时间，CAD的严重程度以及阿司匹林的剂量如何，在四种血小板反应测定中，氯吡格雷均不会增加血小板对ADP的反应方差。
结论：这些研究提供了证据，“氯吡格雷抵抗”是由血小板对ADP的反应中先前存在的变异性引起的，而使用氯吡格雷不会增加这种变异性。

BACKGROUND & AIMS: :The nature of the temporal relationship between antibacterial consumption and Streptococcus pneumoniae penicillin resistance is investigated using population level data across time. IMS Health Global Services provided national outpatient antibiotic prescription data for the years 1996-2003 from France, Spain, Italy, Germany, the United Kingdom, and the United States. Surveillance data consist of S. pneumoniae isolates obtained from a surveillance database in the same geographic regions from 1996 to 2003. A linear mixed model for repeated measures was used to analyze the association between resistance and several antibacterial classes through time. Changes in penicillin resistance through time in any country are better explained by the weighted cumulative antibacterial consumption with a 2-year lag. Narrow-spectrum penicillins are associated with lower resistance rates. Large reductions in consumption at the population level are needed to affect resistance. There is a peak level of penicillin resistance associated with cumulative exposure to a combination of antibiotic classes that is unique for every country.

背景与目标： ：使用跨时间的人口水平数据调查了抗菌药物消费与肺炎链球菌青霉素耐药性之间时间关系的性质。 IMS Health Global Services提供了1996-2003年法国，西班牙，意大利，德国，英国和美国的国家门诊抗生素处方数据。监测数据由1996年至2003年从同一地理区域的监测数据库中获得的肺炎链球菌分离株组成。采用线性混合模型进行重复测量，以分析耐药性与一段时间内几种抗菌剂类别之间的关联。在任何国家，青霉素耐药性随时间的变化都可以通过加权累积抗菌药消费量（滞后2年）来更好地说明。窄谱青霉素与较低的耐药率有关。需要在人口一级大幅度减少消费量以影响抵抗力。青霉素耐药性的峰值与每个国家所独有的抗生素类药物的累积接触有关。

BACKGROUND & AIMS: :We present the case of an 80-year-old lady known to be sensitive to chlorocresol (4-chloro-3-methyl phenol) who developed severe erythrodermic exfoliative dermatitis with atypical features 2 weeks after commencing subcutaneous insulin. All medications except insulin were stopped, without major improvement. It was noted that the insulin contained m-cresol (m-methyl phenol) so a parabens-based insulin was substituted. There was a significant improvement in her clinical condition within 72 hr. Further patch and intradermal testing to the insulin and m-cresol was planned, but she developed a nosocomial infection and died. We hypothesize that the adverse cutaneous reaction was a systemic manifestation of cresol sensitivity, given the rapid clinical resolution on changing insulins and the previously demonstrated sensitivity to chlorocresol, particularly as cross-reactivity between different low molecular weight methyl phenols is documented. Local injection site reactions and systemic side-effects including nausea, diarrhoea and vomiting have previously been reported with cresol-containing insulins, although to our knowledge, this is the first reported case of a severe cutaneous reaction. It is important to be aware of m-cresol as a potential allergen, as it is contained in most commercially available insulins.

背景与目标： ：我们介绍了一位80岁的女士，她对氯甲酚（4-氯-3-甲基苯酚）敏感，在开始皮下注射胰岛素2周后发展出严重的非典型性红皮病性剥脱性皮炎。除胰岛素外，所有药物均已停止使用，无明显改善。注意到胰岛素包含间甲酚（间甲基苯酚），因此取代了基于对羟基苯甲酸酯的胰岛素。她的临床状况在72小时内有了显着改善。计划对胰岛素和间甲酚进行进一步的贴片和皮内测试，但她发生了医院感染并死亡。我们假设不利的皮肤反应是对甲酚敏感性的全身表现，考虑到快速变化的胰岛素临床解决方案和先前证明的对氯甲酚的敏感性，特别是由于记录了不同低分子量甲基酚之间的交叉反应性。含甲酚的胰岛素以前曾报道过局部注射部位反应和全身副作用，包括恶心，腹泻和呕吐，尽管据我们所知，这是首次报道的严重皮肤反应病例。重要的是要意识到间甲酚是一种潜在的过敏原，因为它包含在大多数市售胰岛素中。

BACKGROUND & AIMS: :Multiple traits of stress resistance were investigated in the epedaphic springtail Orchesella cincta. Second generation adults from five laboratory populations were compared with respect to resistance to extreme temperatures and desiccation, and traits relevant to climatic adaptation. Populations were collected along a 2000-km latitudinal gradient ranging from Denmark to southern Italy and reared under the same standard laboratory conditions. Traits investigated were resistance to high and low temperature, desiccation resistance, body size and water loss rate (WLR). Results showed genetically based differences in resistance to high and low temperature, desiccation, WLR, water pool and body size between populations. Individuals from the most northern population had the highest desiccation-and cold shock resistance, and the lowest heat shock resistance. Females were significantly more desiccation resistant than males. The results of cold shock resistance showed a positive increase with lowest environmental temperature recorded at the sites of population origin, whereas heat shock resistance showed a positive increase with highest recorded temperature at the sites of population origin. Desiccation resistance increased towards the most southern and northern population, suggesting that both low and high temperature extremes affect desiccation resistance. Body mass, water pool and WLR showed interpopulation as well as sex specific variation. This provides evidence for geographical variation in stress resistance of springtails related to climatic conditions.

背景与目标： ：研究了足立跳尾Orchesella cincta的多种抗逆性状。比较了来自五个实验室人群的第二代成年人对极端温度和干燥的抵抗力以及与气候适应有关的性状。从丹麦到意大利南部，沿着2000公里的纬度梯度收集种群，并在相同的标准实验室条件下进行饲养。研究的特征是对高温和低温的抗性，抗干燥性，体型和失水率（WLR）。结果显示，不同人群之间对高温和低温，干燥，WLR，水池和体重的遗传差异。来自最北部人口的个体具有最高的耐干燥性和抗冷震性，以及最低的抗热震性。女性的抗干燥能力明显高于男性。在种群起源点处记录的最低环境温度下，抗冷震性的结果显示为正增加，而在种群起源点处的记录温度最高中，抗热震性的结果显示为正数增加。大部分南部和北部人口的抗旱性增加，这表明低温和高温极端情况都会影响抗旱性。体重，水池和WLR表现出种群数量以及性别差异。这为与气候条件有关的跳尾抗逆性的地理变化提供了证据。

BACKGROUND & AIMS: :Methicillin/oxacillin (Oxa) resistance in Staphylococcus aureus is primarily mediated by the acquired penicillin-binding protein (PBP2a) encoded by mecA. PBP2a acts together with native PBP2 to mediate oxacillin resistance by contributing complementary transpeptidase and transglycosylase activities, respectively. The VraS/VraR two-component regulatory system is inducible by cell-wall antimicrobials (beta-lactams, glycopeptides) and controls transcriptional induction of many cell-wall genes including pbp2 and itself. We investigated the role of VraS/VraR in the phenotypic expression of oxacillin resistance by inactivating vraS in community-acquired MRSA clinical isolates that lack functional genes encoding the mecA regulatory sequences mecI and mecR1. Inactivation of vraS abrogated oxacillin resistance, and complementation with the vraS operon restored the resistance phenotype. mecA transcription increased in the vraS mutants; however, PBP2a abundance was similar to that of the wild type. Although pbp2 transcription decreased in the vraS mutants, overexpression of the pbp2 operon did not restore resistance. These data demonstrate that although expressions of mecA and pbp2 are required for oxacillin resistance, they are not sufficient. Therefore, the vraS/vraR regulatory system plays a crucial role in allowing MRSA to respond to beta-lactams by regulation of a gene target other than the known effectors of methicillin resistance.

背景与目标： 金黄色葡萄球菌对甲氧西林/奥沙西林（Oxa）的耐药性主要由mecA编码的获得性青霉素结合蛋白（PBP2a）介导。 PBP2a与天然PBP2共同发挥作用，通过分别贡献互补的转肽酶和转糖基酶活性来介导奥沙西林抗性。 VraS / VraR两组分调节系统可通过细胞壁抗微生物剂（β-内酰胺，糖肽）诱导，并控制包括pbp2及其本身在内的许多细胞壁基因的转录诱导。我们通过灭活社区获得的MRSA临床分离株中的vraS而失活，研究了VraS / VraR在奥沙西林抗性表型表达中的作用，该分离株缺乏编码mecA调控序列mecI和mecR1的功能基因。 vraS的失活消除了奥沙西林的耐药性，与vraS操纵子的互补恢复了耐药性表型。在vraS突变体中，mecA转录增加；但是，PBP2a的丰度与野生型相似。尽管在vraS突变体中pbp2转录降低，但是pbp2操纵子的过表达不能恢复抗性。这些数据表明，尽管抗mecA和pbp2的表达是奥沙西林耐药性所必需的，但它们还不够。因此，vraS / vraR调节系统在允许MRSA通过调节除已知的甲氧西林抗性效应子以外的基因靶标而对β-内酰胺作出响应中起着至关重要的作用。

BACKGROUND & AIMS: :Rhizoxin is an antineoplastic drug that inhibits tubulin polymerization. In this study, we demonstrated that rhizoxin was approximately twice as active in vitro against a human small-cell lung cancer cell line with non-P-glycoprotein-mediated resistance to vindesine, H69/VDS, as against its parental line, H69. Tubulin polymerization in H69/VDS, demonstrated by Western blot analysis, was inhibited markedly by rhizoxin compared with that in H69, in a concentration-dependent manner. A drug-accumulation study showed that the intracellular rhizoxin level in H69/VDS was 15% lower than that in H69, whereas efflux from H69/VDS was enhanced slightly. These results indicate that enhanced inhibition of tubulin polymerization rather than increased intracellular drug concentration accounted for the higher sensitivity of H69/VDS to rhizoxin. In an experiment using mice with severe combined immunodeficiency and inoculated subcutaneously with H69/VDS, in vivo tumor growth was reduced markedly by three intermittent intraperitoneal doses of rhizoxin compared with that in mice inoculated with H69. Three weeks after the last rhizoxin dose, the relative treated/untreated tumor volumes were 0.29 for H69, but only 0.06 for H69/VDS, indicating that H69/VDS regrowth was minimal even after a 3-week treatment-free period. In conclusion, rhizoxin conquers vindesine resistance of a human small-cell lung cancer cell line in vitro and in vivo.

背景与目标： ：Rhizoxin是一种抑制微管蛋白聚合的抗肿瘤药。在这项研究中，我们证明了根霉毒素在体外对人小细胞肺癌细胞株的活性约为非亲本糖蛋白对长春地辛H69 / VDS的抗性（相对于其亲本株H69）的两倍。 Western blot分析表明，与H69相比，根瘤菌素显着抑制了H69 / VDS中的微管蛋白聚合，且呈浓度依赖性。一项药物蓄积研究表明，H69 / VDS中的细胞内根瘤菌素水平比H69低15％，而H69 / VDS的外排量则略有提高。这些结果表明，增强的对微管蛋白聚合的抑制而不是增加的细胞内药物浓度，说明了H69 / VDS对根瘤菌素的敏感性更高。在一项使用严重联合免疫缺陷小鼠并皮下接种H69 / VDS的小鼠进行的实验中，与接种H69的小鼠相比，腹膜内三剂间断性的根瘤菌素显着降低了体内肿瘤的生长。在最后一剂根瘤菌素给药后三周，H69的相对治疗/未治疗肿瘤体积为0.29，而H69 / VDS仅为0.06，这表明即使经过3周的无治疗期，H69 / VDS的再生长也很小。总之，根瘤菌素可在体外和体内克服人类小细胞肺癌细胞株的长春地辛耐药性。

BACKGROUND & AIMS: :Chondrogenesis occurs in vivo in a hypoxic environment, in which the hypoxia inducible factor 1, HIF-1, plays a regulatory role, possibly mediated through the transcription factor DEC1. We have analyzed the effect of hypoxia (1% oxygen) alone and in combination with insulin on the chondrogenic differentiation of the mouse embryonic stem cell line ATDC5. Hypoxic treatment alone induced early chondrogenesis as evidenced by enhanced expression of aggrecan and collagen II, whereas hypoxic incubation of insulin-treated cells delayed and suppressed insulin-mediated early chondrogenesis and almost completely blocked hypertrophic differentiation. Paradoxically, the transcriptional activation of DEC1 was invariably enhanced by the hypoxic exposure.

背景与目标： ：软骨形成发生在体内低氧环境中，在该环境中，缺氧诱导因子1（HIF-1）发挥调节作用，可能是通过转录因子DEC1介导的。我们已经分析了单独和与胰岛素联合使用低氧（1％氧气）对小鼠胚胎干细胞系ATDC5软骨分化的影响。单用低氧治疗可诱导早期软骨形成，聚集蛋白聚糖和胶原II的表达增强证明了这一点，而对胰岛素处理的细胞进行低氧培养可延迟并抑制胰岛素介导的早期软骨形成，并且几乎完全阻断了肥大细胞的分化。矛盾的是，低氧暴露总是增强了DEC1的转录激活。

BACKGROUND & AIMS: :Gliomas are highly lethal neoplasms that cannot be cured by currently available therapies. Temozolomide is a recently introduced alkylating agent that has yielded a significant benefit in the treatment of high-grade gliomas. However, either de novo or acquired chemoresistance occurs frequently and has been attributed to increased levels of O6-methylguanine-DNA methyltransferase or to the loss of mismatch repair capacity. However, very few gliomas overexpress O6-methylguanine-DNA methyltransferase or are mismatch repair-deficient, suggesting that other mechanisms may be involved in the resistance to temozolomide. The purpose of the present study was to generate temozolomide-resistant variants from a human glioma cell line (SNB-19) and to use large-scale genomic and transcriptional analyses to study the molecular basis of acquired temozolomide resistance. Two independently obtained temozolomide-resistant variants exhibited no cross-resistance to other alkylating agents [1,3-bis(2-chloroethyl)-1-nitrosourea and carboplatin] and shared genetic alterations, such as loss of a 2p region and loss of amplification of chromosome 4 and 16q regions. The karyotypic alterations were compatible with clonal selection of preexistent resistant cells in the parental SNB-19 cell line. Microarray analysis showed that 78 out of 17,000 genes were differentially expressed between parental cells and both temozolomide-resistant variants. None are implicated in known resistance mechanisms, such as DNA repair, whereas interestingly, several genes involved in differentiation were down-regulated. The data suggest that the acquisition of resistance to temozolomide in this model resulted from the selection of less differentiated preexistent resistant cells in the parental tumor.

背景与目标： ：胶质瘤是高度致死性的肿瘤，目前尚无法治愈。替莫唑胺是最近引入的烷基化剂，已在治疗高级神经胶质瘤中产生了显着的益处。然而，从头发生或获得性抗药性经常发生，并且归因于O6-甲基鸟嘌呤-DNA甲基转移酶水平的增加或错配修复能力的丧失。但是，极少的神经胶质瘤过表达O6-甲基鸟嘌呤-DNA甲基转移酶或错配修复缺陷，提示其他机制可能与对替莫唑胺的抗性有关。本研究的目的是从人类神经胶质瘤细胞系（SNB-19）产生抗替莫唑胺的变体，并使用大规模的基因组和转录分析来研究获得的替莫唑胺抗性的分子基础。两个独立获得的替莫唑胺抗性变体对其他烷基化剂[1,3-双（2-氯乙基）-1-亚硝基脲和卡铂]无交叉抗性，并且共有遗传变异，例如2p区域丢失和扩增丢失染色体4和16q区域。核型改变与亲本SNB-19细胞系中先前存在的抗性细胞的克隆选择相容。基因芯片分析显示，在17,000个基因中，有78个在亲代细胞和两种替莫唑胺耐药变体之间差异表达。没有人参与已知的抗性机制，例如DNA修复，而有趣的是，参与分化的几个基因被下调。数据表明，在该模型中获得对替莫唑胺的抗药性是由于在亲本肿瘤中选择了分化程度较低的抗药性细胞而引起的。

BACKGROUND & AIMS: :In the last few years, our knowledge of genetically determined causes of short stature has greatly increased by reports of challenging patients, who offered the opportunity to study genes that play a role in growth. Since the first paper that showed the etiology of Laron syndrome [Godowski PJ, et al: Proc Natl Acad Sci USA 1989;86:8083-8087], many mutations in the growth hormone (GH) receptor have been identified. Recently, new mutations or deletions have been found in several components of the GH-insulin-like growth factor-I (IGF-I) axis: a homozygous mutation of the GH1 gene, resulting in a bio-inactive GH; mutations in the STAT5b gene, which plays a major role in the GH signal transduction; a homozygous missense mutation in the IGF-I gene; heterozygous mutations in the IGF-I receptor gene and a homozygous deletion of the acid-labile subunit gene. In this mini review, we describe the clinical and biochemical features of these genetic defects. Genetic analysis has become essential in the diagnostic workup of a patient with short stature. However, regarding the time consuming nature of molecular analysis, it is important to carefully select the patient for specific genetic evaluation. To help in this selection process, we developed flowcharts, based on the recently described patients, that can be used as guidelines in the diagnostic process of patients with severe short stature of unknown origin.

背景与目标： ：在过去的几年中，由于对挑战性患者的报道，我们对遗传决定的矮小身高原因的了解大大增加了，这些患者为研究在生长中起作用的基因提供了机会。自从第一篇显示Laron综合征病因的论文[Godowski PJ等人：Proc Natl Acad Sci USA 1989; 86：8083-8087]以来，已经确定了生长激素（GH）受体的许多突变。最近，在GH-胰岛素样生长因子-I（IGF-I）轴的几个组成部分中发现了新的突变或缺失：GH1基因的纯合突变，导致了生物失活的GH； STAT5b基因的突变，在GH信号转导中起主要作用； IGF-I基因的纯合错义突变； IGF-1受体基因中的杂合突变和对酸不稳定的亚基基因的纯合缺失。在这个小型综述中，我们描述了这些遗传缺陷的临床和生化特征。遗传分析已成为身材矮小的患者的诊断检查中必不可少的。但是，考虑到分子分析的耗时性质，重要的是要仔细选择患者进行特定的基因评估。为了帮助选择过程，我们根据最近描述的患者制定了流程图，可以将其用作诊断患有严重身材矮小，来源不明的患者的诊断过程中的指导原则。

BACKGROUND & AIMS: CONTEXT:Concern has been raised about the safety of assisted reproduction techniques for the offspring. OBJECTIVES:The objective of the study was to investigate postnatal growth and growth factors in children born after intra-cytoplasmatic sperm injection (ICSI) and in vitro fertilization (IVF). DESIGN:The study had two cohorts: a population-based longitudinal infant cohort 0-36 months [236 ICSI, 173 IVF, 1530 naturally conceived (NC)], and a cross-sectional child cohort at 5 yr (68 ICSI, 67 IVF, 70 NC). INTERVENTION:Anthropometrical measurements were made at birth, 3, 18, 36 (infant cohort), and 60 months (child cohort), and blood samples were collected at 3 or 60 months. MAIN OUTCOME MEASURES:Serum IGF-I, IGFBP-3, height, weight, head and abdominal circumference, body mass index, and fat folds were the main outcome measures. RESULTS:Anthropometrical measurements showed no significant differences between ICSI and IVF children and controls in either cohort. However, singleton ICSI girls [3.4 (0.6) kg, P = 0.008] had a slightly lower birth weight than IVF [3.5 (0.5) kg] and NC girls [3.5 (0.5) kg]. Birth weights of singleton boys [3.6 (0.5) kg], twin boys [2.6 (0.6) kg], and twin girls [2.4 (0.5) kg] did not differ between types of conception. In the infant cohort in 3-month-old singletons, serum IGF-I was lower in ICSI [78 (26) ng/ml] than NC boys [94 (27) ng/ml, P < 0.001] and IVF [74 (34) ng/ml], compared with NC girls [93 (43) ng/ml, P = 0.011]. ICSI children were also smaller than their target height (sd score) at 3 yr of age [mean -0.91 (1.2)], compared with NC children [-0.61 (0.9), P = 0.033]. In the child cohort, target height attainment (sd score) and growth factors did not differ among the three groups. CONCLUSIONS:The overall growth pattern of ICSI and IVF children in both cohorts was normal. Our findings of subtle differences in target height attainment and serum IGF-I levels between infants born after assisted reproduction techniques and controls may not be clinically significant. However, these observations indicate that further systematic follow-up of growth and puberty in these children is needed.

背景与目标： 背景：人们对后代辅助生殖技术的安全性表示关注。
目的：本研究的目的是调查胞浆内精子注射（ICSI）和体外受精（IVF）后出生的儿童的出生后生长和生长因子。
设计：该研究有两个队列：基于人群的纵向婴儿队列0-36个月[236 ICSI，173 IVF，1530自然受孕（NC）]和5岁时的横断面儿童队列（68 ICSI，67 IVF ，70 NC）。
干预措施：分别在出生时，3、18、36（婴儿队列）和60个月（儿童队列）进行人体测量，并在3或60个月时采集血样。
主要观察指标：血清IGF-I，IGFBP-3，身高，体重，头围和腹围，体重指数和脂肪褶皱是主要的观察指标。
结果：人体测量结果显示，ICSI和IVF儿童与对照组之间均无显着差异。但是，单身ICSI女孩[3.4（0.6）千克，P = 0.008]的出生体重略低于IVF [3.5（0.5）千克]和NC女孩[3.5（0.5）千克]。单胎男孩[3.6（0.5）千克]，双胞胎男孩[2.6（0.6）千克]和双胞胎女孩[2.4（0.5）千克]的出生体重在不同的受孕类型之间没有差异。在3个月大的单胎婴儿队列中，ICSI的血清IGF-I低于NC男孩[94（27）ng / ml，P <0.001]和IVF [74（ 34）ng / ml]，而NC女生则为[93（43）ng / ml，P = 0.011]。与3岁儿童相比，ICSI儿童在3岁时也小于其目标身高（sd评分）[平均-0.91（1.2）]，而NC儿童则为[-0.61（0.9），P = 0.033]。在儿童队列中，三组之间的目标身高获得（sd得分）和生长因子没有差异。
结论：两组人群ICSI和IVF儿童的总体生长方式均正常。我们在辅助生殖技术和对照后出生的婴儿之间的目标身高获得和血清IGF-I水平细微差异的发现可能在临床上并不重要。但是，这些观察结果表明，需要对这些儿童的生长和青春期进行进一步的系统随访。

BACKGROUND & AIMS: :Reports on the efficacy of physical activity intervention trials usually only include discussion of the primary outcomes. However, assessing factors such as participant retention, adherence and compliance can assist in the accurate interpretation of the overall impact of a program in terms of reach and appeal. A quasi-randomised trial was carried out to assess and compare retention and adherence rates, and compliance with, a twice weekly resistance training program provided either individually at home or in a group format. Retirement villages (n=6) were assigned to either 'Have A Try' (HAT, home-based) or 'Come Have A Try' (CHAT, group-based); both programs included nine strength and two balance exercises. The program involved a 20-week Intervention Phase a 24-week Maintenance Phase and a 20-week On-going Maintenance Phase. One hundred and nineteen participants (mean age 80+/-6 years) were recruited (HAT=38, CHAT=81). There was no difference in retention rates at the end of the Intervention Phase, but significantly more HAT than CHAT participants had dropped out of the study (p<0.01) after the Maintenance Phase and the On-going Maintenance Phase. During the Intervention Phase, over half the HAT and CHAT participants completed > or =75% of the prescribed activity sessions, but adherence was significantly greater in CHAT than HAT during the Maintenance Phase (p<0.01). Participants in CHAT were significantly more compliant than HAT participants (p<0.05). Both home- and group-based formats were successful over the short-term, but, in retirement villages, the group program had better adherence and compliance in the longer-term.

背景与目标： ：有关体育锻炼干预试验功效的报告通常仅包括对主要结局的讨论。但是，评估参与者的保留，遵守和遵守等因素可以帮助准确地解释计划在影响力和吸引力方面的总体影响。进行了一项半随机试验，以评估和比较保留率和依从率，以及是否遵守每周两次的在家中或以小组形式提供的每周两次阻力训练计划。退休村（n = 6）被分配为“尝试一下”（HAT，基于家庭）或“来一下尝试”（CHAT，基于组）；这两个程序都包括九项力量和两项平衡练习。该计划包括20周的干预阶段，24周的维护阶段和20周的持续维护阶段。招募了119名参与者（平均年龄80 / -6岁）（HAT = 38，CHAT = 81）。在干预阶段结束时，保留率没有差异，但是在维护阶段和正在进行的维护阶段之后，HAT的退出人数比CHAT参与者退出研究的次数多（p <0.01）。在干预阶段，超过一半的HAT和CHAT参与者完成了规定活动的>或= 75％，但是在维持阶段，CHAT中的依从性明显高​​于HAT（p <0.01）。与CHAT参与者相比，CHAT参与者的依从性更高（p <0.05）。以家庭为基础和以团体为基础的形式在短期内都是成功的，但是在退休村，从长期来看，团体计划具有更好的遵守性和合规性。

BACKGROUND & AIMS: :The biological actions of the insulin-like growth factors, IGF-I and IGF-II, are mediated by the ligand-induced activation of the IGF-I receptor (IGF-IR), a transmembrane heterotetramer linked to the ras-raf-mitogen-activated protein kinase (MAPK) and phosphatidyl inositol 3 kinase (PI3K)-protein kinase B (PKB)/Akt signal transduction cascades. The Wilms' tumor suppressor gene (wt1) encodes a zinc finger transcription factor, WT1, which has been implicated in various cellular processes including proliferation, differentiation and apoptosis. In the present study we demonstrated that IGF-I modulates the WT1 gene expression in neurally derived PC12 cells in a dose- and time-dependent manner. This effect was mediated through both the MAPK and PI3-kinase signaling pathways, as shown by the ability of the specific inhibitors UO126 and LY294002 to abrogate IGF-I action. Moreover, using RT-PCR and transient transfection assays, we demonstrated that the IGF-I effect was associated with corresponding changes in WT1 mRNA levels and WT1 promoter activity. In addition, the results of the present study revealed that high WT1 levels were associated with the induction of apoptosis, whereas low WT1 levels were correlated with the inhibition of apoptosis, as demonstrated by poly ADP ribose polymerase (PARP) cleavage, Bax expression, Annexin V-FITC staining, and by the use of antisense oligonucleotides against WT1. In summary, our results show that the wt1 gene is a novel target for IGF-I action in neurally derived cells.

背景与目标： 胰岛素样生长因子IGF-I和IGF-II的生物学作用是由配体诱导的IGF-I受体（IGF-IR）活化而介导的，IGF-IR受体是与ras-raf-连接的跨膜异四聚体丝裂原活化蛋白激酶（MAPK）和磷脂酰肌醇3激酶（PI3K）-蛋白激酶B（PKB）/ Akt信号转导级联反应。威尔姆斯的肿瘤抑制基因（wt1）编码锌指转录因子WT1，该因子已参与多种细胞过程，包括增殖，分化和凋亡。在本研究中，我们证明了IGF-1以剂量和时间依赖性的方式调节神经源性PC12细胞中WT1基因的表达。这种作用是通过MAPK和PI3激酶信号传导途径介导的，如特异性抑制剂UO126和LY294002消除IGF-I作用的能力所示。此外，使用RT-PCR和瞬时转染试验，我们证明了IGF-I的作用与WT1 mRNA水平和WT1启动子活性的相应变化有关。此外，本研究结果表明，高WT1水平与凋亡诱导相关，而低WT1水平与凋亡抑制相关，如聚ADP核糖聚合酶（PARP）裂解，Bax表达，膜联蛋白所证明的。 V-FITC染色，并使用针对WT1的反义寡核苷酸。总而言之，我们的结果表明wt1基因是神经衍生细胞中IGF-I作用的新靶标。

BACKGROUND & AIMS: :Insulin resistance affecting skeletal muscle metabolism is present in the prehypertensive state. The aim of our study was to test the hypothesis that blood pressure value is related to skeletal muscle composition, measured by (31)P magnetic resonance (MR) spectroscopy, and to insulin sensitivity in the offspring of hypertensive parents (OH) and healthy controls. Study groups consisted of 10 healthy young lean OH with normal glucose tolerance, confirmed with oral glucose tolerance test, and 13 controls matched for age, sex, and body mass index. Insulin action was estimated as glucose disposal (M), glucose metabolic clearance rate (MCR), and insulin sensitivity index (M/I) during a 10-hour hyperinsulinemic euglycemic clamp. The sum of immunoreactive insulin values from the oral glucose tolerance test was calculated. (31)P MR spectroscopy was performed on a whole-body MR scanner (Siemens Vision, Erlangen, Germany) operating at 1.5 T and equipped with actively shielded gradient coils. There were no differences in common metabolic and anthropometric parameters between OH and controls except for the blood pressure, which was in the range of normal to high-normal level in OH. Mean blood pressure was significantly higher in OH (95.73 +/- 4.39 vs 83.76 +/- 3.95 mm Hg; P < .001). Trend toward insulin resistance was registered in OH with significantly lower M/I (0.74 +/- 0.47 vs 1.42 +/- 0.65 mg x kg(-1) x min(-1) x mIU(-1) x L(-1); P < .05). There were no significant differences in total serum magnesium (sMg) levels between OH and controls, although a positive correlation exists between sMg and insulin sensitivity expressed as M (r = 0.63, P < .01), MCR (r = 0.54, P < .01), and M/I (r = 0.51, P < .05). No differences in signal intensities of phosphocreatine (PCr), phosphomonoesters, phosphodiesters, inorganic phosphates (Pi), adenosine triphosphates (Patp and betaATP), and calculated concentrations of intracellular ionized magnesium (Mgi) and H(+) ions between the groups were detected. Systolic blood pressure correlates positively with PCr/Patp (r = 0.43, P < .05), Pi/Patp (r = 0.413, P < .05), and Pi/betaATP (r = 0.48, P < .05). Diastolic blood pressure correlates positively only with the ratio Pi/betaATP (r = 0.42, P < .05). The sum of immunoreactive insulin values correlates with PCr/betaATP (r = 0.53, P < .01) and with Pi/betaATP (r = 0.6, P < .01). In conclusion, increase in blood pressure and insulin resistance were confirmed in offspring of OH. Insulin sensitivity is related to sMg and the elevation of blood pressure is associated with the activation of energy metabolism in skeletal muscle. The relationship between muscle energetic characteristics and markers of insulin resistance suggests that the alteration of energy metabolism may be present in early stages of metabolic syndrome.

背景与目标： ：在高血压前状态下，会影响骨骼肌新陈代谢的胰岛素抵抗。我们研究的目的是检验以下假设：血压值与通过（31）P磁共振（MR）光谱法测量的骨骼肌成分以及高血压父母（OH）和健康对照的后代的胰岛素敏感性有关。研究组包括10名健康正常的年轻瘦肉OH，其葡萄糖耐量正常，经口服葡萄糖耐量试验确认，另有13个对照的年龄，性别和体重指数匹配。在10小时高胰岛素正常血糖钳制期间，胰岛素作用估计为葡萄糖处置（M），葡萄糖代谢清除率（MCR）和胰岛素敏感性指数（M / I）。计算来自口服葡萄糖耐量试验的免疫反应性胰岛素值的总和。 （31）P MR光谱是在全身MR扫描仪（Siemens Vision，Erlangen，德国）上以1.5 T操作并配备有源屏蔽梯度线圈进行的。 OH和对照组之间的共同代谢和人体测量学参数没有差异，除了血压处于OH正常水平到高正常水平的范围之内。 OH的平均血压显着升高（95.73 /-4.39与83.76 /-3.95 mm Hg； P <.001）。在OH中出现胰岛素抵抗的趋势，M / I显着降低（0.74 /-0.47对1.42 /-0.65 mg x kg（-1）x min（-1）x mIU（-1）x L（-1）; P <.05）。尽管sMg与胰岛素敏感性之间呈正相关，以M（r = 0.63，P <.01），MCR（r = 0.54，P < .01）和M / I（r = 0.51，P <.05）。在两组之间没有发现磷酸肌酸（PCr），磷酸单酯，磷酸二酯，无机磷酸盐（Pi），三磷酸腺苷（Patp和betaATP）的信号强度以及计算出的细胞内离子化镁（Mgi）和H（）浓度的差异。收缩压与PCr / Patp（r = 0.43，P <.05），Pi / Patp（r = 0.413，P <.05）和Pi / betaATP（r = 0.48，P <.05）正相关。舒张压仅与Pi / betaATP比率呈正相关（r = 0.42，P <.05）。免疫反应性胰岛素值的总和与PCr / betaATP（r = 0.53，P <.01）和Pi / betaATP（r = 0.6，P <.01）相关。总之，在OH的后代中证实了血压升高和胰岛素抵抗。胰岛素敏感性与sMg有关，血压升高与骨骼肌能量代谢的激活有关。肌肉能量特性与胰岛素抵抗标志物之间的关系表明，能量代谢的改变可能在代谢综合征的早期出现。