BACKGROUND & AIMS: The present study was designed to elucidate the neurotransmitters involved in activation of the noradrenergic nucleus, locus coeruleus, by distention of the distal colon. Locus coeruleus spontaneous discharge rate was recorded from halothane-anesthetized rats before, during and after distention of the colon produced by inflation of a balloon catheter with varying volumes of water. Locus coeruleus activation by colon distention was volume-dependent and reversible. Activation of cortical electroencephalographic activity was temporally correlated with locus coeruleus activation during colon distention and prolonged distention (greater than 2 min) resulted in tachyphalaxis to both locus coeruleus and cortical electroencephalographic activation. The corticotropin-releasing factor antagonist, DPheCRF(12-41), administered intracerebroventricularly (3 microg) or microinfused into the locus coeruleus (10 ng) significantly attenuated locus coeruleus activation produced by lower, but not higher magnitudes of colon distention, implicating corticotropin-releasing factor afferents to the locus coeruleus in this response. Consistent with this, prior exposure to 30 min of footshock stress, which desensitizes locus coeruleus neurons to corticotropin-releasing factor, produced a similar attenuation of locus coeruleus activation by low, but not high magnitudes of distention. Kynurenic acid, administered intracerebroventricularly (5 micromol), significantly antagonized locus coeruleus activation by all magnitudes of colon distention. However, this excitatory amino acid antagonist was ineffective when administered directly into the locus coeruleus (0.3 nmol). Together, these findings suggest that low magnitudes of colon distention activate the locus coeruleus-noradrenergic system via corticotropin-releasing factor release within the locus coeruleus and that excitatory amino acid neurotransmission at a site distal to the locus coeruleus is necessary for this response. Activation of the locus coeruleus-noradrenergic system during colon distention may serve as a cognitive limb of the peripheral parasympathetic response. This activation may also play a role in disorders characterized by comorbidity of colonic and psychiatric symptoms, such as irritable bowel syndrome.

背景与目标： 本研究旨在阐明远端结肠扩张引起的去甲肾上腺素能核激活的神经递质。记录了氟烷麻醉大鼠在用不同体积的水充入球囊导管使结肠扩张之前，期间和之后自发排出蓝藻的频率。结肠扩张引起的蓝斑轨迹激活是体积依赖性的和可逆的。皮质脑电图活动的激活在时间上与结肠扩张过程中蓝斑蓝素的激活相关，长期扩张（大于2分钟）导致蓝斑和皮质脑电图激活都受到速动。皮质激素释放因子拮抗剂DPheCRF（12-41），经脑室内（3微克）或微输注到蓝斑（10 ng）时，可显着减弱由较低但不是较高程度的结肠扩张产生的蓝斑激活，这暗示促肾上腺皮质激素-在这种反应中，释放因子传入蓝斑。与此相一致，事先暴露于30分钟的足底震荡中，使蓝斑蓝皮病的神经元对促肾上腺皮质激素释放因子不敏感，通过低但不高的扩张程度，蓝斑蓝皮病的激活也有类似的减弱。脑室内（5微摩尔）施用的犬尿酸通过各种程度的结肠扩张显着拮抗蓝斑轨迹激活。但是，这种兴奋性氨基酸拮抗剂当直接施用于蓝斑（0.3 nmol）时无效。在一起，这些发现表明低程度的结肠扩张通过蓝藻中的促肾上腺皮质激素释放因子释放来激活蓝藻-去甲肾上腺素能系统，并且在蓝藻远侧的部位，兴奋性氨基酸神经传递对于该反应是必需的。结肠扩张期间蓝斑-去甲肾上腺素能系统的激活可能充当外周副交感反应的认知肢体。这种活化作用还可能在以结肠和精神症状合并症为特征的疾病中起作用，例如肠易激综合症。

BACKGROUND & AIMS: :The 6-h plasma profiles of adrenocorticotropic hormone (ACTH), cortisol, alpha-melanocyte-stimulating hormone (alpha-MSH), and GH were studied in 17 dogs with pituitary-dependent hyperadrenocorticism (PDH) before and after hypophysectomy. The aim of the study was to investigate the relation between the hormone profile characteristics and recurrence of PDH after surgery. The hormones were secreted in a pulsatile fashion. The basal plasma cortisol concentration and area under the curve (AUC) for cortisol were significantly higher in the PDH cases than in eight controls. The characteristics of the plasma profiles of ACTH and alpha-MSH were not significantly different between the PDH cases and the controls. In the PDH cases, less GH was secreted in pulses than in the controls, but the difference was not significant. The basal plasma cortisol concentration, the AUC for ACTH and cortisol, and the pulse frequency of ACTH and cortisol decreased significantly after hypophysectomy for the group of PDH cases. The basal plasma concentrations of ACTH and alpha-MSH, the AUC for alpha-MSH, and the characteristics of the plasma GH profiles of the PDH cases remained unchanged after hypophysectomy. No pulses of alpha-MSH were observed after hypophysectomy. The co-occurrence between the ACTH and cortisol pulses decreased significantly with hypophysectomy. The postoperative pulse frequency of ACTH was the only characteristic with predictive value for the recurrence of PDH after hypophysectomy. The results of this study demonstrate that ACTH, cortisol, alpha-MSH, and GH are secreted in a pulsatile fashion in dogs with PDH. Hypophysectomy effectively reduces the secretion of ACTH and cortisol. The presence of ACTH pulses after hypophysectomy is a risk factor for the recurrence of hyperadrenocorticism.

背景与目标： ：在垂体切除术前后，对17例垂体依赖性肾上腺皮质功能亢进症（PDH）的狗进行了肾上腺皮质激素（ACTH），皮质醇，α-黑素细胞刺激激素（α-MSH）和GH的6小时血浆谱研究。该研究的目的是研究激素谱特征与PDH术后复发之间的关系。激素以搏动的方式分泌。 PDH患者的基础血浆皮质醇浓度和皮质醇曲线下面积（AUC）显着高于八个对照组。在PDH病例和对照组之间，ACTH和α-MSH的血浆分布特征没有显着差异。在PDH病例中，与对照相比，脉冲中分泌的GH少，但差异不显着。对于PDH组，在进行了植体切除后，基础血浆皮质醇浓度，ACTH和皮质醇的AUC以及ACTH和皮质醇的脉冲频率均显着降低。垂体切除后，PDH病例的ACTH和α-MSH的基础血浆浓度，α-MSH的AUC以及血浆GH谱的特征保持不变。垂体切除术后未观察到α-MSH脉冲。垂体后叶切除术使ACTH和皮质醇脉冲之间的同时发生显着降低。 ACTH的术后脉冲频率是对垂体切除术后PDH复发的唯一具有预测价值的特征。这项研究的结果表明，PDH犬的搏动性分泌ACTH，皮质醇，α-MSH和GH。垂体切除术可有效减少ACTH和皮质醇的分泌。垂体切除术后ACTH脉冲的存在是肾上腺皮质功能亢进复发的危险因素。

BACKGROUND & AIMS: :The ovarian steroid hormone estrogen (E2) elicits a multiplicity of both systemic and uterotropic responses in vivo. For example, the administration of E2 to ovariectomized (Ovx) and sexually immature rodents leads to uterine-specific inflammatory infiltrates. In this study, we quantitated the number of eosinophils and BM8+, Ia+, and CD4+ cells in uteri obtained from adult Ovx control and E2-treated C57BL/6J, C3H/HeJ, and (C57BL/6J x C3H/HeJ) (B6C3) F1 hybrid mice. All three strains exhibited a significant increase in the number of uterine eosinophils and BM8+ macrophages after E2 treatment. However, C57BL/6J and B6C3 F1 hybrid mice responded with a greater number of infiltrating eosinophils and macrophages as compared with C3H/HeJ. A similar analysis of Ia+ and CD4+ cells showed that E2 treatment either down-regulates or does not affect the number of such cells in all three strains. Genome exclusion mapping using a (C57BL/6J x C3H/HeJ) x C3H/HeJ backcross population localized Est1, the major locus controlling the number of eosinophils infiltrating the uterus after E2 treatment, to chromosome 4. In addition, suggestive linkage to marker loci on chromosomes 10 and 16 was detected and evidence for locus interaction is presented. Our results conclusively demonstrate that E2-regulated/ dependent responses can be genetically controlled, indicating that the phenotypic variation observed in both the normal and pathological effects of E2 may, in part, be due to a genetic component.

背景与目标： ：卵巢类固醇激素雌激素（E2）在体内引起多种全身和子宫促反应。例如，将E2给予去卵巢（Ovx）和性不成熟的啮齿动物会导致子宫特异性炎症浸润。在这项研究中，我们量化了从成年Ovx对照和经E2处理的C57BL / 6J，C3H / HeJ和（C57BL / 6J x C3H / HeJ）（B6C3）获得的子宫中嗜酸性粒细胞和BM8，Ia和CD4细胞的数量F1杂种小鼠。在E2处理后，所有三个菌株均表现出子宫嗜酸性粒细胞和BM8巨噬细胞数量的显着增加。但是，与C3H / HeJ相比，C57BL / 6J和B6C3 F1杂种小鼠反应的浸润性嗜酸性粒细胞和巨噬细胞数量更多。对Ia和CD4细胞的类似分析显示，E2处理在所有三个菌株中均下调或不影响此类细胞的数量。使用（C57BL / 6J x C3H / HeJ）x C3H / HeJ回交群体定位的基因组排斥定位于Est1，Est1是控制E2处理后浸润子宫的嗜酸性粒细胞数量的主要基因座，并指向染色体4。检测到10号和16号染色体上的DNA，并提供了基因座相互作用的证据。我们的结果最终证明，E2调节/依赖性反应可以通过基因控制，这表明在E2的正常和病理效应中观察到的表型变异可能部分归因于遗传成分。

BACKGROUND & AIMS: :Following surgery, the hormone dependence of breast tumors is exploited for therapy using antagonists such as tamoxifen, although occasional hormone-resistant clones do appear. Another chemotherapeutic strategy uses microtubule inhibitors such as taxanes. Unfortunately, these agents elicit toxicities such as leukocytopenia, diarrhea, alopecia, and peripheral neuropathies and are also associated with the emergence of drug resistance. We have previously described a tubulin-binding, natural compound, noscapine, that was nontoxic and triggered apoptosis in many cancer types albeit at 10 mumol/L or higher concentrations depending on the cell type. We now show that a synthetic analogue of noscapine, 9-bromonoscapine, is approximately 10-fold to 15-fold more potent than noscapine in inhibiting cell proliferation and induces apoptosis following G2-M arrest in hormone-insensitive human breast cancers (MDA-MB-231). Furthermore, a clear loss of mitochondrial membrane potential, release of cytochrome c, activation of the terminal caspase-3, and the cleavage of its substrates such as poly(ADP-ribose) polymerase, suggest an intrinsic apoptotic mechanism. Taken together, these data point to a mitochondrially mediated apoptosis of hormone-insensitive breast cancer cells. Human tumor xenografts in nude mice showed significant tumor volume reduction and a surprising increase in longevity without signs of obvious toxicity. Thus, our data provide compelling evidence that 9-bromonoscapine can be useful for the therapy of hormone-refractory breast cancer.

背景与目标： ：手术后，尽管偶尔出现激素抵抗性克隆，但利用他莫昔芬等拮抗剂开发了乳腺肿瘤的激素依赖性疗法。另一种化学治疗策略是使用微管抑制剂，例如紫杉烷类。不幸的是，这些药物引起毒性，例如白细胞减少，腹泻，脱发和周围神经病，并且还与耐药性的出现有关。先前我们已经描述了微管蛋白结合的天然化合物Noscapine，尽管在10μmol/ L或更高的浓度（取决于细胞类型）下，但在许多类型的癌症中均无毒并引发细胞凋亡。我们现在显示，Noscapine的合成类似物9-bromonoscapine在抑制细胞增殖方面比Noscapine的效力高约10倍至15倍，并在激素不敏感的人类乳腺癌（MDA-MB -231）。此外，线粒体膜电位的明显损失，细胞色素c的释放，末端caspase-3的活化以及其底物（如聚（ADP-核糖）聚合酶）的裂解表明了内在的凋亡机制。综上所述，这些数据表明了激素不敏感的乳腺癌细胞由线粒体介导的凋亡。裸鼠中的人类肿瘤异种移植物显示出明显的肿瘤体积减少和寿命的惊人增加，而没有明显的毒性迹象。因此，我们的数据提供了令人信服的证据，表明9-溴莫可可碱可用于治疗激素难治性乳腺癌。

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: :Angiogenesis is a crucial step in many pathologies, including tumor growth and metastasis. Here, we show that tilted peptides exert antiangiogenic activity. Tilted (or oblique-oriented) peptides are short peptides known to destabilize membranes and lipid cores and characterized by an asymmetric distribution of hydrophobic residues along the axis when helical. We have previously shown that 16-kDa fragments of the human prolactin/growth hormone (PRL/GH) family members are potent angiogenesis inhibitors. Here, we demonstrate that all these fragments possess a 14-aa sequence having the characteristics of a tilted peptide. The tilted peptides of human prolactin and human growth hormone induce endothelial cell apoptosis, inhibit endothelial cell proliferation, and inhibit capillary formation both in vitro and in vivo. These antiangiogenic effects are abolished when the peptides' hydrophobicity gradient is altered by mutation. We further demonstrate that the well known tilted peptides of simian immunodeficiency virus gp32 and Alzheimer's beta-amyloid peptide are also angiogenesis inhibitors. Taken together, these results point to a potential new role for tilted peptides in regulating angiogenesis.

背景与目标： ：血管生成是包括肿瘤生长和转移在内的许多病理学中至关重要的一步。在这里，我们表明倾斜的肽发挥抗血管生成活性。倾斜（或倾斜定向）的肽是已知的使膜和脂质核心不稳定的短肽，其特征是当螺旋状时，疏水性残基沿轴不对称分布。我们以前已经表明，人类催乳激素/生长激素（PRL / GH）家族成员的16 kDa片段是有效的血管生成抑制剂。在这里，我们证明所有这些片段均具有具有倾斜肽特征的14-aa序列。人催乳激素和人生长激素的倾斜肽在体外和体内均可诱导内皮细胞凋亡，抑制内皮细胞增殖和抑制毛细血管形成。当肽的疏水性梯度因突变而改变时，这些抗血管生成作用被消除。我们进一步证明了猿猴免疫缺陷病毒gp32和阿尔茨海默氏β-淀粉样蛋白肽的众所周知的倾斜肽也是血管生成抑制剂。综上所述，这些结果表明倾斜的肽在调节血管生成中具有潜在的新作用。

BACKGROUND & AIMS: :Thyroid hormone (TH) regulates such crucial biological functions as normal growth, development and metabolism of nearly all vertebrate tissues. In skeletal muscle, TH plays a critical role in regulating the function of satellite cells, the bona fide skeletal muscle stem cells. Deiodinases (D2 and D3) have been found to modulate the expression of various TH target genes in satellite cells. Regulation of the expression and activity of the deiodinases constitutes a cell-autonomous, pre-receptor mechanism that controls crucial steps during the various phases of myogenesis. Here, we review the roles of deiodinases in skeletal muscle stem cells, particularly in muscle homeostasis and upon regeneration. We focus on the role of T3 in stem cell functions and in commitment towards lineage progression. We also discuss how deiodinases might be therapeutically exploited to improve satellite-cell-mediated muscle repair in skeletal muscle disorders or injury.

背景与目标： 甲状腺激素（TH）调节着至关重要的生物学功能，例如几乎所有脊椎动物组织的正常生长，发育和代谢。在骨骼肌中，TH在调节卫星细胞（真正的骨骼肌干细胞）的功能中起着至关重要的作用。已发现脱碘酶（D2和D3）可调节卫星细胞中各种TH靶基因的表达。脱碘酶的表达和活性的调节构成了细胞自主的前受体机制，该机制在肌生成的各个阶段中控制关键步骤。在这里，我们回顾了脱碘酶在骨骼肌干细胞中的作用，特别是在肌肉稳态和再生中。我们专注于T3在干细胞功能中的作用以及对谱系进展的承诺。我们还将讨论如何在骨骼肌疾病或损伤中治疗性利用脱碘酶来改善卫星细胞介导的肌肉修复。

BACKGROUND & AIMS: PURPOSE:The incidence of poor ovarian response in controlled ovarian stimulation (COH) has been reported in 9-24 % of IVF-ET cycles. Growth hormone augments the effect of gonadotropin on granulosa and theca cells, and plays an essential role in ovarian function, including follicular development, estrogen synthesis and oocyte maturation. The aim of this study was to assess IVF-ET cycle outcome after the addition of growth hormone in antagonist protocol in poor responders. MATERIALS AND METHODS:Eighty-two poor responder patients selected for ART enrolled the study and were randomly divided into two groups. Group I (GH/HMG/GnRHant group, n = 40) received growth hormone/gonadotropin/GnRH antagonist protocol and group II (HMG/GnRHant group, n = 42) received gonadotropin/GnRH antagonist protocol. RESULTS:The number of retrieved oocytes was significantly higher in GH/HMG/GnRHant group than HMG/GnRHant group, 6.10 ± 2.90 vs. 4.80 ± 2.40 (p = 0.035) and the number of obtained embryos was also significantly higher in GH/HMG/GnRHant group than HMG/GnRHant group, 3.7 ± 2.89 as compared to 2.7 ± 1.29 (p = 0.018). There were no significant differences between groups regarding implantation, and chemical and clinical pregnancy rates. CONCLUSION:Our study showed that co-treatment with growth hormone in antagonist protocol in patients with a history of poor response in previous IVF-ET cycles did not increase pregnancy rates.

背景与目标： 目的：在IVF-ET周期的9-24％中，有报道称在受控卵巢刺激（COH）中卵巢反应不良的发生率。生长激素增强了促性腺激素对颗粒和卵泡膜细胞的作用，并且在卵巢功能（包括卵泡发育，雌激素合成和卵母细胞成熟）中起着至关重要的作用。这项研究的目的是评估在不良反应者的拮抗剂方案中添加生长激素后的IVF-ET周期结果。
材料与方法：选择接受抗逆转录病毒治疗的82位反应较差的患者作为研究对象，并将其随机分为两组。第一组（GH / HMG / GnRHant组，n = 40）接受生长激素/促性腺激素/ GnRH拮抗剂方案，而第二组（HMG / GnRHant组，n = 42）接受促性腺激素/ GnRH拮抗剂方案。
结果：GH / HMG / GnRHant组的回收卵母细胞数量显着高于HMG / GnRHant组，分别为6.10±2.90和4.80±2.40（p = 0.035），并且GH / HMG中获得的胚胎数量也明显更高/ GnRHant组比HMG / GnRHant组为3.7±2.89，而2.7±1.29（p = 0.018）。两组之间在植入，化学和临床妊娠率方面无显着差异。
结论：我们的研究表明，在先前的IVF-ET周期中有不良反应史的患者中，在拮抗剂方案中与生长激素共同治疗不会增加妊娠率。

BACKGROUND & AIMS: OBJECTIVE:Anticipated pain with intrauterine device (IUD) insertion may be a barrier to widespread use. Our objective was to evaluate the efficacy of intracervical 2% lidocaine gel for pain relief with IUD insertion. STUDY DESIGN:We performed a double-blind, randomized controlled trial of women undergoing IUD insertion. Participants were randomly assigned to 2% lidocaine or placebo gel. Study gel (3 mL) was placed 3 minutes prior to IUD insertion. Pain scores were measured at various time points using a 10-point visual analog scale. RESULTS:Of the 200 participants randomized, 199 completed the study. Pain scores among lidocaine and placebo arms were similar at tenaculum placement (lidocaine and placebo: median, 4; range, 0-10; P = .15) and with insertion (lidocaine: median, 5; range, 1-10; placebo: median, 6; range, 0-10; P = .16). These results did not differ by parity. CONCLUSION:Topical or intracervical 2% lidocaine gel prior to IUD insertion does not decrease pain scores.

背景与目标： 目的：宫内节育器（IUD）插入会导致预期的疼痛可能是广泛使用的障碍。我们的目标是评估2％利多卡因腹腔内凝胶治疗宫内节育器疼痛缓解的效果。
研究设计：我们对接受宫内节育器植入的妇女进行了一项双盲，随机对照试验。参与者被随机分配到2％利多卡因或安慰剂凝胶中。在插入宫内节育器之前3分钟放置研究凝胶（3 mL）。使用10点视觉模拟量表在各个时间点测量疼痛评分。
结果：在随机分配的200名参与者中，有199名完成了研究。利多卡因和安慰剂组之间的疼痛评分在触角放置（利多卡因和安慰剂：中位数，4；范围，0-10； P = .15）和插入时（利多卡因：中位数，5；范围，1-10；安慰剂：中位数为6；范围为0-10； P = 0.16）。这些结果在均等方面没有差异。
结论：在宫内节育器插入前局部或颅内使用2％利多卡因凝胶不会降低疼痛评分。

BACKGROUND & AIMS: This article describes the use and prescribing of menopausal and postmenopausal hormone therapy (HT) in one example country, Finland, and the trends and levels of HT use in other western countries for comparison. Previously published studies were reviewed and reanalyzed, and some additional unpublished data from Finnish surveys were compiled. The use of HT increased in Finland up to 1994. In Finland the initiative for HT use came more often from physicians than women themselves, physicians valued HT more than women, women's period of use of HT was shorter than physicians' recommendations, women's reasons for using HT were usually to treat symptoms, but physicians considered HT also useful in the prevention of later diseases. Gynecologists were more favorable toward HT than other physicians. HT has become common in very different times in different countries, but with the exception of the US experience in the 1970s, the trend has been towards increasing use. One motivation to do surveys on physicians' prescribing or women's use of HT has been to facilitate HT use. The large variation in HT use may reflect the uncertainty concerning its true value. The reasons for the large-scale prevention with HT have not been systematically studied, but it is likely due to various social and commercial forces.

背景与目标： 本文介绍了一个示例国家芬兰的绝经和绝经后激素治疗（HT）的使用和处方，并比较了其他西方国家使用HT的趋势和水平，以进行比较。审查并重新分析了以前发表的研究，并汇编了芬兰调查中的一些其他未发表的数据。直到1994年，芬兰对HT的使用有所增加。在芬兰，使用HT的倡议更多地是来自医生而不是女性本身，医生对HT的重视程度高于女性，女性使用HT的时间短于医师的建议，这是妇女的原因。通常使用HT来治疗症状，但医生认为HT还可用于预防以后的疾病。妇科医生比其他医生更倾向于HT。 HT在不同国家的不同时代已经很普遍，但是除了美国在1970年代的经验外，趋势是越来越多地使用它。对医生的处方或女性使用HT进行调查的动机之一是促进HT的使用。 HT使用量的巨大差异可能反映了其真实价值的不确定性。大规模预防HT的原因尚未得到系统的研究，但这可能是由于各种社会和商业力量造成的。

BACKGROUND & AIMS: :The level of cyclic AMP in various fractions of rat skeletal tissue was measured after in vitro or in vivo administration of parathyroid hormone and calcitonin. Incubations of bone fractions prepared from young (5 weeks of age thyroparathyroidectomized rats revealed that both parathyroid hormone and calcitonin increased the cyclic AMP level in fractions of epiphysis, metaphysis and marrow cells. Cyclic AMP accumulation in incubated perisoteum and diaphysis were induced solely by parathyroid hormone. In in vivo experiments the cyclic AMP level in the tibia of the thyroparathyroidectomized rat was increased by infusion of either parathyroid hormone or calcitonin, and the simultaneous administration of each maximally effective dose of the two hormones exhibited an additive effect. Within 2 min, parathyroid hormone infusion caused an elevation of cyclic AMP content in periosteum and metaphysis. Rapid increase of cyclic AMP in the metaphysis was also induced by calcitonin, and the effect of the two hormones on cyclic AMP accumulation in this fraction was additive. Small but significant increase of cyclic AMP in the diaphysis was detected at 5 min after the administration of parathyroid hormone. Calcitonin infusion did not show any consistent effects on periosteum and diaphysis.

背景与目标： ：在体外或体内给予甲状旁腺激素和降钙素后，测量大鼠骨骼组织各部分中环AMP的水平。从年轻（5周龄甲状腺副甲状腺切除的大鼠）制备的骨级分的培养表明，甲状旁腺激素和降钙素均会增加骨epi，干physi端和骨髓细胞部分中的环AMP含量。仅在甲状旁腺激素的诱导下，骨膜和骨干中的循环AMP积累是诱因。在体内实验中，通过注射甲状旁腺激素或降钙素可增加甲状旁腺切除大鼠的胫骨中的环AMP含量，同时最大剂量的两种激素同时给药显示出加和作用，在2分钟内，甲状旁腺激素注入引起骨膜和干meta端的环AMP含量升高，降钙素还引起干physi端的环AMP迅速增加，这两种激素对该部分中环AMP的积累具有累加作用。在5 min时检测到骨干中的环状AMP服用甲状旁腺激素后。降钙素输注对骨膜和骨干没有显示出任何一致的影响。

BACKGROUND & AIMS: PURPOSE:Steroid sulfatase (STS) inhibitors that can decrease or prevent the biosynthesis of estrogenic steroids via the sulfatase route may play an important role in the treatment of breast cancer. We compare the in vivo efficacy of two potent STS inhibitors, STX64 and STX213, in a xenograft breast cancer model. EXPERIMENTAL DESIGN:MCF-7 cells stably expressing STS cDNA (MCF-7STS) were generated. Ovariectomized MF-1 female nude mice receiving s.c. injections of estradiol sulfate (E2S) and bearing both MCF-7STS and wild-type MCF-7 (MCF-7WT) tumors were orally treated with STX64 and STX213. Treatment was given for 49 days followed by a recovery period of 35 days in which animals received only E2S. Mice were weighed, and tumor measurements were taken weekly. RESULTS:STX64 and STX213 exhibited potent STS inhibition in vivo. However, STX213 showed a greater duration of activity. In vehicle-treated nude mice receiving E2S, tumor volumes increased 5.5-fold for MCF-7WT and 3.8-fold for MCF-7STS after 49 days compared with day 0. MCF-7WT tumor growth was reduced by 56% by STX213 over the dosing period, and subsequent growth was retarded during the recovery period. All treatments fully inhibited growth of MCF-7STS tumors, and recovery of these tumors was significantly retarded (P<0.01). All compounds completely inhibited liver and tumor STS activity. Additionally, STS mRNA expression in the MCF-7STS tumors directly correlated with the corresponding STS enzyme activity. CONCLUSIONS:This study indicates that STS inhibitors attenuate hormone-dependent human breast cancer growth and therefore offer a potentially novel treatment for this condition.

背景与目标： 用途：类固醇硫酸酯酶（STS）抑制剂可通过硫酸酯酶途径减少或阻止雌激素类固醇的生物合成，可能在乳腺癌的治疗中起重要作用。我们比较了两种有效的STS抑制剂STX64和STX213在异种移植乳腺癌模型中的体内疗效。
实验设计：产生稳定表达STS cDNA（MCF-7STS）的MCF-7细胞。接受皮下切除的卵巢切除的MF-1雌性裸鼠注射雌二醇硫酸盐（E2S）并同时携带MCF-7STS和野生型MCF-7（MCF-7WT）肿瘤的患者，应使用STX64和STX213口服治疗。给予49天的治疗，然后恢复35天，其中动物仅接受E2S。称重小鼠，每周进行一次肿瘤测量。
结果：STX64和STX213在体内表现出有效的STS抑制作用。但是，STX213显示了更长的活动时间。在接受E2S的媒介物治疗的裸鼠中，与第0天相比，在49天后，MCF-7WT的肿瘤体积增加了5.5倍，MCF-7STS的肿瘤体积增加了3.8倍。STX213使MCF-7WT的肿瘤生长比给药减少了56％期间，随后的生长在恢复期受到阻碍。所有治疗均完全抑制MCF-7STS肿瘤的生长，并且这些肿瘤的恢复显着受阻（P <0.01）。所有化合物均完全抑制肝脏和肿瘤STS活性。此外，MCF-7STS肿瘤中的STS mRNA表达与相应的STS酶活性直接相关。
结论：这项研究表明，STS抑制剂可减弱激素依赖性人类乳腺癌的生长，因此可为这种情况提供潜在的新颖治疗方法。

BACKGROUND & AIMS: :The serum concentrations of a specific GH-binding protein, derived from the GH receptor, were assayed in sera from 62 African pygmies and 101 normal statured controls. Samples were assayed in the absence and presence of excess GH using 2 separatory procedures. Interassay variability for samples was corrected by a standard reference pool of sera from adults assayed with all unknown samples. Results were expressed as specific binding relative to this standard. The mean percent relative specific binding for GH increased with age in normal-statured controls throughout childhood and adolescence. Relative specific binding for GH was 37.0 +/- 2.0% (mean +/- SEM) in control subjects between the ages of 1-5 yr (mean age, 2.9 yr) and increased progressively to 93.0 +/- 7.0% in young adults (mean age, 23 yr). The relative specific binding of GH by serum from pygmies did not exceed 30.1 +/- 3.4% of the control adult standard at any age period (P less than 0.001), and there was no progressive age-related increase in binding. The decrease from normal binding was minimal in pygmies during childhood (29%), but the decrease from normal was 60-70% in adolescents and adults. Thus, short stature in pygmies probably results not from an absolute deficiency of GH receptors per se, as in Laron dwarfism, but from a failure of cellular GH receptors to increase in a normal manner. This is most compatible with a change in regulating expression of the GH receptor gene, rather than a structural defect in the coding sequence of the GH receptor gene.

背景与目标： ：在来自62个非洲py鼠和101个正常对照的血清中测定了从GH受体衍生的特定GH结合蛋白的血清浓度。使用2种分离方法在不存在和存在过量GH的情况下分析样品。通过使用所有未知样品进行分析的成人血清标准参比库对样品的测定间变异性进行了校正。结果表示为相对于该标准的特异性结合。在整个童年和青春期，正常控制的对照组中GH的平均相对特异性结合百分比随年龄增加而增加。在1-5岁（平均年龄为2.9岁）之间的对照受试者中，GH的相对特异性结合为37.0 /-2.0％（平均水平/-SEM），而在年轻人（平均年龄）中逐渐增加至93.0 /-7.0％ ，23年）。在任何年龄段，侏儒血清中GH的相对特异性结合率均不超过对照成人标准的30.1 /-3.4％（P小于0.001），并且没有与年龄相关的进行性结合增加。在侏儒时期，正常binding缩的减少极少（29％），但在青少年和成人中，normal缩比正常的减少为60-70％。因此，侏儒矮小可能不是由于GH受体本身的绝对缺乏（如Laron侏儒症），而是由于细胞GH受体不能以正常方式增加。这与调节GH受体基因表达的变化最相容，而不是与GH受体基因编码序列的结构缺陷最相容。

BACKGROUND & AIMS: BACKGROUND:The majority of patients receive HT after biochemical progression despite primary therapy of prostate cancer with curative intent. It is difficult to differentiate at a low rise in PSA level, e.g.,

BACKGROUND & AIMS: -2

背景与目标： -2