BACKGROUND & AIMS: OBJECTIVE:A forearm fracture (Colles' fracture) is often the first sign of osteoporosis and should alert the patient and physician to the possibility of underlying skeletal fragility. Therefore, the establishment of a more accurate and reliable method for the measurement of bone mineral density (BMD) at the distal radius would be beneficial for the patients who suffer from osteoporosis. The objective of the present study was to evaluate the usefulness of peripheral quantitative computed tomography (pQCT) to assess the change of BMD at the distal radius in early postmenopausal women who receive hormone replacement therapy (HRT). METHODS:Twenty healthy early postmenopausal women who were diagnosed as osteoporosis or osteopenia were randomized to either HRT or placebo treatment. We analyzed BMD of the distal radius by pQCT, lumbar spine by dual-energy X-ray absorptiometry (DXA) and the biochemical markers of bone turn over (osteocalcin, deoxypyridinoline) every 6 months. RESULTS:The placebo group showed a significant decrease from the baseline in the trabecular BMD of the radius at 12 months (7.4+/-2.5%) (p<0.05), whereas the HRT group showed a slight increase (0.7+/-2.2%). The changes in the trabecular BMD of the radius between the HRT and placebo groups were statistically different at 12 months (p<0.05). On the other hand, in the cortical BMD of the radius, no significant differences were seen between the changes of bone densities in the HRT and control groups after 1 year of treatment. pQCT could detect a significant loss of BMD of the radius in early postmenopausal women after 1 year and HRT prevented its loss. CONCLUSION:Our preliminary clinical trial showed that pQCT might be useful for the early detection of bone loss in early postmenopausal women and for the monitoring BMD of the patients who receive HRT.

背景与目标： 目的：前臂骨折（Colles骨折）通常是骨质疏松的最初征兆，应提醒患者和医生潜在的骨骼脆弱性。因此，建立一种更准确和可靠的方法来测量远端radius骨的骨矿物质密度（BMD）对于患有骨质疏松症的患者将是有益的。本研究的目的是评估外围定量计算机体层摄影术（pQCT）的有效性，以评估接受激素替代疗法（HRT）的绝经后早期女性the骨远端骨密度的变化。
方法：将20名被诊断为骨质疏松或骨质减少的健康早期绝经后妇女随机分为HRT或安慰剂治疗组。我们每6个月分析一次pQCT对远端B骨的BMD，双能X射线吸收法（DXA）对腰椎的影响，以及骨翻倒的生化标志物（骨钙蛋白，脱氧吡啶并啉）。
结果：安慰剂组在12个月时the骨小梁BMD较基线显着降低（7.4 /-2.5%）（p <0.05），而HRT组则略有增加（0.7 /-2.2%） 。 HRT组与安慰剂组之间的radius骨小梁BMD变化在12个月时有统计学差异（p <0.05）。另一方面，在治疗1年后，HRT和对照组的骨密度变化在B骨的BMD中没有显着差异。 pQCT可以检测到绝经后早期女性在1年后B骨BMD的显着减少，而HRT可以防止这种情况的发生。
结论：我们的初步临床试验表明，pQCT可能对早期绝经后妇女的骨丢失早期检测以及监测接受HRT的患者的BMD有用。

BACKGROUND & AIMS: The efficacy and safety of highly purified follicle stimulating hormone (FSH) associated with human chorionic gonadotrophin (HCG) was studied in 60 men with hypogonadotrophic hypogonadism. Of these men, 16 suffered from Kallmann's syndrome, 19 from idiopathic hypogonadotrophic hypogonadism and 25 from hypopituitarism. Basal testosterone concentrations were found to be far below the normal range. At baseline, 26 patients were able to ejaculate and all of them showed azoospermia, while the remaining patients were aspermic. All patients self-administered s.c. injections of FSH (150 IU x three/week) and HCG (2500 IU x two/week) for at least 6 months and underwent periodic assessments of testicular function. Testosterone concentrations increased rapidly during treatment and all but one patient reached normal values. Testicular volume showed a sustained increase reaching almost 3-fold its baseline value. At the end of treatment, 48 patients (80.0%) had achieved a positive sperm count. The maximum sperm concentration during treatment was 24.5 +/- 8.1 x 10(6)/ml (mean +/- SEM). The median time to induce spermatogenesis was 5 months. Eleven patients reported adverse events, generally not related to treatment. Three patients experienced gynaecomastia. No local reactions at injection site were observed. In conclusion, the s.c. self-administration of highly purified FSH + HCG was well tolerated and effective in stimulating spermatogenesis and steroidogenesis in these patients.

背景与目标： 在60名患有促性腺激素缺乏性性腺功能减退症的男性中研究了与人绒毛膜促性腺激素（HCG）相关的高纯度卵泡刺激素（FSH）的疗效和安全性。这些人中，有16人患有卡曼综合症，特发性性腺功能减退性性腺功能减退症19名，垂体功能减退症25名。发现基础睾丸激素浓度远低于正常范围。在基线时，有26位患者能够射精，所有患者均表现出无精子症，而其余患者均为无精子症。所有患者均自给自足注射FSH（150 IU x 3 /周）和HCG（2500 IU x 2 /周）至少6个月，并定期评估睾丸功能。治疗期间睾丸激素浓度迅速增加，除一名患者外，其他所有患者均达到正常值。睾丸体积持续增加，几乎达到其基线值的三倍。在治疗结束时，有48名患者（80.0％）的精子计数为阳性。治疗期间最大精子浓度为24.5 /-8.1 x 10（6）/ ml（平均值/-SEM）。诱导精子发生的中位时间为5个月。 11名患者报告了不良事件，通常与治疗无关。三例患者出现了妇科发育不全。在注射部位未观察到局部反应。总而言之自我给予高纯度FSH HCG的耐受性良好，可有效刺激这些患者的精子发生和类固醇生成。

BACKGROUND & AIMS: :Growth hormone deficiency (GHD) related to standard dose chemotherapy has rarely been described. We report on a case of localized ganglioneuroblastoma treated by carboplatin/etoposide for 2 courses and surgery, which developed a serious GHD after 56 months. At present, the child is growing on by GH replacement therapy. We discuss about the hypothesis that GHD may be related to chemotherapy and we report a review of previous published cases.

背景与目标： ：很少有人描述与标准剂量化疗有关的生长激素缺乏症（GHD）。我们报告了一例通过卡铂/依托泊苷治疗的局部神经节神经母细胞瘤的疗程为2个疗程和手术，该病例在56个月后出现了严重的GHD。目前，孩子正在通过GH替代疗法长大。我们讨论了GHD可能与化学疗法有关的假说，并且我们报告了以前发表过的病例的综述。

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： ：在垂体切除术前后垂体依赖性肾上腺皮质激素过多（PDH）的17只狗中研究了促肾上腺皮质激素（ACTH），皮质醇，α-黑素细胞刺激激素（α-MSH）和GH的6小时血浆分布。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号染色体上的基因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效力高约10倍至15倍，并在激素不敏感的人类乳腺癌（MDA-MB）中引起G2-M阻滞后诱导凋亡-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。已经发现脱碘酶（D2和D3）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: :Histamine H2 antagonists are widely used in treating patients with hematemesis and melena, despite the lack of reliable evidence of benefit from any of the randomized trials, considered separately. Examination of the data from all 27 available randomized trials, in which over 2500 patients were entered, suggests that treatment may reduce the rates of rebleeding, surgery, and death by about 10, 20, and 30 per cent, respectively, although these results were only marginally significant for surgery and death. Any benefit appeared to be confined to patients with bleeding gastric ulcers, but since this subgroup analysis was prompted by preliminary examination of the data in some of the individual trials reviewed here, it should be treated with particular caution. The implications of this overview are that treatment with histamine H2 antagonists appears to be moderately promising, but its effects on important end points, such as death, still need to be assessed reliably. Prevention of "only" about 20 per cent of all deaths could well be worthwhile, for the condition is common, and the treatment widely practicable. To detect such a moderate effect reliably, however, might require the randomization of 10,000 patients (or more), which would be possible only in an extremely simple multicenter collaborative trial.

背景与目标： ：Histamine H2拮抗剂被广泛用于治疗呕血和黑便患者，尽管缺乏可靠的证据表明任何随机试验均不能从中获益。对所有27项随机试验的数据进行了检查，其中输入了2500多例患者，这表明治疗可能分别使再出血，手术和死亡的发生率分别降低10％，20％和30％，尽管这些结果是仅对手术和死亡意义微乎其微。任何益处似乎仅限于胃溃疡出血患者，但由于该亚组分析是由在此综述的一些个体试验中对数据进行初步检查而引起的，因此应格外小心。该概述的含义是，用组胺H2拮抗剂治疗似乎有一定希望，但仍需可靠地评估其对重要终点（例如死亡）的影响。预防“仅”所有死亡人数的20％是很值得的，因为这种情况很普遍，而且这种治疗是广泛可行的。但是，要可靠地检测这种中等效果，可能需要将10,000名患者（或更多名患者）随机分组，这只有在极其简单的多中心协作试验中才有可能。

BACKGROUND & AIMS: :In human cerebral cortex slices noradrenaline, isoproterenol (a beta-adrenergic agonist), dopamine, apomorphine (a dopaminergic agonist), and serotonin stimulated cyclic AMP formation: noradrenaline greater than or equal to isoproterenol greater than dopamine = apomorphine = serotonin. Clonidine (and alpha-adrenergic agonist) was ineffective in stimulating cyclic AMP formation in temporal cortex slices. The stimulatory effect of noradrenaline and isoproterenol was blocked by propranolol (a beta-adrenergic blocker) but not by phentolamine (an alpha-adrenergic blocker). Pimozide (a selective dopaminergic antagonist) inhibited the increase of cyclic AMP formation induced by dopamine or apomorphine but not that induced by noradrenaline, isoproterenol, or serotonin. Neither propranolol or phentolamine had any effect on dopamine- or serotonin-stimulated cyclic AMP formation. Chlorpromazine blocked the increase of cyclic AMP formation induced by noradrenaline, dopamine or serotonin, while cyproheptadine, a putative central serotonergic antagonist, was ineffective. These observations suggest that there may be at least two monoamine-sensitive adenylate cyclases in human cerebral cortex which have the characteristics of a beta-adrenergic and a dopaminergic receptor, respectively, and also possibly a serotonergic receptor.

背景与目标： 在人大脑皮层切片中，去甲肾上腺素，异丙肾上腺素（β-肾上腺素能激动剂），多巴胺，阿扑吗啡（多巴胺能激动剂）和5-羟色胺刺激的环状AMP形成：去甲肾上腺素大于或等于异丙肾上腺素大于多巴胺=阿扑吗啡= 5-羟色胺。可乐定（和α-肾上腺素激动剂）在刺激颞叶皮质切片中的环状AMP形成方面无效。去甲肾上腺素和异丙肾上腺素的刺激作用被普萘洛尔（一种β-肾上腺素受体阻滞剂）阻断，但未被酚妥拉明（一种α-肾上腺素能阻断剂）阻断。 Pimozide（一种选择性的多巴胺能拮抗剂）抑制多巴胺或阿扑吗啡诱导的环状AMP形成的增加，但不抑制去甲肾上腺素，异丙肾上腺素或5-羟色胺诱导的环状AMP形成的增加。普萘洛尔或酚妥拉明均未对多巴胺或5-羟色胺刺激的环状AMP的形成产生任何影响。氯丙嗪阻断了去甲肾上腺素，多巴胺或5-羟色胺诱导的环AMP形成的增加，而环丙庚定（一种假定的中枢5-羟色胺能拮抗剂）无效。这些观察结果表明，人大脑皮层中可能至少存在两种​​单胺敏感的腺苷酸环化酶，它们分别具有β-肾上腺素能和多巴胺能受体的特征，还可能具有血清素能受体的特征。

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: 1. Selective 5-hydroxytryptamine (5-HT; serotonin) reuptake inhibitors (SSRIs) cause a greater increase in extracellular 5-HT in the forebrain when the somatodendritic 5-HT1A autoreceptor is blocked. Here, we investigated whether blockade of the terminal 5-HT1B autoreceptor influences a selective 5-HT reuptake inhibitor in the same way, and whether there is an additional effect of blocking both the 5-HT1A and 5-HT1B autoreceptors. 2. Extracellular 5-HT was measured in frontal cortex of the anaesthetized rat by use of brain microdialysis. In vivo extracellular recordings of 5-HT neuronal activity in the dorsal raphe nucleus (DRN) were also carried out. 3. The selective 5-HT reuptake inhibitor, paroxetine (0.8 mg kg-1, i.v.), increased extracellular 5-HT about 2 fold in rats pretreated with the 5-HT1A receptor antagonist, WAY100635. When administered alone neither paroxetine (0.8 mg kg-1, i.v.) nor WAY100635 (0.1 mg kg-1, i.v.) altered extracellular 5-HT levels. 4. Paroxetine (0.8 mg kg-1, i.v.) did not increase 5-HT in rats pretreated with the 5-HT1B/D receptor antagonist, GR127935 (1 mg kg-1, i.v.). GR127935 (1 and 5 mg kg-1, i.v.) had no effect on extracellular 5-HT when administered alone. 5. Interestingly, paroxetine (0.8 mg kg-1, i.v.) caused the greatest increase in 5-HT (up to 5 fold) when GR127935 (1 or 5 mg kg-1, i.v.) was administered in combination with WAY100635 (0.1 mg kg-1, i.v.). Administration of GR127935 (5 mg kg-1, i.v.) plus WAY100635 (0.1 mg kg-1, i.v.) without paroxetine, had no effect on extracellular 5-HT in the frontal cortex. 6. Despite the lack of effect of GR127935 on 5-HT under basal conditions, when 5-HT output was elevated about 3 fold (by adding 1 microM paroxetine to the perfusion medium), the drug caused a dose-related (1 and 5 mg kg-1, i.v.) increase in 5-HT. 7. By itself, GR127935 slightly but significantly decreased 5-HT cell firing in the DRN at higher doses (2.0-5.0 mg kg-1, i.v.), but did not prevent the inhibition of 5-HT cell firing induced by paroxetine. 8. In summary, our results suggest that selective 5-HT reuptake inhibitors may cause a large increase in 5-HT in the frontal cortex when 5-HT autoreceptors on both the somatodendrites (5-HT1A) and nerve terminals (5-HT1B) are blocked. This increase is greater than when either set of autoreceptors are blocked separately. The failure of a 5-HT1B receptor antagonist alone to enhance the effect of the selective 5-HT reuptake inhibitor in our experiments may be related to a lack of tone on the terminal 5-HT1B autoreceptor due to a continued inhibition of 5-HT cell firing. These results are discussed in relation to the use of 5-HT autoreceptor antagonists to augment the antidepressant effect of selective 5-HT reuptake inhibitors.

背景与目标： 1.当抑制体树突状5-HT1A自体受体时，选择性5-羟色胺（5-HT； 5-羟色胺）再摄取抑制剂（SSRIs）导致前脑细胞外5-HT的增加。在这里，我们调查了终端5-HT1B自身受体的阻断作用是否以相同的方式影响选择性5-HT再摄取抑制剂，以及是否存在阻断5-HT1A和5-HT1B自身受体的其他作用。 2.通过使用脑微透析在麻醉的大鼠的额皮质中测量细胞外5-HT。还进行了背缝核（DRN）中5-HT神经元活性的体内细胞外记录。 3.选择性5-HT再摄取抑制剂帕罗西汀（0.8mg kg-1，静脉内）在用5-HT1A受体拮抗剂WAY100635预处理的大鼠中使细胞外5-HT增加约2倍。当单独给药时，帕罗西汀（0.8 mg kg-1，i.v.）和WAY100635（0.1 mg kg-1，i.v.）均未改变细胞外5-HT水平。 4.在用5-HT1B / D受体拮抗剂GR127935（1 mg kg-1，i.v.）预处理的大鼠中，帕罗西汀（0.8 mg kg-1，i.v.）不会增加5-HT。单独给药时，GR127935（1和5 mg kg-1，静脉内）对细胞外5-HT无效。 5.有趣的是，当GR127935（1或5 mg kg-1，iv）与WAY100635（0.1 mg）联合使用时，帕罗西汀（0.8 mg kg-1，iv）引起5-HT的最大增加（最多5倍）。千克-1，iv）。不含帕罗西汀的GR127935（5 mg kg-1，i.v.）加上WAY100635（0.1 mg kg-1，i.v.）的给药对额皮质中的细胞外5-HT没有影响。 6.尽管在基本条件下GR127935对5-HT缺乏影响，但当5-HT产量提高了约3倍时（通过向灌注培养基中添加1 microM帕罗西汀），该药物引起了剂量相关（1和5 mg kg-1，iv）5-HT升高。 7.就其本身而言，GR127935在较高剂量（2.0-5.0 mg kg-1，i.v.）的DRN中略微但显着降低了5-HT细胞的发射，但并未阻止帕罗西汀诱导的5-HT细胞发射的抑制。 8.总而言之，我们的研究结果表明，当在肢体树突（5-HT1A）和神经末梢（5-HT1B）上都存在5-HT自身受体时，选择性5-HT再摄取抑制剂可能会导致额叶皮层5-HT大量增加。被阻止。该增加量大于分别封闭任一组自动受体时的增加量。在我们的实验中，单独使用5-HT1B受体拮抗剂未能增强选择性5-HT再摄取抑制剂的作用可能与由于持续抑制5-HT细胞而导致末端5-HT1B自体受体缺乏音调有关射击。这些结果与使用5-HT自身受体拮抗剂增强选择性5-HT再摄取抑制剂的抗抑郁作用有关。

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: :Based on the previously reported clinical candidate, AMG 517 (compound 1), a series of related piperazinylpyrimidine analogues were synthesized and evaluated as antagonists of the vanilloid 1 receptor (VR1 or TRPV1). Optimization of in vitro potency and physicochemical and pharmacokinetic properties led to the discovery of (R)-N-(4-(6-(4-(1-(4-fluorophenyl)ethyl)piperazin-1-yl)pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamide (16p), a potent TRPV1 antagonist [rTRPV1(CAP) IC50 = 3.7 nM] with excellent aqueous solubility (>or=200 microg/mL in 0.01 N HCl) and a reduced half-life (rat t1/2 = 3.8 h, dog t1/2 = 2.7 h, monkey t1/2 = 3.2 h) as compared to AMG 517. In addition, compound 16p was shown to be efficacious at blocking a TRPV1-mediated physiological response in vivo (ED50 = 1.9 mg/kg, p.o. in the capsaicin-induced flinch model in rats) and was also effective at reducing thermal hyperalgesia induced by complete Freund's adjuvant in rats (MED = 1 mg/kg, p.o). Based on its improved overall profile, compound 16p (AMG 628) was selected as a second-generation candidate for further evaluation in human clinical trials as a potential new treatment for chronic pain.

背景与目标： ：基于先前报道的临床候选药物AMG 517（化合物1），合成了一系列相关的哌嗪基嘧啶类似物，并将其评估为香草素1受体（VR1或TRPV1）的拮抗剂。体外效能，理化和药代动力学特性的优化导致发现（R）-N-（4-（6-（4-（4-（1-（4-（1-（4-氟苯基）乙基））哌嗪-1-基）嘧啶-4-烷氧基）苯并[d]噻唑-2-基）乙酰胺（16p），有效的TRPV1拮抗剂[rTRPV1（CAP）IC50 = 3.7 nM]，具有优异的水溶性（在0.01 N HCl中≥200 microg / mL）和与AMG 517相比，降低了半衰期（大鼠t1 / 2 = 3.8小时，狗t1 / 2 = 2.7小时，猴子t1 / 2 = 3.2小时）。此外，化合物16p在阻断TRPV1-介导的体内生理反应（ED50 = 1.9 mg / kg，在辣椒素诱导的雀斑模型中的大鼠口服），并且在减轻大鼠完全弗氏佐剂诱导的热痛觉过敏中也有效（MED = 1 mg / kg，口服）。基于其改善的总体特性，化合物16p（AMG 628）被选为第二代候选药物，可在人类临床试验中进一步评估，作为潜在的治疗慢性疼痛的新方法。