Effects of loperamide on the human hypothalamo-pituitary-adrenal axis in vivo and in vitro.

Loperamide, an opiate agonist of high specificity for p-receptors, was recently reported to suppress ACTH and cortisol levels in normal subjects, but not in patients with proven ACTH-dependent Cushing’s disease. However, there is little information on the site of action of loperamide in the hypothalamo-pituitary-adrenal axis of man. We investigated the effect of loperamide on pituitary hormone secretion in uiuo and in vitro. In seven normal subjects, basal ACTH plasma levels were significantly suppressed 3 h after loperamide administration (16 mg, orally) from 5 + 1 to 2 f 0 pmol/L (P < 0.0001). After the combined pituitary stimulation test (100 pg human CRH, 100 rg GnRH, 100 pg GH-releasing hormone, and 200 pg TRH), the ACTH peak (maximum increase at 30 min) was significantly blunted by loperamide from 9 + 1 to 4 of: 1 pmol/L (P < 0.001) and the area under the curve of ACTH from O-120 min was reduced from 35 + 5 to 23 + 4 pmol/L.2 h (P < 0.05). In the insulin-hypoglycemia test (0.15 IU/kg BW), neither the ACTH peak nor the area under the curve of ACTH was affected by loperamide. In six patients with Cushing’s disease and one patient with secondary adrenal insufficency due to hypothalamic failure, neither basal ACTH and cortisol levels nor CRH-stimulated levels were influenced by loperamide. In four cultured human corticotropic adenomas, loperamide was not able to reduce basal and CRH-induced ACTH secretion. In summary, loperamide is able to reduce basal and CRHinduced ACTH and cortisol levels in normal subjects, but not in patients with Cushing’s disease or secondary adrenal failure of hypothalamic origin. Loperamide has no significant effect on insulin-hypoglycemia- induced ACTH and cortisol levels and, therefore, no effect on stress-induced elevation of cortisol levels. Loperamide might act at a suprapituitary site in man in viuo, but, nevertheless, a pituitary site cannot be excluded

A content-linking-context model for “notice-and-takedown” procedures

The US Digital Millennium Copyright Act (DMCA) of 1998 adopted a notice-and-take-down procedure to help tackle alleged online infringements through online service providers’ actions. The European Directive 2000/31/EC (e-Commerce Directive) introduced similar liability exemptions, but did not specify any take-down procedure. Many intermediary (host, and online search engine) service providers even in Europe have followed this notice-and-take-down procedure to enable copyright owners to issue notices to take down allegedly infringing Web resources. However, the accuracy of take-down is not known, and notice receivers do not reveal clear information about how they check the legitimacy of these requests, about whether and how they check the lawfulness of allegedly infringing content, or what criteria they use for these actions. In this paper, we use Google’s Transparency Report as the benchmark to investigate the information content of take-down notices and the accuracy of the resulting take-downs of allegedly infringing Web resources. The analysis of copyright infringement is limited to the five scenarios most frequently encountered in our study of Web resources. Based on our investigation, we propose a Content-Linking-Context (CLC) model of the criteria to be considered by intermediary service providers to achieve more accurate take-down

Growth Hormone (GH)-Releasing Peptide Stimulation of GH Release from Human Somatotroph Adenoma Cells: Interaction with GH-Releasing Hormone, Thyrotropin- Releasing Hormone, and Octreotide.

The synthetic hexapeptide GH-releasing peptide (GHRP; His-D-Trp-Ala-Trp-D-Phe-Lys-NH2) specifically stimulates GH secretion in humans in vivo and in animals in vitro and in vivo via a still unknown receptor and mechanism. To determine the effect of GHRP on human somatotroph cells in vitro, we stimulated cell cultures derived from 12 different human somatotroph adenomas with GHRP alone and in combination with GH-releasing hormone (GHRH), TRH, and the somatostatin analog octreotide. GH secretion of all 12 adenoma cultures could be stimulated with GHRP, whereas GHRH was active only in 6 adenoma cultures. In GHRH-responsive cell cultures, simultaneous application of GHRH and GHRP had an additive effect on GH secretion. TRH stimulated GH release in 4 of 7 adenoma cultures; in TRH-responsive cell cultures there was also an additive effect of GHRP and TRH on GH secretion. In 5 of 9 adenoma cultures investigated, octreotide inhibited basal GH secretion. In these cell cultures, GHRP-induced GH release was suppressed by octreotide. In 5 of 5 cases, the protein kinase-C inhibitor phloretin partly inhibited GHRP-stimulated GH release, but not basal GH secretion. In summary, GH secretion was stimulated by GHRP in all somatotroph adenomas investigated, indicating that its unknown receptor and signaling pathway are expressed more consistently in somatotroph adenoma cells than those for GHRH, TRH, and somatostatin. Our data give further evidence that GHRP-stimulated GH secretion is mediated by a receptor different from that for GHRH or TRH, respectively, and that protein kinase-C is involved in the signal transduction pathway. Because human somatotroph adenoma cell cultures respond differently to various neuropeptides (GHRH, TRH, somatostatin, and others), they provide a model for further investigation of the mechanism of action of GHRP-induced GH secretion

Transgender Transitioning and Change of Self-Reported Sexual Orientation

Objective: Sexual orientation is usually considered to be determined in early life and stable in the course of adulthood. In contrast, some transgender individuals report a change in sexual orientation. A common reason for this phenomenon is not known. Methods: We included 115 transsexual persons (70 male-to-female "MtF" and 45 female-to-male "FtM") patients from our endocrine outpatient clinic, who completed a questionnaire, retrospectively evaluating the history of their gender transition phase. The questionnaire focused on sexual orientation and recalled time points of changes in sexual orientation in the context of transition. Participants were further asked to provide a personal concept for a potential change in sexual orientation. Results: In total, 32.9% (n = 23) MtF reported a change in sexual orientation in contrast to 22.2% (n = 10) FtM transsexual persons (p = 0.132). Out of these patients, 39.1% (MtF) and 60% (FtM) reported a change in sexual orientation before having undergone any sex reassignment surgery. FtM that had initially been sexually oriented towards males (= androphilic), were significantly more likely to report on a change in sexual orientation than gynephilic, analloerotic or bisexual FtM (p = 0.012). Similarly, gynephilic MtF reported a change in sexual orientation more frequently than androphilic, analloerotic or bisexual MtF transsexual persons (p = 0.05). Conclusion: In line with earlier reports, we reveal that a change in self-reported sexual orientation is frequent and does not solely occur in the context of particular transition events. Transsexual persons that are attracted by individuals of the opposite biological sex are more likely to change sexual orientation. Qualitative reports suggest that the individual's biography, autogynephilic and autoandrophilic sexual arousal, confusion before and after transitioning, social and self-acceptance, as well as concept of sexual orientation itself may explain this phenomenon

Hypopituitarism and brain injury: recent advances in screening and management

This review gives an overview of the research on hypothalamopituitary dysfunction as a potential consequence of traumatic brain injury, including the natural history of this complication and its clinical and public health implications

The somatostatin analogue octreotide confers sensitivity to rapamycin treatment on pituitary tumor cells

Rapamycin and its analogues have significant antiproliferative action against a variety of tumors. However, sensitivity to rapamycin is reduced by Akt activation that results from the ablative effects of rapamycin on a p70 S6K-induced negative feedback loop that blunts phosphoinositide 3-kinase (PI3K)-mediated support for Akt activity. Thus, sensitivity to rapamycin might be increased by imposing an upstream blockade to the PI3K/Akt pathway. Here, we investigated this model using the somatostatin analogue octreotide as a tool to decrease levels of activated Ser(473)-phosphorylated Akt (pAkt-Ser(473)) in pituitary tumor cells that express somatostatin receptors. Octreotide increased levels of phosphorylated insulin receptor substrate-1 that were suppressed by rapamycin, subsequently decreasing levels of pAkt-Ser(473) through effects on phosphotyrosine phosphatase SHP-1. Octreotide potentiated the antiproliferative effects of rapamycin in immortalized pituitary tumor cells or human nonfunctioning pituitary adenoma cells in primary cell culture, sensitizing tumor cells even to low rapamycin concentrations. Combined treatment of octreotide and rapamycin triggered G(1) cell cycle arrest, decreasing E2F transcriptional activity and cyclin E levels by increasing levels of p27/Kip1. These findings show that adjuvant treatment with a somatostatin analogue can sensitize pituitary tumor cells to the antiproliferative effects of rapamycin

Metabolic and hormonal studies of Type 1 (insulin-dependent) diabetic patients after successful pancreas and kidney transplantation

Long-term normalization of glucose metabolism is necessary to prevent or ameliorate diabetic complications. Although pancreatic grafting is able to restore normal blood glucose and glycated haemoglobin, the degree of normalization of the deranged diabetic metabolism after pancreas transplantation is still questionable. Consequently glucose, insulin, C-peptide, glucagon, and pancreatic polypeptide responses to oral glucose and i.v. arginine were measured in 36 Type 1 (insulin-dependent) diabetic recipients of pancreas and kidney allografts and compared to ten healthy control subjects. Despite normal HbA1 (7.2±0.2%; normal <8%) glucose disposal was normal only in 44% and impaired in 56% of the graft recipients. Normalization of glucose tolerance was achieved at the expense of hyperinsulinaemia in 52% of the subjects. C-peptide and glucagon were normal, while pancreatic polypeptide was significantly higher in the graft recipients. Intravenous glucose tolerance (n=21) was normal in 67% and borderline in 23%. Biphasic insulin release was seen in patients with normal glucose tolerance. Glucose tolerance did not deteriorate up to 7 years post-transplant. In addition, stress hormone release (cortisol, growth hormone, prolactin, glucagon, catecholamines) to insulin-induced hypoglycaemia was examined in 20 graft recipients and compared to eight healthy subjects. Reduced blood glucose decline indicates insulin resistance, but glucose recovery was normal, despite markedly reduced catecholamine and glucagon release. These data demonstrate the effectiveness of pancreatic grafting in normalizing glucose metabolism, although hyperinsulinaemia and deranged counterregulatory hormone response are observed frequently

RSUME is implicated in tumorigenesis and metastasis of pancreatic neuroendocrine tumors

The factors triggering pancreatic neuroendocrine tumor (PanNET) progression are largely unknown. Here we investigated the role and mechanisms of the sumoylation enhancing protein RSUME in PanNET tumorigenesis. Immunohistochemical studies showed that RSUME is strongly expressed in normal human pancreas, in particular in β-cells. RSUME expression is reduced in insulinomas and is nearly absent in other types of PanNETs suggesting a role in PanNET tumorigenesis. In human pancreatic neuroendocrine BON1 cells, RSUME stimulates hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor-A (VEGF-A), which are key components of tumor neovascularisation. In contrast, RSUME suppresses nuclear factor-κB (NF-κB) and its target interleukin-8 (IL-8). Correspondingly, PanNET cells with RSUME knockdown showed decreased HIF-1α activity and increased NF-κB and IL-8 production leading to a moderate reduction of VEGF-A release as reduced HIF-1α/VEGF-A production is partly compensated by NF-κB/IL-8-induced VEGF-A. Notably, RSUME stabilizes the tumor suppressor PTEN, which is frequently lost in PanNETs and whose absence is associated with metastasis formation. In vivo orthotopic transplantation of PanNET cells with or without RSUME expression into nude mice showed that PanNETs without RSUME have reduced PTEN expression, grow faster and form multiple liver metastases. In sum, RSUME differentially regulates key components of PanNET formation suggesting that the observed loss of RSUME in advanced PanNETs is critically involved in PanNET tumorigenesis, particularly in metastasis formation.Fil: Wu, Yonghe. Max Planck Institute of Psychiatry; AlemaniaFil: Tedesco, Lucas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Kristin, Lucia. Max Planck Institute of Psychiatry; AlemaniaFil: Schlitter, Anna M.. Universitat Technical Zu Munich; AlemaniaFil: Monteserin Garcia, Jose. Max Planck Institute of Psychiatry; AlemaniaFil: Esposito, Irene. Universitat Technical Zu Munich; AlemaniaFil: Auernhammer, Christoph J.. Universitat Technical Zu Munich; AlemaniaFil: Theodoropoulou, Marily. Max Planck Institute of Psychiatry; AlemaniaFil: Arzt, Eduardo Simon. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Renner, Ulrich. Max Planck Institute of Psychiatry; AlemaniaFil: Stalla, Günter K.. Max Planck Institute of Psychiatry; Alemani

Laser-Scribed Conductive, Photoactive Transition Metal Oxide on Soft Elastomers for Janus On-Skin Electronics and Soft Actuators

Laser-assisted fabrication of conductive materials on flexible substrates has attracted intense interests because of its simplicity, easy customization, and broad applications. However, it remains challenging to achieve laser scribing of conductive materials on tissue-like soft elastomers, which can serve as the basis to construct bioelectronics and soft actuators. Here, we report laser scribing of metallic conductive, photoactive transition metal oxide (molybdenum dioxide) on soft elastomers, coated with molybdenum chloride precursors, under ambient conditions. Laser-scribed molybdenum dioxide (LSM) exhibits high electrical conductivity, biocompatibility, chemical stability, and compatibility with magnetic resonance imaging. In addition, LSM can be made on various substrates (polyimide, glass, and hair), showing high generality. Furthermore, LSM-based Janus on-skin electronics are developed to record information from human skin, human breath, and environments. Taking advantage of its outstanding photothermal effect, LSM-based soft actuators are developed to build light-driven reconfigurable three-dimensional architectures, reshapable airflow sensors, and smart robotic worms with bioelectronic sensors