Sample records for acting somatostatin analog

  1. Long-acting somatostatin analog therapy of acromegaly: A meta-analysis

    NARCIS (Netherlands)

    P.U. Freda (Pamela); L. Katznelson (Laurence); A-J. van der Lely (Aart-Jan); F. Reyes; S. Zhao (Shouhao); D. Rabinowitz (Daniel)


    textabstractContext: Although considerable data exist on the use of long-acting somatostatin analogs to treat acromegaly, their reported efficacy differs substantially among trials. Objective: We conducted a meta-analysis to derive definitive estimates of their efficacy for biochemical control and

  2. Double benefit of long-acting somatostatin analogs in a patient with coexistence of acromegaly and ulcerative colitis. (United States)

    Yarman, S; Yalın, G Y; Dogansen, S C; Canbaz, B; Tanrıkulu, S; Akyuz, F


    Somatostatin analogs control GH/IGF-1 excess in acromegaly. Somatostatin receptors also mediate the complex effects of somatostatin on the gastrointestinal tract and may be defensive in inflammatory bowel diseases, such as ulcerative colitis. We present a patient who showed good response to long-acting octreotide (OCT-LAR) treatment in terms of both acromegaly and ulcerative colitis (UC). A 58-year-old female patient with diagnosis of acromegaly and ulcerative colitis was started on long-acting somatostatin treatment as a first-line treatment for acromegaly as she refused to undergo transsphenoidal surgery. During the follow-up period, a significant amelioration was also observed in the course of ulcerative colitis, and clinical remission of both diseases was achieved uneventfully. Somatostatin appears to be a promising candidate in the treatment of inflammatory bowel diseases. © 2016 John Wiley & Sons Ltd.

  3. Conversion of daily pegvisomant to weekly pegvisomant combined with long-acting somatostatin analogs, in controlled acromegaly patients

    NARCIS (Netherlands)

    S.J.C.M.M. Neggers (Bas); W.W. de Herder (Wouter); R.A. Feelders (Richard); A-J. van der Lely (Aart-Jan)


    textabstractThe efficacy of combined treatment in active acromegaly with both long-acting somatostatin analogs (SRIF) and pegvisomant (PEG-V) has been well established. The aim was to describe the PEG-V dose reductions after the conversion from daily PEG-V to combination treatment. To clarify the in

  4. Conversion of daily pegvisomant to weekly pegvisomant combined with long-acting somatostatin analogs, in controlled acromegaly patients

    NARCIS (Netherlands)

    S.J.C.M.M. Neggers (Bas); W.W. de Herder (Wouter); R.A. Feelders (Richard); A-J. van der Lely (Aart-Jan)


    textabstractThe efficacy of combined treatment in active acromegaly with both long-acting somatostatin analogs (SRIF) and pegvisomant (PEG-V) has been well established. The aim was to describe the PEG-V dose reductions after the conversion from daily PEG-V to combination treatment. To clarify the

  5. Octreotide, a long-acting somatostatin analog, in the management of postoperative dumping syndrome. An update. (United States)

    Lamers, C B; Bijlstra, A M; Harris, A G


    Severe long-term complaints of dumping occur in a small number of patients after gastric surgery. Dietary modification, fiber preparations, and medical therapy are often ineffective. In these severely affected patients administration of the somatostatin analog octreotide before meals appears to be a promising new strategy. The effects of octreotide on both gastrointestinal transit time and hormonal changes appear to contribute to the benefits seen in dumping syndrome. However, as the majority of studies conducted have employed only a single dose of octreotide, careful long-term assessment of the nutritional and metabolic effects will be required. Recent results suggest that octreotide may be administered up to 2 hr before a meal and therefore has a sufficiently long duration of action to be of practical long-term use. Moreover, general improvements in life-style, as well as beneficial effects on symptoms, have been reported with long-term treatment, although the potential development of diarrhea will require careful monitoring. The development of an oral or nasal formulation should further improve the practical application of octreotide as a treatment for dumping syndrome.

  6. Conversion of daily pegvisomant to weekly pegvisomant combined with long-acting somatostatin analogs, in controlled acromegaly patients. (United States)

    Neggers, Sebastian J C M M; de Herder, Wouter W; Feelders, Richard A; van der Lely, A J


    The efficacy of combined treatment in active acromegaly with both long-acting somatostatin analogs (SRIF) and pegvisomant (PEG-V) has been well established. The aim was to describe the PEG-V dose reductions after the conversion from daily PEG-V to combination treatment. To clarify the individual beneficial and adverse effects, in two acromegaly patients, who only normalized their insulin like growth factor (IGF-I) levels with high-dose pegvisomant therapy. We present two cases of a 31 and 44 years old male with gigantism and acromegaly that were controlled subsequently by surgery, radiotherapy, SRIF analogs and daily PEG-V treatment. They were converted to combined treatment of monthly SSA and (twice) weekly PEG-V. High dose SSA treatment was added while the PEG-V dose was decreased during carful monitoring of the IGF-I. After switching from PEG-V monotherapy to SRIF analogs plus pegvisomant combination therapy IGF-I remained normal. However, the necessary PEG-V dose, to normalize IGF-I differed significantly between these two patients. One patient needed twice weekly 100 mg, the second needed 60 mg once weekly on top of their monthly lanreotide Autosolution injections of 120 mg. The weekly dose reduction was 80 and 150 mg. After the introducing of lanreotide, fasting glucose and glycosylated haemoglobin concentrations increased. Diabetic medication had to be introduced or increased. No changes in liver tests or in pituitary adenoma size were observed. In these two patients, PEG-V in combination with long-acting SRIF analogs was as effective as PEG-V monotherapy in normalizing IGF-I levels, although significant dose-reductions in PEG-V could be achieved. However, there seems to be a wide variation in the reduction of PEG-V dose, which can be obtained after conversion to combined treatment.

  7. Metastatic Insulinoma Managed with Radiolabeled Somatostatin Analog (United States)

    Costa, Ricardo; Bacchi, Carlos E.; Almeida Filho, Paulo


    Insulinoma is a rare pancreatic neuroendocrine tumor. Overproduction of insulin and associated hypoglycemia are hallmark features of this disease. Diagnosis can be made through demonstration of hypoglycemia and elevated plasma levels of insulin or C-Peptide. Metastatic disease can be detected through computerized tomography (CT) scans, magnetic resonance imaging (MRI), and positron emission tomography (PET)/CT. Somatostatin receptor scintigraphy can be used not only to document metastatic disease but also as a predictive marker of the benefit from therapy with radiolabeled somatostatin analog. Unresectable metastatic insulinomas may present as a major therapeutic challenge for the treating physician. When feasible, resection is the mainstay of treatment. Prevention of hypoglycemia is a crucial goal of therapy for unresectable/metastatic tumors. Diazoxide, hydrochlorothiazide, glucagon, and intravenous glucose infusions have been used for glycemic control yielding temporary and inconsistent results. Sandostatin and its long-acting depot forms have occasionally been used in the treatment of Octreoscan-positive insulinomas. Herein, we report a case of metastatic insulinoma with very difficult glycemic control successfully treated with the radiolabeled somatostatin analog lutetium (177LU). PMID:24455330

  8. Metastatic Insulinoma Managed with Radiolabeled Somatostatin Analog

    Directory of Open Access Journals (Sweden)

    Ricardo Costa


    Full Text Available Insulinoma is a rare pancreatic neuroendocrine tumor. Overproduction of insulin and associated hypoglycemia are hallmark features of this disease. Diagnosis can be made through demonstration of hypoglycemia and elevated plasma levels of insulin or C-Peptide. Metastatic disease can be detected through computerized tomography (CT scans, magnetic resonance imaging (MRI, and positron emission tomography (PET/CT. Somatostatin receptor scintigraphy can be used not only to document metastatic disease but also as a predictive marker of the benefit from therapy with radiolabeled somatostatin analog. Unresectable metastatic insulinomas may present as a major therapeutic challenge for the treating physician. When feasible, resection is the mainstay of treatment. Prevention of hypoglycemia is a crucial goal of therapy for unresectable/metastatic tumors. Diazoxide, hydrochlorothiazide, glucagon, and intravenous glucose infusions have been used for glycemic control yielding temporary and inconsistent results. Sandostatin and its long-acting depot forms have occasionally been used in the treatment of Octreoscan-positive insulinomas. Herein, we report a case of metastatic insulinoma with very difficult glycemic control successfully treated with the radiolabeled somatostatin analog lutetium (177LU.

  9. Nonpeptide somatostatin analogs: recent advances in its application and research

    Institute of Scientific and Technical Information of China (English)


    Along with its wide anatomical distribution, somatostatin (SST) acts on multiple targets via a family of 5 receptors to produce a broad spectrum of biological effects. Therefore, a variety of peptide analogs have been produced and are widely used in clinical treatment. However, because of their flaws in the structure of peptide, the clinical efficacy is limited. In this review, we summarize the structure, pharmacological effects and the potential clinical value of non-peptide SST analogs. We focus on the research and development of non-peptide SST analogs since 1998, and discuss the problems and potential prospects for non-peptide SST analogs. We believe that as more non-peptide somatostatin analogs are successfully developed, the extensive clinical application of SSTs will contribute a great deal to medical science.

  10. Somatostatin analog treatment of acromegaly: new aspects. (United States)

    Lamberts, S W; del Pozo, E


    Ten acromegalics received daily doses of 200-300 micrograms of a long-acting somatostatin analog, SMS 201-995 (Sandostatin, SMS), for an average of 64 weeks. Basal mean GH values of 44 +/- (SE) 7.8 ng/ml had fallen into the normal range at the end of the observation period (mean 64 weeks). This effect was accompanied by a substantial drop in somatomedin-C values. Reduction of pituitary tumor size could be documented in 3 of 6 patients. Whereas SMS did not affect high plasma PRL in 4 microprolactinoma patients, lactotrophs turned sensitive to this agent in mixed GH/PRL tumors. In a comparative study between SMS and bromocriptine, the former normalized circulating GH in 10 of 17 acromegalics in an acute trial, whereas bromocriptine was effective in only 5. A combination of both substances was effective in 2 of 3 patients who were insensitive to single drug administration. Cultures of GH-secreting tumor cells showed a statistically significant hormone decrease in the medium when exposed to SMS. However, in some instances, a diminution of the GH contents of the tumor cells was also observed, presumably as the basis for intracellular breakdown and clinical tumor shrinkage.

  11. Radiolabeled somatostatin analogs in prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Thakur, M.L.; Kolan, H.; Li, J.; Wiaderkiewicz, R.; Pallela, V.R.; Duggaraju, R.; Schally, A.V


    Vapreotide (RC-160), a somatostatin analog, was labeled with {sup 99m}Tc by a direct method and also by using CPTA [1,4,8,11-tetraazacyclotetradecane] as a bifunctional chelating agent. The labeled compounds were evaluated in nude mice bearing experimental human prostate cancers. In these studies, {sup 111}In-DTPA-D-Phe-Octreotide ({sup 111}In-DTPA-octreotide) served as a standard and {sup 99m}Tc-oxytocin as a receptor-non-specific control. {sup 99m}Tc-octreotide was also used. The 24 htumor uptake of {sup 99m}Tc-RC-160 was nearly 400% higher, (p < 0.05), than that of {sup 111}In-DTPA-octreotide and diminished upon receptor blocking. In all tissues except the kidneys, the uptake of {sup 99m}Tc-RC-160 was also higher than that of {sup 111}In-DTPA-octreotide. The uptake of {sup 99m}Tc-RC-160 was influenced by the amount of peptide injected and the best tumor/muscle and tumor/blood ratios were obtained when only one {mu}g of the peptide (200 Ci/mmol) was administered.

  12. Somatostatin, somatostatin analogs and somatostatin receptor dynamics in the biology of cancer progression. (United States)

    Ruscica, M; Arvigo, M; Steffani, L; Ferone, D; Magni, P


    The pharmacological effects (i.e., inhibition of endocrine secretion and cell proliferation) mediated by the hormone somatostatin (SRIF) are derived from its universal high-affinity binding to five different G proteincoupled receptors (GPCRs), named sst1-5. However, SRIF has a half-life of less than 3 min, whereas the available mono- and bi-specific SRIF preferential analogs show prolonged half-life and increased potency. These compounds may control tumor development, cell proliferation and metastatization by direct actions, including cell division arrest in G0/G1 phase (i.e., induction of cyclin-dependent kinase inhibitor p27(kip1) or p21(Cip1)), induction of apoptosis (i.e., induction of p53 and Bax) and suppression of cell invasion. Along with these direct actions on the biology of cancer progression, in vivo SRIF analogs may also regulate tumor growth through indirect actions, by suppressing the secretion of growth-promoting hormones and growth factors and angiogenesis. Interestingly, when ssts are co-expressed, they may interact forming homo- or heterodimers, also with other GPCRs such as type 2 dopamine receptor and the μ-opioid receptor 1, altering their original pharmacological and functional properties. Dimers can be not only constitutive, but perhaps also ligandpromoted: hence, compounds with high affinity for different ssts isoforms may be used to achieve effects elicited by specific dimers. Future developments in the knowledge of ssts dynamics upon SRIF and SRIF analogs binding in neoplastic tissues may allow the full elucidation of the pathophysiological role of this system and the exploitation of the therapeutic potential of its modulation.

  13. Technetium-99m direct radiolabeling of Lanreotide: a Somatostatin analog

    Energy Technology Data Exchange (ETDEWEB)

    Pervez, Shahid; Mushtaq, A. E-mail:; Arif, Muhammad


    Lanreotide, a synthetic octapeptide analog of a native hormone somatostatin, was labeled with a commonly available, inexpensive radionuclide {sup 99m}Tc. Labeling was accomplished by reduction of the cysteine bridge, which provided sulfhydryl groups for chelation with {sup 99m}Tc. Stannous chloride was used as reducing agent, while tartrate acted as transchelating agent. Lanreotide (100 {mu}g), stannous chloride dihydrate (100 {mu}g) and tartaric acid (64 {mu}g) were dissolved in acetate/acetic acid buffer (pH 2.8). After overnight ({approx}18 h) incubation, {approx}444 MBq (12 mCi) {sup 99m}Tc was added and kept in boiling water for 30 min. More than 97% labeling efficiency was confirmed by RP-HPLC, ITLC-SG and C{sub 18} cartridge analysis. Radiolabeling results in one major peak when analyzed by reverse-phase HPLC. The stability of the {sup 99m}Tc-peptide bond was evaluated by cysteine challenge studies.

  14. Treatment with Sandostatin and in vivo localization of tumors with radiolabeled somatostatin analogs

    Energy Technology Data Exchange (ETDEWEB)

    Lamberts, S.W.; Bakker, W.H.; Reubi, J.C.; Krenning, E.P. (Erasmus Univ., Rotterdam (Netherland))


    The presence of high numbers of somatostatin receptors seems to be the basis for the successful control by Sandostatin of hormonal hypersecretion by most growth hormone-secreting pituitary adenomas, endocrine pancreatic tumors, and carcinoids. In this report, we present preliminary data on in vivo somatostatin receptor imaging with a {sup 123}I-coupled somatostatin analog (204-090) in patients with these types of tumors.

  15. Quality of life is impaired in association with the need for prolonged postoperative therapy by somatostatin analogs in patients with acromegaly

    NARCIS (Netherlands)

    Postma, M.R.; Netea-Maier, R.T.; van den Berg, G.; Homan, J.; Sluiter, W.J.; Wagenmakers, M.A.; van den Bergh, A.C.M.; Wolffenbuttel, B.H.R.; Hermus, A.R.M.M.; van Beek, A.P.

    Objective: To assess the influence of long-acting somatostatin analogs (SSTA) after initial pituitary surgery on long-term health-related quality of life (HR-QoL) in relation to disease control in patients with acromegaly. Design: This is a cross-sectional study in two tertiary referral centers in

  16. Quality of life is impaired in association with the need for prolonged postoperative therapy by somatostatin analogs in patients with acromegaly.

    NARCIS (Netherlands)

    Postma, M.R.; Netea-Maier, R.T.; Berg, G. van den; Homan, J.; Sluiter, W.J.; Wagenmakers, M.A.E.M.; Bergh, A.C. van den; Wolffenbuttel, B.H.R.; Hermus, A.R.M.M.; Beek, A.P. van


    OBJECTIVE: To assess the influence of long-acting somatostatin analogs (SSTA) after initial pituitary surgery on long-term health-related quality of life (HR-QoL) in relation to disease control in patients with acromegaly. DESIGN: This is a cross-sectional study in two tertiary referral centers in

  17. Quality of life is impaired in association with the need for prolonged postoperative therapy by somatostatin analogs in patients with acromegaly

    NARCIS (Netherlands)

    Postma, M.R.; Netea-Maier, R.T.; van den Berg, G.; Homan, J.; Sluiter, W.J.; Wagenmakers, M.A.; van den Bergh, A.C.M.; Wolffenbuttel, B.H.R.; Hermus, A.R.M.M.; van Beek, A.P.


    Objective: To assess the influence of long-acting somatostatin analogs (SSTA) after initial pituitary surgery on long-term health-related quality of life (HR-QoL) in relation to disease control in patients with acromegaly. Design: This is a cross-sectional study in two tertiary referral centers in T

  18. Efficacy and tolerability of the long-acting somatostatin analog lanreotide in acromegaly. A 12-month multicenter study of 58 acromegalic patients. French Multicenter Study Group on Lanreotide in Acromegaly. (United States)

    Chanson, P; Leselbaum, A; Blumberg, J; Schaison, G


    .1 +/- 4.3 g/24 h, p = 0.3) in mean steatorrhea was observed during treatment. Before treatment, steatorrhea was present in 9 (19%) patients. During the study, 15 additional patients (32%) developed persistent steatorrhea, and there was a transient increase in fecal fat content above 6 g/24 h in another 11 patients. After exclusion of the 7 patients (12%) with gallstones at enrollment, new gall-stones were diagnosed in 6 out of 50 patients (12%) during the study. Two or three monthly injections of lanreotide PR decreased GH concentration to less than 2.5 micrograms/L and normalized IGF-I levels in 41% of patients treated during 12 months. The good tolerability of this treatment, and the reduction in the frequency of injections, plus the sustained drug serum concentrations, confirm the usefulness of this new somatostatin analog formulation.

  19. Switch from antagonist to agonist after addition of a DOTA chelator to a somatostatin analog

    Energy Technology Data Exchange (ETDEWEB)

    Reubi, Jean Claude; Cescato, Renzo; Waser, Beatrice [University of Berne, Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, PO Box 62, Berne (Switzerland); Erchegyi, Judit; Rivier, Jean E. [The Salk Institute for Biological Studies, The Clayton Foundation Laboratories for Peptide Biology, La Jolla, CA (United States)


    Peptide receptor targeting has become an increasingly attractive method to target tumors diagnostically and radiotherapeutically. Peptides linked to a variety of chelators have been developed for this purpose. They have, however, rarely been tested for their agonistic or antagonistic properties. We report here on a somatostatin antagonist that switched to an agonist upon coupling to a DOTA chelator. Two novel somatostatin analogs, 406-040-15 and its DOTA-coupled counterpart 406-051-20, with and without cold Indium labeling, were tested for their somatostatin receptor subtypes 1-5 (sst{sub 1}-sst{sub 5}) binding affinity using receptor autoradiography. Moreover, they were tested functionally for their ability to affect sst{sub 2} and sst{sub 3} internalization in vitro in HEK293 cells stably expressing the human sst{sub 2} or sst{sub 3} receptor, using an immunofluorescence microscopy-based internalization assay. All three compounds were characterized as pan-somatostatin analogs having a high affinity for all five sst. In the sst{sub 2} internalization assay, all three compounds showed an identical behavior, namely, a weak agonistic effect complemented by a weak antagonistic effect, compatible with the behavior of a partial agonist. Conversely, in the sst{sub 3} internalization assay, 406-040-15 was a full antagonist whereas its DOTA-coupled counterpart, 406-051-20, with and without Indium labeling, switched to a full agonist. Adding the DOTA chelator to the somatostatin analog 406-040-15 triggers a switch at sst{sub 3} receptor from an antagonist to an agonist. This indicates that potential radioligands for tumor targeting should always be tested functionally before further development, in particular if a chelator is added. (orig.)

  20. Clinical applications of somatostatin analogs for growth hormone-secreting pituitary adenomas

    Directory of Open Access Journals (Sweden)

    Wang JW


    Full Text Available Ji-wen Wang,1,2 Ying Li,3 Zhi-gang Mao,1,2 Bin Hu,1,2 Xiao-bing Jiang,1,2 Bing-bing Song,4 Xin Wang,4 Yong-hong Zhu,4 Hai-jun Wang1,21Department of Neurosurgery and Pituitary Tumor Center, The First Affiliated Hospital, Sun Yat-sen University, 2Key Laboratory of Pituitary Adenoma in Guangdong Province, 3State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 4Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, People's Republic of ChinaAbstract: Excessive growth hormone (GH is usually secreted by GH-secreting pituitary adenomas and causes gigantism in juveniles or acromegaly in adults. The clinical complications involving cardiovascular, respiratory, and metabolic systems lead to elevated morbidity in acromegaly. Control of serum GH and insulin-like growth factor (IGF 1 hypersecretion by surgery or pharmacotherapy can decrease morbidity. Current pharmacotherapy includes somatostatin analogs (SAs and GH receptor antagonist; the former consists of lanreotide Autogel (ATG and octreotide long-acting release (LAR, and the latter refers to pegvisomant. As primary medical therapy, lanreotide ATG and octreotide LAR can be supplied in a long-lasting formulation to achieve biochemical control of GH and IGF-1 by subcutaneous injection every 4–6 weeks. Lanreotide ATG and octreotide LAR provide an effective medical treatment, whether as a primary or secondary therapy, for the treatment of GH-secreting pituitary adenoma; however, to maximize benefits with the least cost, several points should be emphasized before the application of SAs. A comprehensive assessment, especially of the observation of clinical predictors and preselection of SA treatment, should be completed in advance. A treatment process lasting at least 3 months should be implemented to achieve a long-term stable blood concentration. More satisfactory surgical outcomes for noninvasive macroadenomas treated

  1. Review of recent advances in medical treatment for neuroendocrine neoplasms:somatostatin analogs and chemotherapy

    Institute of Scientific and Technical Information of China (English)

    Francesca Spada; Monica Valente


    Neuroendocrine neoplasms (NENs) are a heterogeneous group of rare tumours often producing high levels of hormones and causing symptoms. There are a number of different types of NENs. They usually arise as advanced and low/intermediate grade only in a minority of cases, as high grade. Treatment depends on which type and may include surgery, interventional radiology, and systemic treatment, including chemotherapy, somatostatin analogs, interferon α2b, peptide receptor radionuclide therapy, and only for pancreatic neuroendocrine tumors, molecular targeted agents, including everolimus and sunitinib. The aim of the article is to review the medical approaches with somatostatin analogs and chemotherapy. The treatment of NENs is mainly based on their biological characteristics of aggressiveness and functional features, such as symptoms and endocrine markers.

  2. Clinical applications of somatostatin analogs for growth hormone-secreting pituitary adenomas (United States)

    Wang, Ji-wen; Li, Ying; Mao, Zhi-gang; Hu, Bin; Jiang, Xiao-bing; Song, Bing-bing; Wang, Xin; Zhu, Yong-hong; Wang, Hai-jun


    Excessive growth hormone (GH) is usually secreted by GH-secreting pituitary adenomas and causes gigantism in juveniles or acromegaly in adults. The clinical complications involving cardiovascular, respiratory, and metabolic systems lead to elevated morbidity in acromegaly. Control of serum GH and insulin-like growth factor (IGF) 1 hypersecretion by surgery or pharmacotherapy can decrease morbidity. Current pharmacotherapy includes somatostatin analogs (SAs) and GH receptor antagonist; the former consists of lanreotide Autogel (ATG) and octreotide long-acting release (LAR), and the latter refers to pegvisomant. As primary medical therapy, lanreotide ATG and octreotide LAR can be supplied in a long-lasting formulation to achieve biochemical control of GH and IGF-1 by subcutaneous injection every 4–6 weeks. Lanreotide ATG and octreotide LAR provide an effective medical treatment, whether as a primary or secondary therapy, for the treatment of GH-secreting pituitary adenoma; however, to maximize benefits with the least cost, several points should be emphasized before the application of SAs. A comprehensive assessment, especially of the observation of clinical predictors and preselection of SA treatment, should be completed in advance. A treatment process lasting at least 3 months should be implemented to achieve a long-term stable blood concentration. More satisfactory surgical outcomes for noninvasive macroadenomas treated with presurgical SA may be achieved, although controversy of such adjuvant therapy exists. Combination of SA and pegvisomant or cabergoline shows advantages in some specific cases. Thus, an individual treatment program should be established for each patient under a full evaluation of the risks and benefits. PMID:24421637

  3. Tamoxifen enhances the control of acromegaly treated with somatostatin analog lanreotide. (United States)

    Maiza, Jean-Christophe; Castillo-Ros, Stéphane; Matta, Maria; Bennet, Antoine; Caron, Philippe


    We present the case of a 51-year old female patient with acromegaly that was resistant to somatostatin analogs and dopamine agonists. The patient was diagnosed with breast cancer requiring treatment with the anti-estrogen tamoxifen. Prior to initiating the treatment with tamoxifen, the IGF-I level was very high at 415% of the upper limit of normal for the patient's age and sex. During the tamoxifen treatment, the level of IGF-I dropped spectacularly down to normal levels. This observation highlights the effect of an anti-estrogen treatment in certain female patients with acromegaly.

  4. Long-term Primary Medical Therapy with Somatostatin Analogs in Acromegaly

    Directory of Open Access Journals (Sweden)

    Deng-Huang Su


    Full Text Available To cure acromegalic patients, transsphenoidal surgery is considered first, especially for microadenoma. However, less than 50% of patients with macroadenoma achieve satisfactory biochemical control. Moreover, surgery may cause hypopituitarism. Medical therapy may offer the prospect of near normalization of growth hormone (GH/insulin-like growth factor-1 levels with substantial tumor shrinkage in a significant number of patients. Here, we report two cases of acromegaly under treatment with somato-statin analogs alone for more than 10 years. Case 1 was a 54-year-old man with a pituitary macro-adenoma. He received 4 years of octreotide treatment followed by 6 years of prolonged-release (PR lanreotide resulting in normal GH level. Case 2 was a 60-year-old woman with a 1.3 cm pituitary tumor. She received 8 years of octreotide treatment followed by 6 years of PR lanreotide resulting in subnormal GH level and gallbladder sludge. She had received bilateral total hip replacement for hip osteoarthritis at the age of 59 years. These cases illustrate that long-term treatment with somatostatin analogs offers an alternative choice in selected acromegalic patients, such as those with pituitary tumor who cannot be cured by surgery, those who have unacceptable anesthetic risk and those who refuse surgery.

  5. P10: Is the OctreoScan score a predictive factor of response to somatostatin analogs treatment? (United States)

    Damiano, Vincenzo; Ottaviano, Margaret; Del Vecchio, Silvana; Segreto, Sabrina; Tucci, Irene; von Arx, Claudia; Palumbo, Giuliano; Pellegrino, Sara; De Placido, Sabino; Marino, Mirella; Palmieri, Giovannella


    Background The somatostatin receptor expression in thymic neoplasms is assessed in vivo imaging by 111In-octreotide SPECT (OctreoScan). This retrospective study aimed to verify the predictive role of intensity expression of OctreoScan to somatostatin analogues treatment. Methods We evaluated 28 patients (14 male and 14 female with a median age of 54 years, range, 27–78 years) with thymic tumors candidated to somatostatine analogs therapy as second or third line of treatment or maintenance treatment. For this reason all of them performed OctreoScan of the thorax and tumor-to-background ratio was determined on the 24-h coronal sections. Thymic tumors were classified by WHO 2004 and staged according to Masaoka-Koga system. Specifically, AB three patients; B1 two patients; B2 five patients; B3 nine patients; B2/B3 three patients; thymic carcinoma five patients; B3/thymic carcinoma one patient. All the patients had a III of IV stage of disease. Lesions with pathologically increased tracer uptake were categorized according to the following 3-pointscore: equivocal, probably pathologic, and definitely pathologic. Results All patients were OctreoScan positive, four with an equivocal point score, nineteen and five with a probably and definitely pathological score respectively. Somatostatin analogs were administrated as second or third line of therapy in 10 patients, as maintenance therapy in 16 patients and as both of modality in two patients. Median time to progression was 16 months (range, 6–77 months) and it was not influenced by uptake pathological score. Conclusions The intensity of uptake of Indium-111-DTPA-D-Phe1-octreotide in thymic tumors is not a predictive factor of response to somatostatin analogues treatment. The OctreoScan positivity is the best rationale for treating thymic epithelial tumors (TETs) with somatostatin analogs.

  6. FGFR4 polymorphic alleles modulate mitochondrial respiration: A novel target for somatostatin analog action in pituitary tumors. (United States)

    Ezzat, Shereen; Wang, Ri; Pintilie, Melania; Asa, Sylvia L


    We reported that a single nucleotide polymorphism (SNP) at codon 388 of the fibroblast growth factor receptor 4 (FGFR4-Gly388Arg) can result in distinct proteins that alter pituitary cell growth and function. Here, we examined the differential properties of the available therapeutic somatostatin analogs, octreotide and pasireotide, in pituitary tumor cells expressing the different FGFR4 isoforms. Consistent with their enhanced growth properties, FGFR4-R388-expressing cells show higher mitochondrial STAT3 serine phosphorylation driving basal and maximal oxygen consumption rate (OCR) than pituitary cells expressing the more common FGFR4-G388 isoform. While both somatostatin analogs reduce the OCR in FGFR4-G388 cells, pasireotide was more effective in decreasing OCR in cells expressing the variant FGFR4-R388 isoform. Down-regulation of somatostatin receptor 5 (SSTR5) abrogated the effect of pasireotide, demonstrating its involvement in mediating this action. The effects on OCR were recapitulated by introducing a constitutively active serine STAT3 but not by a tyrosine-active mutant. Moreover, pharmacologic inhibition demonstrated the role for the phosphatase PP2A in mediating the dephosphorylation of STAT3-S727 by pasireotide. Our data indicate that FGFR4 polymorphic isoforms mediate signaling that yields mitochondrial therapeutic targets of relevance to the actions of different somatostatin analogs.

  7. Immunoreactivity score using an anti-sst2A receptor monoclonal antibody strongly predicts the biochemical response to adjuvant treatment with somatostatin analogs in acromegaly

    NARCIS (Netherlands)

    F. Gatto (Federico); R.A. Feelders (Richard); R. van der Pas (Rob); J.M. Kros (Johan); M. Waaijers (Marlijn); D. Sprij-Mooij (Diana); S.J.C.M.M. Neggers (Bas); A. van der Lelij (Allegonda); F. Minuto (Francesco); S.W.J. Lamberts (Steven); W.W. de Herder (Wouter); D. Ferone (Diego); L.J. Hofland (Leo)


    textabstractContext: Somatostatin receptor subtype 2 (sst2A) protein expression has been demonstrated to positively correlate with somatostatin analog treatment outcome in GH-secreting adenomas. Recently, a new rabbit monoclonal anti-sst2A antibody (clone UMB-1) has been validated as a reliable meth

  8. The long-acting somatostatin analogue SMS 201-995 causes malabsorption

    DEFF Research Database (Denmark)

    Witt, K; Pedersen, N T


    Somatostatin and its long-acting analogue SMS 201-995 (Sandostatin) have been suspected of causing steatorrhoea. The aim of this study was to examine the effect of SMS 201-995 on fat assimilation in healthy subjects, using 14C-triolein and 3H-oleic acid as tracers of dietary triglycerides and free...

  9. Somatostatin receptor expression in vivo and response to somatostatin analog therapy with or without other antineoplastic treatments in advanced medullary thyroid carcinoma. (United States)

    Vainas, I; Koussis, Ch; Pazaitou-Panayiotou, K; Drimonitis, A; Chrisoulidou, A; Iakovou, I; Boudina, M; Kaprara, A; Maladaki, A


    The long-term treatment of metastatic medullary thyroid carcinoma (MTC) with somatostatin (SST) analogs was evaluated in 22 patients with persistant or relapsed disease and with in vivo positive SST receptor (SSTR) tumors. After surgical intervention all patients but one, initially or at a later time, had persistenly (15) or after relapse (7) elevated serum calcitonin (CT, 252-69482 pg/ml) and carcinoembryonic antigen (CEA, 8-1130 ng/ml) concentrations; also, all of them showed positive uptake in 111In-pentetreotide scanning. Daily doses of 0.4-1.0 mg octreotide subcutaneously, or monthly doses of 20-30 mg long-acting octreotide (LAR) intramuscularly for 3-21 months were administered. Systemic chemotherapy (Ch) with or without external radiotherapy (eRT) was given to 13 patients simultaneously. A beneficial effect on pre-existing diarrhea was observed in 8 patients (subjective partial remmission, sPR 36.4%); 10 other patients showed stable disease, while in 4 a worsening of pre-existing diarrhea was observed. CT and CEA concentrations decreased more than 25% in 4 out of 22 patients (18%) and 11 patients showed a decrease of less than 25% (biological SD). No objective response in tumour growth was demonstrated. Patients (10 survivors in group B) treated with Ch+eRT plus Octerotide showed higher sR (92.5%), lower mortality (23.1%), longer mean time to death (130 months) and longer mean total survival (mts) time (145 months) in comparison to group A patients who had 66.7% sR, 33.3% mortality, only 88.5 months mean time to death and 101 months mts-time. Long-term octreotide and octreotide-LAR treatment offers a subjective and biological partial remission in one third and in one fourth of the MTC patients respectively, but it does not improve the natural course of the tumor. It remains to be answered if these drugs, combined with other antineoplastic therapies, have a synergistic effect relating to treatment response and to patient survival and mortality.

  10. Excessive grooming induced by somatostatin or its analog SMS 201-995

    NARCIS (Netherlands)

    Wimersma Greidanus, T.B. van; Maigret, C.; Krechting, B.


    Intracerebroventricular (i.c.v.) administration of somatostatin or SMS 201-995 induces excessive grooming behavior in rats. The grooming inducing effect of somatostatin is rather weak, as doses of 300 ng or less did not result in increased total grooming scores. In contrast a dose of 10 ng SMS 201-9

  11. Somatostatin analogs in the treatment of castrate-resistant prostate cancer: efficacy and tolerability

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    G. P. Kolesnikov


    Full Text Available Castrate-resistant prostate cancer (CRPC is one of the most complex and currently completely unsolved problems of oncourology. Possible novel treatment of CRPC is administration of Octreotide Long, long-acting somatostatin analogue.In this paper we have shown an experience of treatment with Octreotide Long 30 mg and dexamethasone in 69 CRPC patients from February 2014 to March 2016. We have assessed an efficacy and safety of the therapy. Age of patients ranged from 56 to 89 years, all patients had continued androgen deprivation. Response to the treatment was assessed clinically by the following factors: change in the level of prostate specific antigen (PSA in serum, dynamics of indicators of general and biochemical blood tests, the level of pain syndrome and improvement in the patient’s quality of life. Total response to reduction and stabilization of PSA level was achieved in 70.9 % of patients. In general, the best results were observed in the group of patients treated with Octreotide Long before first-line chemotherapy with docetaxel. Tolerability of Octreotide Long in combination with dexamethasone in all cases was good. No significant side effects – neither hematological, nor clinical were noted. We also did not register any cases of drug discontinuation due to its intolerance. 

  12. Somatostatin analogs and gallstones: a retrospective survey on a large series of acromegalic patients. (United States)

    Attanasio, R; Mainolfi, A; Grimaldi, F; Cozzi, R; Montini, M; Carzaniga, C; Grottoli, S; Cortesi, L; Albizzi, M; Testa, R M; Fatti, L; De Giorgio, D; Scaroni, C; Cavagnini, F; Loli, P; Pagani, G; Ghigo, E


    Development of gallstones (GS) is reported during the use of somatostatin analogs (SA) that are at present the mainstay for the medical treatment of acromegaly. To review the prevalence and clinical and biochemical correlates of GS in acromegalic patients. Retrospective survey on hospital records in acromegalic patients followed up in the last 20 yr in tertiary referral centers. Four hundred and fifty-nine patients (272 females). According to SA use and GS occurrence, patients were divided in 4 groups: 1) treated with SA without GS (SA+GS-), 2) GS developed while on SA (SA+GS+), 3) GS without SA use (SA-GS+), 4) neither GS nor SA (SA-GS-). Patients were unevenly distributed in the 4 groups: 232, 125, 38, 64, respectively, pointing to a prevalence of GS in acromegaly of 8.3% at diagnosis with an additional 35% developing GS during SA. GS occurred after 3 months-18 yr (median 3 yr) of SA treatment, were diagnosed after symptoms in 17.6%, were associated to steatosis, ultrasound biliary dilation, and biochemical cholestasis, in 25.6%, 12.8%, and 4% of patients, respectively. Ursodehoxicolic acid was administered after GS occurrence, causing their dissolution in 39% of patients after 3-48 months (median 12). Cholecystectomy was performed in 16.8%of patients in group 2. At multivariate analysis obesity, dyslipidemia, and SA treatment were independent predictors of GS onset, whereas gender and age were not. GS are a frequent occurrence in acromegalic patients treated with SA, may occur at any time, but are seldom symptomatic or prompt acute surgery. Obesity and dyslipidemia appear to play a major role in the occurrence of GS in acromegalic patients on SA treatment.

  13. T2-weighted MRI signal predicts hormone and tumor responses to somatostatin analogs in acromegaly. (United States)

    Potorac, Iulia; Petrossians, Patrick; Daly, Adrian F; Alexopoulou, Orsalia; Borot, Sophie; Sahnoun-Fathallah, Mona; Castinetti, Frederic; Devuyst, France; Jaffrain-Rea, Marie-Lise; Briet, Claire; Luca, Florina; Lapoirie, Marion; Zoicas, Flavius; Simoneau, Isabelle; Diallo, Alpha M; Muhammad, Ammar; Kelestimur, Fahrettin; Nazzari, Elena; Centeno, Rogelio Garcia; Webb, Susan M; Nunes, Marie-Laure; Hana, Vaclav; Pascal-Vigneron, Véronique; Ilovayskaya, Irena; Nasybullina, Farida; Achir, Samia; Ferone, Diego; Neggers, Sebastian J C M M; Delemer, Brigitte; Petit, Jean-Michel; Schöfl, Christof; Raverot, Gerald; Goichot, Bernard; Rodien, Patrice; Corvilain, Bernard; Brue, Thierry; Schillo, Franck; Tshibanda, Luaba; Maiter, Dominique; Bonneville, Jean-François; Beckers, Albert


    GH-secreting pituitary adenomas can be hypo-, iso- or hyper-intense on T2-weighted MRI sequences. We conducted the current multicenter study in a large population of patients with acromegaly to analyze the relationship between T2-weighted signal intensity on diagnostic MRI and hormonal and tumoral responses to somatostatin analogs (SSA) as primary monotherapy. Acromegaly patients receiving primary SSA for at least 3 months were included in the study. Hormonal, clinical and general MRI assessments were performed and assessed centrally. We included 120 patients with acromegaly. At diagnosis, 84, 17 and 19 tumors were T2-hypo-, iso- and hyper-intense, respectively. SSA treatment duration, cumulative and mean monthly doses were similar in the three groups. Patients with T2-hypo-intense adenomas had median SSA-induced decreases in GH and IGF-1 of 88% and 59% respectively, which were significantly greater than the decreases observed in the T2-iso- and hyper-intense groups (P < 0.001). Tumor shrinkage on SSA was also significantly greater in the T2-hypo-intense group (38%) compared with the T2-iso- and hyper-intense groups (8% and 3%, respectively; P < 0.0001). The response to SSA correlated with the calculated T2 intensity: the lower the T2-weighted intensity, the greater the decrease in random GH (P < 0.0001, r = 0.22), IGF-1 (P < 0.0001, r = 0.14) and adenoma volume (P < 0.0001, r = 0.33). The T2-weighted signal intensity of GH-secreting adenomas at diagnosis correlates with hormone reduction and tumor shrinkage in response to primary SSA treatment in acromegaly. This study supports its use as a generally available predictive tool at diagnosis that could help to guide subsequent treatment choices in acromegaly. © 2016 Society for Endocrinology.

  14. Glucose status in patients with acromegaly receiving primary treatment with the somatostatin analog lanreotide. (United States)

    Couture, Elisabeth; Bongard, Vanina; Maiza, Jean-Christophe; Bennet, Antoine; Caron, Philippe


    To describe glucose status changes in patients with acromegaly receiving somatostatin analog lanreotide as primary treatment. This retrospective, single-center study conducted during 1996-2008, included acromegalic patients receiving primary lanreotide treatment. Baseline and last follow-up visit assessments included glucose status (according to American Diabetes Association criteria), growth hormone (GH), and insulin-like growth factor-1 (IGF-1) levels. Glucose control was considered improved when fasting plasma glucose or antidiabetic treatments were reduced, and deteriorated if fasting glucose was the same/higher but with increased antidiabetic treatments. 42 patients (median age 50 years; range 29-75 years) were included. At baseline, 26 (62%) were normoglycemic, eight (19%) had impaired glucose tolerance/fasting glycemia, and eight (19%) had diabetes mellitus; family history of diabetes mellitus was significantly associated with abnormal glucose status. At final visit, the mean (SE) lanreotide dose was 108 (21) mg/month. Median treatment duration was 23 months, range 3-138 months, and 74% of patients received the 120-mg dose. Median GH levels decreased significantly (baseline, 12 [5-20] μg/l; final visit, 2.1 [1.0-4.7] μg/l; P < 0.0001); IGF-1 levels were age- and sex-normalized in 33% of patients. Glucose control deteriorated in seven patients (17%) and improved from abnormal levels in 10 (24%). Deterioration was associated with smaller GH decreases (median change, -3.4 μg/l vs. -10.7 μg/l, P = 0.014) and improvement with trend to lower BMI and younger age. During primary lanreotide treated acromegalic patients 60% had no change, 24% had an improvement and 17% had a worsening of glucose status. Deterioration was significantly associated with smaller GH decreases during primary lanreotide treatment.

  15. Place of preoperative treatment of acromegaly with somatostatin analog on surgical outcome: a systematic review and meta-analysis.

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    Francisco Pita-Gutierrez

    Full Text Available CONTEXT: Transsphenoidal neurosurgery is the accepted first-line treatment of acromegaly in the majority of patients. Previous studies addressing preoperative somatostatin analog (SSA treatment and subsequent surgical cure rates are conflicting, reporting either benefits or no significant differences. OBJECTIVE: The aim of this study, based on a meta-analysis of all published reports, was to investigate whether treatment with SSA before surgery improves the surgical outcome of acromegaly. DATA SOURCES: All studies of preoperative treatment of acromegaly with SSA were systematically reviewed up to December 2011. We searched the Medline, Embase, Cochrane and Google Scholar electronic databases. STUDY SELECTION: The primary endpoint was the biochemical postoperative cure rate. We identified 286 studies, out of which 10 studies (3.49% fulfilling the eligibility criteria were selected for analysis; five retrospective studies with a control group, two prospective non-randomized trials, and three prospective controlled trials. The meta-analysis was conducted using the random-effects model. DATA EXTRACTION: Data were extracted from published reports by two independent observers. DATA SYNTHESIS: A borderline effect was detected in the analysis of all of the trials with control groups, with a pooled odds ratio (OR for biochemical cure with SSA treatment of 1.62 (95% CI, 0.93-2.82. In the analysis of the three prospective controlled trials, a statistically significant effect was identified OR: 3.62 (95% CI, 1.88-6.96. CONCLUSIONS: Preoperative treatment with SSA og GH-secreting pituitary adenomas shows a significant improvement on surgical results. This meta-analysis suggests that in centers without optimal results all patients with a GH-secreting pituitary macroadenoma should be treated with a long-acting SSA prior to surgical treatment.

  16. Budget impact of somatostatin analogs as treatment for metastatic gastroenteropancreatic neuroendocrine tumors in US hospitals

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    Ortendahl JD


    Full Text Available Jesse D Ortendahl,1 Sonia J Pulgar,2 Beloo Mirakhur,3 David Cox,3 Tanya GK Bentley,1 Alexandria T Phan4 1Health Economics, Partnership for Health, LLC, Beverly Hills, CA, USA; 2Health Economics and Outcomes Research, Ipsen Biopharmaceuticals, Basking Ridge, NJ, USA; 3Medical Affairs, Oncology, Ipsen Biopharmaceuticals, Basking Ridge, NJ, USA; 4GI Medical Oncology, University of New Mexico Comprehensive Cancer Center, Albuquerque, NM, USA Objective: With the introduction of new therapies, hospitals have to plan spending limited resources in a cost-effective manner. To assist in identifying the optimal treatment for patients with locally advanced or metastatic gastroenteropancreatic neuroendocrine tumors, budget impact modeling was used to estimate the financial implications of adoption and diffusion of somatostatin analogs (SSAs. Patients and methods: A hypothetical cohort of 500 gastroenteropancreatic neuroendocrine tumor patients was assessed in an economic model, with the proportion with metastatic disease treated with an SSA estimated using published data. Drug acquisition, preparation, and administration costs were based on national pricing databases and published literature. Octreotide dosing was based on published estimates of real-world data, whereas for lanreotide, real-world dosing was unavailable and we therefore used the highest indicated dosing. Alternative scenarios reflecting the proportion of patients receiving lanreotide or octreotide were considered to estimate the incremental budget impact to the hospital. Results: In the base case, 313 of the initial 500 gastroenteropancreatic neuroendocrine tumor patients were treated with an SSA. The model-predicted per-patient cost was US$83,473 for lanreotide and US$89,673 for octreotide. With a hypothetical increase in lanreotide utilization from 5% to 30% of this population, the annual model-projected hospital costs decreased by US$488,615. When varying the inputs in one-way sensitivity

  17. The novel somatostatin analog SOM230 is a potent inhibitor of hormone release by growth hormone- and prolactin-secreting pituitary adenomas in vitro

    NARCIS (Netherlands)

    L.J. Hofland (Leo); A-J. van der Lely (Aart-Jan); S.W.J. Lamberts (Steven); A. Beckers (Albert); J. van der Hoek (Joost); P.M. van Koetsveld (Peter); W.W. de Herder (Wouter); M. Waaijers (Marlijn); D. Sprij-Mooij (Diana); C. Bruns (Christian); G. Weckbecker (Gisbert); R.A. Feelders (Richard)


    textabstractTo determine the inhibitory profile of the novel somatostatin (SRIF) analog SOM230 with broad SRIF receptor binding, we compared the in vitro effects of SOM230, octreotide (OCT), and SRIF-14 on hormone release by cultures of different types of secreting pituitary adenom

  18. Dissociation between the effects of somatostatin (SS) and octapeptide SS-analogs on hormone release in a small subgroup of pituitary- and islet cell tumors

    NARCIS (Netherlands)

    L.J. Hofland (Leo); W.W. de Herder (Wouter); H.A. Visser-Wisselaar (Heleen); C. van Uffelen; M. Waaijers (Marlijn); J. Zuyderwijk; P. Uitterlinden (Piet); P.M. van Koetsveld (Peter); S.W.J. Lamberts (Steven); J.M. Kros (Johan)


    textabstractThe effects of somatostatin (SS-14 and/or SS-28) and of the three octapeptide SS-analogs that are available for clinical use (octreotide, BIM-23014 and RC-160) on hormone release by primary cultures of 15 clinically nonfunctioning pituitary adenomas (NFA), 7

  19. Predictive value of T2 relative signal intensity for response to somatostatin analogs in newly diagnosed acromegaly

    Energy Technology Data Exchange (ETDEWEB)

    Shen, Ming; Zhang, Qilin [Fudan University, Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Shanghai (China); Shanghai Pituitary Tumor Center, Shanghai (China); Liu, Wenjuan; Li, Yiming; Zhang, Zhaoyun; Ye, Hongying; He, Min; Lu, Bin; Yang, Yeping [Shanghai Pituitary Tumor Center, Shanghai (China); Fudan University, Department of Endocrinology and Metabolism, Huashan Hospital, Shanghai Medical College, Shanghai (China); Wang, Meng [Fudan University, Department of Endocrinology and Metabolism, Huashan Hospital, Shanghai Medical College, Shanghai (China); Soochow University, Division of Endocrinology, the Second Affiliated Hospital, Suzhou (China); Zhu, Jingjing [Shanghai Pituitary Tumor Center, Shanghai (China); Fudan University, Department of Neuropathology, Huashan Hospital, Shanghai Medical College, Shanghai (China); Ma, Zengyi; He, Wenqiang; Li, Shiqi; Shou, Xuefei; Qiao, Nidan; Ye, Zhao; Zhang, Yichao; Zhao, Yao; Wang, Yongfei [Fudan University, Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Shanghai (China); Shanghai Pituitary Tumor Center, Shanghai (China); Yao, Zhenwei [Shanghai Pituitary Tumor Center, Shanghai (China); Fudan University, Department of Radiology, Huashan Hospital, Shanghai Medical College, Shanghai (China); Lu, Yun [Fudan University, Department of Nuclear Medicine, Huashan Hospital, Shanghai Medical College, Shanghai (China)


    The difficulty of predicting the efficacy of somatostatin analogs (SSA) is not fully resolved. Here, we quantitatively evaluated the predictive value of relative signal intensity (rSI) on T1- and T2-weighted magnetic resonance imaging (MRI) for the short-term efficacy (3 months) of SSA therapy in patients with active acromegaly and assessed the correlation between MRI rSI and expression of somatostatin receptors (SSTR). This was a retrospective review of prospectively recorded data. Ninety-two newly diagnosed patients (37 males and 55 females) with active acromegaly were recruited. All patients were treated with pre-surgical SSA, followed by reassessment and transspenoidal surgery. rSI values were generated by calculating the ratio of SI in the tumor to the SI of normal frontal white matter. The Youden indices were calculated to determine the optimal cutoff of rSI to determine the efficacy of SSA. The correlation between rSI and expression of SSTR2/5 was analyzed by the Spearman rank correlation coefficient. T2 rSI was strongly correlated with biochemical sensitivity to SSA. The cutoff value of T2 rSI to distinguish biochemical sensitivity was 1.205, with a positive predictive value (PPV) of 81.5 % and a negative predictive value (NPV) of 77.3 %. No correlation was found between MRI and tumor size sensitivity. Moreover, T2 rSI was negatively correlated with the expression of SSTR5. T2 rSI correlates with the expression of SSTR5 and quantitatively predicts the biochemical efficacy of SSA in acromegaly. (orig.)

  20. Treatment of advanced pancreatic cancer with the long-acting somatostatin analogue lanreotide: in vitro and in vivo results (United States)

    Raderer, M; Hamilton, G; Kurtaran, A; Valencak, J; Haberl, I; Hoffmann, O; Kornek, G V; Vorbeck, F; Hejna, M H L; Virgolini, I; Scheithauer, W


    Fourteen patients with metastatic pancreatic adenocarcinoma were treated with the long-acting somatostatin (SST) analogue lanreotide. No objective response was obtained, and the median survival was 4 months (range 1.8–7 months). Pancreatic cancer could not be visualized by means of SST-receptor (R) scintigraphy in our patients. In vitro data also demonstrated absence of SSTR2 expression, suggesting pancreatic cancer not to be a potential target for treatment with SST analogues. © 1999 Cancer Research Campaign PMID:10027326

  1. In vivo detection of somatostatin receptors in patients with functionless pituitary adenomas by means of a radioiodinated analog of somatostatin ((123I)SDZ 204-090)

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    Faglia, G.; Bazzoni, N.; Spada, A.; Arosio, M.; Ambrosi, B.; Spinelli, F.; Sara, R.; Bonino, C.; Lunghi, F. (Institute of Endocrine Sciences, University of Milan, Ospedale Maggiore IRCCS (Italy))


    The recent availability of a Tyr3-substituted octreotide (SDZ 204-090) for radioiodination has allowed somatostatin (SRIH) receptor binding to be studied in vivo, and receptor-positive tumors of different origins to be visualized with a gamma-camera. This prompted us to investigate whether this compound could be used for external imaging of functionless pituitary adenomas displaying SRIH receptors. Eight patients with functionless pituitary adenomas, three patients with acromegaly, and three with macroprolactinoma were injected iv with 123I-labeled Tyr3-octreotide and then scanned with a gamma-camera. Positive scans were obtained in the three acromegalics and in two of the eight patients with functionless pituitary tumors. The patients with macroprolactinoma had negative scans. The diagnosis of functionless pituitary adenomas was confirmed by light and electron microscopic examination as well as immunocytochemical studies. In vitro binding of (125I)Tyr11-SRIH to cell membranes was evaluated in four functionless and three GH-secreting adenomas removed from seven of the patients. All of the GH-secreting as well as one of the four functionless adenomas had high affinity SRIH-binding sites, without differences in number or affinity, whereas SRIH-binding sites were not detected in the others. Positive scans were observed only in patients bearing tumors with high affinity SRIH-binding sites. In conclusion, (123I)Tyr3-octreotide appears to be a promising tool for singling out, in vivo, patients with functionless pituitary tumors displaying SRIH receptors who might potentially benefit from octreotide treatment.

  2. A 25-Year Experience of Gastroenteropancreatic Neuroendocrine Tumors and Somatostatin (Congeners) Analogs: From Symptom Control to Antineoplastic Therapy. (United States)

    O'Dorisio, Thomas M; Anthony, Lowell B


    Radioimmunoassay technology was utilized in the discovery of somatostatin and was quickly brought into therapeutics; however, it took the development of somatostatin congeners to solve its limitations of a short half-life. Therapeutic medical control of hyperhormonal states such as acromegaly, carcinoid syndrome and VIPoma significantly advanced from a nonspecific approach to one that specifically and effectively targeted the underlying pathophysiology. Clinical care was transformed from nonspecific symptom control to one of a significant improvement in not only quality of life, but also quantity of life. These data submitted to US and European regulatory authorities for approval included many investigative sites with no uniform protocol and multiple investigational new drugs, and have not been previously published. This review includes the original data demonstrating the transformational impact this class of agents had on specific disease subsets resulting in regulatory approval 25 years ago. Autoradiography techniques using somatostatin resulted in identifying, localizing and characterizing its receptor subtypes. Translating in vitro data to in vivo resulted in scintigraphic whole body and SPECT scans with (111)In-pentetreotide and was incorporated into standard clinical care 20 years ago. (68)Ga-octreotide congeners using PET scanning offers a major imaging advance. Peptide receptor radiotherapy has evolved over the last 2 decades and utilizes several therapeutic isotopes, including (90)Y and (177)Lu. © 2015 S. Karger AG, Basel.

  3. Hepatic Cyst Infection During Use of the Somatostatin Analog Lanreotide in Autosomal Dominant Polycystic Kidney Disease: An Interim Analysis of the Randomized Open-Label Multicenter DIPAK-1 Study

    NARCIS (Netherlands)

    Lantinga, M.A.; D'Agnolo, H.M.A.; Casteleijn, N.F.; Fijter, J.W. de; Meijer, E.; Messchendorp, A.L.; Peters, D.J.; Salih, M.; Spithoven, E.M.; Soonawala, D.; Visser, F.W.; Wetzels, J.F.M.; Zietse, R.; Drenth, J.P.H.; Gansevoort, R.T.


    INTRODUCTION AND AIMS: The DIPAK-1 Study investigates the reno- and hepatoprotective efficacy of the somatostatin analog lanreotide compared with standard care in patients with later stage autosomal dominant polycystic kidney disease (ADPKD). During this trial, we witnessed several episodes of hepat

  4. Hepatic Cyst Infection During Use of the Somatostatin Analog Lanreotide in Autosomal Dominant Polycystic Kidney Disease : An Interim Analysis of the Randomized Open-Label Multicenter DIPAK-1 Study

    NARCIS (Netherlands)

    Lantinga, Marten A; D'Agnolo, Hedwig M. A.; Casteleijn, Niek F.; de Fijter, Johan W.; Meijer, Esther; Messchendorp, Annemarie L.; Peters, Dorien J. M.; Salih, Mahdi; Spithoven, Edwin M.; Soonawala, Darius; Visser, Folkert W.; Wetzels, Jack F. M.; Zietse, Robert; Drenth, Joost P. H.; Gansevoort, Ron T.

    Introduction and Aims The DIPAK-1 Study investigates the reno-and hepatoprotective efficacy of the somatostatin analog lanreotide compared with standard care in patients with later stage autosomal dominant polycystic kidney disease (ADPKD). During this trial, we witnessed several episodes of hepatic

  5. Hepatic Cyst Infection During Use of the Somatostatin Analog Lanreotide in Autosomal Dominant Polycystic Kidney Disease: An Interim Analysis of the Randomized Open-Label Multicenter DIPAK-1 Study

    NARCIS (Netherlands)

    Lantinga, M.A.; D'Agnolo, H.M.A.; Casteleijn, N.F.; Fijter, J.W. de; Meijer, E.; Messchendorp, A.L.; Peters, D.J.; Salih, M.; Spithoven, E.M.; Soonawala, D.; Visser, F.W.; Wetzels, J.F.M.; Zietse, R.; Drenth, J.P.H.; Gansevoort, R.T.


    INTRODUCTION AND AIMS: The DIPAK-1 Study investigates the reno- and hepatoprotective efficacy of the somatostatin analog lanreotide compared with standard care in patients with later stage autosomal dominant polycystic kidney disease (ADPKD). During this trial, we witnessed several episodes of

  6. Hepatic Cyst Infection During Use of the Somatostatin Analog Lanreotide in Autosomal Dominant Polycystic Kidney Disease: An Interim Analysis of the Randomized Open-Label Multicenter DIPAK-1 Study

    NARCIS (Netherlands)

    Lantinga, M.A. (Marten A.); D’Agnolo, H.M.A. (Hedwig M. A.); E. Casteleijn (Eric); de Fijter, J.W. (Johan W.); E. Meijer (Esther); A.L. Messchendorp (A. Lianne); D. Peters (Dorien); M. Salih (Mahdi); E.M. Spithoven (Edwin); D. Soonawala (Darius); F.W. Visser (Folkert); Wetzels, J.F.M. (Jack F. M.); R. Zietse (Bob); J.P.H. Drenth (Joost); R.T. Gansevoort (Ron); Drenth, J.P.H.; J.W. de Fijter (Johan); Gansevoort, R.T.; D.J.M. Peters (Dorien J.M.); J.F.M. Wetzels (Jack); Zietse, R.


    textabstractIntroduction and Aims: The DIPAK-1 Study investigates the reno- and hepatoprotective efficacy of the somatostatin analog lanreotide compared with standard care in patients with later stage autosomal dominant polycystic kidney disease (ADPKD). During this trial, we witnessed several

  7. A clinical and radiological objective tumor response with somatostatin analogs (SSA in well-differentiated neuroendocrine metastatic tumor of the ileum: a case report

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    De Divitiis C


    Full Text Available Chiara De Divitiis,1 Claudia von Arx,2 Roberto Carbone,3 Fabiana Tatangelo,4 Elena di Girolamo,5 Giovanni Maria Romano,1 Alessandro Ottaiano,1 Elisabetta de Lutio di Castelguidone,3 Rosario Vincenzo Iaffaioli,1 Salvatore Tafuto1 On behalf of the European Neuroendocrine Tumor Society (ENETS Center of Excellence Multidisciplinary Group for Neuroendocrine Tumors in Naples (Italy 1Department of Abdominal Oncology, National Cancer Institute “Fondazione G. Pascale”, Naples, Italy; 2Department of Clinical Medicine and Surgery, “Federico II” University, Naples, Italy; 3Department of Radiology, 4Department of Pathology, 5Department of Endoscopy, National Cancer Institute “Fondazione G Pascale”, Naples, Italy Abstract: Somatostatin analogs (SSAs are typically used to treat the symptoms caused by neuroendocrine tumors (NETs, but they are not used as the primary treatment to induce tumor shrinkage. We report a case of a 63-year-old woman with a symptomatic metastatic NET of the ileum. Complete symptomatic response was achieved after 1 month of treatment with SSAs. In addition, there was an objective response in the liver, with the disappearance of secondary lesions noted on computed tomography scan after 3 months of octreotide treatment. Our experience suggests that SSAs could be useful for downstaging and/or downsizing well-differentiated NETs, and they could allow surgery to be performed. Such presurgery therapy could be a promising tool in the management of patients with initially inoperable NETs. Keywords: neuroendocrine tumor, somatostatin analogs, octreotide, metastatic tumor of the ileum, radiological tumor response

  8. A first-in-man study to evaluate the safety, tolerability, and pharmacokinetics of pasireotide (SOM230, a multireceptor-targeted somatostatin analog, in healthy volunteers

    Directory of Open Access Journals (Sweden)

    Golor G


    Full Text Available Georg Golor1, Ke Hu2, Matthieu Ruffin3, Alexandra Buchelt3, Emmanuel Bouillaud3, Yanfeng Wang2, Mario Maldonado31Parexel International GmbH, Berlin, Germany; 2Novartis Pharmaceuticals, East Hanover, NJ, USA; 3Novartis Pharma AG, Basel, SwitzerlandAbstract: Pasireotide (SOM230 is a multireceptor-targeted somatostatin analog with high binding affinity for four of the five somatostatin receptor subtypes (sst1,2,3 and sst5, and potential clinical activity in several neuroendocrine and oncologic conditions, including acromegaly, Cushing’s disease, and neuroendocrine tumors (NET. This manuscript reports the first-in-man dose-escalation study of pasireotide, evaluating its safety, tolerability, and pharmacokinetics (PK in healthy male volunteers. A single dose of pasireotide 1–1200 µg was administered subcutaneously in four to eight subjects per dose level, with two additional subjects per cohort administered placebo. PK and safety evaluations were carried out over 7 days post-dose. Growth hormone (GH suppression was evaluated using a GH-releasing hormone stimulation test on Day –1 and Day 1 at 3–5 hours post-injection. Seventy-two subjects completed the study. Pasireotide was well tolerated with no serious adverse events observed at any dose. Transient elevations in blood glucose levels were observed 2–6 hours after administration of pasireotide at doses between 200 µg and 1200 µg, but this resolved without intervention by 23 hours post-dosing. The maximum tolerable dose was not established within the tested range. Pasireotide demonstrated a favorable PK profile with fast absorption (tmax: 0.25–0.5 hours, low clearance (CL/F: 8–13 L/hour, long effective elimination half-life (mean t½,ß: 7–11 hours, and a proportional dose-exposure relationship. GH suppression of 79%–96% was observed at single pasireotide doses between 200 µg and 1200 µg. In conclusion, pasireotide demonstrated favorable safety, tolerability, and PK profiles

  9. Gene transcript analysis blood values correlate with {sup 68}Ga-DOTA-somatostatin analog (SSA) PET/CT imaging in neuroendocrine tumors and can define disease status

    Energy Technology Data Exchange (ETDEWEB)

    Bodei, L. [European Institute of Oncology, Division of Nuclear Medicine, Milan (Italy); Kidd, M.; Modlin, I.M.; Drozdov, I. [Wren Laboratories, Branford, CT (United States); Prasad, V. [Charite University Hospital, Department of Nuclear Medicine, Berlin (Germany); Severi, S.; Paganelli, G. [Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Nuclear Medicine and Radiometabolic Units, Meldola (Italy); Ambrosini, V. [S. Orsola-Malpighi University Hospital, Nuclear Medicine, Bologna (Italy); Kwekkeboom, D.J.; Krenning, E.P. [Erasmus Medical Center Rotterdam, Nuclear Medicine Department, Rotterdam (Netherlands); Baum, R.P. [Zentralklinik Bad Berka, THERANOSTICS Center for Molecular Radiotherapy and Imaging, Bad Berka (Germany)


    Precise determination of neuroendocrine tumor (NET) disease status and response to therapy remains a rate-limiting concern for disease management. This reflects limitations in biomarker specificity and resolution capacity of imaging. In order to evaluate biomarker precision and identify if combinatorial blood molecular markers and imaging could provide added diagnostic value, we assessed the concordance between {sup 68}Ga-somatostatin analog (SSA) positron emission tomography (PET), circulating NET gene transcripts (NETest), chromogranin A (CgA), and Ki-67 in NETs. We utilized two independent patient groups with positive {sup 68}Ga-SSA PET: data set 1 ({sup 68}Ga-SSA PETs undertaken for peptide receptor radionuclide therapy (PRRT), as primary or salvage treatment, n = 27) and data set 2 ({sup 68}Ga-SSA PETs performed in patients referred for initial disease staging or restaging after various therapies, n = 22). We examined the maximum standardized uptake value (SUV{sub max}), circulating gene transcripts, CgA levels, and baseline Ki-67. Regression analyses, generalized linear modeling, and receiver-operating characteristic (ROC) analyses were undertaken to determine the strength of the relationships. SUV{sub max} measured in two centers were mathematically evaluated (regression modeling) and determined to be comparable. Of 49 patients, 47 (96 %) exhibited a positive NETest. Twenty-six (54 %) had elevated CgA (χ{sup 2} = 20.1, p < 2.5 x 10{sup -6}). The majority (78 %) had Ki-67 < 20 %. Gene transcript scores were predictive of imaging with >95 % concordance and significantly correlated with SUV{sub max} (R {sup 2} = 0.31, root-mean-square error = 9.4). The genes MORF4L2 and somatostatin receptors SSTR1, 3, and 5 exhibited the highest correlation with SUV{sub max}. Progressive disease was identified by elevated levels of a quotient of MORF4L2 expression and SUV{sub max} [ROC-derived AUC (R {sup 2} = 0.7, p < 0.05)]. No statistical relationship was identified

  10. Evaluation of somatostatin and nucleolin receptors for therapeutic delivery in non-small cell lung cancer stem cells applying the somatostatin-analog DOTATATE and the nucleolin-targeting aptamer AS1411

    DEFF Research Database (Denmark)

    Holmboe, Sif; Hansen, Pernille Lund; Thisgaard, Helge


    Cancer stem cells represent the putative tumor-driving subpopulation thought to account for drug resistance, relapse, and metastatic spread of epithelial and other cancer types. Accordingly, cell surface markers for therapeutic delivery to cancer stem cells are subject of intense research....... Somatostatin receptor 2 and nucleolin are known to be overexpressed by various cancer types, which have elicited comprehensive efforts to explore their therapeutic utilization. Here, we evaluated somatostatin receptor 2 targeting and nucleolin targeting for therapeutic delivery to cancer stem cells from lung...

  11. Long acting octreotide in the treatment of advanced hepatocellular cancer and overexpression of somatostatin receptors: Randomized placebo-controlled trial

    Institute of Scientific and Technical Information of China (English)

    D Dimitroulopoulos; D Daskalopoulou; E Paraskevas; D Xinopoulos; K Tsamakidis; A Zisimopoulos; E Andriotis; D Panagiotakos; A Fotopoulou; C Chrysohoou; A Bazinis


    AIM: To estimate if and to what extent long acting octreotide (LAR) improves survival and quality of life in patients with advanced hepatocellular carcinoma (HCC).METHODS: A total of 127 cirrhotics, stages A-B, due to chronic viral infections and with advanced HCC, were enrolled in the study. Scintigraphy with 111Indium labeled octreotide was performed in all cases. The patients with increased accumulation of radionuclear compound were randomized to receive either oral placebo only or octreotide/octreotide LAR only as follows: octreotide 0.5mg s.c. Every 8 h for 6 wk, at the end of wk 4-8 octreotide LAR 20 mg I.m. And at the end of wk 12 and every 4 wk octreotide LAR 30mg I.m.. Follow-up was worked out monthly as well as the estimation of quality of life (QLQ-C30 questionnaire). Patients with negative somatostatin receptors (SSTR) detection were followed up in the same manner.RESULTS: Scintigraphy demonstrated SSTR in 61 patients. Thirty were randomized to receive only placebo and 31 only octreotide. A significantly higher survival time was observed for the octreotide group (49±6 wk)as compared to the control group (28±1 wk) and to the SSTR negative group (28±2 wk), LR=20.39, df=2,P<0.01. The octreotide group presented 68.5% lower hazard ratio [95% CI (47.4%-81.2%)]. During the first year, a 22%, 39% and 43% decrease in the QLQ-C30 score was observed in each group respectively.CONCLUSION: The proposed therapeutic approach has shown to improve the survival and quality of life in SSTR positive patients with advanced HCC.

  12. Analogical acts as conceptual strategies in science, engineering and the humanities (United States)

    Winkler, V. M.


    The composing models which operate by means of analogy are identified. The importance of analogical acts in the prewriting stage of the composing process is discussed. The relations between analogical acts and concept formation are explored. A basic correspondence between the analogical thinking employed in successful learning and analogical thinking as a composing strategy is discussed. Teaching analogical acts as conceptual strategies for exploring problems and generating the form and content of discourse is presented in support of the contention that writing is a unique mode of learning.

  13. Somatostatin receptor expression, tumour response, and quality of life in patients with advanced hepatocellular carcinoma treated with long-acting octreotide. (United States)

    Cebon, J; Findlay, M; Hargreaves, C; Stockler, M; Thompson, P; Boyer, M; Roberts, S; Poon, A; Scott, A M; Kalff, V; Garas, G; Dowling, A; Crawford, D; Ring, J; Basser, R; Strickland, A; Macdonald, G; Green, M; Nowak, A; Dickman, B; Dhillon, H; Gebski, V


    Octreotide may extend survival in hepatocellular carcinoma (HCC). Forty-one per cent of HCCs have high-affinity somatostatin receptors. We aimed to determine the feasibility, safety, and activity of long-acting octreotide in advanced HCC; to identify the best method for assessing somatostatin receptor expression; to relate receptor expression to clinical outcomes; and to evaluate toxicity. Sixty-three patients with advanced HCC received intramuscular long-acting octreotide 20 mg monthly until progression or toxicity. Median age was 67 years (range 28-81 years), male 81%, Child-Pugh A 83%, and B 17%. The aetiologies of chronic liver disease were alcohol (22%), viral hepatitis (44%), and haemochromatosis (6%). Prior treatments for HCC included surgery (8%), chemotherapy (2%), local ablation (11%), and chemoembolisation (6%). One patient had an objective partial tumour response (2%, 95% CI 0-9%). Serum alpha-fetoprotein levels decreased more than 50% in four (6%). Median survival was 8 months. Thirty four of 61 patients (56%) had receptor expression detected by scintigraphy; no clear relationship with clinical outcomes was identified. There were few grade 3 or 4 toxicities: hyperglycaemia (8%), hypoglycaemia (2%), diarrhoea (5%), and anorexia (2%). Patients reported improvements in some symptoms, but no major changes in quality of life were detected. Long-acting octreotide is safe in advanced HCC. We found little evidence of anticancer activity. A definitive randomised trial would identify whether patients benefit from this treatment in other ways.

  14. Hepatic Cyst Infection During Use of the Somatostatin Analog Lanreotide in Autosomal Dominant Polycystic Kidney Disease: An Interim Analysis of the Randomized Open-Label Multicenter DIPAK-1 Study. (United States)

    Lantinga, Marten A; D'Agnolo, Hedwig M A; Casteleijn, Niek F; de Fijter, Johan W; Meijer, Esther; Messchendorp, Annemarie L; Peters, Dorien J M; Salih, Mahdi; Spithoven, Edwin M; Soonawala, Darius; Visser, Folkert W; Wetzels, Jack F M; Zietse, Robert; Drenth, Joost P H; Gansevoort, Ron T


    The DIPAK-1 Study investigates the reno- and hepatoprotective efficacy of the somatostatin analog lanreotide compared with standard care in patients with later stage autosomal dominant polycystic kidney disease (ADPKD). During this trial, we witnessed several episodes of hepatic cyst infection, all during lanreotide treatment. We describe these events and provide a review of the literature. The DIPAK-1 Study is an ongoing investigator-driven, randomized, controlled, open-label multicenter trial. Patients (ADPKD, ages 18-60 years, estimated glomerular filtration rate 30-60 mL/min/1.73 m(2)) were randomized 1:1 to receive lanreotide 120 mg subcutaneously every 28 days or standard care during 120 weeks. Hepatic cyst infection was diagnosed by local physicians. We included 309 ADPKD patients of which seven (median age 53 years [interquartile range: 48-55], 71% female, median estimated glomerular filtration rate 42 mL/min/1.73 m(2) [interquartile range: 41-58]) developed eight episodes of hepatic cyst infection during 342 patient-years of lanreotide use (0.23 cases per 10 patient-years). These events were limited to patients receiving lanreotide (p < 0.001 vs. standard care). Baseline characteristics were similar between subjects who did or did not develop a hepatic cyst infection during lanreotide use, except for a history of hepatic cyst infection (29 vs. 0.7%, p < 0.001). Previous studies with somatostatin analogs reported cyst infections, but did not identify a causal relationship. These data suggest an increased risk for hepatic cyst infection during use of somatostatin analogs, especially in ADPKD patients with a history of hepatic cyst infection. The main results are still awaited to fully appreciate the risk-benefit ratio. CLINICALTRIALS. NCT 01616927.

  15. Osilodrostat (LCI699), a potent 11β-hydroxylase inhibitor, administered in combination with the multireceptor-targeted somatostatin analog pasireotide: A 13-week study in rats

    Energy Technology Data Exchange (ETDEWEB)

    Li, Li, E-mail: [Preclinical Safety, Novartis Institutes for BioMedical Research, East Hanover, NJ (United States); Vashisht, Kapil; Boisclair, Julie [Preclinical Safety, Novartis Institutes for BioMedical Research, East Hanover, NJ (United States); Li, Wenkui; Lin, Tsu-han [Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, East Hanover, NJ (United States); Schmid, Herbert A. [Novartis Oncology Development, Basel (Switzerland); Kluwe, William; Schoenfeld, Heidi; Hoffmann, Peter [Preclinical Safety, Novartis Institutes for BioMedical Research, East Hanover, NJ (United States)


    The somatostatin analog pasireotide and the 11β-hydroxylase inhibitor osilodrostat (LCI699) reduce cortisol levels by distinct mechanisms of action. There exists a scientific rationale to investigate the clinical efficacy of these two agents in combination. This manuscript reports the results of a toxicology study in rats, evaluating different doses of osilodrostat and pasireotide alone and in combination. Sixty male and 60 female rats were randomized into single-sex groups to receive daily doses of pasireotide (0.3 mg/kg/day, subcutaneously), osilodrostat (20 mg/kg/day, orally), osilodrostat/pasireotide in combination (low dose, 1.5/0.03 mg/kg/day; mid-dose, 5/0.1 mg/kg/day; or high dose, 20/0.3 mg/kg/day), or vehicle for 13 weeks. Mean body-weight gains from baseline to Week 13 were significantly lower in the pasireotide-alone and combined-treatment groups compared to controls, and were significantly higher in female rats receiving osilodrostat monotherapy. Osilodrostat and pasireotide monotherapies were associated with significant changes in the histology and mean weights of the pituitary and adrenal glands, liver, and ovary/oviduct. Osilodrostat alone was associated with adrenocortical hypertrophy and hepatocellular hypertrophy. In combination, osilodrostat/pasireotide did not exacerbate any target organ changes and ameliorated the liver and adrenal gland changes observed with monotherapy. C{sub max} and AUC{sub 0–24h} of osilodrostat and pasireotide increased in an approximately dose-proportional manner. In conclusion, the pasireotide and osilodrostat combination did not exacerbate changes in target organ weight or toxicity compared with either monotherapy, and had an acceptable safety profile; addition of pasireotide to the osilodrostat regimen may attenuate potential adrenal gland hyperactivation and hepatocellular hypertrophy, which are potential side effects of osilodrostat monotherapy. - Highlights: • We examined the target organ toxicity of SOM230

  16. Internalization of the radioiodinated somatostatin analog [125I-Tyr3]octreotide by mouse and human pituitary tumor cells: increase by unlabeled octreotide

    NARCIS (Netherlands)

    L.J. Hofland (Leo); P.M. van Koetsveld (Peter); M. Waaijers (Marlijn); J. Zuyderwijk; W.A.P. Breeman (Wouter); S.W.J. Lamberts (Steven)


    textabstractRecently, we developed a technique that allows the in vivo visualization in man of somatostatin receptor-positive neuroendocrine tumors after i.v. injection of [125I-Tyr3]octreotide or [111In-DTPA-D-Phe1]octreotide. Radiotherapy of such tumors using somatost

  17. Polyunsaturated fatty acid analogs act antiarrhythmically on the cardiac IKs channel

    DEFF Research Database (Denmark)

    Liin, Sara I.; Silverå Ejneby, Malin; Barro-Soria, Rene;


    charge at neutral pH, restore the sensitivity to open IKs channels. PUFA analogs with a positively charged head group inhibit IKs channels. These different PUFA analogs could be developed into drugs to treat cardiac arrhythmias. In support of this possibility, we show that PUFA analogs act...

  18. Use of Long-Acting Somatostatin Analogue (Lanreotide) in an Adolescent with Diazoxide-Responsive Congenital Hyperinsulinism and Its Psychological Impact. (United States)

    Shah, Pratik; Rahman, Sofia A; McElroy, Sharon; Gilbert, Clare; Morgan, Kate; Hinchey, Louise; Senniappan, Senthil; Levy, Hannah; Amin, Rakesh; Hussain, Khalid


    Congenital hyperinsulinism (CHI) is a common cause of hypoglycaemia due to unregulated insulin secretion from pancreatic β cells. Medical management includes use of oral diazoxide (a KATP channel agonist) and daily injectable octreotide (somatostatin analogue) therapy. However, diazoxide is associated with severe sideeffects such as coarse facies, hypertrichosis and psychosocial/compliance issues in adolescents. Lanreotide (a long-acting somatostatin analogue) is used in adults with neuroendocrine tumours; however, its role in patients with CHI has not been well described. A 15-year-old girl with diazoxide-responsive CHI had severe hypertrichosis secondary to diazoxide and subsequent compliance/psychosocial issues. She was commenced on 30 mg of lanreotide every 4 weeks as a deep subcutaneous injection, in an attempt to address these issues. She was able to come off diazoxide treatment 2 months after starting lanreotide. Presently, after 2.5 years of lanreotide treatment, her blood glucose control is stable with complete resolution of hypertrichosis. Clinically significant improvements in the self-reported Paediatric Quality of Life (PedsQL) questionnaire and Strengths and Difficulties Questionnaire (SDQ) were reported after 1 year on lanreotide. No side effects were found, and her liver/thyroid function and abdominal ultrasound have been normal. We report the first case on the use of lanreotide in an adolescent girl with diazoxide-responsive CHI with significant improvement of quality of life. © 2015 S. Karger AG, Basel.

  19. The future of somatostatin analogue therapy. (United States)

    Stewart, P M; James, R A


    Since its discovery almost 30 years ago, the mode of action and therapeutic applications of somatostatin have been defined. In particular the cloning and characterization of somatostatin receptor subtypes has facilitated the development of high affinity analogues. In the context of pituitary disease, long-acting somatostatin analogues (octreotide, lanreotide) have been used to treat a variety of pituitary tumours but are most efficacious for the treatment of GH and TSH-secreting adenomas. In patients with acromegaly, depot preparations of these analogues are administered intramuscularly every 10-28 days and provide consistent suppression of GH levels to < 5 mU/l in approximately 50-65% of all cases. Even more specific somatostatin receptor analogues are under development. Finally, radiolabelled somatostatin analogue scintigraphy and, in larger doses, therapy, are now established tools in the evaluation and treatment of neuroendocrine tumours.

  20. 生长抑素类似物治疗Graves眼病有效性的Meta分析%Effectiveness of Somatostatin Analogs versus Placebo for Graves' Ophthalmopathy:A Meta-Analysis

    Institute of Scientific and Technical Information of China (English)

    石少敏; 贺冶冰


    Objective To systematically evaluate the effectiveness of somatostatin analogs versus placebo for Graves' ophthalmopathy (GO). Methods Such databases as PubMed, EMbase, The Cochrane Library, WanFang Data, CNKI, VIP and CBM were searched to collect the randomized controlled trails (RCTs) about somatostatin analogs for Graves' Ophthalmopathy (GO) pulished by March 2012, while the bibliographies of the included literatue were also retrieved. According to the inclusion criteria, two reviewers screened literature, extracted data and assessed the quality of the included studies. Then meta-analysis was conducted using RevMan 5.0 software. Results A total of 5 RCTs involving 210 patients were included. The results of meta-analysis showed that somatostatin analogs could reduce the clinical activity score (CAS) of GO patients (MD=0.58, 95%CI 0.02 to 1.13, P=0.04), but the effects in reducing the degree of proptosis (mm) was still unverifiable (MD=0.21, 95%CI -0.14 to 0.56, P=0.24). It did not show obvious effects for diplopia, orbital volume, intraocular pressure, visual acuity or the restriction of eye movements. The existing evidence could not confirm that somatostatin analogs were effective for GO (OR=1.32, 95%CI 0.45 to 3.9, P=0.61). Conclusion Somatostatin analogs can reduce the CAS of GO patients, but without significantly clinical significance. Moreover, the effect of reducing proptosis is sitll unverifiable. So the existing evidence cannot confirm that somatostatin analogs are effective for GO. For the quality and quantity limitation of the included studies, this conclusion needs to be proved by performing more high quality RCTs.%目的 系统评价生长抑素类似物治疗Graves眼病(GO)的有效性.方法 计算机检索PubMed、EMbase、The Cochrane Library、WanFang Data、CNKI、VIP和CBM中关于生长抑素类似物治疗Graves眼病的随机对照试验(RCT),检索时间截至2012年3月,并追溯纳入文献的参考文献.由2位研究者按照纳入标

  1. Somatostatin and Somatostatin-Containing Neurons in Shaping Neuronal Activity and Plasticity. (United States)

    Liguz-Lecznar, Monika; Urban-Ciecko, Joanna; Kossut, Malgorzata


    Since its discovery over four decades ago, somatostatin (SOM) receives growing scientific and clinical interest. Being localized in the nervous system in a subset of interneurons somatostatin acts as a neurotransmitter or neuromodulator and its role in the fine-tuning of neuronal activity and involvement in synaptic plasticity and memory formation are widely recognized in the recent literature. Combining transgenic animals with electrophysiological, anatomical and molecular methods allowed to characterize several subpopulations of somatostatin-containing interneurons possessing specific anatomical and physiological features engaged in controlling the output of cortical excitatory neurons. Special characteristic and connectivity of somatostatin-containing neurons set them up as significant players in shaping activity and plasticity of the nervous system. However, somatostatin is not just a marker of particular interneuronal subpopulation. Somatostatin itself acts pre- and postsynaptically, modulating excitability and neuronal responses. In the present review, we combine the knowledge regarding somatostatin and somatostatin-containing interneurons, trying to incorporate it into the current view concerning the role of the somatostatinergic system in cortical plasticity.

  2. Pharmacokinetic and pharmacodynamic properties of a long-acting formulation of the new somatostatin analogue, lanreotide, in normal healthy volunteers. (United States)

    Kuhn, J M; Legrand, A; Ruiz, J M; Obach, R; De Ronzan, J; Thomas, F


    1. The aims of the study were to assess the pharmacokinetic parameters and the hormonal effects of the slow-release formulation of the somatostatin analogue (SR-L) in normal male volunteers. 2. Eight healthy males were studied. For the determination of basal values blood was sampled before the injection of vehicle and then every other hour for 8 h in order to measure plasma GH, prolactin (PRL), TSH, free thyroxin (fT4), insulin and glucagon levels. Plasma insulin-like growth factor 1 (IGF-1) levels were measured on a single sample. On day 1 of the study, 30 mg SR-L was administered intramuscularly. Blood was drawn just before injection and then every other hour for a period of 8 h. Thereafter, blood was sampled three times a week for 3 weeks in order to measure lanreotide, IGF-1, TSH, fT4 and PRL concentrations. Plasma GH was determined on days 6 and 11 of the study. 3. Plasma lanreotide concentrations rose to 38.3 +/- 4.1 ng ml-1 2 h following injection. The levels then progressively decreased, remaining above 1.5 ng ml-1 until day 11 and reaching 0.92 +/- 0.28 ng ml-1 2 weeks after injection. The apparent plasma half-life and mean residence time were 4.52 +/- 0.50 and 5.48 +/- 0.51 days respectively. 4. By comparison with the control day, plasma insulin concentrations only decreased 2 h following injection, whereas plasma glucagon did not change at any time. 5. Plasma TSH concentrations were significantly (P < 0.01) reduced from 2 h to day 4 following SR-L injection.2+ ' PMID:7826822

  3. The treatment of neuroendocrine tumors with long-acting somatostatin analogs: a single center experience with lanreotide autogel. (United States)

    Bianchi, A; De Marinis, L; Fusco, A; Lugli, F; Tartaglione, L; Milardi, D; Mormando, M; Lassandro, A P; Paragliola, R; Rota, C A; Della Casa, S; Corsello, S M; Brizi, M G; Pontecorvi, A


    The aim of this retrospective study was to evaluate the efficacy, safety, and tolerability of lanreotide autogel given to metastatic well-differentiated (WD) neuroendocrine tumors (NET) patients observed in our Institute between 2005 and 2008. Patients with metastatic NET referred to our tertiary referral center were given lanreotide autogel 120 mg/month by deep sc injection for a period of at least 24 months. The efficacy was evaluated by the relief of disease symptoms, behavior of tumor markers and response rate in terms of time to tumor progression. Safety and tolerability were evaluated by assessing the onset of adverse events and treatment feasibility. Twenty-three patients (13 males), median age 62 yr (range 32-87) were considered for the study. All patients were affected by WD metastatic NET and had tumor progression in the last 6 months before the enrolment in the study. Median duration of response was 28 months (range 6-50 months). Fourteen patients (60.9%) showed flushing and diarrhea which improved by 85.7% and 55.6%, respectively, bronchoconstrinction and abdominal pain also ameliorated. A complete, partial or no-changed response in the tumor markers behavior was observed, respectively, in 42.9%, 22.9%, and 17.1% of cases. According to RECIST (Response Evaluation Criteria In Solid Tumors) criteria (version 1.1), there were 2 partial regression (8.7%) and 15 stable disease (65.3%); 6 patients (26.0%) progressed. No patient complained from any severe adverse reaction. The results of our study suggest that lanreotide autogel is effective in the symptoms, biochemical markers, and tumor progression control of WD metastatic NET and confirm that the treatment is well tolerated.

  4. Pasiretide, a new kind of somatostatin analogs for treating Cushing disease%治疗库欣病的新生长抑素类似物帕瑞肽

    Institute of Scientific and Technical Information of China (English)

    张大明; 李乃适


    帕瑞肽是一种能与多受体结合的生长抑素类似物,与生长抑素受体sst1-3和sst5有高结合力.帕瑞肽能抑制GH,IGF-I和ACTH的分泌,提示其可能用于肢端肥大症与库欣病的治疗;而其在细胞试验中抑制神经内分泌肿瘤细胞增殖、在动物实验中显示能延长抑制激素分泌的时间以及类癌表达多个sst显示帕瑞肽在治疗类癌方面可能优于奥曲肽.目前帕瑞肽在肢端肥大症、类癌的Ⅱ期临床试验已经结束,有关库欣病方面Ⅲ期临床试验也已完成,3项试验证实其对于肢端肥大症、类癌是一种新的治疗手段,并成为治疗库欣病的新方法.%Pasireotide is a kind of somatostatin analogs which can bind with multiple receptors and especially has a high affinity with the somatostatin receptors sst,, sst2, sst3 and sst5. It inhibits release of GH, IGF-I and ACTH, suggesting a potency for the treatment of acromegaly and Cushing disease. Pasireotide inhibits proliferation of neuroendocrine tumor cells, prolongs the inhibition duration of the hormone secretion and carcinoid expressing multiple somatostatin receptors, which may have advantage in carcinoid treatment. Currently, the phrase IJ clinical trails of pasireotide in acromegaly and carcinoid have been completed, and the phrase III in Cushing disease has been accomplished too, all of which suggest that pasireotide holds the promise as a new treatment for acromegaly and carcinoid, and the first medicine for Cushing disease.

  5. Effect of a long-acting somatostatin analogue (SMS 201-995 on a growth hormone and thyroid stimulating hormone-producing pituitary tumor.

    Directory of Open Access Journals (Sweden)



    Full Text Available A 46-year-old woman with acromegaly and hyperthyroidism due to a pituitary adenoma. She had high serum thyroid-stimulating hormone (TSH levels and very high serum growth hormone (GH levels. Transsphenoidal removal of the tumor, post-operative irradiation, frontal craniotomy for removal of residual tumor and large-dose bromocriptine therapy were carried out consecutively. After therapy, serum GH levels gradually decreased, but not to the normal range, and serum TSH levels remained at inappropriately normal levels. Using immunoperoxidase techniques, GH-, TSH- and follicle-stimulating hormone (FSH-containing cells were demonstrated in the adenoma. A long-acting somatostatin analogue (SMS 201-995, 600 micrograms/day suppressed the serum GH level to the normal range with a concomitant suppression of TSH. Furthermore, the paradoxical serum GH responses to TRH and LH-RH were slightly improved. No important subjective side-effects were noted. Therefore, SMS 201-995 appeared to be a very effective drug in this patient with a GH- and TSH-producing pituitary tumor.

  6. Somatostatin and dopamine receptor regulation of pituitary somatotroph adenomas. (United States)

    Ben-Shlomo, Anat; Liu, Ning-Ai; Melmed, Shlomo


    Somatostatin and dopamine receptors are expressed in normal and tumoral somatotroph cells. Upon receptor stimulation, somatostatin and the somatostatin receptor ligands octreotide, lanreotide, and pasireotide, and to a lesser extent, dopamine and the dopamine analogs bromocriptine and cabergoline, suppress growth hormone (GH) secretion from a GH-secreting pituitary somatotroph adenoma. Somatostatin and dopamine receptors are Gαi-protein coupled that inhibit adenylate cyclase activity and cAMP production and reduce intracellular calcium concentration and calcium flux oscillations. Although their main action on somatotroph cells is acute inhibition of GH secretion, they also may inhibit GH production and possibly somatotroph proliferation. These receptors have been reported to create complexes that exhibit functions distinct from that of receptor monomers. Somatostatin suppression of GH is mediated mainly by somatostatin receptor subtype 2 and to a lesser extent by SST5. Human somatostatin receptor subtype 5 has also been shown to harbor mutations associated with GH levels, somatotroph tumor behavior, and somatostatin receptor ligand (SRL) responsiveness. Reviewing current knowledge of somatostatin and dopamine receptor expression and signaling in normal and tumoral somatotroph cells offers insights into mechanisms underlying SRL and dopamine agonist effectiveness in patients with acromegaly.

  7. 'Reverse discordance' between 68Ga-DOTA-NOC PET/CT and 177Lu-DOTA-TATE posttherapy scan: the plausible explanations and its implications for high-dose therapy with radiolabeled somatostatin receptor analogs. (United States)

    Basu, Sandip; Abhyankar, Amit; Kand, Purushottam; Kumar, Rakesh; Asopa, Ramesh; Rajan, Mysore Govinda Ramakrishna; Nayak, Uday; Shimpi, Hemant; Das, Tapas; Venkatesh, Meera; Chakrabarty, Sudipta; Banerjee, Sharmila


    In this technical note, an unusual discordance between diagnostic and posttherapeutic scan resulting from the use of different somatostatin receptor ligands in two settings is described. Such observation, we believe, is multifactorial, but most importantly arises due to different receptor affinity profile of the ligands and different somatostatin receptor subtype expression in different tumors. It is important for the treating physician to be aware of this phenomenon that would aid in improving our understanding of complex ligand-receptor interactions in various somatostatin receptor-positive tumors with its possible implications for therapeutic decision making with radiolabeled somatostatin receptor analogues.

  8. Somatostatin receptor scintigraphy using (99m)Tc-EDDA/HYNIC-TOC in patients with medullary thyroid carcinoma

    NARCIS (Netherlands)

    Czepczynski, Rafal; Parisella, Maria Gemma; Kosowicz, Jerzy; Mikolajczak, Renata; Ziemnicka, Katarzyna; Gryczynska, Maria; Sowinski, Jerzy; Signore, Alberto


    Purpose Several new somatostatin analogues have been developed for the diagnosis and therapy of different tumours. Since somatostatin receptors are often over-expressed in medullary thyroid carcinoma (MTC), the aim of our study was to evaluate the utility of scintigraphy with the somatostatin analog

  9. Somatostatin, somatostatin receptors, and pancreatic cancer. (United States)

    Li, Min; Fisher, William E; Kim, Hee Joon; Wang, Xiaoping; Brunicardi, Charles F; Chen, Changyi; Yao, Qizhi


    Somatostatin may play an important role in the regulation of cancer growth including pancreatic cancer by interaction with somatostatin receptors (SSTRs) on the cell surface. Five SSTRs were cloned, and the function of these SSTRs is addressed in this review. SSTR-2, SSTR-5, and SSTR-1 are thought to play major roles in inhibiting pancreatic cancer growth both in vitro and in vivo. SSTR-3 may be involved in mediating apoptosis, but the role of SSTR-4 is not clear. In most pancreatic cancers, functional SSTRs are absent. Reintroduction of SSTR genes has been shown to inhibit pancreatic cancer growth in cell cultures and animal models.

  10. Evolutionary history of the somatostatin and somatostatin receptors

    Indian Academy of Sciences (India)

    Muhammad Moaeen-Ud-Din; Li Guo Yang


    Somatostatin and its receptors have a critical role in mammalian growth through their control pattern of secretion of growth hormone, but the evolutionary history of somatostatin and somatostatin receptors are ill defined. We used comparative whole genome analysis of Danio rerio, Carassius auratus, Xenopus tropicalis, Gallus gallus, Monodelphis domestica, Homo sapiens, Sus scrofa, Bos taurus, Mus musculus, Rattus norvegicus, Canis lupus familiaris, Ovis aries, Equus caballus, Pan troglodytes and Macaca mulatto to identify somatostatin and somatostatin receptors in each species. To date, we have identified a minimum of two genes of somatostatin and five somatostatin receptor genes in mammalian species with variable forms. We established a clear evolutionary history of the somatostatin system and traced the origin of the somatostatin system to 395 million years ago (MYA), identifying critical steps in their evolution.

  11. Somatostatin receptor skintigrafi

    DEFF Research Database (Denmark)

    Rasmussen, Karin; Nielsen, Jørn Theil; Rehling, Michael


    Somatostatin receptor scintigraphy (SRS) is a very valuable imaging technique for visualisation of a diversity of neuroendocrine tumours. The sensitivity for localisation of carcinoid tumours is high, but somewhat lower for other neuroendocrine tumours. The methodology, multiple clinical aspects...

  12. Somatostatin: a metabolic regulator

    Energy Technology Data Exchange (ETDEWEB)

    Dileepan, K.N.; Wagle, S.R.


    Somatostatin, the hypothalamic release-inhibiting factor, has been found to stimulate gluconeogenesis in rat kidney cortical slices. Stimulation by somatostatin was linear and dose-dependent. Other bioactive peptides such as cholecystokinin, gastro-intestinal peptide, secretin, neurotensin, vasoactive intestinal peptide, pancreatic polypeptide, beta endorphin and substance P did not affect the renal gluconeogenic activity. Somatostatin-induced gluconeogenesis was blocked by phentolamine (alpha adrenergic antagonist) and prazosin (alpha/sub 1/ adrenergic antagonist) but not by propranolol (beta adrenergic antagonist) and yohimbine (alpha/sub 2/ adrenergic antagonist) suggesting that the effect is via alpha/sub 1/ adrenergic stimuli. Studies on the involvement of Ca/sup 2 +/ revealed that tissue depletion and omission of Ca/sup 2 +/ from the reaction mixture would abolish the stimulatory effect of somatostatin. Furthermore, somatostatin enhanced the uptake of /sup 45/calcium in renal cortical slices which could be blocked by lanthanum, an inhibitor of Ca/sup 2 +/ influx. It is proposed that the stimulatory effect of somatostatin on renal gluconeogenesis is mediated by alpha/sub 1/ adrenergic receptors, or those which functionally resemble the alpha/sub 1/ receptors and that the increased influx of Ca/sup 2 +/ may be the causative factor for carrying out the stimulus. 88 references.

  13. Electrochemical separation of 90-yttrium in the electrochemical 90Sr/90Y generator and its use for radiolabelling of DOTA-conjugated somatostatin analog [DOTA0, Tyr3] octreotate

    Directory of Open Access Journals (Sweden)

    Petrović Đorđe Ž.


    Full Text Available Radiopharmaceuticals based on 90Y are widely used in the treatment of malignant deseases. In order to meet the requirements for their future application, a 90Sr/90Y generator was developed and 90Y eluted from this locally produced generator was used for the radiolabelling of the DOTA-conjugated somatostatin analog [DOTA0,Tyr3] octreotate and the preparation of [90Y-DOTA0,Tyr3] octreotate (90Y-DOTATATE for peptide receptore radionuclide therapy. 90Sr/90Y generator was based on the electrochemical separation of 90Y from 90Sr in a two-cycle electrolysis procedure. Three electrode cells were used to perform both electrolyses. In both cycles, working electrodes were kept on constant potential. The pH of the solution was adjusted to 2.7 of the value before the electrolyses. The radionuclidic purity of the 90Y solution was analysed by ITLC and extraction paper chromatography. The labelling of peptide (100 mg DOTATATE with 90YCl3 was performed at 95°C for 30 minutes. Radiochemical purity was determined by HPLC and chromatographic separation, using a solid SepPak C-18 column. Results obtained confirmed the efficiency of our electrochemical separation technique and quality control methods for 90Y. The achieved efficiency of the 90Sr/90Y generator above 96% of the theoretical value represents a good basis for the further development of this generator. The labelling of the DOTATATE with 90Y exhibited a high efficiency, too: there was less than 1% of 90Y3+in the 90Y-DOTATATE.

  14. Low frequency of cardniac arrhythmias and lack of structural heart disease in medically-naïve acromegaly patients: a prospective study at baseline and after 1 year of somatostatin analogs treatment. (United States)

    Warszawski, Leila; Kasuki, Leandro; Sá, Rodrigo; Dos Santos Silva, Cintia Marques; Volschan, Isabela; Gottlieb, Ilan; Pedrosa, Roberto Coury; Gadelha, Mônica R


    The incidence of arrhythmias may be increased in acromegaly, but the pathophysiologic mechanisms involved are still unclear, and it has never been correlated with structural heart changes analyzed by the gold-standard method cardiac magnetic resonance (CMR). Evaluate the frequency of arrhythmias in drug-naïve acromegaly patients at baseline and after 1 year of somatostatin analogs (SA) treatment and to correlate the occurrence of arrhythmias with the presence of structural heart changes. Consecutive drug-naïve acromegaly patients were recruited. The occurrence of arrhythmias and structural heart changes were studied through 24-h Holter and CMR, respectively, at baseline and after 1-year SA treatment. Thirty-six patients were studied at baseline and 28 were re-evaluated after 1 year of SA treatment. There were 13 females and median age was 48 years (20-73 years). Nine patients (32 %) were controlled after treatment. No sustained arrhythmias were reported in the 24-h Holter. No arrhythmia-related symptoms were observed. Only two patients presented left ventricular hypertrophy and three patients presented fibrosis at baseline. There was no correlation of the left ventricular mass with the number of episodes of arrhythmias and they were not more prevalent in the patients presenting cardiac fibrosis. We found no sustained arrhythmias and a lack of arrhythmia-related symptoms at baseline and after 1 year of SA treatment in a contemporary cohort of acromegaly patients that also present a low frequency of structural heart changes, indicating that these patients may have a lower frequency of heart disease than previously reported.

  15. Validation of somatostatin receptor scintigraphy in the localization of neuroendocrine tumors

    Energy Technology Data Exchange (ETDEWEB)

    Lamberts, S.W.J. (Depts. of Medicine and Nuclear Medicine, Erasmus Univ., Rotterdam (Netherlands) Div. of Cell Biology and Experimental Cancer Research, Institution of Pathology, Bern Univ. (Switzerland)); Reubi, J.C. (Depts. of Medicine and Nuclear Medicine, Erasmus Univ., Rotterdam (Netherlands) Div. of Cell Biology and Experimental Cancer Research, Institution of Pathology, Bern Univ. (Switzerland)); Krenning, E.P. (Depts. of Medicine and Nuclear Medicine, Erasmus Univ., Rotterdam (Netherlands) Div. of Cell Biology and Experimental Cancer Research, Institution of Pathology, Bern Univ. (Switzerland))


    Somatostatin analogs are used in the control of hormonal hypersecretion and tumor growth of patients with acromegaly, islet cell carcinomas and carcinoids. Recently we showed that somatostatin receptor positive tumors can be visualized in vivo after the administration of radionuclide-labeled somatostatin analogs. Receptor imaging was positive in 18/21 islet cell tumors, 32/37 carcinoids, 26/28 paragangliomas, 9/14 medullary thyroid carcinomas, and 5/7 small cell lung cancers. Somatostatin receptor imaging is an easy, harmless and painless diagnostic method. It localizes multiple and/or metastatic tumors, predicts the successful control of hormonal hypersecretion by octreotide and seems to be of prognostic value in certain types of cancer. This scintigraphic method might help in patient selection for clinical trials with somatostatin analogs in the treatment of neuroendocrine cancers. (orig.).

  16. Long-acting GLP-1 analogs for the treatment of type 2 diabetes mellitus

    DEFF Research Database (Denmark)

    Vilsbøll, Tina; Knop, Filip K


    Type 2 diabetes mellitus is characterized by insulin resistance, impaired glucose-induced insulin secretion, and inappropriately elevated glucagon levels which eventually result in hyperglycemia. The currently available treatment modalities for type 2 diabetes are often unsatisfactory in getting...... for the treatment of type 2 diabetes has become available in the US (since October 2005) and in Europe (since May 2007): the incretin-based therapies. The incretin-based therapies fall into two different classes: (i) incretin mimetics, i.e. injectable peptide preparations with actions similar to the natural...... for the development of glucagon-like peptide-1 (GLP-1) analogs, reviews clinical experience gained so far, and discusses future expectations for long-acting forms of GLP-1 analogs....

  17. Comparative Pharmacokinetics and Insulin Action for Three Rapid-Acting Insulin Analogs Injected Subcutaneously With and Without Hyaluronidase


    Morrow, Linda; Muchmore, Douglas B.; Hompesch, Marcus; Ludington, Elizabeth A.; Vaughn, Daniel E.


    OBJECTIVE To compare the pharmacokinetics and glucodynamics of three rapid-acting insulin analogs (aspart, glulisine, and lispro) injected subcutaneously with or without recombinant human hyaluronidase (rHuPH20). RESEARCH DESIGN AND METHODS This double-blind six-way crossover euglycemic glucose clamp study was conducted in 14 healthy volunteers. Each analog was injected subcutaneously (0.15 units/kg) with or without rHuPH20. RESULTS The commercial formulations had comparable insulin time-expo...

  18. Effect of subcutaneous injection of a long-acting analogue of somatostatin (SMS 201-995) on plasma thyroid-stimulating hormone in normal human subjects

    Energy Technology Data Exchange (ETDEWEB)

    Itoh, S.; Tanaka, K.; Kumagae, M.; Takeda, F.; Morio, K.; Kogure, M.; Hasegawa, M.; Horiuchi, T.; Watabe, T.; Miyabe, S.


    SMS 201-995 (SMS), a synthetic analogue of somatostatin (SRIF) has been shown to be effective in the treatment of the hypersecretion of hormones such as in acromegaly. However, little is known about the effects of SMS on the secretion of thyroid-stimulating hormone (TSH) in normal subjects. In this study, plasma TSH was determined with a highly sensitive immunoradiometric assay, in addition to the concentration of SMS in plasma and urine with a radioimmunoassay, following subcutaneous injection of 25, 50, 100 of SMS or a placebo to normal male subjects, at 0900 h after an overnight fast. The plasma concentrations of SMS were dose-responsive and the peak levels were 1.61 +/- 0.09, 4.91 +/- 0.30 and 8.52 +/- 1.18 ng/ml, which were observed at 30, 15 and 45 min after the injection of 25, 50, and 100 of SMS, respectively. Mean plasma disappearance half-time of SMS was estimated to be 110 +/- 3 min. Plasma TSH was suppressed in a dose dependent manner and the suppression lasted for at least 8 hours. At 8 hours after the injection of 25, 50, and 100 of SMS, the plasma TSH levels were 43.8 +/- 19.4, 33.9 +/- 9.4 and 24.9 +/- 3.2%, respectively, of the basal values.

  19. Geniposide and its iridoid analogs exhibit antinociception by acting at the spinal GLP-1 receptors. (United States)

    Gong, Nian; Fan, Hui; Ma, Ai-Niu; Xiao, Qi; Wang, Yong-Xiang


    We recently discovered that the activation of the spinal glucagon-like peptide-1 receptors (GLP-1Rs) by the peptidic agonist exenatide produced antinociception in chronic pain. We suggested that the spinal GLP-1Rs are a potential target molecule for the management of chronic pain. This study evaluated the antinociceptive activities of geniposide, a presumed small molecule GLP-1R agonist. Geniposide produced concentration-dependent, complete protection against hydrogen peroxide-induced oxidative damage in PC12 and HEK293 cells expressing rat and human GLP-1Rs, but not in HEK293T cells that do not express GLP-1Rs. The orthosteric GLP-1R antagonist exendin(9-39) right-shifted the concentration-response curve of geniposide without changing the maximal protection, with identical pA2 values in both cell lines. Subcutaneous and oral geniposide dose-dependently blocked the formalin-induced tonic response but not the acute flinching response. Subcutaneous and oral geniposide had maximum inhibition of 72% and 68%, and ED50s of 13.1 and 52.7 mg/kg, respectively. Seven days of multidaily subcutaneous geniposide and exenatide injections did not induce antinociceptive tolerance. Intrathecal geniposide induced dose-dependent antinociception, which was completely prevented by spinal exendin(9-39), siRNA/GLP-1R and cyclic AMP/PKA pathway inhibitors. The geniposide iridoid analogs geniposidic acid, genipin methyl ether, 1,10-anhydrogenipin, loganin and catalpol effectively inhibited hydrogen peroxide-induced oxidative damage and formalin pain in an exendin(9-39)-reversible manner. Our results suggest that geniposide and its iridoid analogs produce antinociception during persistent pain by activating the spinal GLP-1Rs and that the iridoids represented by geniposide are orthosteric agonists of GLP-1Rs that function similarly in humans and rats and presumably act at the same binding site as exendin(9-39).

  20. Combined treatment of somatostatin analogues with pegvisomant in acromegaly

    NARCIS (Netherlands)

    S.E. Franck (Sanne); A. Muhammad (Ammar); A-J. van der Lely (Aart-Jan); S.J.C.M.M. Neggers (Bas)


    textabstractTreatment of acromegaly with monotherapy long-acting somatostatin analogues (LA-SSA) as primary treatment or after neurosurgery can only achieve complete normalization of insulin-like growth factor I (IGF-I) in roughly 40 % of patients. Recently, one of the acromegaly consensus groups

  1. Combined treatment of somatostatin analogues with pegvisomant in acromegaly

    NARCIS (Netherlands)

    S.E. Franck; A. Muhammad; A-J. van der Lely (Aart-Jan); S.J.C.M.M. Neggers (Bas)


    textabstractTreatment of acromegaly with monotherapy long-acting somatostatin analogues (LA-SSA) as primary treatment or after neurosurgery can only achieve complete normalization of insulin-like growth factor I (IGF-I) in roughly 40 % of patients. Recently, one of the acromegaly consensus groups ha

  2. Identification of Phosphorylation Sites Regulating sst3 Somatostatin Receptor Trafficking. (United States)

    Lehmann, Andreas; Kliewer, Andrea; Günther, Thomas; Nagel, Falko; Schulz, Stefan


    The human somatostatin receptor 3 (sst3) is expressed in about 50% of all neuroendocrine tumors and hence a promising target for multireceptor somatostatin analogs. The sst3 receptor is unique among ssts in that it exhibits a very long intracellular C-terminal tail containing a huge number of potential phosphate acceptor sites. Consequently, our knowledge about the functional role of the C-terminal tail in sst3 receptor regulation is very limited. Here, we have generated a series of phosphorylation-deficient mutants that enabled us to determine crucial sites for its agonist-induced β-arrestin mobilization, internalization, and down-regulation. Based on this information, we generated phosphosite-specific antibodies for C-terminal Ser(337)/Thr(341), Thr(348), and Ser(361) that enabled us to investigate the temporal patterns of sst3 phosphorylation and dephosphorylation. We found that the endogenous ligand somatostatin induced a rapid and robust phosphorylation that was completely blocked by the sst3 antagonist NVP-ACQ090. The stable somatostatin analogs pasireotide and octreotide promoted clearly less phosphorylation compared with somatostatin. We also show that sst3 phosphorylation occurred within seconds to minutes, whereas dephosphorylation of the sst3 receptor occurred at a considerable slower rate. In addition, we also identified G protein-coupled receptor kinases 2 and 3 and protein phosphatase 1α and 1β as key regulators of sst3 phosphorylation and dephosphorylation, respectively. Thus, we here define the C-terminal phosphorylation motif of the human sst3 receptor that regulates its agonist-promoted phosphorylation, β-arrestin recruitment, and internalization of this clinically relevant receptor.

  3. Neuroendocrine tumor targeting: study of novel gallium-labeled somatostatin radiopeptides in a rat pancreatic tumor model. (United States)

    Froidevaux, Sylvie; Eberle, Alex N; Christe, Martine; Sumanovski, Lazar; Heppeler, Axel; Schmitt, Jörg S; Eisenwiener, Klaus; Beglinger, Christoph; Mäcke, Helmut R


    Somatostatin analogs labeled with radionuclides are of considerable interest in the diagnosis and therapy of SSTR-expressing tumors, such as gastroenteropancreatic, small cell lung, breast and frequently nervous system tumors. In view of the favorable physical characteristics of the Ga isotopes (67)Ga and (68)Ga, enabling conventional tumor scintigraphy, PET and possibly internal radiotherapy, we focused on the development of a Ga-labeled somatostatin analog suitable for targeting SSTR-expressing tumors. For this purpose, 3 somatostatin analogs, OC, TOC and TATE were conjugated to the metal chelator DOTA and labeled with the radiometals (111)In, (90)Y and (67)Ga. They were then evaluated for their performance in the AR4-2J pancreatic tumor model by testing SSTR2-binding affinity, internalization/externalization in isolated cells and biodistribution in tumor-bearing nude mice. Surprisingly, we found that, compared to (111)In or (90)Y, labeling with (67)Ga considerably improved the biologic performance of the tested somatostatin analogs with respect to SSTR2 affinity and tissue distribution. (67)Ga-labeled DOTA-somatostatin analogs were rapidly excreted from nontarget tissues, leading to excellent tumor-to-nontarget tissue uptake ratios. Of interest for radiotherapeutic application, [(67)Ga]DOTATOC was strongly internalized by AR4-2J cells. Furthermore, our results suggest a link between the radioligand charge and its kidney retention. The excellent tumor selectivity of Ga-DOTA somatostatin analogs together with the different applications of Ga in nuclear oncology suggests that Ga-DOTA somatostatin analogs will become an important tool in the management of SSTR-positive tumors.

  4. Molecular mechanisms of somatostatin receptor trafficking. (United States)

    Csaba, Zsolt; Peineau, Stéphane; Dournaud, Pascal


    The neuropeptide somatostatin (SRIF) is an important modulator of neurotransmission in the central nervous system and acts as a potent inhibitor of hormone and exocrine secretion. In addition, SRIF regulates cell proliferation in normal and tumorous tissues. The six somatostatin receptor subtypes (sst1, sst2A, sst2B, sst3, sst4, and sst5), which belong to the G protein-coupled receptor (GPCR) family, share a common molecular topology: a hydrophobic core of seven transmembrane-spanning α-helices, three intracellular loops, three extracellular loops, an amino-terminus outside the cell, and a carboxyl-terminus inside the cell. For most of the GPCRs, intracytosolic sequences, and more particularly the C-terminus, are believed to interact with proteins that are mandatory for either exporting neosynthesized receptor, anchoring receptor at the plasma membrane, internalization, recycling, or degradation after ligand binding. Accordingly, most of the SRIF receptors can traffic not only in vitro within different cell types but also in vivo. A picture of the pathways and proteins involved in these processes is beginning to emerge.

  5. Somatostatin-14 and somatostatin-28 levels are light-driven and vary during development in the chicken retina. (United States)

    Dowton, M; Boelen, M K; Morgan, I G


    The relative levels of somatostatin-14 and somatostatin-28 were determined during both perinatal development and variations in lighting conditions in the chicken retina. During perinatal development of the retina, somatostatin-14 predominated in recently hatched chickens, whereas somatostatin-28 predominated in the retinas of older chickens. In mature chickens, the levels of both somatostatin-14 and somatostatin-28 increased during the light and decreased during the dark. Our results suggest that these two forms of somatostatin are released proportionally and in parallel.

  6. Carboxyl-terminal multi-site phosphorylation regulates internalization and desensitization of the human sst2 somatostatin receptor. (United States)

    Lehmann, Andreas; Kliewer, Andrea; Schütz, Dagmar; Nagel, Falko; Stumm, Ralf; Schulz, Stefan


    The somatostatin receptor 2 (sst2) is the pharmacological target of somatostatin analogs that are widely used in the diagnosis and treatment of human neuroendocrine tumors. We have recently shown that the stable somatostatin analogs octreotide and pasireotide (SOM230) stimulate distinct patterns of sst2 receptor phosphorylation and internalization. Like somatostatin, octreotide promotes the phosphorylation of at least six carboxyl-terminal serine and threonine residues namely S341, S343, T353, T354, T356 and T359, which in turn leads to a robust receptor endocytosis. Unlike somatostatin, pasireotide stimulates a selective phosphorylation of S341 and S343 of the human sst2 receptor followed by a partial receptor internalization. Here, we show that exchange of S341 and S343 by alanine is sufficient to block pasireotide-driven internalization, whereas mutation of T353, T354, T356 and T359 to alanine is required to strongly inhibited both octreotide- and somatostatin-induced internalization. Yet, combined mutation of T353, T354, T356 and T359 is not sufficient to prevent somatostatin-driven β-arrestin mobilization and receptor desensitization. Replacement of all fourteen carboxyl-terminal serine and threonine residues by alanine completely abrogates sst2 receptor internalization and β-arrestin mobilization in HEK293 cells. Together, our findings demonstrate for the first time that agonist-selective sst2 receptor internalization is regulated by multi-site phosphorylation of its carboxyl-terminal tail.

  7. Beyond the era of NPH insulin--long-acting insulin analogs: chemistry, comparative pharmacology, and clinical application. (United States)

    Owens, D R; Bolli, G B


    The new rDNA and DNA-derived "basal" insulin analogs, glargine and detemir, represent significant advancement in the treatment of diabetes compared with conventional NPH insulin. This review describes blood glucose homeostasis by insulin in people without diabetes and outlines the physiological application of exogenous insulin in patients with type 1 and type 2 diabetes. The requirements for optimal basal insulin treatment are discussed and the methods used in the evaluation of basal insulins are presented. An essential criterion in the development of an "ideal" basal insulin preparation is that the molecular modifications made to the human insulin molecule do not compromise safety. It is also necessary to obtain a clear understanding of the pharmacokinetic and pharmacodynamic characteristics of the two currently available basal insulin analogs. When comparing glargine and detemir, the different molar concentration ratios of the two insulin formulations should be considered along with the nonspecificity of assay systems used to determine insulin concentrations. However, euglycemic clamp studies in crossover study design provide a good basis for comparing the pharmacodynamic responses. When the latter is analyzed by results of intervention clinical trials, it is concluded that both glargine and detemir are superior to NPH in type 1 and type 2 diabetes. However, there is sufficient evidence to demonstrate that these two long-acting insulin analogs are different in both their pharmacokinetic and pharmacodynamic profiles. These differences should be taken into consideration when the individual analogs are introduced to provide basal insulin supplementation to optimize blood glucose control in patients with type 1 and type 2 diabetes as well. PubMed-Medline was searched for articles relating to pharmacokinetics and pharmacodynamics of glargine and detemir. Articles retrieved were reviewed and selected for inclusion if (1) the euglycemic clamp method was used with a

  8. Self-assembled nanostructures of long-acting GnRH analogs modified at position 7. (United States)

    Zhou, Ning; Gao, Xing; Lv, Yujian; Cheng, Junping; Zhou, Wenxia; Liu, Keliang


    It is well known that GnRH analogs can self-assemble into amyloid fibrils and that the duration of action of GnRH analogs depends on the ability of the amyloid to slowly release active peptides. The aim of this study was to investigate the influence of the amino acid residues at position 7 of GnRH analogues on peptide self-assembly. It was found that the dominant shape of the nanostructure can be changed when the structures of the residues at position 7 differ significantly from that of leucine in Degarelix. When the backbone length was extended (peptide 9), or the side chain of the residue at position 7 was replaced by an aromatic ring (peptide 6), or the rotation of the amide bond was restricted (peptide 8), the nanostructure changed from fibrils to vesicles. The results also indicate that the increasing hydrophilicity had little influence on the nanostructure morphology. In addition, a suitable release rate was found to play a more important role for the duration of the peptide action by maintaining the equilibrium between the drug concentration and the persistent release time, while the nanostructure shape was found to exert little influence on the duration of the peptide action.

  9. Somatostatin in the caudal spinal cord

    DEFF Research Database (Denmark)

    Schrøder, H D


    The distribution of somatostatin in the rat spinal cord was studied immunohistochemically with particular reference to the localization in the caudal centers that innervate the pelvic organs. For detailed studies of the laminar distribution of somatostatin the combination of immunohistochemistry...... was particularly low in the motoneuron neuropil. However, a dense somatostatin network was found in the sixth lumbar segment in relation to the neurons in Onuf's nucleus X complex, the nucleus that innervates the small pelvic muscles including the striated sphincters. It is concluded that somatostatin, besides...

  10. [Olfactory esthesioneuroblastoma: scintigraphic expression of somatostatin receptors]. (United States)

    García Vicente, A; García Del Castillo, E; Soriano Castrejón, A; Alonso Farto, J


    Esthesioneuroblastoma is an uncommon tumor originating in the upper nasal cavity and constitutes 3% of all intranasal neoplasms. Few references exist about the expression of somatostatin receptors in these tumors. Our case demonstrates a good correlation between the somatostatin receptor scintigraphy and magnetic resonance imaging.

  11. Localization of somatostatin receptors at the light and electron microscopical level by using antibodies raised against fusion proteins

    DEFF Research Database (Denmark)

    Helboe, Lone; Møller, Morten


    Somatostatin, antibodies against somatostatin receptors, hypothalamus, Müller cells, fusion protein technique......Somatostatin, antibodies against somatostatin receptors, hypothalamus, Müller cells, fusion protein technique...

  12. Differential expression of somatostatin receptor subtype-related genes and proteins in non-functioning and functioning adrenal cortex adenomas. (United States)

    Pisarek, Hanna; Krupiński, Roman; Kubiak, Robert; Borkowska, Edyta; Pawlikowski, Marek; Winczyk, Katarzyna


    Adrenocortical adenomas display highly variable expressions of somatostatin receptor (SSTR) subtypes, whose expression is mandatory (although not always sufficient) to achieve the positive effects of somatostatin (SST) analog therapy. Immunohistochemistry (IHC) is the main method used to investigate receptor protein expression. The molecular biology method - polymerase chain reaction (PCR) - is also often used to investigate receptor expression. Nevertheless, the expression of receptor mRNA and the respective receptor protein is not always synchronized. The aim of this study was to investigate SSTR expression by IHC in adrenal adenomas, to compare the results to data obtained by real-time PCR and to determine whether hormonally functioning and non-functioning adenomas differ in this respect. Adrenocortical adenomas were removed surgically from 13 females and 2 males. The tissues were obtained from 9 non-functioning and 6 functioning adenomas. The intensity of IHC reaction was scored semiquantitatively by two independent observers. Real-time PCR was performed using pairs of primers in a reaction amplified along a gradient of temperatures. Amplified DNA was measured by monitoring SYBR-Green fluorescence. In non-functioning tumors, compatibility between IHC and PCR results was observed for SSTR 1 and 2 in 62.5% of the samples. Fifty percent of patients demonstrated compatibility for SSTR 4 and 5 and 37.5% for SSTR 3. In hormonally active adenomas, total compatibility of both methods was noted for SSTR 2 (100%). The compatibility obtained for SSTR 5 was 66.6%. We conclude that receptor gene and respective receptor protein expression are not always synchronized. Messenger RNA detection alone is not sufficient to predict the presence of the receptor protein acting as a target for SST and its analogs.

  13. Octreotide scintigraphy localizes somatostatin receptor-positive islet cell carcinomas

    NARCIS (Netherlands)

    W. Becker (W.); J. Marienhagen (J.); R. Scheubel (R.); A. Saptogino (A.); W.H. Bakker (Willem); W.A.P. Breeman (Wouter); F. Wolf (F.)


    textabstractTyr-3-Octreotide is a synthetic derivative of somatostatin and a somatostatin-receptor analogue. The iodine-123-labelled compound localizes somatostatin-receptor-positive tumours. In this paper two patients are reported in whom somatostatin receptors were demonstrated in vitro. In a 60-y

  14. Serial follow-up of presurgical treatment using pasireotide long-acting release with or without octreotide long-acting release for naïve active acromegaly

    Directory of Open Access Journals (Sweden)

    Jan-Shun Chang


    Full Text Available The aim of the present study was to evaluate the serial changes of GH and IGF-1 in seven patients with naïve, active acromegaly following presurgical treatment of the somatostatin analog pasireotide long-acting release (LAR and octreotide LAR. The patients were treated with pasireotide LAR with or without octreotide LAR for two years and underwent transsphenoidal adenomectomy. After treatment with the somatostatin analogs, the surgical cure rate was similar to that in patients who underwent transsphenoidal surgery alone. Diabetes insipidus was not identified in any patients after the operation. Pasireotide LAR was effective on GH as well as IGF-1 suppression and tumor size decreasing when used as the primary therapy. Future large-population studies to investigate the surgical curative rate after presurgical treatment with somatostatin analogs in patients with acromegaly and macroadenomas close to the cavernous sinus are warranted. However, that hyperglycemia developed following pre-surgical treatment with pasireotide should take into consideration.

  15. Dulaglutide, a long-acting GLP-1 analog fused with an Fc antibody fragment for the potential treatment of type 2 diabetes

    DEFF Research Database (Denmark)

    Jimenez-Solem, Espen; Rasmussen, Mette H; Christensen, Mikkel


    Dulaglutide (LY-2189265) is a novel, long-acting glucagon-like peptide 1 (GLP-1) analog being developed by Eli Lilly for the treatment of type 2 diabetes mellitus (T2DM). Dulaglutide consists of GLP-1(7-37) covalently linked to an Fc fragment of human IgG4, thereby protecting the GLP-1 moiety from...... effects on HbA1c and body weight. If dulaglutide possesses similar efficacy to other GLP-1 analogs, the once-weekly treatment will most likely be welcomed by patients with T2DM....

  16. [The effect of somatostatin in dumping syndrome]. (United States)

    Tulassay, Z; Tulassay, T; Szathmári, M; Gohér, A; Tamás, G


    The effect of cyclic somatostatin on early and late dumping syndrome was studied in 12 patients with gastric resection. Each patient underwent two glucose challenges with 75 grams of glucose administered orally. In the control study isotonic sodium chloride was given, while in the other study cyclic somatostatin in a dose of 250 micrograms bolus injection followed by infusion of 80 ng/kg/min for a period of 270 minutes. In the control study all patients showed subjective symptoms of the early dumping syndrome with significant increases in pulse rate, hematocrit, and vasoactive intestinal polypeptide. Ten patients showed asymptomatic hypoglycemia, as a sign of the late dumping syndrome associated with a significant increases of insulin, gastric inhibitory peptide and glucagon levels. During the administration of somatostatin these changes failed to develop. These results indicate that somatostatin alleviates the symptoms of early and late postprandial dumping syndrome.

  17. Resistance to dopamine agonists and somatostatin analogues in pituitary tumors: focus on cytoskeleton involvement

    Directory of Open Access Journals (Sweden)

    Erika ePeverelli


    Full Text Available Pituitary tumors, that origin from excessive proliferation of a specific subtype of pituitary cell, are mostly benign tumors, but may cause significant morbidity in affected patients, including visual and neurologic manifestations from mass-effect, or endocrine syndromes caused by hormone hypersecretion. Dopamine (DA receptor DRD2 and somatostatin (SS receptors (SSTRs represent the main targets of pharmacological treatment of pituitary tumors since they mediate inhibitory effects on both hormone secretion and cell proliferation, and their expression is retained by most of these tumors. Although long acting DA and SS analogs are currently used in the treatment of prolactin (PRL- and growth hormone (GH-secreting pituitary tumors, respectively, clinical practice indicates a great variability in the frequency and entity of favourable responses. The molecular basis of the pharmacological resistance are still poorly understood, and several potential molecular mechanisms have been proposed, including defective expression or genetic alterations of DRD2 and SSTRs, or an impaired signal transduction. Recently, a role for cytoskeleton protein filamin A (FLNA in DRD2 and SSTRs receptors expression and signalling in PRL- and GH- secreting tumors, respectively, has been demonstrated, first revealing a link between FLNA expression and responsiveness of pituitary tumors to pharmacological therapy. This review provides an overview of the known molecular events involved in SS and DA resistance, focusing on the role played by FLNA.

  18. Activation of somatostatin 2 receptors in the brain and the periphery induces opposite changes in circulating ghrelin levels: functional implications

    Directory of Open Access Journals (Sweden)

    Andreas eStengel


    Full Text Available Somatostatin is an important modulator of neurotransmission in the central nervous system and acts as a potent inhibitor of hormone and exocrine secretion and regulator of cell proliferation in the periphery. These pleiotropic actions occur through interaction with five G-protein coupled somatostatin receptor subtypes (sst1-5 that are widely expressed in the brain and peripheral organs. The characterization of somatostatin’s effects can be investigated by pharmacological or genetic approaches using newly developed selective sst agonists and antagonists and mice lacking specific sst subtypes. Recent evidence points towards a divergent action of somatostatin in the brain and in the periphery to regulate circulating levels of ghrelin, an orexigenic hormone produced by the endocrine X/A-like cells in the gastric mucosa. Somatostatin interacts with the sst2 in the brain to induce an increase in basal ghrelin plasma levels and counteracts the visceral stress-related decrease in circulating ghrelin in rats. By contrast, stimulation of peripheral somatostatin-sst2 signaling results in the inhibition of basal ghrelin release and mediates the postoperative decrease in circulating ghrelin in rats. The peripheral sst2-mediated reduction of plasma ghrelin is likely to involve a paracrine action of D-cell derived somatostatin acting on sst2 bearing X/A-like ghrelin cells in the gastric mucosa. The other member of the somatostatin family, named cortistatin, in addition to binding to sst1-5 also directly interacts with the ghrelin receptor and therefore may simultaneously modulate ghrelin release and actions at target sites bearing ghrelin receptors representing a link between the ghrelin and somatostatin systems.

  19. Expression of somatostatin mRNA and peptide in rat hippocampus after cerebral ischemia

    DEFF Research Database (Denmark)

    Bering, Robert; Johansen, Flemming Fryd


    Somatostatin, ischemia, hippocampus, rat, in situ hybridisation, immunocytochemistry, neuropathology......Somatostatin, ischemia, hippocampus, rat, in situ hybridisation, immunocytochemistry, neuropathology...

  20. Immuno-reactive somatostatin in the cerebro-spinal fluid. Immunreaktives Somatostatin im Liquor cerebrospinalis

    Energy Technology Data Exchange (ETDEWEB)

    Kohler, J.


    In the present work the lumbar cerebro-spinal fluid of 178 patients with different neurological affections was examined with the aid of a specific radioimmunoassay for somatostatin. 18 patients without any pathologic neurological findings served as controls. In degenerative diseases of the brain, reduced somatostatin levels in the cerebro-spinal fluid as compared to the controls were measured. In 3 patients with isolated cerebellar atrophy no reduction of the somatostatin content was found; rather the values were highly normal. Huntington-Chorea also is a case apart. In patients with manifest affections, the somatostatin reduction, amounting to 54.6%, was particularly notable as compared to the controls. By contrast, degenerative diseases with predominant medullary and spastic affection are characterized by significantly increased somatostatin levels. Again, in non-spastic patients the values were not significantly different from those of the controls. Patients with inflammations of the brain and meminges as well as with tumors of the nervous system showed somatostatin levels increased by about 60.8% respectively 51.8% as compared to the controls. Epileptic patients normally exhibit a reduced somatostatin level in the cerebro-spinal fluid, but the reduction is not significant. Disseminated encephalomyclitis, whether chromic or acute, is not found to be associated with significant modifications of the somatostatin level in the cerebro-spinal fluid. Strikingly, however, patients in which the disease took a serious or very serious clinical course showed also the lowest somatostatin levels in the cerebro-spinal fluid. In patients exhibiting the roof compression symptom in consequence of a prolapse of the disk, no significant modifications were found. By contrast, in patients with the symptoms of a transverse lesion, significantly increased somatostatin values were measured.

  1. Somatostatin receptor imaging in patients with sarcoidosis

    Energy Technology Data Exchange (ETDEWEB)

    Kwekkeboom, D.J.; Breeman, W.A.P. [Department of Nuclear Medicine, University Hospital Dijkzigt, Rotterdam (Netherlands); Krenning, E.P. [Department of Nuclear Medicine, University Hospital Dijkzigt, Rotterdam (Netherlands)]|[Department of Internal Medicine, University Hospital Dijkzigt, Rotterdam (Netherlands); Kho, G.S. [Department of Pulmonology, University Hospital Dijkzigt, Rotterdam (Netherlands); Van Hagen, P.M. [Department of Internal Medicine, University Hospital Dijkzigt, Rotterdam (Netherlands)]|[Department of Immunology, University Hospital Dijkzigt, Rotterdam (Netherlands)


    Granulomatous diseases can be visualized in vivo after the injection of indium-111-DTPA-octreotide ({sup 111}In-pentetreotide), a radiolabelled somatostatin analogue. We evaluated whether somatostatin receptor imaging reflects disease activity, whether certain scintigraphic characteristics can predict the disease prognosis and whether repeat scintigraphy correlates with the clinical course in patients with sarcoidosis. {sup 111}In-pentetreotide was injected in 46 patients and images were obtained 24 h later. Known mediastinal, hilar and interstitial disease was recognized in 36 of 37 patients. Also, such pathology was found in seven other patients who had normal chest X-rays. In five of these, somatostatin receptor imaging pointed to interstitial disease. Frequently, accumulation of radioactivity in parotid glands and supraclavicular lymph nodes was found. Neither the degree of radioactive accumulation in the thorax nor a specific pattern of pathological uptake was correlated with disease severity or clinical course. The degree of uptake of radioactivity in the parotid glands was correlated with significantly higher serum angiotensin-converting enzyme (ACE) levels. Somatostatin receptor imaging was repeated in 13 patients. In five of six patients in whom chest X-ray monitored improvement of disease activity, the pentetreotide scintigram also showed a decrease in pathological uptake. In two of five patients in whom the chest X-ray was unchanged, but serum ACE concentrations had decreased and lung function improved, normalization on pentetreotide scintigrams was found. It is concluded that: (1) somatostatin receptor imaging can demonstrate active granulomatous disease in patients with sarcoidosis; (2) pathological uptake of radioactivity in the parotid glands during somatostatin receptor imaging is correlated with higher serum ACE concentrations; (3) the value of somatostatin receptor imaging in the follow-up of patients with sarcoidosis will have to be determined in

  2. Elevated circulating somatostatin levels in acromegaly. (United States)

    Arosio, M; Porretti, S; Epaminonda, P; Giavoli, C; Gebbia, C; Penati, C; Beck-Peccoz, P; Peracchi, M


    GH increases hypothalamic somatostatin (SS) synthesis and secretion but it is unknown if chronic GH excess, as found in acromegaly, may influence circulating SS levels, that are mainly of enteropancreatic source and affect several gastrointestinal functions, including motility. Circulating SS occurs in several post-translational forms including somatostatin-14 (SS-14), somatostatin-28 (SS-28) and other small peptides. The aim of the present study was to characterize the fasting and postprandial pattern of plasma circulating somatostatin in normal subjects and patients with acromegaly. Fasting total SS and SS-28 levels were measured in 32 subjects, 16 acromegalic patients with a new diagnosis (A) (8 F, 8 M, median age 48) and 16 matched healthy volunteers (C) (8 F, 8 M, median age 45). SS was also determined after a standard solid-liquid meal (550 kCal) in 24 of the subjects (12 C and 12 A). Fasting SS and SS-28 were significantly higher in acromegalic patients as compared to healthy subjects. In the former, a positive correlation was found between IGF-I and SS levels (r = 0.525 p acromegaly. Excess GH/IGF-I could be a causal factor in somatostatin hypersecretion. Conceivably this abnormality might play a role in some alterations of gastrointestinal function of acromegalic patients such as prolonged bowel transit.

  3. Somatostatin receptors in gastroentero-pancreatic neuroendocrine tumours

    NARCIS (Netherlands)

    W.W. de Herder (Wouter); L.J. Hofland (Leo); A-J. van der Lely (Aart-Jan); S.W.J. Lamberts (Steven)


    textabstractFive somatostatin receptor (sst) subtype genes, sst(1), sst(2), sst(3), sst(4) and sst(5), have been cloned and characterised. The five sst subtypes all bind natural somatostatin-14 and somatostatin-28 with high affinity. Endocrine pancreatic and endocrine digestive

  4. Somatostatin receptor ligands in the treatment of acromegaly. (United States)

    Gadelha, Monica R; Wildemberg, Luiz Eduardo; Bronstein, Marcello D; Gatto, Federico; Ferone, Diego


    First-generation somatostatin receptors ligands (SRL) are the mainstay in the medical treatment of acromegaly, however the percentage of patients controlled with these drugs significantly varies in the different studies. Many factors are involved in the resistance to SRL. In this review, we update the physiology of somatostatin and its receptors (sst), the use of SRL in the treatment of acromegaly and the factors involved in the response to these drugs. The SRL act through interaction with the sst, which up to now have been characterized as five subtypes. The first-generation SRL, octreotide and lanreotide, are considered sst2 specific and have biochemical response rates varying from 20 to 70%. Tumor volume reduction can be found in 36-75% of patients. Several factors may determine the response to these drugs, such as sst, AIP, E-cadherin, ZAC1, filamin A and β-arrestin expression in the somatotropinomas. In patients resistant to first-generation SRL, alternative medical treatment options include: SRL high dose regimens, SRL in combination with cabergoline or pegvisomant, or the use of pasireotide. Pasireotide is a next-generation SRL with a broader pattern of interaction with sst. In the light of the recent increase of treatment options in acromegaly and the deeper knowledge of the determinants of response to the current first-line therapy, a shift from a trial-and-error treatment to a personalized one could be possible.

  5. Lanreotide-conjugated PEG-DSPE micelles: an efficient nanocarrier targeting to somatostatin receptor positive tumors. (United States)

    Zheng, Nan; Dai, Wenbing; Zhang, Hua; Wang, Xueqing; Wang, Jiancheng; Zhang, Xuan; Wang, Kun; Li, Jian; Zhang, Qiang


    Lanreotide is an octapeptide analog of endogenous somatostatin, specifically binding with tumors over-express somatostatin receptor 2 (SSTR2). In this study, we conjugated lanreotide to 1, 2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy (poly-(ethylene glycol))-2000] (PEG-DSPE), constructed active targeted micelles (lanreotide-PM), characterized their in vitro and in vivo targeting effect, and explored the receptor mediated transportion. The uptake of lanreotide-PM was found to be related to the expression level of SSTR2 in different cell lines and the competitive inhibition phenomenon indicated that the cellular uptake of lanreotide-PM was via a receptor meditated mechanism. In vivo, more lanreotide-PM accumulated in SSTR2 high expression tumor xenografts, endocytosed by the tumor cells, induced more apoptosis of tumor cells, and suppressed tumor growth efficiently. In conclusion, lanreotide-modified micelles containing antitumor drugs provide a promising strategy for the treatment of SSTR-expressing tumors.

  6. Phosphorylation of threonine 333 regulates trafficking of the human sst5 somatostatin receptor. (United States)

    Petrich, Aline; Mann, Anika; Kliewer, Andrea; Nagel, Falko; Strigli, Anne; Märtens, Jan Carlo; Pöll, Florian; Schulz, Stefan


    The frequent overexpression of the somatostatin receptors sst2 and sst5 in neuroendocrine tumors provides the molecular basis for therapeutic application of novel multireceptor somatostatin analogs. Although the phosphorylation of the carboxyl-terminal region of the sst2 receptor has been studied in detail, little is known about the agonist-induced regulation of the human sst5 receptor. Here, we have generated phosphosite-specific antibodies for the carboxyl-terminal threonines 333 (T333) and 347 (T347), which enabled us to selectively detect either the T333-phosphorylated or the T347-phosphorylated form of sst5. We show that agonist-mediated phosphorylation occurs at T333, whereas T347 is constitutively phosphorylated in the absence of agonist. We further demonstrate that the multireceptor somatostatin analog pasireotide and the sst5-selective ligand L-817,818 but not octreotide or KE108 were able to promote a detectable T333 phosphorylation. Interestingly, BIM-23268 was the only sst5 agonist that was able to stimulate T333 phosphorylation to the same extent as natural somatostatin. Agonist-induced T333 phosphorylation was dose-dependent and selectively mediated by G protein-coupled receptor kinase 2. Similar to that observed for the sst2 receptor, phosphorylation of sst5 occurred within seconds. However, unlike that seen for the sst2 receptor, dephosphorylation and recycling of sst5 were rapidly completed within minutes. We also identify protein phosphatase 1γ as G protein-coupled receptor phosphatase for the sst5 receptor. Together, we provide direct evidence for agonist-selective phosphorylation of carboxyl-terminal T333. In addition, we identify G protein-coupled receptor kinase 2-mediated phosphorylation and protein phosphatase 1γ-mediated dephosphorylation of T333 as key regulators of rapid internalization and recycling of the human sst5 receptor.

  7. Somatostatin and its receptors in the development of the endocrine pancreas. (United States)

    Ballian, Nikiforos; Brunicardi, F Charles; Wang, Xiao-Ping


    The development of the endocrine pancreas is regulated by numerous transcription and growth factors. Somatostatin (SST) is present in many tissues and acts as a neurotransmitter and autocrine/paracrine/endocrine regulator in response to ions, nutrients, peptides, and hormones as well as neurotransmitters. In the pancreas, there is evidence that SST acts an inhibitory paracrine regulator of hormone secretion. Somatostatin receptors (SSTRs) are a family of 5 transmembrane G protein-coupled receptors, which are widely expressed in mammals including humans. SSTRs regulate multiple downstream signal transduction pathways that mediate inhibitory effects. These receptors also exhibit age- and tissue-specific expression patterns. Interactions of SST and SSTRs are not only important during normal pancreas development, but have also been implicated in many pancreatic diseases such as diabetes mellitus and pancreatic cancer. In this review article, we use evidence from recently published animal studies to present the critical roles of SST and SSTRs proteins in the development of the endocrine pancreas.


    Directory of Open Access Journals (Sweden)



    Full Text Available The role of somatostatin in plasma cortisol level in Rana tigrina (amphibia,anura has beeninvestigated. An inhibitory impact on both, intact (16.32% as well as pharmacologically annuledfrogs(23.27% has been recorded. It is concluded that in both the conditions, it act as a preventiveagent to counteract any excess secretion of cortisol due to the failure of classical regulatorymechanism.

  9. Hormonal secretion and quality of life in Nelson syndrome and Cushing disease after long acting repeatable octreotide: a short series and update. (United States)

    Arregger, Alejandro L; Cardoso, Estela M L; Sandoval, Olga B; Monardes Tumilasci, Elida G; Sanchez, Rocío; Contreras, Liliana N


    Clinical management of persistent adrenocorticotropin hormone (ACTH) excess in Nelson syndrome (NS) and Cushing disease (CD) remains a challenge. Somatostatin and its analogs as octreotide decrease ACTH secretion through somatostatin receptors of pituitary cells. To our knowledge, there are no reports on the effect of long-acting repeatable octreotide (oct-lar) on hormonal secretion and quality of life in patients with NS and CD who failed conventional therapy. Herein, we describe the effects of treatment with oct-lar (20 mg/month intramurally) in 1 woman with NS and 2 women with persistent CD. Oct-lar therapy reduced ACTH secretion and improved the quality of life in NS patient. By contrast, in CD patients, it failed to control ACTH and cortisol secretion, and the quality of life remained unchanged.

  10. Peptide Receptor Radionuclide Therapy with radiolabelled somatostatin analogues in patients with somatostatin receptor positive tumours

    Energy Technology Data Exchange (ETDEWEB)

    Essen, Martijn van; Krenning, Eric P.; Jong, Marion De; Valkema, Roelf; Kwekkeboom, Dik J. [Dept. of Nuclear Medicine, Erasmus MC, ' s Gravendijkwal 230, Rotterdam (Netherlands)


    Peptide Receptor Radionuclide Therapy (PRRT) with radiolabelled somatostatin analogues is a promising treatment option for patients with inoperable or metastasised neuroendocrine tumours. Symptomatic improvement may occur with all of the various {sup 111}In, {sup 90}Y, or {sup 177}Lu-labelled somatostatin analogues that have been used. Since tumour size reduction was seldom achieved with {sup 111}Indium labelled somatostatin analogues, radiolabelled somatostatin analogues with beta-emitting isotopes like {sup 90}Y and {sup 177}Lu were developed. Reported anti-tumour effects of [{sup 90}Y-DOTA0,Tyr3]octreotide vary considerably between various studies: Tumour regression of 50% or more was achieved in 9 to 33% (mean 22%). With [{sup 177}Lu-DOTA0,Tyr3]octreotate treatments, tumour regression of 50% or more was achieved in 28% of patients and tumour regression of 25 to 50% in 19% of patients, stable disease was demonstrated in 35% and progressive disease in 18%. Predictive factors for tumour remission were high tumour uptake on somatostatin receptor scintigraphy and limited amount of liver metastases. The side-effects of PRRT are few and mostly mild, certainly when using renal protective agents: Serious side-effects like myelodysplastic syndrome or renal failure are rare. The median duration of the therapy response for [{sup 90}Y-DOTA0,Tyr3]octreotide and [{sup 177}Lu-DOTA0,Tyr3]octreotate is 30 months and more than 36 months respectively. Lastly, quality of life improves significantly after treatment with [{sup 177}Lu-DOTA0,Tyr3]octreotate. These data compare favourably with the limited number of alternative treatment approaches, like chemotherapy. If more widespread use of PRRT is possible, such therapy might become the therapy of first choice in patients with metastasised or inoperable gastroenteropancreatic neuroendocrine tumours. Also the role in somatostatin receptor expressing non-GEP tumours, like metastasised paraganglioma/pheochromocytoma and non

  11. Structure and pharmaceutical formulation development of a new long-acting recombinant human insulin analog studied by NMR and MS. (United States)

    Bednarek, Elżbieta; Sitkowski, Jerzy; Bocian, Wojciech; Borowicz, Piotr; Płucienniczak, Grażyna; Stadnik, Dorota; Surmacz-Chwedoruk, Weronika; Jaworska, Beata; Kozerski, Lech


    A monomer structure of a novel human insulin analog A22(S)-B3(K)-B31(R) (SK3R) has been characterized by NMR in water/acetonitrile solution and compared with the structure of human insulin (HIS) established in the same medium. The composition of the oligomer ensemble for neat insulins in water was qualitatively assessed by monitoring, derived from NMR experiment, translational diffusion coefficient Dix10(-10)m(2)s(-1), whose value is a population averaged of individual coefficients for species in oligomeric ensemble. Nanospray ESI/MS experiment was used to establish the masses of oligomers in pharmaceutical formulation of the SK3R insulin. The pharmacodynamic data were established and compared to insulin glargine characterized by the same profile of action in diabetics. The oligomerization process of insulin during development of pharmaceutical formulation with routinely used excipients has been studied using translation diffusion coefficient Dix10(-10)m(2)s(-1) established in water solution. These properties were compared with those of human insulin (HIS) which is a standard reference for novel recombinant insulins. Copyright © 2016. Published by Elsevier B.V.

  12. Application of adaptive design methodology in development of a long-acting glucagon-like peptide-1 analog (dulaglutide): statistical design and simulations. (United States)

    Skrivanek, Zachary; Berry, Scott; Berry, Don; Chien, Jenny; Geiger, Mary Jane; Anderson, James H; Gaydos, Brenda


    Dulaglutide (dula, LY2189265), a long-acting glucagon-like peptide-1 analog, is being developed to treat type 2 diabetes mellitus. To foster the development of dula, we designed a two-stage adaptive, dose-finding, inferentially seamless phase 2/3 study. The Bayesian theoretical framework is used to adaptively randomize patients in stage 1 to 7 dula doses and, at the decision point, to either stop for futility or to select up to 2 dula doses for stage 2. After dose selection, patients continue to be randomized to the selected dula doses or comparator arms. Data from patients assigned the selected doses will be pooled across both stages and analyzed with an analysis of covariance model, using baseline hemoglobin A1c and country as covariates. The operating characteristics of the trial were assessed by extensive simulation studies. Simulations demonstrated that the adaptive design would identify the correct doses 88% of the time, compared to as low as 6% for a fixed-dose design (the latter value based on frequentist decision rules analogous to the Bayesian decision rules for adaptive design). This article discusses the decision rules used to select the dula dose(s); the mathematical details of the adaptive algorithm-including a description of the clinical utility index used to mathematically quantify the desirability of a dose based on safety and efficacy measurements; and a description of the simulation process and results that quantify the operating characteristics of the design. © 2012 Diabetes Technology Society.

  13. Effects of CP 55,940 — agonist of CB1 cannabinoid receptors on ghrelin and somatostatin producing cells in the rat pancreas

    Directory of Open Access Journals (Sweden)

    Alicja Lewandowska


    Full Text Available Cannabinoids participate in the modulation of numerous functions in the human organism, increasing the sense of hunger, affecting carbohydrate and lipid metabolism, and controlling systemic energy balance mechanisms. Moreover, they influence the endocrine system functions, acting via two types of receptors, CB1 and CB2. The aim of the present study was to examine the number, distribution and activity of ghrelin and somatostatin producing endocrine cells in the pancreas of rats after a single administration of selective CP 55,940 agonist of CB1 receptor. The study was performed on 20 rats. Neuroendocrine cells were identified by immunohistochemical reactions, involving specific antibodies against ghrelin and somatostatin. The distribution and number of ghrelin- and somatostatin-immunoreactive cells were separately studied in five pancreas islets of each section. A performed analysis showed a decreased number of somatostatin-immunoreactive cells and a weak immunoreactivity of ghrelin and somatostatin containing neuroendocrine cells in the pancreatic islets of experimental rats, compared to control animals. The obtained results suggest that a single administration of a selective CP 55,940 agonist of CB1 receptor influences the immunoreactivity of endocrine cells with ghrelin and somatostatin expression in the pancreas islets.

  14. Lunar Analog (United States)

    Cromwell, Ronita L.


    In this viewgraph presentation, a ground-based lunar analog is developed for the return of manned space flight to the Moon. The contents include: 1) Digital Astronaut; 2) Bed Design; 3) Lunar Analog Feasibility Study; 4) Preliminary Data; 5) Pre-pilot Study; 6) Selection of Stockings; 7) Lunar Analog Pilot Study; 8) Bed Design for Lunar Analog Pilot.

  15. Circulating somatostatin after food and glucose in man. (United States)

    Wass, J A; Penman, E; Dryburgh, J R; Tsiolakis, D; Goldberg, P L; Dawson, A M; Besser, G M; Rees, L H


    Using a recently validated radioimmunoassay, changes in circulating somatostatin have been measured in normal subjects after food (a standard breakfast), and oral and intravenous glucose. After the standard breakfast, a clear and sustained rise in plasma somatostatin was seen in all subjects from a mean value (+/-1 SE) of 28 +/- 7 pg/ml to a mean peak value, at 60 min of 57 +/- 11 pg/ml. When glucose was taken by mouth a significant but smaller rise was seen, but intravenous glucose caused no significant change in plasma somatostatin. A rise in circulating somatostatin after feeding has not previously been demonstrated in normal man and it is suggested that somatostatin may have an important endocrine role in the gut.

  16. Somatostatin-Immunoreactive Pancreaticoduodenal Neuroendocrine Neoplasms

    DEFF Research Database (Denmark)

    Engelund Luna, Iben; Monrad, Nina; Binderup, Tina


    in the pancreas, metastatic disease at diagnosis and higher tumour grade were all associated with a significantly poorer survival. CONCLUSION: None of the patients with p-dSOM presented with the full somatostatinoma syndrome. Prognostic factors are localisation of the primary tumour, dissemination and tumour...... was 2/12. One male had MEN-1. Five had stage 1A-2B and nine had stage 4. The Ki-67 index was 1-40% (median 7%). Plasma somatostatin was elevated in seven patients. Patients reported symptoms related to the somatostatinoma syndrome, but none fulfilled the criteria for a full syndrome. Primary tumour...

  17. Peptide Receptor Targeting in Cancer: The Somatostatin Paradigm

    Directory of Open Access Journals (Sweden)

    Federica Barbieri


    Full Text Available Peptide receptors involved in pathophysiological processes represent promising therapeutic targets. Neuropeptide somatostatin (SST is produced by specialized cells in a large number of human organs and tissues. SST primarily acts as inhibitor of endocrine and exocrine secretion via the activation of five G-protein-coupled receptors, named sst1–5, while in central nervous system, SST acts as a neurotransmitter/neuromodulator, regulating locomotory and cognitive functions. Critical points of SST/SST receptor biology, such as signaling pathways of individual receptor subtypes, homo- and heterodimerization, trafficking, and cross-talk with growth factor receptors, have been extensively studied, although functions associated with several pathological conditions, including cancer, are still not completely unraveled. Importantly, SST exerts antiproliferative and antiangiogenic effects on cancer cells in vitro, and on experimental tumors in vivo. Moreover, SST agonists are clinically effective as antitumor agents for pituitary adenomas and gastro-pancreatic neuroendocrine tumors. However, SST receptors being expressed by tumor cells of various tumor histotypes, their pharmacological use is potentially extendible to other cancer types, although to date no significant results have been obtained. In this paper the most recent findings on the expression and functional roles of SST and SST receptors in tumor cells are discussed.

  18. Redoubling the ring size of an endomorphin-2 analog transforms a centrally acting mu-opioid receptor agonist into a pure peripheral analgesic. (United States)

    Piekielna, Justyna; De Marco, Rossella; Gentilucci, Luca; Cerlesi, Maria Camilla; Calo', Girolamo; Tömböly, Csaba; Artali, Roberto; Janecka, Anna


    The study reports the synthesis and biological evaluation of two opioid analogs, a monomer and a dimer, obtained as products of the solid-phase, side-chain to side-chain cyclization of the pentapeptide Tyr-d-Lys-Phe-Phe-AspNH2 . The binding affinities to the mu, delta, and kappa opioid receptors, as well as results obtained in a calcium mobilization functional assay are reported. Tyr-[d-Lys-Phe-Phe-Asp]2 -NH2 1 was a potent and selective full agonist of mu with sub-nanomolar affinity, while the dimer (Tyr-[d-Lys-Phe-Phe-Asp]2 -NH2 )2 2 showed a significant mixed mu/kappa affinity, acting as an agonist at the mu. Molecular docking computations were utilized to explain the ability of the dimeric cyclopeptide 2 to interact with the receptor. Interestingly, in spite of the increased ring size, the higher flexibility allowed 2 to fold and fit into the mu receptor binding pocket. Both cyclopeptides were shown to elicit strong antinociceptive activity after intraventricular injection but only cyclomonomer 1 was able to cross the blood-brain barrier. However, the cyclodimer 2 displayed a potent peripheral antinociceptive activity in a mouse model of visceral inflammatory pain. © 2016 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 309-317, 2016.

  19. Inhibition by somatostatin interneurons in olfactory cortex

    Directory of Open Access Journals (Sweden)

    Adam M Large


    Full Text Available Inhibitory circuitry plays an integral cortical network activity. The development of transgenic mouse lines targeting unique interneuron classes has significantly advanced our understanding of the functional roles of specific inhibitory circuits in neocortical sensory processing. In contrast, considerably less is known about the circuitry and function of interneuron classes in piriform cortex, a paleocortex responsible for olfactory processing. In this study, we sought to utilize transgenic technology to investigate inhibition mediated by somatostatin (SST interneurons onto pyramidal cells, parvalbumin (PV interneurons and other interneuron classes. As a first step, we characterized the anatomical distributions and intrinsic properties of SST and PV interneurons in four transgenic lines (SST-cre, GIN, PV-cre and G42 that are commonly interbred to investigate inhibitory connectivity. Surprisingly, the distributions SST and PV cell subtypes targeted in the GIN and G42 lines were sparse in piriform cortex compared to neocortex. Moreover, two-thirds of interneurons recorded in the SST-cre line had electrophysiological properties similar to fast spiking (FS interneurons rather than regular (RS or low threshold spiking (LTS phenotypes. Nonetheless, like neocortex, we find that SST-cells broadly inhibit a number of unidentified interneuron classes including putatively identified PV cells and surprisingly, other SST cells. We also confirm that SST-cells inhibit pyramidal cell dendrites and thus, influence dendritic integration of afferent and recurrent inputs to the piriform cortex. Altogether, our findings suggest that somatostatin interneurons play an important role in regulating both excitation and the global inhibitory network during olfactory processing.

  20. Somatostatin modulates generation of inspiratory rhythms and determines asphyxia survival. (United States)

    Ramírez-Jarquín, Josué O; Lara-Hernández, Sergio; López-Guerrero, Juan J; Aguileta, Miguel A; Rivera-Angulo, Ana J; Sampieri, Alicia; Vaca, Luis; Ordaz, Benito; Peña-Ortega, Fernando


    Breathing and the activity of its generator (the pre-Bötzinger complex; pre-BötC) are highly regulated functions. Among neuromodulators of breathing, somatostatin (SST) is unique: it is synthesized by a subset of glutamatergic pre-BötC neurons, but acts as an inhibitory neuromodulator. Moreover, SST regulates breathing both in normoxic and in hypoxic conditions. Although it has been implicated in the neuromodulation of breathing, neither the locus of SST modulation, nor the receptor subtypes involved have been identified. In this study, we aimed to fill in these blanks by characterizing the SST-induced regulation of inspiratory rhythm generation in vitro and in vivo. We found that both endogenous and exogenous SST depress all preBötC-generated rhythms. While SST abolishes sighs, it also decreases the frequency and increases the regularity of eupnea and gasping. Pharmacological experiments showed that SST modulates inspiratory rhythm generation by activating SST receptor type-2, whose mRNA is abundantly expressed in the pre-Bötzinger complex. In vivo, blockade of SST receptor type-2 reduces gasping amplitude and consequently, it precludes auto-resuscitation after asphyxia. Based on our findings, we suggest that SST functions as an inhibitory neuromodulator released by excitatory respiratory neurons when they become overactivated in order to stabilize breathing rhythmicity in normoxic and hypoxic conditions. Copyright © 2012 Elsevier Inc. All rights reserved.

  1. Low concentration structural dynamics of lanreotide and somatostatin-14. (United States)

    Hernández, Belén; Coïc, Yves-Marie; Baron, Bruno; Kruglik, Sergei G; Pflüger, Fernando; Cohen, Régis; Carelli, Claude; Ghomi, Mahmoud


    Lanreotide, a synthetic cyclic octapeptide, analogue of the peptide hormone somatostatin-14 (SST-14), is routinely used as a long-acting medication in the management of neuroendocrine tumors. Despite its therapeutic importance, low concentration structural data is still lacking for lanreotide. In fact, the major part of the previous structural investigations were focused on the remarkable aggregation properties of this peptide, appearing at high concentrations (>5 mM). Here, we have applied three optical spectroscopic techniques, i.e. fluorescence, circular dichroism and Raman scattering, for analyzing the structural dynamics at the concentrations below 5 mM, where lanreotide exists either in a monomer state or at the first stages of aggregation. The obtained data from lanreotide were discussed through their comparison with those collected from SST-14, leading us to the following conclusions: (i) The central D-Trp residue, forming with its adjacent Lys the main receptor interacting part of lanreotide, keeps a constant high rotational freedom whatever the environment (water, water/methanol, methanol). (ii) A solvent-dependent tight β-turn, belonging to the type-II' family, is revealed in lanreotide. (iii) Raman data analyzed by band decomposition in the amide (I and III) regions allowed estimation of different secondary structural elements within the millimolar range. Interestingly, the applied protocol shows a perfect agreement between the structural features provided by the amide I and amide III Raman markers. © 2014 Wiley Periodicals, Inc.

  2. Sleep and Movement Differentiates Actions of Two Types of Somatostatin-Expressing GABAergic Interneuron in Rat Hippocampus


    Katona, Linda; Lapray, Damien; Viney, Tim J.; Oulhaj, Abderrahim; Borhegyi, Zsolt; Micklem, Benjamin R.; Klausberger, Thomas; Somogyi, Peter


    Summary Neuropeptides acting on pre- and postsynaptic receptors are coreleased with GABA by interneurons including bistratified and O-LM cells, both expressing somatostatin but innervating segregated dendritic domains of pyramidal cells. Neuropeptide release requires high-frequency action potentials, but the firing patterns of most peptide/GABA-releasing interneurons during behavior are unknown. We show that behavioral and network states differentiate the activities of bistratified and O-LM c...

  3. Hyperactive Somatostatin Interneurons Contribute to Excitotoxicity in Neurodegenerative Disorders (United States)

    Liang, Bo; Schroeder, David; Zhang, Zhong-wei; Cox, Gregory A.; Li, Yun; Lin, Da-Ting


    Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are overlapping neurodegenerative disorders whose pathogenesis remains largely unknown. Here using TDP-43A315T mice, an ALS and FTD model with profound cortical pathology, we demonstrated that hyperactive somatostatin interneurons disinhibited layer 5 pyramidal neurons (L5-PN) and contributed to their excitotoxicity. Focal ablation of somatostatin interneurons efficiently restored normal excitability of L5-PN and alleviated neurodegeneration, suggesting a novel therapeutic target for ALS and FTD. PMID:26900927

  4. Analog computing

    CERN Document Server

    Ulmann, Bernd


    This book is a comprehensive introduction to analog computing. As most textbooks about this powerful computing paradigm date back to the 1960s and 1970s, it fills a void and forges a bridge from the early days of analog computing to future applications. The idea of analog computing is not new. In fact, this computing paradigm is nearly forgotten, although it offers a path to both high-speed and low-power computing, which are in even more demand now than they were back in the heyday of electronic analog computers.

  5. Partial enterectomy decreases somatostatin-binding sites in residual intestine of rabbits. (United States)

    Colas, B; Bodegas, G; Sanz, M; Prieto, J C; Arilla, E


    1. Three weeks after partial enterectomy in the rabbit there was an increased somatostatin concentration and a decreased number of somatostatin-binding sites (without changes in the corresponding affinity values) in the cytosol of the residual intestinal tissue, except in the terminal ileum and the colon. 2. Five weeks after surgery both the somatostatin concentration and the number of somatostatin-binding sites returned towards control values. 3. These results suggest that an increase in bowel somatostatin content could lead to down-regulation of somatostatin-binding sites in the intestinal mucosa.

  6. Survival prediction in patients undergoing radionuclide therapy based on intratumoral somatostatin-receptor heterogeneity (United States)

    Ilhan, Harun; Higuchi, Takahiro; Buck, Andreas K.; Lehner, Sebastian; Bartenstein, Peter; Bengel, Frank; Schatka, Imke; Muegge, Dirk O.; Papp, László; Zsótér, Norbert; Große-Ophoff, Tobias; Essler, Markus; Bundschuh, Ralph A.


    The NETTER-1 trial demonstrated significantly improved progression-free survival (PFS) for peptide receptor radionuclide therapy (PRRT) in neuroendocrine tumors (NET) emphasizing the high demand for response prediction in appropriate candidates. In this multicenter study, we aimed to elucidate the prognostic value of tumor heterogeneity as assessed by somatostatin receptor (SSTR)-PET/CT. 141 patients with SSTR-expressing tumors were analyzed obtaining SSTR-PET/CT before PRRT (1-6 cycles, 177Lu somatostatin analog). Using the Interview Fusion Workstation (Mediso), a total of 872 metastases were manually segmented. Conventional PET parameters as well as textural features representing intratumoral heterogeneity were computed. The prognostic ability for PFS and overall survival (OS) were examined. After performing Cox regression, independent parameters were determined by ROC analysis to obtain cut-off values to be used for Kaplan-Meier analysis. Within follow-up (median, 43.1 months), 75 patients showed disease progression (median, 22.2 m) and 54 patients died (median, 27.6 m). Cox analysis identified 8 statistically independent heterogeneity parameters for time-to-progression and time-to-death. Among them, the textural feature Entropy predicted both PFS and OS. Conventional PET parameters failed in response prediction. Imaging-based heterogeneity assessment provides prognostic information in PRRT candidates and outperformed conventional PET parameters. Its implementation in clinical practice can pave the way for individualized patient management. PMID:27705948

  7. Mouse hypothalamic growth hormone-releasing hormone and somatostatin responses to probes of signal transduction systems. (United States)

    Sato, M; Downs, T R; Frohman, L A


    Signal transduction mechanisms involved in mouse growth hormone-releasing hormone (GRH) and somatostatin (SRIH) release were investigated using an in vitro perifusion system. Hypothalamic fragments were exposed to depolarizing agents, protein kinase A and C activators, and a calcium ionophore. The depolarizing agents, KCl (60 mM) and veratridine (50 microM), induced similar patterns of GRH and SRIH release. Somatostatin release in response to both agents was twofold greater than that of GRH. Forskolin (10 microM and 100 microM), an adenylate cyclase activator, stimulated both GRH and SRIH release, though with different secretory profiles. The SRIH response was prolonged and persisted beyond removal of the drug from the system, while the GRH response was brief, ending even prior to forskolin removal. Neither GRH nor SRIH were stimulated by 1,9-dideoxy-forskolin (100 microM), a forskolin analog with cAMP-independent actions. A23187 (5 microM), a calcium ionophore, stimulated the release of SRIH to a much greater extent than that of GRH. The GRH and SRIH secretory responses to PMA (1 microM), a protein kinase C activator, were similar, though delayed. The results suggest that 1) GRH and SRIH secretion are regulated by both protein kinase A and C pathways, and 2) depolarizing agents are important for the release of both hormones.

  8. Differentiated expression of somatostatin receptor subtypes in experimental models and clinical neuroblastoma. (United States)

    Georgantzi, Kleopatra; Tsolakis, Apostolos V; Stridsberg, Mats; Jakobson, Ake; Christofferson, Rolf; Janson, Eva Tiensuu


    Neuroblastoma (NB) is a solid tumor of childhood originating from the adrenal medulla or sympathetic nervous system. Somatostatin (SS) is an important regulator of neural and neuroendocrine function, its actions being mediated through five specific membrane receptors. The aim of this study was to investigate the expression of the different somatostatin receptors (SSTRs) in NB tumor cells that may form targets for future therapeutic development. Tumor specimens from 11 children with stage II-IV disease were collected before and/or after chemotherapy. Experimental tumors derived from five human NB cell lines were grown subcutaneously in nude mice. Expression of SSRTs, the neuroendocrine marker chromogranin A (CgA) and SS was detected by immunohistochemistry using specific antibodies. SSTR2 was detected in 90%, SSTR5 in 79%, SSTR1 in 74%, SSTR3 in 68% whereas SSTR4 was expressed in 21% of the clinical tumors. The experimental tumors expressed SSTRs in a high but variable frequency. All clinical tumors showed immunoreactivity for CgA but not for SS. The frequent expression of SSTRs indicates that treatment with unlabeled or radiolabeled SS analogs should be further explored in NB. Copyright © 2010 Wiley-Liss, Inc.

  9. Intrathoracic splenosis: a rare false-positive cause of somatostatin imaging in characterization of solitary pulmonary nodule. (United States)

    Mahmoudian, Babak; Javadrashid, Reza; Fakhrjoo, Ashraf


    Scanning using a somatostatin receptor analog such as Tc-EDDA/HYNIC-TOC has sensitivity and specificity similar to those of FDG-PET, which has high accuracy in the characterization of a solitary pulmonary nodule (SPN). We describe a 63-year-old man with well-defined SPN in the left lung on chest x-ray and CT scan. Whole-body scanning and chest SPECT were performed with Tc-EDDA/HYNIC-TOC for the characterization of SPN. Abnormal focal increased radiotracer uptake in the left hemithorax was detected. In addition, no spleen activity was observed in the anatomical location. Cytopathologic evaluation of SPN revealed splenosis.

  10. Growth hormone and somatostatin in glomerular injury. (United States)

    Baud, L; Fouqueray, B; Bellocq, A; Doublier, S; Dumoulin, A


    Among other neuropeptides and neurohormones, growth hormone (GH) and somatostatin (SRIF) have been shown to modulate the development of glomerular injury in various renal diseases. In particular, GH is implicated in the induction of glomerular hypertrophy and sclerosis in partial nephrectomy and diabetic nephropathy. While GH effects on glomerular hypertrophy are likely mediated by insulin-like growth factor I (IGF-I), GH effects on glomerular sclerosis are independent of IGF-I. Those effects rather require multiple signaling pathways functioning in series, e.g. angiotensin II binding preceding transforming growth factor beta (TGF-beta) release, or pro-inflammatory factor release preceding repair/scarring processes. In contrast with GH, SRIF administration prevents the development of glomerular lesions in experimental diabetes, partial nephrectomy and immune glomerulonephritis. Inhibitory effects of SRIF on glomerular hypotrophy may be through a decrease in GH secretion and/or IGF-I expression or through a direct blockade of glomerular cell proliferation. The mechanisms underlying the anti-inflammatory effects of SRIF are most likely a deactivation of inflammatory cells related in part to an upregulated response of these cells to glucocorticoids. Additional studies will be required to further define the role of GH and SRIF in the development of glomerular injury and, hence, to identify new targets for a therapeutic approach in glomerular diseases.

  11. Neuroendocrine gastric carcinoma expressing somatostatin: A highly malignant, rare tumor

    Institute of Scientific and Technical Information of China (English)

    Jaques Waisberg; Leandro Luongo de Matos; Ana Maria do Amaral Antonio Mader; Sérgio Pezzolo; Esmeralda Miristene Eher; Vera Luiza Capelozzi; Manlio Basilio Speranzini


    Poorly differentiated gastric neuroendocrine carcinomas,although rare, deserve particular attention, as they are aggressive and have an extremely poor prognosis. In this report we describe a gastric neuroendocrine carcinoma with rapidly fatal outcome. Immunohistological staining of the resected specimens revealed that the tumor was an endocrine carcinoma. The tumor disclosed intense immunoreactivity to pan-neuroendocrine markers and diffuse somatostatin immunoreactivity. There were no psammoma bodies and no demonstrable association with von Recklinghausen's neurofibromatosis. In the gastrointestinal tract, neuroendocrine tumors producing predominantly somatostatin have been described only in the duodenum. To the best of our knowledge, the present report is the second case report of a neuroendocrine gastric carcinoma expressing diffusely somatostatin as the only neuroendocrine regulatory peptide.

  12. [Effect of somatostatin on functions of acupuncture meridians]. (United States)

    Guo, Yuan; Luo, Rong; Wang, Jun; Zhao, Yan


    Our previous studies have showed that analogue electroacupuncture (EA) could induce a transmission of electrical signals along meridians, and excitatory neurotransmitters such as substance P and glutamate were involved in the transmission process. In recent studies, our results showed that somatostatin and its receptors played a dose-dependent tonic inhibition on the discharge rates of original and adjacent nerves innervating the acupoints. In addition, there existed an interaction between somatostatin and glutamate. These results suggest that the balance between excitatory and inhibitory neurotransmitters plays an important role in the function activities of acupoints and meridians.

  13. Analog earthquakes

    Energy Technology Data Exchange (ETDEWEB)

    Hofmann, R.B. [Center for Nuclear Waste Regulatory Analyses, San Antonio, TX (United States)


    Analogs are used to understand complex or poorly understood phenomena for which little data may be available at the actual repository site. Earthquakes are complex phenomena, and they can have a large number of effects on the natural system, as well as on engineered structures. Instrumental data close to the source of large earthquakes are rarely obtained. The rare events for which measurements are available may be used, with modfications, as analogs for potential large earthquakes at sites where no earthquake data are available. In the following, several examples of nuclear reactor and liquified natural gas facility siting are discussed. A potential use of analog earthquakes is proposed for a high-level nuclear waste (HLW) repository.

  14. Targeting somatostatin receptors in gastro entero pancreatic neuroendocrine tumours (G.E.P.N.E.T.): Which radiotracers for which tumours?;Ciblage des recepteurs de la somatostatine dans les tumeurs neuroendocrines gastroenteropancreatiques (TNE-GEP): quels radiotraceurs pour quelles tumeurs?

    Energy Technology Data Exchange (ETDEWEB)

    Cuny, T.; Saveanu, A.; Barlier, A. [CRN2M, UMR 6231, CNRS, laboratoire de neurobiologie et neurophysiologie de Marseille, faculte de medecine, 13 - Marseille (France); Saveanu, A.; Barlier, A. [Hotal de la Conception Assistance publique-hopitaux de Marseille, Laboratoire de biochimie, biologie moleculaire, 13 - Marseille (France); Taieb, D. [Hopital de la Timone, Assistance publique des hopitaux de Marseille, Service de medecine nucleaire, 13 - Marseille (France)


    Topographic and functional imaging hold a key position in endocrine oncology. In vivo somatostatin receptor scintigraphy using Indium-111 labeled DTPA-octreotide, a tracer with preferential affinity for the somatostatin receptor subtype 2 (sst2), is the gold-standard for initial diagnosis of gastro entero pancreatic neuroendocrine tumours (G.E.P.N.E.T.). Due to the detection limits of scintigraphy, other metabolic imaging modalities are required. Positron emission topography (PET) offers whole body scanning, facilitates tumour localization, and assesses the metastasis statement of the tumour. {sup 18}F-F.D.G. is the most frequent radiotracer used in clinical practice because of its availability, but its interest is demonstrated only in undifferentiated G.E.P.N.E.T.. More recently, {sup 18}F-DOPA PET showed a high sensitivity in particular in carcinoid tumours detection. PET using different {sup 68}Ga-labeled-somatostatin analogs with high affinity for sst2 displayed better results than somatostatin receptors scintigraphy (S.R.S.) in G.E.P.N.E.T. primary tumour and metastasis detection, especially when fusion with computerized tomography images was performed. Using similar metabolic targets, peptide receptor radionuclide therapy (P.R.R.T.) with {sup 177}Lu-octreotate and {sup 90}Y-DOTA-TOC, is indicated in disseminated G.E.P.N.E.T. forms with an efficiency of 30 % and a minor toxicity. (authors)

  15. Somatostatin, tau, and beta-amyloid within the anterior olfactory nucleus in Alzheimer disease. (United States)

    Saiz-Sanchez, D; Ubeda-Bañon, I; de la Rosa-Prieto, C; Argandoña-Palacios, L; Garcia-Muñozguren, S; Insausti, R; Martinez-Marcos, A


    Impaired olfaction is an early symptom of Alzheimer disease (AD). This likely to reflect neurodegenerative processes taking place in basal telencephalic structures that mediate olfactory processing, including the anterior olfactory nucleus. Betaeta-amyloid (Abeta) accumulation in AD brain may relate to decline in somatostatin levels: somatostatin induces the expression of the Abeta-degrading enzyme neprilysin and somatostatin deficiency in AD may therefore reduce Abeta clearance. We have investigated the expression of somatostatin in the anterior olfactory nucleus of AD and control brain. We report that somatostatin levels were reduced by approximately 50% in AD brain. Furthermore, triple-immunofluorescence revealed co-localization of somatostatin expression with Abeta (65.43%) with Abeta and tau (19.75%) and with tau (2.47%). These data indicate that somatostatin decreases in AD and its expression may be linked with Abeta deposition.

  16. [Effect of somatostatin on the hemodynamic changes induced by acute experimental pancreatitis in the conscious rat]. (United States)

    Ais, G; Novo, C; Ortega, M; González, A; Jiménez, I; López, J; Romeo, J M


    The aim of this study was to determine the hemodynamic effect of somatostatin, either prophylactically or therapeutically, in shock caused by acute necrohemorragic pancreatitis in conscious rats. For this purpose, radioactive microspheres were used in 3 groups (control pancreatitis, therapeutic somatostatin and prophylactic somatostatin), performing a basal and final hemodynamic study. In the control group, acute necrohemorragic pancreatitis resulted in overwhelming shock with decrease of 55% in cardiac output, 58% in renal blood flow, increase in total peripheral resistances of 342%, and death after 70 min. Therapeutic somatostatin decreased cardiac output by 42%, renal blood flow by 47%, and increased total peripheral resistances by 153%. Prophylactic somatostatin decreased cardiac output by 24%, and renal blooded flow by 28%; it increased peripheral resistances by 146%, and improved survival up to 97 min. In conclusion, therapeutic somatostatin, and particularly prophylactic somatostatin, improved hemodynamic shock after acute necrohemorragic pancreatitis in conscious rats.

  17. Somatostatin receptor scintigraphy in patients with cat-scratch disease

    Energy Technology Data Exchange (ETDEWEB)

    Krause, R.; Schnedl, W.J.; Hoier, S. [Div. of Infectious Diseases, Dept. of Internal Medicine, Univ. Graz (Austria); Piswanger-Soelkner, C.; Lipp, R.W. [Div. of Nuclear Medicine, Dept. of Internal Medicine, Univ. Graz (Austria); Daxboeck, F. [Clinical Inst. for Hygiene and Medical Microbiology, Div. of Hospital Hygiene, Univ. of Vienna (Austria); Reisinger, E.C. [Div. of Infectious Diseases and Tropical Medicine, Dept. of Internal Medicine, Univ. Rostock (Germany)


    Aim: somatostatin receptor scintigraphy images various neoplastic, granulomatous, and auto-immun diseases. Cat-scratch disease in an infectious granulomatous disease usually affecting the lymphnodes. It is not known whether cat-scratch disease provides positive somatostatin receptor scintigrams. Patients, methods: twelve patients with lymphadenitis and suspected cat-scratch disease were investigated by immunofluorescence antibody testing and somatostatin receptor scintigraphy. Suppurated lymphnodes were extracted or drained and Bartonella henselae specific PCR was then performed. Results: eleven of 12 patients showed IgG antibodies against B. henselea. SRS showed positive scintigraphic results in 6 of 11 patients with CSD. B. henselae DNA was detected in tissue of lymphnodes from 4 of 5 patients with lymphnode extraction or lymphnode drainage. SRS demonstrated positive scintigrams in all patients with a positive PCR. In one patient with suspected CSD SRS was negative as well as antibody testing. Conclusion: somatostatin receptor scintigraphy correlated with positive Bartonella henselae specific PCR tests and positive Bartonella henselae specific antibody tests in patients with CSD. (orig.)

  18. Chylous ascites:Treated with total parenteral nutrition and somatostatin

    Institute of Scientific and Technical Information of China (English)

    Qi Huang; Zhi-Wei Jiang; Jun Jiang; Ning Li; Jie-Shou Li


    AIM: To determine the effects of total parenteral nutrition and somatostatin on patients with chylous ascites.METHODS: Five patients were diagnosed with chylous ascites on the basis of laboratory findings of ascites sample from Nov 1999 to May 2003. Total parenteral nutrition and somatostatin or its analogue was administered to 4 patients,while the other one only received total parenteral nutrition.All the patients had persistent peritoneal drainage, with the quantity and quality of drainage fluid observed daily.Necessary supportive treatments were given to the patients individually during the therapy.RESULTS: Two of 4 patients who received somatostatin therapy obtained complete recovery within 10 d without any recurrence while on a normal diet. In these 2 patients,the peritoneal drainage reduced to zero in one and the other's decreased from 2 000 mL to 80 mL with a clear appearance and negative qualitative analysis of chyle. Recurrent chylous ascites, though relieved effectively by the same method every time, developed in one patient with advanced pancreatic cancer. The other patient's lymphatic fistula was blocked with the fibrin glue after conservative treatment. The patient who only received total parenteral nutrition was cured 24 d after therapy.CONCLUSION: Total parenteral nutrition along with somatostatin can relieve the symptoms and close the fistula in patients with chylous ascites rapidly. It appears to be an effective therapy available for the treatment of chylous ascites caused by various disorders.

  19. [Effect of cyclic somatostatin on ethanol-induced hypoglycemia]. (United States)

    Piccardo, M G; Marchetti, A M; Breda, E


    The authors examined the activity of the cyclic Somatostatin on Ethanol hypoglycemia. While the peptide is capable of increasing the plasma glucose levels of hypoglicemia starved rats, it does not increase the levels of plasma glucose in normal rats under the action of ethanol perfusion.

  20. Multimodal Somatostatin Receptor Theranostics Using [64Cu]Cu-/[177Lu]Lu-DOTA-(Tyr3)octreotate and AN-238 in a Mouse Pheochromocytoma Model (United States)

    Ullrich, Martin; Bergmann, Ralf; Peitzsch, Mirko; Zenker, Erik F.; Cartellieri, Marc; Bachmann, Michael; Ehrhart-Bornstein, Monika; Block, Norman L.; Schally, Andrew V.; Eisenhofer, Graeme; Bornstein, Stefan R.; Pietzsch, Jens; Ziegler, Christian G.


    Pheochromocytomas and extra-adrenal paragangliomas (PHEO/PGLs) are rare catecholamine-producing chromaffin cell tumors. For metastatic disease, no effective therapy is available. Overexpression of somatostatin type 2 receptors (SSTR2) in PHEO/PGLs promotes interest in applying therapies using somatostatin analogs linked to radionuclides and/or cytotoxic compounds, such as [177Lu]Lu-DOTA-(Tyr3)octreotate (DOTATATE) and AN-238. Systematic evaluation of such therapies for the treatment of PHEO/PGLs requires sophisticated animal models. In this study, the mouse pheochromocytoma (MPC)-mCherry allograft model showed high tumor densities of murine SSTR2 (mSSTR2) and high tumor uptake of [64Cu]Cu-DOTATATE. Using tumor sections, we assessed mSSTR2-specific binding of DOTATATE, AN-238, and somatostatin-14. Therapeutic studies showed substantial reduction of tumor growth and tumor-related renal monoamine excretion in tumor-bearing mice after treatment with [177Lu]Lu-DOTATATE compared to AN-238 and doxorubicin. Analyses did not show agonist-dependent receptor downregulation after single mSSTR2-targeting therapies. This study demonstrates that the MPC-mCherry model is a uniquely powerful tool for the preclinical evaluation of SSTR2-targeting theranostic applications in vivo. Our findings highlight the therapeutic potential of somatostatin analogs, especially of [177Lu]Lu-DOTATATE, for the treatment of metastatic PHEO/PGLs. Repeated treatment cycles, fractionated combinations of SSTR2-targeting radionuclide and cytotoxic therapies, and other adjuvant compounds addressing additional mechanisms may further enhance therapeutic outcome. PMID:27022413

  1. Kidney protection during peptide receptor radionuclide therapy with somatostatin analogues

    Energy Technology Data Exchange (ETDEWEB)

    Rolleman, Edgar J.; Melis, Marleen; Valkema, Roelf; Krenning, Eric P.; Jong, Marion de [Erasmus MC, Department of Nuclear Medicine, V 220, Rotterdam (Netherlands); Boerman, Otto C. [Radboud University Hospital, Department of Nuclear Medicine, Nijmegen (Netherlands)


    This review focuses on the present status of kidney protection during peptide receptor radionuclide therapy (PRRT) using radiolabelled somatostatin analogues. This treatment modality for somatostatin receptor-positive tumours is limited by renal reabsorption and retention of radiolabelled peptides resulting in dose-limiting high kidney radiation doses. Radiation nephropathy has been described in several patients. Studies on the mechanism and localization demonstrate that renal uptake of radiolabelled somatostatin analogues largely depends on the megalin/cubulin system in the proximal tubule cells. Thus methods are needed that interfere with this reabsorption pathway to achieve kidney protection. Such methods include coadministration of basic amino acids, the bovine gelatin-containing solution Gelofusine or albumin fragments. Amino acids are already commonly used in the clinical setting during PRRT. Other compounds that interfere with renal reabsorption capacity (maleic acid and colchicine) are not suitable for clinical use because of potential toxicity. The safe limit for the renal radiation dose during PRRT is not exactly known. Dosimetry studies applying the principle of the biological equivalent dose (correcting for the effect of dose fractionation) suggest that a dose of about 37 Gy is the threshold for development of kidney toxicity. This threshold is lower when risk factors for development of renal damage exist: age over 60 years, hypertension, diabetes mellitus and previous chemotherapy. A still experimental pathway for kidney protection is mitigation of radiation effects, possibly achievable by cotreatment with amifostine (Ethylol), a radiation protector, or with blockers of the renin-angiotensin-aldosterone system. Future perspectives on improving kidney protection during PRRT include combinations of agents to reduce renal retention of radiolabelled peptides, eventually together with mitigating medicines. Moreover, new somatostatin analogues with lower

  2. Cysteamine-induced reduction in gastrointestinal somatostatin: evidence for a region-specific loss in immunoreactivity. (United States)

    McIntosh, C H; Bakich, V; Bokenfohr, K; DiScala-Guenot, D; Kwok, Y N; Brown, J C


    Administration of cysteamine (beta-mercaptoethylamine; 2-aminoethanethiol) to rats has been shown to decrease the levels of somatostatin-like immunoreactivity (SLI) in the gastrointestinal tract and pancreas but its mode of action is unclear. In the current study the effect of cysteamine on gastrointestinal and pancreatic SLI has been studied using two antisera with different regional specificities. In addition, the in vitro effect of cysteamine on SS-14 and SS-28 has been studied by high-performance liquid chromatography (HPLC). Characterization of the two antisera (AS 26.3.2 and AS 1001) with a range of analogs of SS-14 revealed that both were directed against the midportion of the molecule but that AS 1001 was also sensitive to changes at the N- and C-termini. Tissue extracts from cysteamine-treated rats measured with AS 26.3.2 showed no significant change for the stomach, jejunum or pancreas but duodenal levels were reduced. With AS 1001 SLI levels were reduced in all tissues. Gel permeation chromatography of stomach extracts measured with AS 1001 showed a reduction in both SS-14 and SS-28. With AS 26.3.2 an increase in SLI eluting prior to the SS-14 peak occurred explaining why no significant reduction in total SLI was detected. With duodenal extracts the elution profiles with AS 1001 reflected the large reduction in total SLI whereas with AS 26.3.2 a smaller reduction occurred. Both SS-14 and SS-28 were reduced. HPLC analysis of SS-14 and SS-28 following incubation with cysteamine in vitro showed a time-dependent decrease in both somatostatin species with absorbance at 280 nm was measured. New peptide peaks which developed were not all detectable by radioimmunoassay with either antibody. The results suggest that cysteamine causes a change in the structure of somatostatin which probably first involves a reduction of the disulphide bridge and then the N- and C-terminal regions of the molecule thus making it unmeasurable by antisera sensitive to changes in these

  3. Immunohistochemical detection of somatostatin receptor subtypes sst1 and sst2A in human somatostatin receptor positive tumors

    NARCIS (Netherlands)

    L.J. Hofland (Leo); Q. Liu; P.M. van Koetsveld (Peter); J. Zuijderwijk; F. van der Ham (Frieda); R.R. de Krijger (Ronald); A. Schonbrunn; S.W.J. Lamberts (Steven)


    textabstractAlthough in situ hybridization has been used to examine the distribution of messenger RNA for somatostatin receptor subtypes (sst) in human tumors, the cellular localization of sst1 and sst2A receptors has not been reported. In this study, we describe the ce

  4. An update on the treatment of type 1 and type 2 diabetes mellitus: focus on insulin detemir, a long-acting human insulin analog

    Directory of Open Access Journals (Sweden)

    Katarina Raslova


    Full Text Available Katarina RaslovaMetabolic Center Ltd and Slovak Medical University, Bratislava, Slovak RepublicAbstract: Basal insulin analogs are used to minimize unpredictable processes of NPH insulin. Modification of the human insulin molecule results in a slower distribution to peripheral target tissues, a longer duration of action with stable concentrations and thus a lower rate of hypoglycemia. Insulin detemir is a basal insulin analog that provides effective therapeutic options for patients with type 1 and type 2 diabetes. For glycemic control, no significant differences were found in HbA1c levels compared with NPH and insulin glargine. It is comparable with insulin glargine in significantly reducing rates of all types of hypoglycemia. Clinical studies have demonstrated that detemir is responsible for significantly lower within-subject variability and no or less weight gain than NPH insulin and glargine. Recent pharmacodynamic studies have shown that detemir can be used once daily in many patients with diabetes. Together with patient-friendly injection devices and dose adjustments, it provides a treatment option with the potential to lower the key barriers of adherence to insulin therapy in type 2 diabetes. Recent guidelines for treatment of type 2 diabetes suggest starting intensive therapy of hyperglycemia at an early stage of diabetes and recommend therapeutic options that provide the possibility of reaching HbA1c goals individually, with a low risk of hypoglycemia or other adverse effects of treatment. The properties of insulin detemir match these requirements.Keywords: insulin analog, insulin detemir, diabetes mellitus, hypoglycemia, within-subject variability

  5. The truncated isoform of somatostatin receptor5 (sst5TMD4 is associated with poorly differentiated thyroid cancer.

    Directory of Open Access Journals (Sweden)

    Manel Puig-Domingo

    Full Text Available Somatostatin receptors (ssts are expressed in thyroid cancer cells, but their biological significance is not well understood. The aim of this study was to assess ssts in well differentiated (WDTC and poorly differentiated thyroid cancer (PDTC by means of imaging and molecular tools and its relationship with the efficacy of somatostatin analog treatment. Thirty-nine cases of thyroid carcinoma were evaluated (20 PDTC and 19 WDTC. Depreotide scintigraphy and mRNA levels of sst-subtypes, including the truncated variant sst5TMD4, were carried out. Depreotide scans were positive in the recurrent tumor in the neck in 6 of 11 (54% PDTC, and in those with lung metastases in 5/11 cases (45.4%; sst5TMD4 was present in 18/20 (90% of PDTC, being the most densely expressed sst-subtype, with a 20-fold increase in relation to sst2. In WDTC, sst2 was the most represented, while sst5TMD4 was not found; sst2 was significantly increased in PDTC in comparison to WDTC. Five depreotide positive PDTC received octreotide for 3-6 months in a pilot study with no changes in the size of the lesions in 3 of them, and a significant increase in the pulmonary and cervical lesions in the other 2. All PDTC patients treated with octreotide showed high expression of sst5TMD4. ROC curve analysis demonstrated that only sst5TMD4 discriminates between PDTC and WDTC. We conclude that sst5TMD4 is overexpressed in PDTC and may be involved in the lack of response to somatostatin analogue treatment.

  6. Protein acylation in the inhibition of insulin secretion by norepinephrine, somatostatin, galanin, and PGE2. (United States)

    Cheng, Haiying; Straub, Susanne G; Sharp, Geoffrey W G


    The major physiological inhibitors of insulin secretion, norepinephrine, somatostatin, galanin, and prostaglandin E2, act via specific receptors that activate pertussis toxin (PTX)-sensitive G proteins. Four inhibitory mechanisms are known: 1) activation of ATP-sensitive K channels and repolarization of the beta-cell; 2) inhibition of L-type Ca2+ channels; 3) decreased activity of adenylyl cyclase; and 4) inhibition of exocytosis at a "distal" site in stimulus-secretion coupling. We have examined the underlying mechanisms of inhibition at this distal site. In rat pancreatic islets, 2-bromopalmitate, cerulenin, and polyunsaturated fatty acids, all of which suppress protein acyltransferase activity, blocked the distal inhibitory effects of norepinephrine in a concentration-dependent manner. In contrast, control compounds such as palmitate, 16-hydroxypalmitate, and etomoxir, which do not block protein acylation, had no effect. Furthermore, 2-bromopalmitate also blocked the distal inhibitory actions of somatostatin, galanin, and prostaglandin E2. Importantly, neither 2-bromopalmitate nor cerulenin affected the action of norepinephrine to decrease cAMP production. We also examined the effects of norepinephrine, 2-bromopalmitate, and cerulenin on palmitate metabolism. Palmitate oxidation and its incorporation into lipids seemed not to contribute to the effects of 2-bromopalmitate and cerulenin on norepinephrine action. These data suggest that protein acylation mediates the distal inhibitory effect on insulin secretion. We propose that the inhibitors of insulin secretion, acting via PTX-sensitive G proteins, activate a specific protein acyltransferase, causing the acylation of a protein or proteins critical to exocytosis. This particular acylation and subsequent disruption of the essential and precise interactions involved in core complex formation would block exocytosis.

  7. Patient-reported outcomes of parenteral somatostatin analogue injections in 195 patients with acromegaly (United States)

    Strasburger, Christian J; Karavitaki, Niki; Störmann, Sylvère; Trainer, Peter J; Kreitschmann-Andermahr, Ilonka; Droste, Michael; Korbonits, Márta; Feldmann, Berit; Zopf, Kathrin; Sanderson, Violet Fazal; Schwicker, David; Gelbaum, Dana; Haviv, Asi; Bidlingmaier, Martin; Biermasz, Nienke R


    Background Long-acting somatostatin analogues delivered parenterally are the most widely used medical treatment in acromegaly. This patient-reported outcomes survey was designed to assess the impact of chronic injections on subjects with acromegaly. Methods The survey was conducted in nine pituitary centres in Germany, UK and The Netherlands. The questionnaire was developed by endocrinologists and covered aspects of acromegaly symptoms, injection-related manifestations, emotional and daily life impact, treatment satisfaction and unmet medical needs. Results In total, 195 patients participated, of which 112 (57%) were on octreotide (Sandostatin LAR) and 83 (43%) on lanreotide (Somatuline Depot). The majority (>70%) of patients reported acromegaly symptoms despite treatment. A total of 52% of patients reported that their symptoms worsen towards the end of the dosing interval. Administration site pain lasting up to a week following injection was the most frequently reported injection-related symptom (70% of patients). Other injection site reactions included nodules (38%), swelling (28%), bruising (16%), scar tissue (8%) and inflammation (7%). Injection burden was similar between octreotide and lanreotide. Only a minority of patients received injections at home (17%) and 5% were self-injecting. Over a third of patients indicated a feeling of loss of independence due to the injections, and 16% reported repeated work loss days. Despite the physical, emotional and daily life impact of injections, patients were satisfied with their treatment, yet reported that modifications that would offer major improvement over current care would be ‘avoiding injections’ and ‘better symptom control’. Conclusion Lifelong injections of long-acting somatostatin analogues have significant burden on the functioning, well-being and daily lives of patients with acromegaly. PMID:26744896

  8. An adaptive, dose-finding, seamless phase 2/3 study of a long-acting glucagon-like peptide-1 analog (dulaglutide): trial design and baseline characteristics. (United States)

    Geiger, Mary Jane; Skrivanek, Zachary; Gaydos, Brenda; Chien, Jenny; Berry, Scott; Berry, Donald


    Dulaglutide (dula, LY2189265) is a once-weekly glucagon-like peptide-1 analog in development for the treatment of type 2 diabetes mellitus. An adaptive, dose-finding, inferentially seamless phase 2/3 study was designed to support the development of this novel diabetes therapeutic. The study is divided into two stages based on two randomization schemes: a Bayesian adaptive scheme (stage 1) and a fixed scheme (stage 2). Stage 1 of the trial employs an adaptive, dose-finding design to lead to a dula dose-selection decision or early study termination due to futility. If dose selection occurs, the study proceeds to stage 2 to allow continued evaluation of the selected dula doses. At completion, the entire study will serve as a confirmatory phase 3 trial. The final study design is discussed, along with specifics pertaining to the actual execution of this study and selected baseline characteristics of the participants.


    Institute of Scientific and Technical Information of China (English)

    李济宇; 全志伟; 张强; 刘建文


    Objective To explore the effect of somatostatin on the cell cycle of human gallbladder cancer cell. Methods Growth curve of gallbladder cancer cell was measured after somatostatin treated on gradient concentration. Simultaneously, the change of gallbladder cancer cell cycle was detected using flow cytometry.Results Concentration-dependent cell growth inhibition caused by somatostatin was detected in gallbladder cancer cell(P<0.05). Cell growth was arrested in S phase since 12h after somatostatin treated, which reached its peak at 24h, then fell down. The changes in apoptosis index of gallbladder cancer cell caused by somatostatin correlated with that's in cell cycle. Conclusion Somatostatin could inhibit the cell growth of human gallbladder cancer cell in vitro on higher concentration. It might result from inducing growth arrest in S phase in early stage and inducing apoptosis in the late stage.

  10. Hilar somatostatin interneuron loss reduces dentate gyrus inhibition in a mouse model of temporal lobe epilepsy. (United States)

    Hofmann, Gabrielle; Balgooyen, Laura; Mattis, Joanna; Deisseroth, Karl; Buckmaster, Paul S


    In patients with temporal lobe epilepsy, seizures usually start in the hippocampus, and dentate granule cells are hyperexcitable. Somatostatin interneurons are a major subpopulation of inhibitory neurons in the dentate gyrus, and many are lost in patients and animal models. However, surviving somatostatin interneurons sprout axon collaterals and form new synapses, so the net effect on granule cell inhibition remains unclear. The present study uses optogenetics to activate hilar somatostatin interneurons and measure the inhibitory effect on dentate gyrus perforant path-evoked local field potential responses in a mouse model of temporal lobe epilepsy. In controls, light activation of hilar somatostatin interneurons inhibited evoked responses up to 40%. Epileptic pilocarpine-treated mice exhibited loss of hilar somatostatin interneurons and less light-induced inhibition of evoked responses. These findings suggest that severe epilepsy-related loss of hilar somatostatin interneurons can overwhelm the surviving interneurons' capacity to compensate by sprouting axon collaterals. Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.

  11. Effect of cysteamine on cytosolic somatostatin binding sites in rabbit duodenal mucosa. (United States)

    Gonzalez-Guijarro, L; Lopez-Ruiz, M P; Bodegas, G; Prieto, J C; Arilla, E


    Administration of cysteamine in rabbits elicited a rapid depletion of both duodenal mucosa and plasma somatostatin. A significant reduction was observed within 5 min, returning toward control values by 150 min. The depletion of somatostatin was associated with an increase in the binding capacity and a decrease in the affinity of both high- and low-affinity binding sites present in cytosol of duodenal mucosa. Incubation of cytosolic fraction from control rabbits with 1 mM cysteamine did not modify somatostatin binding. Furthermore, addition of cysteamine at the time of binding assay did not affect the integrity of 125I-Tyr11-somatostatin. It is concluded that in vivo administration of cysteamine to rabbits depletes both duodenal mucosa and plasma somatostatin and leads to up-regulation of duodenal somatostatin binding sites.

  12. Reduced Numbers of Somatostatin Receptors in the Cerebral Cortex in Alzheimer's Disease (United States)

    Flint Beal, M.; Mazurek, Michael F.; Tran, Vinh T.; Chattha, Geetinder; Bird, Edward D.; Martin, Joseph B.


    Somatostatin receptor concentrations were measured in patients with Alzheimer's disease and controls. In the frontal cortex (Brodmann areas 6, 9, and 10) and temporal cortex (Brodmann area 21), the concentrations of somatostatin in receptors in the patients were reduced to approximately 50 percent of control values. A 40 percent reduction was seen in the hippocampus, while no significant changes were found in the cingulate cortex, postcentral gyrus, temporal pole, and superior temporal gyrus. Scatchard analysis showed a reduction in receptor number rather than a change in affinity. Somatostatin-like immunoreactivity was significantly reduced in both the frontal and temporal cortex. Somatostatin-like immunoreactivity was linearly related to somatostatin-receptor binding in the cortices of Alzheimer's patients. These findings may reflect degeneration of postsynaptic neurons or cortical afferents in the patients' cerebral cortices. Alternatively, decreased somatostatinlike immunoreactivity in Alzheimer's disease might indicate increased release of somatostatin and down regulation of postsynaptic receptors.

  13. The effect of somatostatin on release and insulinotropic action of gastric inhibitory polypeptide. (United States)

    Pederson, R A; Dryburgh, J R; Brown, J C


    Studies were carried out in conscious dogs in which the effect of intravenous somatostatin on immunoreactive gastric inhibitory polypeptide (IR-GIP) release was investigated. In addition, the inhibitory action of somatostatin on the insulin response to pure porcine GIP was assessed. Intravenous administration of somatostatin resulted in a delayed IR-GIP and immunoreactive insulin (IRI) response to oral glucose. Somatostatin also delayed the IR-GIP response to the ingestion of fat. In both types of experiments, initial depression of IRI levels was followed by a sharp rise in IRI release. Intravenous infusion of somatostatin produced 80% inhibition of the IRI response to pure porcine GIP. It was concluded that somatostatin inhibits the physiological release of IR-GIP and the insulinotropic action of exogenous porcine GIP.

  14. The effect of somatostatin in dumping syndrome after gastric surgery. (United States)

    Tulassay, Z; Tulassay, T; Gupta, R; Tamás, G


    The effect of somatostatin on early and late dumping syndrome was studied in 12 patients with gastric resection. Each patient underwent two glucose challenges with 75 gram of glucose administered orally. In the control study isotonic sodium chloride was given, while in the other study cyclic somatostatin in a dose of 80 ng/kg/min was given for a period of 270 minutes. In the control study all patients showed subjective symptoms of the early dumping syndrome with significant (p dumping syndrome associated with a significant (p dumping syndrome partly by inhibiting the vasoactive intestinal polypeptide, gastric inhibitory peptide and insulin release, which are increased in dumping syndrome and may, therefore, be implicated as to have an etiological role.

  15. Down-regulation of pancreatic and duodenal homeobox-1 by somatostatin receptor subtype 5: a novel mechanism for inhibition of cellular proliferation and insulin secretion by somatostatin

    Directory of Open Access Journals (Sweden)

    Charles eBrunicardi


    Full Text Available Somatostatin is a regulatory peptide and acts as an endogenous inhibitory regulator of the secretory and proliferative responses of target cells. Somatostatin’s actions are mediated by a family of seven transmembrane domain G protein-coupled receptors that comprise five distinct subtypes (SSTR1-5. SSTR5 is one of the major SSTRs in the islets of Langerhans. Homeodomain-containing transcription factor pancreatic and duodenal homeobox-1 (PDX-1 is essential for pancreatic development, β cell differentiation, maintenance of normal β cell functions in adults and tumorigenesis. Recent studies show that SSTR5 acts as a negative regulator for PDX-1 expression and that SSTR5 mediates somatostatin’s inhibitory effect on cell proliferation and insulin expression/excretion through down-regulating PDX-1 expression. SSTR5 exerts its inhibitory effect on PDX-1 expression at both the transcriptional level by down-regulating PDX-1 mRNA and the post-translational level by enhancing PDX-1 ubiquitination. Identification of PDX-1 as a transcriptional target for SSTR5 may help in guiding the choice of therapeutic cancer treatments.

  16. Active postoperative acromegaly: sustained remission after discontinuation of somatostatin analogues (United States)

    Cardenas-Salas, Jersy


    Summary In patients with active acromegaly after pituitary surgery, somatostatin analogues are effective in controlling the disease and can even be curative in some cases. After treatment discontinuation, the likelihood of disease recurrence is high. However, a small subset of patients remains symptom-free after discontinuation, with normalized growth hormone (GH) and insulin-like growth factor (IGF1) levels. The characteristics of patients most likely to achieve sustained remission after treatment discontinuation are not well understood, although limited evidence suggests that sustained remission is more likely in patients with lower GH and IGF1 levels before treatment withdrawal, in those who respond well to low-dose treatment, in those without evidence of adenoma on an MRI scan and/or in patients who receive long-term treatment. In this report, we describe the case of a 56-year-old female patient treated with lanreotide Autogel for 11 years. Treatment was successfully discontinued, and the patient is currently disease-free on all relevant parameters (clinical, biochemical and tumour status). The successful outcome in this case adds to the small body of literature suggesting that some well-selected patients who receive long-term treatment with somatostatin analogues may achieve sustained remission. Learning points: The probability of disease recurrence is high after discontinuation of treatment with somatostatin analogues. Current data indicate that remission after treatment discontinuation may be more likely in patients with low GH and IGF1 levels before treatment withdrawal, in those who respond well to low-dose treatment, in those without evidence of adenoma on MRI, and/or in patients receiving prolonged treatment. This case report suggests that prolonged treatment with somatostatin analogues can be curative in carefully selected patients. PMID:27933171

  17. Somatostatin actions via somatostatin receptors on the ocular surface are modulated by inflammatory processes. (United States)

    Minsel, Ivonne; Mentlein, Rolf; Sel, Saadettin; Diebold, Yolanda; Bräuer, Lars; Mühlbauer, Eckhard; Paulsen, Friedrich P


    Recent investigations support the presence of human somatostatin (SS) in the excretory system of the human lacrimal gland. To get deeper insights into a possible role of SS at the ocular surface and in the lacrimal apparatus, we investigated the distribution pattern of SS and its receptors 1-5 (SSTR1-5) by means of RT-PCR, real-time RT-PCR, Western blot and immunodot blot analysis as well as immunohistochemistry in lacrimal gland, tear fluid, conjunctiva, cornea, nasolacrimal duct epithelium, and conjunctival (HCjE) and corneal (HCE) epithelial cell lines. Cell culture experiments with HCjE and HCE were performed to analyze a possible impact of SS and inflammatory mediators on the regulation of SSTR. The results confirmed the presence of SS in lacrimal gland and tear fluid, whereas it was absent at the protein level in all other tissues and cell lines investigated. Expression of SSTR1, -2, and -5 was detectable in lacrimal gland, conjunctiva, cornea, and nasolacrimal ducts. HCjE expressed only hSSTR1 and -2, and HCE revealed only SSTR2. SSTR3 and -4 were not detected in any of the analyzed samples or cell lines. In vitro on cultured immortalized HCjE cells SS leads to a concentration-dependent down-regulation of SSTR1 mRNA but does not affect SSTR2 mRNA expression. Relative expression of SSTR1 and -2 is differentially modulated by proinflammatory cytokines and bacterial components, suggesting that the expression of both receptors is immunomodulated. Our data support an autocrine and paracrine role of SS in the lacrimal system and at the ocular surface and implicate a role of SS in corneal immunology.

  18. Homogeneity in the growth hormone-lowering effect of dopamine and somatostatin in acromegaly. (United States)

    Oppizzi, G; Botalla, L; Verde, G; Cozzi, R; Liuzzi, A; Chiodini, P G


    We have studied the effect of maximally inhibiting doses of dopamine (DA) or somatostatin on GH levels in 39 acromegalic patients. The GH-lowering effects of the two drugs were highly variable in different patients. A significant correlation (r = 0.45; P affect the response to somatostatin. We conclude that the GH-secreting cells of acromegalic patients contain separate receptors for DA and somatostatin. We hypothesize that the partial or total lack of responsiveness to DA or somatostatin may be due to the loss of receptors for these agents on the GH-secreting neoplastic cells.

  19. Immunohistochemical and cytochemical localization of the somatostatin receptor subtype sst1 in the somatostatinergic parvocellular neuronal system of the rat hypothalamus

    DEFF Research Database (Denmark)

    Helboe, Lone; Stidsen, Cartsen E.; Møller, Morten


    Somatostatin receptor, sst1, immunohistochemistry, ultrastructure, autoreceptor, hypothalamus, median eminence, synapse......Somatostatin receptor, sst1, immunohistochemistry, ultrastructure, autoreceptor, hypothalamus, median eminence, synapse...

  20. Therapy of neuroendocrine tumors with radiolabeled somatostatin-analogues

    Energy Technology Data Exchange (ETDEWEB)

    De Jong, M.; Breeman, A.P.; Bernard, H.F.; Kooij, P.P.M.; Kwekkeboom, D.J.; Valkema, R. [Rotterdam University Hospital and Erasmus University, Rotterdam (Netherlands). Internal Medicine; Van Eijck, C.H.J.; Slooter, G.D. [Basel Surgery, Basel (Switzerland). Dept. of Nuclear Medicine; Maecke, H.R.; Krenning, E.P. [Basel Kantonspital, Basel (Switzerland). Dept. of Nuclear Medicine


    Peptide receptor scintigraphy with the radioactive somatostatin-analogue ({sup 111}In-DTPA{sup 0})octreotide (DTPA=diethylenetriaminepentaacetic acid) is a sensitive and specific technique to show in vivo the presence and abundance of somatostatin receptors on various tumors. With this technique primary tumors and metastases of neuroendocrine cancers as well as of many other cancer types can be localised. A new application is the use of peptide receptor radionuclide therapy, administrating high doses of {sup 111}In- or {sup 90}Y-labeled octreotide-analogues. In the preclinical situation it was investigated on the radiotherapeutic effect of {sup 90}Y- and {sup 111}In-labeled (DOTA{sup 0}, Tyr{sup 3})octreotide (DOTA=tetraazacyclododecanetetraacetic acid) or ({sup 111}In-DTPA{sup 0})octreotide in Lewis rats bearing the somatostatin receptor-positive rat pancreatic tumor CA20948 in (A) the flank of (B) in the liver. Thirty end-stage patients with mostly neuroendocrine progressing tumors were treated with ({sup 111}In-DTPA{sup 0})octreotide, up to a maximal cumulative patient dose of about 74 GBq, in a phase 1 trial. (A) Flank model: at least two 111MBq injections of ({sup 111}In-DOTA{sup 0}, Tyr{sup 3})octreotide were needed to reach tumor response, in 40% of the animals complete tumor remission was found after a follow-up period of 10 months. One or two injections of ({sup 90}Y-DOTA{sup 0}, Tyr{sup 3})octreotide yielded transient stable disease. (B) Liver model: it was found that peptide receptor radionuclide therapy is only effective if somatostatin receptors are present on the tumors, and is therefore receptor-mediated. High radioactive doses of 370 MBq ({sup 111}In-DTPA{sup 0})octreotide or 93 MBq ({sup 90}Y-DOTA{sup 0}, Tyr{sup 3})octreotide can inhibit the growth of somatostatin receptor-positive metastases. There were no major clinical side effects after up to 2 years treatment, except that a transient decline in platelet counts and lymphocyte subsets can occur

  1. BA321, a novel carborane analog that binds to androgen and estrogen receptors, acts as a new selective androgen receptor modulator of bone in male mice

    Energy Technology Data Exchange (ETDEWEB)

    Watanabe, Kenta [Department of Biotechnology and Life Science, Tokyo University of Agriculture and Technology, 2-24-16 Nakamachi, Koganei, Tokyo 184-8588 (Japan); Cooperative Major in Advanced Health Science, Tokyo University of Agriculture and Technology, 2-24-16 Nakamachi, Koganei, Tokyo 184-8588 (Japan); Hirata, Michiko [Department of Biotechnology and Life Science, Tokyo University of Agriculture and Technology, 2-24-16 Nakamachi, Koganei, Tokyo 184-8588 (Japan); Tominari, Tsukasa [Department of Biotechnology and Life Science, Tokyo University of Agriculture and Technology, 2-24-16 Nakamachi, Koganei, Tokyo 184-8588 (Japan); Institute of Global Innovation Research, Tokyo University of Agriculture and Technology, 2-24-16 Nakamachi, Koganei, Tokyo 184-8588 (Japan); Matsumoto, Chiho [Department of Biotechnology and Life Science, Tokyo University of Agriculture and Technology, 2-24-16 Nakamachi, Koganei, Tokyo 184-8588 (Japan); Endo, Yasuyuki [Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1, Komatsushima, Aoba-ku, Sendai, 981-8558 (Japan); Murphy, Gillian [Department of Oncology, University of Cambridge, Cancer Research UK, Cambridge Institute, Li Ka Shing Centre, Cambridge, CB2 0RE (United Kingdom); Nagase, Hideaki [Institute of Global Innovation Research, Tokyo University of Agriculture and Technology, 2-24-16 Nakamachi, Koganei, Tokyo 184-8588 (Japan); Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, OX3 7FY (United Kingdom); and others


    Carboranes are a class of carbon-containing polyhedral boron cluster compounds with globular geometry and hydrophobic surface that interact with hormone receptors such as estrogen receptor (ER) and androgen receptor (AR). We have synthesized BA321, a novel carborane compound, which binds to AR. We found here that it also binds to ERs, ERα and ERβ. In orchidectomized (ORX) mice, femoral bone mass was markedly reduced due to androgen deficiency and BA321 restored bone loss in the male, whilst the decreased weight of seminal vesicle in ORX mice was not recovered by administration of BA321. In female mice, BA321 acts as a pure estrogen agonist, and restored both the loss of bone mass and uterine atrophy due to estrogen deficiency in ovariectomized (OVX) mice. In bone tissues, the trabecular bone loss occurred in both ORX and OVX mice, and BA321 completely restored the trabecular bone loss in both sexes. Cortical bone loss occurred in ORX mice but not in OVX mice, and BA321 clearly restored cortical bone loss due to androgen deficiency in ORX mice. Therefore, BA321 is a novel selective androgen receptor modulator (SARM) that may offer a new therapy option for osteoporosis in the male. - Highlights: • A novel carborane compound BA321 binds to both AR and ERs, ERα and ERβ. • BA321 restores bone loss in orchidectomized mice without effects on sex organ. • BA321 acts as an estrogen agonist in bone and uterus in ovariectomized mice. • BA321 may be a new SARM to prevent the loss of musculoskeletal mass in elder men.

  2. VIP and Calcitonin-Producing Pancreatic Neuroendocrine Tumor with Watery Diarrhea: Clinicopathological Features and the Effect of Somatostatin Analogue

    Directory of Open Access Journals (Sweden)

    Tomoya Kon


    Full Text Available Context Pancreatic neuroendocrine tumor (pNET secretes various peptide hormones; however, calcitonin hypersecretion is rare. Its clinicopathological significance and treatment is still controversial. Case report A 43 year-old Japanese man presented severe watery diarrhea and a large mass in the pancreatic tail. Blood concentration of VIP was elevated to 649 pg/mL (reference range: 0- 100 pg/mL, and calcitonin to 66,700 pg/mL (reference range: 15-86 pg/mL. There was no tumor in other endocrine organs. The resected tumor was composed of 80% calcitonin-positive cells and 10% VIP-positive cells. After the operation, the levels of VIP and calcitonin were decreased to 44 and 553 pg/mL, respectively, and diarrhea was improved. The mRNA of somatostatin receptor (SSTR subtypes 2, 3 and 5 in the tumor tissue were increased 22.8, 25.1, and 37.0-fold of those of normal pancreas, respectively. At 19 months after the operation, blood calcitonin was again raised to 3,980 pg/mL, and metastatic tumors were found in the liver. With the treatment of long-acting somatostatin analogue, calcitonin was reduced to 803 pg/mL. The patient does not present endocrine symptom, and the size of the metastatic tumors appears stable. Conclusion From the world literature to date, co-secretion of VIP and calcitonin was documented in only 10 cases of pNET including the current case. Although VIP is a primary cause of diarrhea in these cases, high level of calcitonin may also influence on the clinical symptoms. Somatostatin analogue suppresses the levels of VIP and calcitonin, and the control proliferation is also expected when tumor cells express SSTRs.

  3. BA321, a novel carborane analog that binds to androgen and estrogen receptors, acts as a new selective androgen receptor modulator of bone in male mice. (United States)

    Watanabe, Kenta; Hirata, Michiko; Tominari, Tsukasa; Matsumoto, Chiho; Endo, Yasuyuki; Murphy, Gillian; Nagase, Hideaki; Inada, Masaki; Miyaura, Chisato


    Carboranes are a class of carbon-containing polyhedral boron cluster compounds with globular geometry and hydrophobic surface that interact with hormone receptors such as estrogen receptor (ER) and androgen receptor (AR). We have synthesized BA321, a novel carborane compound, which binds to AR. We found here that it also binds to ERs, ERα and ERβ. In orchidectomized (ORX) mice, femoral bone mass was markedly reduced due to androgen deficiency and BA321 restored bone loss in the male, whilst the decreased weight of seminal vesicle in ORX mice was not recovered by administration of BA321. In female mice, BA321 acts as a pure estrogen agonist, and restored both the loss of bone mass and uterine atrophy due to estrogen deficiency in ovariectomized (OVX) mice. In bone tissues, the trabecular bone loss occurred in both ORX and OVX mice, and BA321 completely restored the trabecular bone loss in both sexes. Cortical bone loss occurred in ORX mice but not in OVX mice, and BA321 clearly restored cortical bone loss due to androgen deficiency in ORX mice. Therefore, BA321 is a novel selective androgen receptor modulator (SARM) that may offer a new therapy option for osteoporosis in the male. Copyright © 2016 Elsevier Inc. All rights reserved.

  4. Somatostatin receptor scintigraphy using (99m)Tc-EDDA/HYNIC-TOC in patients with medullary thyroid carcinoma

    NARCIS (Netherlands)

    Czepczynski, Rafal; Parisella, Maria Gemma; Kosowicz, Jerzy; Mikolajczak, Renata; Ziemnicka, Katarzyna; Gryczynska, Maria; Sowinski, Jerzy; Signore, Alberto


    Purpose Several new somatostatin analogues have been developed for the diagnosis and therapy of different tumours. Since somatostatin receptors are often over-expressed in medullary thyroid carcinoma (MTC), the aim of our study was to evaluate the utility of scintigraphy with the somatostatin

  5. Somatostatin receptor scintigraphy in patients with rheumatoid arthritis and secondary Sjogren's syndrome treated with Infliximab : a pilot study

    NARCIS (Netherlands)

    Anzola-Fuentes, L. K.; Chianelli, M.; Galli, F.; Glaudemans, A. W. J. M.; Martin, L. Martin; Todino, V.; Migliore, A.; Signore, A.


    Background: Human T lymphocytes infiltrating tissues in autoimmune diseases are known to express somatostatin receptors amongst other activation markers. In this study, we evaluated whether somatostatin receptor scintigraphy (SRS) using a radiolabelled somatostatin analogue (Tc-99m-EDDA/tricine-HYNI

  6. Localisation and mechanism of renal retention of radiolabelled somatostatin analogues

    Energy Technology Data Exchange (ETDEWEB)

    Melis, Marleen; Krenning, Eric P.; Bernard, Bert F.; Jong, Marion de [Erasmus MC, Department of Nuclear Medicine, Rotterdam (Netherlands); Barone, Raffaella [UCL, Centre of Nuclear Medicine and Laboratory of PET, Brussels (Belgium); Visser, Theo J. [Erasmus MC, Department of Internal Medicine, Rotterdam (Netherlands)


    Radiolabelled somatostatin analogues, such as octreotide and octreotate, are used for tumour scintigraphy and radionuclide therapy. The kidney is the most important critical organ during such therapy owing to the reabsorption and retention of radiolabelled peptides. The aim of this study was to investigate in a rat model both the localisation and the mechanism of renal uptake after intravenous injection of radiolabelled somatostatin analogues. The multi-ligand megalin/cubilin receptor complex, responsible for reabsorption of many peptides and proteins in the kidney, is an interesting candidate for renal endocytosis of these peptide analogues. For localisation studies, ex vivo autoradiography and micro-autoradiography of rat kidneys were performed 1-24 h after injection of radiolabelled somatostatin analogues and compared with the renal anti-megalin immunohistochemical staining pattern. To confirm a role of megalin in the mechanism of renal retention of [{sup 111}In-DTPA]octreotide, the effects of three inhibitory substances were explored in rats. Renal ex vivo autoradiography showed high cortical radioactivity and lower radioactivity in the outer medulla. The distribution of cortical radioactivity was inhomogeneous. Micro-autoradiography indicated that radioactivity was only retained in the proximal tubules. The anti-megalin immunohistochemical staining pattern showed a strong similarity with the renal [{sup 111}In-DTPA]octreotide ex vivo autoradiograms. Biodistribution studies showed that co-injection of positively charged d-lysine reduced renal uptake to 60% of control. Sodium maleate reduced renal [{sup 111}In-DTPA]octreotide uptake to 15% of control. Finally, cisplatin pre-treatment of rats reduced kidney uptake to 70% of control. Renal retention of [{sup 111}In-DTPA]octreotide is confined to proximal tubules in the rat kidney, in which megalin-mediated endocytosis may play an important part. (orig.)

  7. Somatostatin modulates insulin-degrading-enzyme metabolism: implications for the regulation of microglia activity in AD.

    Directory of Open Access Journals (Sweden)

    Grazia Tundo

    Full Text Available The deposition of β-amyloid (Aβ into senile plaques and the impairment of somatostatin-mediated neurotransmission are key pathological events in the onset of Alzheimer's disease (AD. Insulin-degrading-enzyme (IDE is one of the main extracellular protease targeting Aβ, and thus it represents an interesting pharmacological target for AD therapy. We show that the active form of somatostatin-14 regulates IDE activity by affecting its expression and secretion in microglia cells. A similar effect can also be observed when adding octreotide. Following a previous observation where somatostatin directly interacts with IDE, here we demonstrate that somatostatin regulates Aβ catabolism by modulating IDE proteolytic activity in IDE gene-silencing experiments. As a whole, these data indicate the relevant role played by somatostatin and, potentially, by analogue octreotide, in preventing Aβ accumulation by partially restoring IDE activity.

  8. Ontogeny of somatostatin mRNA-containing perikarya in the rat central nervous system

    Energy Technology Data Exchange (ETDEWEB)

    Fitzpatrick-McElligott, S.; Card, J.P.; O' Kane, T.M.; Baldino, F. Jr. (E.I. du Pont de Nemours and Co., Wilmington, DE (USA))


    The distribution of neuronal perikarya containing somatostatin mRNA in the developing rat brain was investigated with in situ hybridization histochemistry. This study describes the expression of somatostatin mRNA during selected perinatal stages and demonstrates regional changes in somatostatin mRNA expression at the single cell level. The mRNA expression closely parallels previously reported developmental localization of the peptide. As early as embryonic day 13 (E13), somatostatin mRNA was observed in discrete spinal cord and brainstem regions. At birth, densely hybridized somata could be seen primarily in ventral and caudal brain areas with small scattered neurons in the hippocampus and dorsal neocortex. After birth, somatostatin mRNA increased in forebrain regions, such as the hippocampus, dorsal neocortex, and caudate. By postnatal day 14 (P14), the distribution in the telencephalic and diencephalic regions approached that of the adult brain. Several brain regions manifested large changes in the density of somatostatin mRNA hybridization during development. For example, the cerebellar vermis and brainstem contained somatostatin mRNA perikarya during early postnatal development but decreased in these regions in the adult. During perinatal development, increases in somatostatin mRNA content were the results of increases in both the number of neurons containing somatostatin mRNA as well as in the amount of this mRNA expressed in each cell. As the brain differentiates, the apparent numbers of somatostatin mRNA containing neurons in certain brain regions are reduced. These data provide evidence for transient somatostatinergic neurons during early development in discrete areas of the occipital cortex, pyriform cortex, cerebellum, and brainstem and suggest that this peptide may play a role in the development of these regions.

  9. Cell-to-cell communication and cellular environment alter the somatostatin status of delta cells

    Energy Technology Data Exchange (ETDEWEB)

    Kelly, Catriona, E-mail: [SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine (United Kingdom); Flatt, Peter R.; McClenaghan, Neville H. [SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine (United Kingdom)


    Research highlights: {yields} TGP52 cells display enhanced functionality in pseudoislet form. {yields} Somatostatin content was reduced, but secretion increased in high glucose conditions. {yields} Cellular interactions and environment alter the somatostatin status of TGP52 cells. -- Abstract: Introduction: Somatostatin, released from pancreatic delta cells, is a potent paracrine inhibitor of insulin and glucagon secretion. Islet cellular interactions and glucose homeostasis are essential to maintain normal patterns of insulin secretion. However, the importance of cell-to-cell communication and cellular environment in the regulation of somatostatin release remains unclear. Methods: This study employed the somatostatin-secreting TGP52 cell line maintained in DMEM:F12 (17.5 mM glucose) or DMEM (25 mM glucose) culture media. The effect of pseudoislet formation and culture medium on somatostatin content and release in response to a variety of stimuli was measured by somatostatin EIA. In addition, the effect of pseudoislet formation on cellular viability (MTT and LDH assays) and proliferation (BrdU ELISA) was determined. Results: TGP52 cells readily formed pseudoislets and showed enhanced functionality in three-dimensional form with increased E-cadherin expression irrespective of the culture environment used. However, culture in DMEM decreased cellular somatostatin content (P < 0.01) and increased somatostatin secretion in response to a variety of stimuli including arginine, calcium and PMA (P < 0.001) when compared with cells grown in DMEM:F12. Configuration of TGP52 cells as pseudoislets reduced the proliferative rate and increased cellular cytotoxicity irrespective of culture medium used. Conclusions: Somatostatin secretion is greatly facilitated by cell-to-cell interactions and E-cadherin expression. Cellular environment and extracellular glucose also significantly influence the function of delta cells.

  10. Alteration of somatostatin receptor subtype 2 gene expression in pancreatic tumor angiogenesis

    Institute of Scientific and Technical Information of China (English)

    Ren-Yi Qin; Ru-Liang Fang; Manoj Kumar Gupta; Zheng-Ren Liu; Da-Yu Wang; Qing Chang; Yi-Bei Chen


    AIM: To explore the difference of somatostatin receptorsubtype 2 (SST2R) gene expression in pancreatic canceroustissue and its adjacent tissue, and the relationship betweenthe change of SST2R gene expression and pancreatic tumorangiogenesis related genes.METHODS: The expressions of SST2R, DPC4, p53 and ras genes in cancer tissues of 40 patients with primary pancreatic cancer, and the expression of SST2R gene in its adjacent tissue were determined by immunohistochemiscal LSAB method and EnVisionTM method. Chi-square test was used to analyze the difference in expression of SST2R in pancreatic cancer tissue and its adjacent tissue, and the correlation of SST2R gene expression with the expression of p53, ras and DPC4 genes.RESULTS: Of the tissue specimens from 40 patients with primary pancreatic cancer, 35 (87.5%) cancer tissues showed a negative expression of SST2R gene, whereas 34 (85%) a positive expression of SST2R gene in its adjacent tissues.Five (12.5%) cancer tissues and its adjacent tissues simultaneously expressed SST2R. The expression of SST2R gene was markedly higher in pancreatic tissues adjacent to cancer than in pancreatic cancer tissues (P<0.05). The expression rates of p53, ras and DPC4 genes were 50%,60% and 72.5%, respectively. There was a significant negative correlation of SST2R with p53 and ras genes (X12=9.33,X22=15.43, P<0.01), but no significant correlation with DPC4 gene (X2=2.08, P >0.05).CONCLUSION: There was a significant difference of SST2R gene expression in pancreatic cancer tissues and its adjacent tissues, which might be one cause for the different therapeutic effects of somatostatin and its analogs on pancreatic cancer patients. There were abnormal expressions of SST2R, DPC4, p53 and ras genes in pancreatic carcinogenesis, and moreover, the loss or decrease of SST2R gene expression was significantly negatively correlated with the overexpression of tumor angiogenesis correlated p53 and ras genes, suggesting that SST2R gene

  11. Somatostatin and dopamine receptor expression in neuroendocrine neoplasms: correlation of immunohistochemical findings with somatostatin receptor scintigraphy visual scores. (United States)

    Diakatou, Evanthia; Alexandraki, Krystallenia I; Tsolakis, Apostolos V; Kontogeorgos, George; Chatzellis, Eleftherios; Leonti, Anastasia; Kaltsas, Gregory A


    The expression of somatostatin (sstr1-5) and dopamine (DR) receptors in neuroendocrine neoplasms (NENs) facilitates diagnosis by tumour visualization with somatostatin receptor scintigraphy (SRS) and directs towards specific treatment with peptide receptor radionuclide therapy (PRRT) with radiolabelled somatostatin analogues. To investigate the co-expression of sstrs, D2R in relation to pre-operative SRSs in NENs. Prospective two-centre study. We analysed pre-operative SRS of 60 patients [44 with gastrointestinal (GI) NENs and 16 with lung NENs] and compared SRS results with immunohistochemical (IHC) reactivity for sstr2, sstr3, sstr5 in sample tissues from primary (n = 54) and metastatic (n = 27) lesions and IHC reactivity for D2R in 23 samples from primary GI-NENs lesions. Sstr2 was the commonest sstr expressed (65·4%) and was co-expressed with sstr3 and sstr5 in 32·1% and 24·7% of the specimens, respectively. In 67 of 81 specimens (82·7%), there was concordance of sstr2 immunohistochemistry with SRS findings (P 2 cm) tumours and GI-NENs, whereas sstr2 intensity was greater in GI compared to lung NENs. SRS grade showed higher correlation with sstr2 (r = 0·6, P < 0·001) and D2R (r = 0·5, P < 0·001) IHC intensity scores than tumour size (r = 0·4, P < 0·001) and sstr3 (r = 0·4, P < 0·001) intensity score. Sstr2 IHC expression and SRS are useful tools for the diagnosis and management of NENs because they display a high concordance. IHC expression of DR2 seems to be of potential clinical significance in GI-NENs tumours. © 2015 John Wiley & Sons Ltd.

  12. Sleep and movement differentiates actions of two types of somatostatin-expressing GABAergic interneuron in rat hippocampus. (United States)

    Katona, Linda; Lapray, Damien; Viney, Tim J; Oulhaj, Abderrahim; Borhegyi, Zsolt; Micklem, Benjamin R; Klausberger, Thomas; Somogyi, Peter


    Neuropeptides acting on pre- and postsynaptic receptors are coreleased with GABA by interneurons including bistratified and O-LM cells, both expressing somatostatin but innervating segregated dendritic domains of pyramidal cells. Neuropeptide release requires high-frequency action potentials, but the firing patterns of most peptide/GABA-releasing interneurons during behavior are unknown. We show that behavioral and network states differentiate the activities of bistratified and O-LM cells in freely moving rats. Bistratified cells fire at higher rates during sleep than O-LM cells and, unlike O-LM cells, strongly increase spiking during sharp wave-associated ripples (SWRs). In contrast, O-LM interneurons decrease firing during sleep relative to awake states and are mostly inhibited during SWRs. During movement, both cell types fire cooperatively at the troughs of theta oscillations but with different frequencies. Somatostatin and GABA are differentially released to distinct dendritic zones of CA1 pyramidal cells during sleep and wakefulness to coordinate segregated glutamatergic inputs from entorhinal cortex and CA3.

  13. Improved glycemic control with no weight increase in patients with type 2 diabetes after once-daily treatment with the long-acting glucagon-like peptide 1 analog liraglutide (NN2211): a 12-week, double-blind, randomized, controlled trial

    DEFF Research Database (Denmark)

    Madsbad, Sten; Schmitz, Ole; Ranstam, Jonas;


    OBJECTIVE: Liraglutide is a long-acting glucagon-like peptide 1 analog designed for once daily injection. This study assessed the efficacy and safety of liraglutide after 12 weeks of treatment in type 2 diabetic patients. RESEARCH DESIGN AND METHODS: A double-blind, randomized, parallel...

  14. Improved glycemic control with no weight increase in patients with type 2 diabetes after once-daily treatment with the long-acting glucagon-like peptide 1 analog liraglutide (NN2211): a 12-week, double-blind, randomized, controlled trial

    DEFF Research Database (Denmark)

    Madsbad, Sten; Schmitz, Ole; Ranstam, Jonas


    OBJECTIVE: Liraglutide is a long-acting glucagon-like peptide 1 analog designed for once daily injection. This study assessed the efficacy and safety of liraglutide after 12 weeks of treatment in type 2 diabetic patients. RESEARCH DESIGN AND METHODS: A double-blind, randomized, parallel...

  15. Active postoperative acromegaly: sustained remission after discontinuation of somatostatin analogues

    Directory of Open Access Journals (Sweden)

    Cristina Alvarez-Escola


    Full Text Available In patients with active acromegaly after pituitary surgery, somatostatin analogues are effective in controlling the disease and can even be curative in some cases. After treatment discontinuation, the likelihood of disease recurrence is high. However, a small subset of patients remains symptom-free after discontinuation, with normalized growth hormone (GH and insulin-like growth factor (IGF1 levels. The characteristics of patients most likely to achieve sustained remission after treatment discontinuation are not well understood, although limited evidence suggests that sustained remission is more likely in patients with lower GH and IGF1 levels before treatment withdrawal, in those who respond well to low-dose treatment, in those without evidence of adenoma on an MRI scan and/or in patients who receive long-term treatment. In this report, we describe the case of a 56-year-old female patient treated with lanreotide Autogel for 11 years. Treatment was successfully discontinued, and the patient is currently disease-free on all relevant parameters (clinical, biochemical and tumour status. The successful outcome in this case adds to the small body of literature suggesting that some well-selected patients who receive long-term treatment with somatostatin analogues may achieve sustained remission.

  16. Somatostatin Negatively Regulates Parasite Burden and Granulomatous Responses in Cysticercosis

    Directory of Open Access Journals (Sweden)

    Mitra Khumbatta


    Full Text Available Cysticercosis is an infection of tissues with the larval cysts of the cestode, Taenia  solium. While live parasites elicit little or no inflammation, dying parasites initiate a granulomatous reaction presenting as painful muscle nodules or seizures when cysts are located in the brain. We previously showed in the T. crassiceps murine model of cysticercosis that substance P (SP, a neuropeptide, was detected in early granulomas and was responsible for promoting granuloma formation, while somatostatin (SOM, another neuropeptide and immunomodulatory hormone, was detected in late granulomas; SOM’s contribution to granuloma formation was not examined. In the current studies, we used somatostatin knockout (SOM−/− mice to examine the hypothesis that SOM downmodulates granulomatous inflammation in cysticercosis, thereby promoting parasite growth. Our results demonstrated that parasite burden was reduced 5.9-fold in SOM−/− mice compared to WT mice (P<0.05. This reduction in parasite burden in SOM−/− mice was accompanied by a 95% increase in size of their granulomas (P<0.05, which contained a 1.5-fold increase in levels of IFN-γ and a 26-fold decrease in levels of IL-1β (P<0.05 for both compared to granulomas from WT mice. Thus, SOM regulates both parasite burden and granulomatous inflammation perhaps through modulating granuloma production of IFN-γ and IL-1β.

  17. Feasibility of Imaging Esophageal Cancer with Labeled Somatostatin Analogue

    Directory of Open Access Journals (Sweden)

    Gunnar Herlin


    Full Text Available Background. While the surface of a cell normally has some amount of somatostatin receptors, these receptors are overexpressed to a very high degree in multiple neoplastic diseases. No data exist for esophageal carcinoma. Purpose. To find out whether esophageal carcinoma could be imaged using somatostatin receptor scintigraphy. Material and Methods. 34 patients with esophageal lesions were prospectively examined by 99mTc-depreotide scintigraphy 2 and 4 hours after injection. Quantitative evaluation of 99mTc-depreotide uptake was performed around the lesion (T and in healthy lung parenchyma (B. The relative uptake was calculated as T−B/B. Scintigraphy results were compared with histopathology from surgery or biopsy specimens from endoscopic ultrasonography. Results. 21 patients had esophageal cancer, and 13 lesions were benign. Visual assessment revealed positive 99mTc-depreotide uptake in 16 of the 21 cancers. The 13 patients without cancer had no depreotide uptake. The Mann-Whitney U test showed a statistically significant difference (<.005 between 99mTc-depreotide uptake in malignant and benign lesions, for both the 2-hour and the 4-hour measurements. Conclusion. Scintigraphic examination with 99mTc-depreotide is feasible for imaging esophageal cancer, but the method is not suitable neither for screening or primary diagnosis, because of methods modest sensitivity. Our first results showed high specificity which should be used with caution, as the number of patients was relatively low. Further studies are needed to determine the role of the method.

  18. The therapeutic effect of the neuropeptide hormone somatostatin on Schistosoma mansoni caused liver fibrosis

    Directory of Open Access Journals (Sweden)

    Peeters Theo


    Full Text Available Abstract Background The neuropeptide somatostatin is one of the major regulatory peptides in the central nervous system and the digestive tract. Our recent work has delineated an association between fibrosis and low levels of endogenous somatostatin plasma levels in Schistosoma mansoni infected subjects. Based on these results this paper explores the therapeutic potential of somatostatin in a mouse model of hepatic fibrosis associated with S. mansoni infections. Methods Groups of outbred Swiss mice were infected with 100 S. mansoni cercariae, infection maintained till weeks 10 or 14, and then somatostatin therapy delivered in two regimens – Either a one or a two-day treatment. All animals were sacrificed one week after therapy and controlled for liver, spleen and total body weight. Circulating somatostatin levels in mice plasma were measured at the time of sacrifice by means of a radio-immuno assay. GraphPad Prism® was used for statistical calculations. Results Somatostatin administration showed little toxicity, probably due to its short half-life. Total liver and spleen weights of S. mansoni infected animals increased over time, with no changes observed due to somatostatin therapy. Total body weights were decreased after infection but were not affected by somatostatin therapy. Snap frozen liver sections were stained with haematoxylin-eosin or Masson's trichrome to study parasite count, hepatocyte status, granuloma size and cellularity. After somatostatin treatment mean egg counts per liver section (43.76 ± 3.56 were significantly reduced as compared to the egg counts in untreated mice after 10 weeks of infection (56.01 ± 3.34 (P = 0.03. Similar significant reduction in parasite egg counts were also observed after somatostatin treatment at 14 weeks of infection (56.62 ± 3.02 as compared to untreated animals (69.82 ± 2.77(P = 0.006. Fibrosis was assessed from the spectrophotometric determination of tissue hydroxyproline. Infection with S

  19. Role of the somatostatin system in contextual fear memory and hippocampal synaptic plasticity. (United States)

    Kluge, Christian; Stoppel, Christian; Szinyei, Csaba; Stork, Oliver; Pape, Hans-Christian


    Somatostatin has been implicated in various cognitive and emotional functions, but its precise role is still poorly understood. Here, we have made use of mice with somatostatin deficiency, based upon genetic invalidation or pharmacologically induced depletion, and Pavlovian fear conditioning in order to address the contribution of the somatostatin system to associative fear memory. The results demonstrate an impairment of foreground and background contextual but not tone fear conditioning in mice with targeted ablation of the somatostatin gene. These deficits were associated with a decrease in long-term potentiation in the CA1 area of the hippocampus. Both the behavioral and the electrophysiological phenotypes were mimicked in wild-type mice through application of the somatostatin-depleting substance cysteamine prior to fear training, whereas no further deficits were observed upon application in the somatostatin null mutants. These results suggest that the somatostatin system plays a critical role in the acquisition of contextual fear memory, but not tone fear learning, and further highlights the role of hippocampal synaptic plasticity for information processing concerning contextual information.

  20. A cost analysis of somatostatin use in the prevention of pancreatic fistula after pancreatectomy. (United States)

    Anderson, R; Dunki-Jacobs, E; Burnett, N; Scoggins, C; McMasters, K; Martin, R C G


    Studies have shown that somatostatin reduces the occurrence of postoperative pancreatic fistula. However, no study to date has analyzed the cost effectiveness of this treatment. The purpose of this study was to analyze the cost effectiveness of prophylactic somatostatin use with respect to pancreatectomy. Review of prospectively collected 2002 patient hepato-pancreatico-biliary database from January 2007 to May 2012. Patients received somatostatin prophylactically at the discretion of their surgeon. Data were analyzed using univariate analysis to determine if somatostatin had an effect on imaging costs, lab costs, "other" costs, PT/OT costs, surgery costs, room and board costs, and total hospital costs. A total of 179 patients underwent pancreatectomy at a single teaching institution. Median total hospital costs were 90,673.50 (59,979-743,667) for patients who developed a postoperative pancreatic fistula versus 86,563 (39,190-463,601) for those who did not (p = 0.004). Median total hospital costs were 89,369 (39,190-743,667) for patients who were administered somatostatin versus 85,291 (40,092-463,601) for patients who did not (p = 0.821). Pancreatic fistulas significantly increase hospital costs, and somatostatin has been shown to decrease the rate of pancreatic fistula formation. Somatostatin has no significant effect on hospital costs.

  1. Analog and VLSI circuits

    CERN Document Server

    Chen, Wai-Kai


    Featuring hundreds of illustrations and references, this book provides the information on analog and VLSI circuits. It focuses on analog integrated circuits, presenting the knowledge on monolithic device models, analog circuit cells, high performance analog circuits, RF communication circuits, and PLL circuits.

  2. Activation of Brain Somatostatin Signaling Suppresses CRF Receptor-Mediated Stress Response

    Directory of Open Access Journals (Sweden)

    Andreas Stengel


    Full Text Available Corticotropin-releasing factor (CRF is the hallmark brain peptide triggering the response to stress and mediates—in addition to the stimulation of the hypothalamus-pituitary-adrenal (HPA axis—other hormonal, behavioral, autonomic and visceral components. Earlier reports indicate that somatostatin-28 injected intracerebroventricularly counteracts the acute stress-induced ACTH and catecholamine release. Mounting evidence now supports that activation of brain somatostatin signaling exerts a broader anti-stress effect by blunting the endocrine, autonomic, behavioral (with a focus on food intake and visceral gastrointestinal motor responses through the involvement of distinct somatostatin receptor subtypes.

  3. Lumbar cerebrospinal fluid concentrations of somatostatin and neuropeptide Y in multiple sclerosis

    Energy Technology Data Exchange (ETDEWEB)

    Vecsei, L.; Csala, B.; Widerloev, E.E.; Ekman, R.; Czopf, J.; Palffy, G. (Univ. of Lund (Sweden))


    The cerebrospinal fluid (CSF) concentrations of somatostatin and neuropeptide Y were investigated by use of radioimmunoassay in patients suffering from chronic progressive multiple sclerosis. The somatostatin level was significantly decreased in the CSF of patients with multiple sclerosis compared to the control group. The magnitude of this change was more pronounced in patients with severe clinical symptoms of the illness. The CSF neuropeptide Y concentration did not differ from the control values. These findings suggest a selective involvement of somatostatin neurotransmission in multiple sclerosis.

  4. Somatostatin receptor scintigraphy during treatment with lanreotide in patients with neuroendocrine tumors

    Energy Technology Data Exchange (ETDEWEB)

    Janson, Eva Tiensuu E-mail:; Kaelkner, Karl Mikael; Eriksson, Barbro; Westlin, Jan-Erik; Oeberg, Kjell


    To investigate possible changes in somatostatin receptor expression during treatment with high dose lanreotide, eight patients with neuroendocrine tumors were investigated by [{sup 111}In-DTPA-D-Phe{sup 1}]-octreotide scintigraphy before and during treatment. The spleen-to-background ratio decreased in all patients, whereas tumor-to-background ratio revealed a heterogeneous pattern with an average increase of 50% (-79% to +1,087%). This finding indicates that lanreotide treatment may influence the binding of radioactively labeled somatostatin to the spleen, while changes in the binding to functioning somatostatin receptors in tumor cells are more complex and not clearly related to treatment.

  5. When Gesture Becomes Analogy. (United States)

    Cooperrider, Kensy; Goldin-Meadow, Susan


    Analogy researchers do not often examine gesture, and gesture researchers do not often borrow ideas from the study of analogy. One borrowable idea from the world of analogy is the importance of distinguishing between attributes and relations. Gentner (, ) observed that some metaphors highlight attributes and others highlight relations, and called the latter analogies. Mirroring this logic, we observe that some metaphoric gestures represent attributes and others represent relations, and propose to call the latter analogical gestures. We provide examples of such analogical gestures and show how they relate to the categories of iconic and metaphoric gestures described previously. Analogical gestures represent different types of relations and different degrees of relational complexity, and sometimes cohere into larger analogical models. Treating analogical gestures as a distinct phenomenon prompts new questions and predictions, and illustrates one way that the study of gesture and the study of analogy can be mutually informative. Copyright © 2017 Cognitive Science Society, Inc.

  6. [Effect of calcitonin, somatostatin and cimetidine on stress ulcer in rats]. (United States)

    Jakesz, R; Hofbauer, F; Lehr, L; Schiessel, R


    The prophylactic effect of calcitonin, somatostatin and cimetidine on stress ulcer formation in rats was investigated in two stress models: restraint + ketamin (4 h) and hypovolemia (4 h). The basis of the comparative study was a 70% inhibition of acid secretion for 4 h in pyloric ligated animals. This was achieved with 1000 microgram/kg somatostatin s.c., 10 microgram/kg calcitonin s.c., and 2 X 100 mumol/kg cimetidine s.c. In restraint stress and ketamin with calcitonin and cimetidine a significantly lower frequency of gastric lesions was found than with somatostatin. The most potent substance in hypovolemia was calcitonin, with a significant difference in the frequency of mucosal lesions to the groups with cimetidine and somatostatin.

  7. Alkaline phosphatase predicts response in polycystic liver disease during somatostatin analogue therapy: a pooled analysis

    NARCIS (Netherlands)

    Gevers, T.J.; Nevens, F.; Torres, V.E.; Hogan, M.C.; Drenth, J.P.


    BACKGROUND & AIMS: Somatostatin analogues reduce liver volumes in polycystic liver disease. However, patients show considerable variability in treatment responses. Our aim was to identify specific patient, disease or treatment characteristics that predict response in polycystic liver disease during

  8. Learning by Analogy: Discriminating between Potential Analogs (United States)

    Richland, Lindsey E.; McDonough, Ian M.


    The ability to successfully discriminate between multiple potentially relevant source analogs when solving new problems is crucial to proficiency in a mathematics domain. Experimental findings in two different mathematical contexts demonstrate that providing cues to support comparative reasoning during an initial instructional analogy, relative to…

  9. Intuitive analog circuit design

    CERN Document Server

    Thompson, Marc


    Intuitive Analog Circuit Design outlines ways of thinking about analog circuits and systems that let you develop a feel for what a good, working analog circuit design should be. This book reflects author Marc Thompson's 30 years of experience designing analog and power electronics circuits and teaching graduate-level analog circuit design, and is the ideal reference for anyone who needs a straightforward introduction to the subject. In this book, Dr. Thompson describes intuitive and ""back-of-the-envelope"" techniques for designing and analyzing analog circuits, including transistor amplifi

  10. Somatostatin signaling system as an ancestral mechanism: Myoregulatory activity of an Allatostatin-C peptide in Hydra. (United States)

    Alzugaray, María Eugenia; Hernández-Martínez, Salvador; Ronderos, Jorge Rafael


    The coordination of physiological processes requires precise communication between cells. Cellular interactions allow cells to be functionally related, facilitating the maintaining of homeostasis. Neuropeptides functioning as intercellular signals are widely distributed in Metazoa. It is assumed that neuropeptides were the first intercellular transmitters, appearing early during the evolution. In Cnidarians, neuropeptides are mainly involved in neurotransmission, acting directly or indirectly on epithelial muscle cells, and thereby controlling coordinated movements. Allatostatins are a group of chemically unrelated neuropeptides that were originally characterized based on their ability to inhibit juvenil hormone synthesis in insects. Allatostatin-C has pleiotropic functions, acting as myoregulator in several insects. In these studies, we analyzed the myoregulatory effect of Aedes aegypti Allatostatin-C in Hydra sp., a member of the phylum Cnidaria. Allatostatin-C peptide conjugated with Qdots revealed specifically distributed cell populations that respond to the peptide in different regions of hydroids. In vivo physiological assays using Allatostatin-C showed that the peptide induced changes in shape and length in tentacles, peduncle and gastrovascular cavity. The observed changes were dose and time dependent suggesting the physiological nature of the response. Furthermore, at highest doses, Allatostatin-C induced peristaltic movements of the gastrovascular cavity resembling those that occur during feeding. In silico search of putative Allatostatin-C receptors in Cnidaria showed that genomes predict the existence of proteins of the somatostatin/Allatostatin-C receptors family. Altogether, these results suggest that Allatostatin-C has myoregulatory activity in Hydra sp, playing a role in the control of coordinated movements during feeding, indicating that Allatostatin-C/Somatostatin based signaling might be an ancestral mechanism.

  11. Effects of somatostatin on splanchnic hemodynamics in cirrhotic patients with portal hypertension

    Institute of Scientific and Technical Information of China (English)

    Ji Ye Zhu; Xi Sheng Leng; Dong Wang; Ru Yu Du


    @@ INTRODUCTION Esophageal variceal bleeding (EVB) is one of the most common complications of cirrhosis with portal hypertension. In recent years, great progress has been made in medicinal treatment. Somatostatin has been widely used in clinics, for it can effectively lower the portal venous pressure (PVP) with little side effect. The aim of this study is to assess the effect of somatostatin on portal venous pressue and splanchnic hemodynamics in patients with liver cirrhosis and portal hypertension.

  12. In vivo somatostatin, vasopressin, and oxytocin synthesis in diabetic rat hypothalamus

    Energy Technology Data Exchange (ETDEWEB)

    Fernstrom, J.D.; Fernstrom, M.H.; Kwok, R.P. (Univ. of Pittsburgh School of Medicine, PA (USA))


    The in vivo labeling of somatostatin-14, somatostatin-28, arginine vasopressin, and oxytocin was studied in rat hypothalamus after third ventricular administration of (35S)cysteine to streptozotocin-diabetic and normal rats. Immunoreactive somatostatin levels in hypothalamus were unaffected by diabetes, as was the incorporation of (35S)cysteine into hypothalamic somatostatin-14 and somatostatin-28. In contrast, immunoreactive vasopressin levels in hypothalamus and posterior pituitary (and oxytocin levels in posterior pituitary) were below normal in diabetic rats. Moreover, (35S)cysteine incorporation into hypothalamic vasopressin and oxytocin (probably mainly in the paraventricular nucleus because of its proximity to the third ventricular site of label injection) was significantly above normal. The increments in vasopressin and oxytocin labeling were reversed by insulin administration. In vivo cysteine specific activity and the labeling of acid-precipitable protein did not differ between normal and diabetic animals; effects of diabetes on vasopressin and oxytocin labeling were therefore not caused by simple differences in cysteine specific activity. These results suggest that diabetes (1) does not influence the production of somatostatin peptides in hypothalamus but (2) stimulates the synthesis of vasopressin and oxytocin. For vasopressin at least, the increase in synthesis may be a compensatory response to the known increase in its secretion that occurs in uncontrolled diabetes.

  13. Critical role of somatostatin receptor 2 in the vulnerability of the central noradrenergic system

    DEFF Research Database (Denmark)

    Ádori, Csaba; Glück, Laura; Barde, Swapnali;


    Alzheimer’s disease and other age-related neurodegenerative disorders are associated with deterioration of the noradrenergic locus coeruleus (LC), a probable trigger for mood and memory dysfunction. LC noradrenergic neurons exhibit particularly high levels of somatostatin binding sites. This is n......Alzheimer’s disease and other age-related neurodegenerative disorders are associated with deterioration of the noradrenergic locus coeruleus (LC), a probable trigger for mood and memory dysfunction. LC noradrenergic neurons exhibit particularly high levels of somatostatin binding sites...... morphometry and mRNA profiling in a cohort of Alzheimer’s and age-matched control brains in combination with genetic models of somatostatin receptor deficiency to establish causality between defunct somatostatin signalling and noradrenergic neurodegeneration. In Alzheimer’s disease, we found significantly...... reduced somatostatin protein expression in the temporal cortex, with aberrant clustering and bulging of tyrosine hydroxylase-immunoreactive afferents. As such, somatostatin receptor 2 (SSTR2) mRNA was highly expressed in the human LC, with its levels significantly decreasing from Braak stages III...

  14. Identification of human somatostatin receptor 2 domains involved in internalization and signaling in QGP-1 pancreatic neuroendocrine tumor cell line. (United States)

    Cambiaghi, Valeria; Vitali, Eleonora; Morone, Diego; Peverelli, Erika; Spada, Anna; Mantovani, Giovanna; Lania, Andrea Gerardo


    Somatostatin exerts inhibitory effects on hormone secretion and cell proliferation via five receptor subtypes (SST1-SST5), whose internalization is regulated by β-arrestins. The receptor domains involved in these effects have been only partially elucidated. The aim of the study is to characterize the molecular mechanism and determinants responsible for somatostatin receptor 2 internalization and signaling in pancreatic neuroendocrine QGP-1 cell line, focusing on the third intracellular loop and carboxyl terminal domains. We demonstrated that in cells transfected with somatostatin receptor 2 third intracellular loop mutant, no differences in β-arrestins recruitment and receptor internalization were observed after somatostatin receptor 2 activation in comparison with cells bearing wild-type somatostatin receptor 2. Conversely, the truncated somatostatin receptor 2 failed to recruit β-arrestins and to internalize after somatostatin receptor 2 agonist (BIM23120) incubation. Moreover, the inhibitory effect of BIM23120 on cell proliferation, cyclin D1 expression, P-ERK1/2 levels, apoptosis and vascular endothelial growth factor secretion was completely lost in cells transfected with either third intracellular loop or carboxyl terminal mutants. In conclusion, we demonstrated that somatostatin receptor 2 internalization requires intact carboxyl terminal while the effects of SS on cell proliferation, angiogenesis and apoptosis mediated by somatostatin receptor 2 need the integrity of both third intracellular loop and carboxyl terminal.

  15. Analog and hybrid computing

    CERN Document Server

    Hyndman, D E


    Analog and Hybrid Computing focuses on the operations of analog and hybrid computers. The book first outlines the history of computing devices that influenced the creation of analog and digital computers. The types of problems to be solved on computers, computing systems, and digital computers are discussed. The text looks at the theory and operation of electronic analog computers, including linear and non-linear computing units and use of analog computers as operational amplifiers. The monograph examines the preparation of problems to be deciphered on computers. Flow diagrams, methods of ampl

  16. Structured Analog CMOS Design

    CERN Document Server

    Stefanovic, Danica


    Structured Analog CMOS Design describes a structured analog design approach that makes it possible to simplify complex analog design problems and develop a design strategy that can be used for the design of large number of analog cells. It intentionally avoids treating the analog design as a mathematical problem, developing a design procedure based on the understanding of device physics and approximations that give insight into parameter interdependences. The proposed transistor-level design procedure is based on the EKV modeling approach and relies on the device inversion level as a fundament

  17. Somatostatin analogue scintigraphy and tuberculosis: case report; Scintigraphie des analogues de la somatostatine et tuberculose: a propos d'un cas

    Energy Technology Data Exchange (ETDEWEB)

    Biancheri, I.; Rudenko, B.; Vautrin, P.; Raddoul, J.; Lamfichek, N. [Centre Hospitalier General Andre Boulloche, 25 - Montbeliard (France); Kantelip, B.; Mantion, G. [Centre Hospitalier Universitaire Jean Minjoz, 25 - Besancon (France)


    Scintigraphy using a radiolabelled somatostatin analogue (111 In-pentetreotide) is useful in the detection of neuroendocrine tumors. But this radiopharmaceutical accumulates also in solid tumours or in inflammatory diseases such as granulomatosis. We present a case of 111 In-pentetreotide uptake in a tuberculous adenopathy. (author)

  18. Positron emission tomography study on pancreatic somatostatin receptors in normal and diabetic rats with {sup 68}Ga-DOTA-octreotide: A potential PET tracer for beta cell mass measurement

    Energy Technology Data Exchange (ETDEWEB)

    Sako, Takeo [Division of Bio-function Dynamics Imaging, RIKEN Center for Life Science Technologies, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047 (Japan); Division of Molecular Imaging, Institute of Biomedical Research and Innovation, 2-2 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047 (Japan); Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017 (Japan); Hasegawa, Koki; Nishimura, Mie; Kanayama, Yousuke; Wada, Yasuhiro; Hayashinaka, Emi; Cui, Yilong; Kataoka, Yosky [Division of Bio-function Dynamics Imaging, RIKEN Center for Life Science Technologies, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047 (Japan); Senda, Michio [Division of Bio-function Dynamics Imaging, RIKEN Center for Life Science Technologies, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047 (Japan); Division of Molecular Imaging, Institute of Biomedical Research and Innovation, 2-2 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047 (Japan); Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017 (Japan); Watanabe, Yasuyoshi, E-mail: [Division of Bio-function Dynamics Imaging, RIKEN Center for Life Science Technologies, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047 (Japan)


    Highlights: •PET images showed high uptake of {sup 68}Ga-DOTA-octreotide in the normal pancreas. •{sup 68}Ga-DOTA-octreotide specifically binds to somatostatin receptors in the pancreas. •The pancreatic uptake of {sup 68}Ga-DOTA-octreotide was decreased in the diabetic rats. •{sup 68}Ga-DOTA-octreotide could be a candidate PET probe to measure the beta cell mass. -- Abstract: Diabetes mellitus (DM) is a metabolic disorder characterized by hyperglycemia, and the loss or dysfunction of pancreatic beta cells has been reported before the appearance of clinical symptoms and hyperglycemia. To evaluate beta cell mass (BCM) for improving the detection and treatment of DM at earlier stages, we focused on somatostatin receptors that are highly expressed in the pancreatic beta cells, and developed a positron emission tomography (PET) probe derived from octreotide, a metabolically stable somatostatin analog. Octreotide was conjugated with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), a chelating agent, and labeled with {sup 68}Gallium ({sup 68}Ga). After intravenous injection of {sup 68}Ga-DOTA-octreotide, a 90-min emission scan of the abdomen was performed in normal and DM model rats. The PET studies showed that {sup 68}Ga-DOTA-octreotide radioactivity was highly accumulated in the pancreas of normal rats and that the pancreatic accumulation was significantly reduced in the rats administered with an excess amount of unlabeled octreotide or after treatment with streptozotocin, which was used for the chemical induction of DM in rats. These results were in good agreement with the ex vivo biodistribution data. These results indicated that the pancreatic accumulation of {sup 68}Ga-DOTA-octreotide represented specific binding to the somatostatin receptors and reflected BCM. Therefore, PET imaging with {sup 68}Ga-DOTA-octreotide could be a potential tool for evaluating BCM.


    Institute of Scientific and Technical Information of China (English)

    潘勤; 李定国; 陆汉明; 尤汉宁; 徐芹芳; 陆良勇


    Objective To investigate the relationship between expression of somatostatin receptors (SSTRs) and activation of rat hepatic stellate cell (HSC). Methods HSCs were isolated from rats by in situ perfusion and single-step density gradient centrifugation, and then SSTR1 ~5 mRNA levels in the differentiated first passage HSCs were detected by means of reverse transcription polymerase chain reaction. On the other hand, hepatic fibrosis was induced in adult male Sprague-Dawley rats by carbon tetrachloride intoxication, and the expression of SSTR1 ~5 in normal as well as fibrotic liver was measured by immunohistochemical staining. Results SSTR mRNA and SSTR could not be found in freshly isolated rat HSCs and normal rat liver. But SSTR1~3 mRNA appeared as HSCs became wholly activated, and SSTR1 ~3 could also be identified on the membrane of activated HSCs in the perisinusoid space, fibrous septa, etc Conclusion The expression of SSTR1~3 in the rat HSC is closely related to its activation. This may reflect one of the main negative regulation mechanisms in the course of HSC activation.

  20. Relationship between somatostatin receptors and activation of hepatic stellate cells

    Institute of Scientific and Technical Information of China (English)

    潘勤; 李定国; 陆汉明; 陆良勇; 尤汉宁; 徐芹芳


    Background Somafostatin receptors (SSTRs) have been suggested to involve in mediating the effect of somatostatin on hepatic stellate cells (HSCs) in an activation-dependent way. We, therefore, try to investigate the relationship between expression of SSTRs and activation of rat HSCs.Methods HSCs were isolated from rats by in situ perfusion and single-step density gradient centrifugation.SSTR1-5 mRNA levels in the differentiated first passage HSCs were detected by means of a reverse transcription polymerase chain reaction. On the other hand, hepatic fibrosis was induced in adult male Sprague-Dawley rats by carbon tetrachloride intoxication, and the expression of SSTR1-5 in normal as well as fibrotic livers was measured by immunohistochemical staining.Results SSTR mRNA and SSTR could not be found in freshly isolated rat HSCs or normal rat liver. However, SSTR1-3 mRNA appeared as HSCs became wholly activated, and could also be identified on the membrane of activated HSCs in the perisinusoid space, fibrous septa, etc.Conclusion The expression of SSTR1-3 in the rat HSC is closely related to its activation. This may reflect one of the main negative regulation mechanisms in the course of HSC activation.

  1. Somatostatin-expressing inhibitory interneurons in cortical circuits

    Directory of Open Access Journals (Sweden)

    Iryna Yavorska


    Full Text Available Cortical inhibitory neurons exhibit remarkable diversity in their morphology, connectivity, and synaptic properties. Here, we review the function of somatostatin-expressing (SOM inhibitory interneurons, focusing largely on sensory cortex. SOM neurons also comprise a number of subpopulations that can be distinguished by their morphology, input and output connectivity, laminar location, firing properties, and expression of molecular markers. Several of these classes of SOM neurons show unique dynamics and characteristics, such as facilitating synapses, specific axonal projections, intralaminar input, and top-down modulation, which suggest possible computational roles. SOM cells can be differentially modulated by behavioral state depending on their class, sensory system, and behavioral paradigm. The functional effects of such modulation have been studied with optogenetic manipulation of SOM cells, which produces effects on learning and memory, task performance, and the integration of cortical activity. Different classes of SOM cells participate in distinct disinhibitory circuits with different inhibitory partners and in different cortical layers. Through these disinhibitory circuits, SOM cells help encode the behavioral relevance of sensory stimuli by regulating the activity of cortical neurons based on subcortical and intracortical modulatory input. Associative learning leads to long-term changes in the strength of connectivity of SOM cells with other neurons, often influencing the strength of inhibitory input they receive. Thus despite their heterogeneity and variability across cortical areas, current evidence shows that SOM neurons perform unique neural computations, forming not only distinct molecular but also functional subclasses of cortical inhibitory interneurons.

  2. Effect of environmental hyperthermia on gastrin,somatostatin and motilin in rat ulcerated antral mucosa

    Institute of Scientific and Technical Information of China (English)

    Feng-Peng Sun; Yu-Gang Song


    AIM: To study the effect of environmental hyperthermia on gastrin, somatostatin and motilin in rat ulcerated antral mucosa.METHODS: Forty-two Wistar rats were equally divided into six groups, according to the room temperature (high and normal) and the treatment (acetic acid, normal saline and no treatment). Levels of gastrin, somatostatin and motilin in rat ulcerated antral mucosa were measured with a radioimmunoassay method.RESULTS: The average temperature and humidity were 32.5 ℃ and 66.7% for the high temperature group, and 21.1 ℃ and 49.3% for the normal temperature group,respectively. Gastric ulcer model was successfully induced in rat injected with 0.05 mL acetic acid into the antrum. In rats with gastric ulcers, the levels of gastrin and motilin increased, whereas the somatostatin level declined in antral mucosa, compared with those in rats treated with normal saline and the controls. However, the change extent in the levels of gastrin, motilin and somatostatin in antral mucosa was less in the high temperature group than in the normal temperature group.CONCLUSION: The levels of gastrin, somatostatin and motilin in rat ulcerated antral mucosal tissue remain relatively stable in a high temperature environment, which may relate to the equilibration of the dynamic system.

  3. Urotensin II and urotensin II-related peptide activate somatostatin receptor subtypes 2 and 5. (United States)

    Malagon, Maria M; Molina, Marcelo; Gahete, Manuel D; Duran-Prado, Mario; Martinez-Fuentes, Antonio J; Alcain, Francisco J; Tonon, Marie-Christine; Leprince, Jérôme; Vaudry, Hubert; Castaño, Justo P; Vazquez-Martinez, Rafael


    The UII and urotensin II-related peptide (URP) genes belong to the same superfamily as the somatostatin gene. It has been previously shown that somatostatin activates the UII-receptor (UTR). In contrast, the possible interaction between UII and URP and somatostatin receptors has remained scarcely analyzed. Herein, we have investigated the effects of UII and URP on cell proliferation and free cytosolic Ca2+ concentration ([Ca2+]i) in CHO-K1 cells stably expressing the porcine somatostatin receptor subtypes sst2 and sst5. Results show that both UII and URP induce stimulation of cell proliferation mediated by sst2 receptors and UII provokes inhibition of cell proliferation mediated by sst5 receptors. UII and URP also provoked an increase of [Ca2+]i in both sst2- and sst5-transfected cells. Together, our present data demonstrate that UII and URP directly activate sst2 and sst5 and thus mimic the effect of somatostatin on its cognate receptors.

  4. Analogies of Information Security


    Sole, Amund Bauck


    In this thesis it will be tested wither analogies and metaphors would make it easier to teach the fundamental subjects of information security and hacking to people with no previous background in computer science and only basic computer skills. This will be done by conducting interview on people with no background in computer science to see what analogies work the best for different topics in information security. From the analogy getting the best response, a small game will be designed with ...

  5. Analog circuit design

    CERN Document Server

    Dobkin, Bob


    Analog circuit and system design today is more essential than ever before. With the growth of digital systems, wireless communications, complex industrial and automotive systems, designers are being challenged to develop sophisticated analog solutions. This comprehensive source book of circuit design solutions aids engineers with elegant and practical design techniques that focus on common analog challenges. The book's in-depth application examples provide insight into circuit design and application solutions that you can apply in today's demanding designs. <

  6. Analogy in CLAM


    Melis, Erica


    CL A M is a proof planner, developed by the Dream group in Edinburgh,that mainly operates for inductive proofs. This paper addresses the questionhow an analogy model that I developed independently of CL A M can beapplied to CL A M and it presents analogy-driven proof plan construction as acontrol strategy of CL A M . This strategy is realized as a derivational analogythat includes the reformulation of proof plans. The analogical replay checkswhether the reformulated justifications of the sour...

  7. Glucagon-like peptide-1, but not glucose-dependent insulinotropic peptide, inhibits glucagon secretion via somatostatin (receptor subtype 2) in the perfused rat pancreas

    DEFF Research Database (Denmark)

    de Heer, J; Rasmussen, C; Coy, D H


    and somatostatin were studied in the presence of a high-affinity monoclonal somatostatin antibody and of a highly specific somatostatin receptor subtype 2 (SSTR2) antagonist (PRL-2903) in the isolated perfused rat pancreas. RESULTS: In control experiments, GLP-1 at 1 and 10 nmol/l reduced glucagon secretion...

  8. Sex-related toxicity of somatostatin and its interaction with pentobarbital and strychnine. (United States)

    Caprino, L; Borrelli, F; Antonetti, F; Cantelmo, A


    The intravenous LD50 of the hypothalamic tetradecapeptide somatostatin was determined in mice and rats of both sexes. It was found that somatostatin has a sex-related toxicity both in mice and rats. The interaction of low and high doses of peptide with the LD50s of two central nervous system (CNS) drugs, namely pentobarbital and strychnine, was also studied in male and female mice. Differential effects were observed as follows: a very low dose (0.1 mg/kg) of somatostatin does not affect the toxicity of these compounds, whereas the injection of 1 mg/kg of peptide increased pentobarbital toxicity and decreased the toxicity of strychnine. However, an increase in the toxicity of both substances was obtained with very high non-lethal doses of peptide (20 and 30 mg/kg, in female and male mice, respectively).

  9. Somatostatin Receptor Scintigraphy Findings in a Patient with Metastatic Gastrinoma and MEN 1 Syndrome

    Directory of Open Access Journals (Sweden)

    Gözde Mütevelizade


    Full Text Available Liver metastases from neuroendocrine tumours frequently occur and significantly worsen their prognosis. Somatostatin receptor scintigraphy (SRS is a valuable method for the detection of somatostatin receptor-positive lesions like gastrinoma. In this case report, the importance of SRS to localize the primary tumor and the spread of disease is emphasized in a patient with neuroendocrine liver metastases. A 45-year-old man was admitted to hospital with multiple liver metastasis of neuroendocrine carcinoma. Somatostatin receptor scintigraphy showed multiple intense radiotracer uptakes in the liver and a focal tracer uptake at the right side of the upper abdominal region corresponding to duodenum or pancreas. Elevated serum gastrin levels confirmed the gastrinoma diagnosis. (MRT 2011;20:117-120

  10. Somatostatin-like immunoreactivity in the amygdala of the pig.

    Directory of Open Access Journals (Sweden)

    Agnieszka Bossowska


    Full Text Available The distribution and morphology of neurons containing somatostatin (SOM was investigated in the amygdala (CA of the pig. The SOM-immunoreactive (SOM-IR cell bodies and fibres were present in all subdivisions of the porcine CA, however, their number and density varied depending on the nucleus studied. The highest density of SOM-positive somata was observed in the layer III of the cortical nuclei, in the anterior (magnocellular part of the basomedial nucleus and in the caudal (large-celled part of the lateral nucleus. Moderate to high numbers of SOM-IR cells were also observed in the medial and basolateral nuclei. Many labeled neurons were also consistently observed in the lateral part of the central nucleus. In the remaining CA regions, the density of SOM-positive cell bodies varied from moderate to low. In any CA region studied SOM-IR neurons formed heterogeneous population consisting of small, rounded or slightly elongated cell bodies, with a few poorly branched smooth dendrites. In general, morphological features of these cells clearly resembled the non-pyramidal Golgi type II interneurons. The routine double-labeling studies with antisera directed against SOM and neuropeptide Y (NPY demonstrated that a large number of SOM-IR cell bodies and fibers in all studied CA areas contained simultaneously NPY. In contrast, co-localization of SOM and cholecystokinin (CCK or SOM and vasoactive intestinal polypeptide (VIP was never seen in cell bodies and fibres in any of nuclei studied. In conclusion, SOM-IR neurons of the porcine amygdala form large and heterogeneous subpopulation of, most probably, interneurons that often contain additionally NPY. On the other hand, CCK- and/or VIP-IR neurons belonged to another, discrete subpopulations of porcine CA neurons.

  11. Effect of secretin and somatostatin on secretion of epidermal growth factor from Brunner's glands in the rat

    DEFF Research Database (Denmark)

    Olsen, P S; Kirkegaard, P; Poulsen, Steen Seier;


    The effect of secretin and somatostatin on secretion of epidermal growth factor (EGF) from Brunner's glands was investigated in rats. Secretin increased volume secretion and the median output of EGF rose from 720 fmol/5 hr (total range 460-1320) in controls to 2065 fmol/5 hr (total range 1560......-2730) at a dose of 50 pmol/kg/hr of secretin. Somatostatin inhibited Brunner's gland secretion, but the total output of EGF remained unchanged. Secretin-stimulated volume secretion and secretion of EGF was significantly reduced by simultaneous infusion of somatostatin. This study has shown that secretin...... stimulates secretion of EGF as well as volume secretion from Brunner's glands. Somatostatin prevents the effect of secretin on Brunner's glands, which suggests a role for somatostatin in control of Brunner's gland secretion....

  12. Clinical value of somatostatin receptor imaging in patients with suspected head and neck paragangliomas

    Energy Technology Data Exchange (ETDEWEB)

    Schmidt, Matthias; Dietlein, Markus; Weber, Kerstin; Moka, Detlef; Schicha, Harald [Klinik und Poliklinik fuer Nuklearmedizin, Universitaet zu Koeln, Joseph-Stelzmann-Strasse 9, 50924 Koeln (Germany); Fischer, Eva; Michel, Olaf; Stennert, Eberhard [Klinik und Poliklinik fuer Hals-, Nasen- und Ohrenheilkunde, Universitaet zu Koeln, Koeln (Germany)


    Paragangliomas or glomus tumours of the head and neck region are rare somatostatin receptor-expressing neuroendocrine tumours. Precise preoperative diagnosis is of special importance in order to adequately weigh the potential benefit of the operation against the inherent risks of the procedure. In this study, the clinical value of somatostatin receptor imaging was assessed in 19 patients who underwent somatostatin receptor scintigraphy because of known or suspected paraganglioma of the head and neck region. The results were compared with the results of computed tomography and/or magnetic resonance imaging, histology and clinical follow-up. [{sup 111}In-DTPA-D-Phe{sup 1}]-octreotide scintigraphy was performed 4-6 and 24 h after i.v. injection of 140-220 MBq {sup 111}In-octreotide. Whole-body and planar images as well as single-photon emission tomography images were acquired and lesions were graded according to qualitative tracer uptake. Somatostatin receptor imaging was positive in nine patients, identifying paragangliomas for the first time in three patients and recurrent disease in six patients. In one patient, a second, previously unknown paraganglioma site was identified. Negative results were obtained in ten patients. These patients included one suffering from chronic hyperplastic otitis externa, one with granuloma tissue and an organised haematoma, one with an acoustic neuroma, one with an asymmetric internal carotid artery, two with ectasia of the bulbus venae jugularis and one with a jugular vein thrombosis. In two patients with a strong family history of paraganglioma, individual involvement could be excluded. In only one patient did somatostatin receptor imaging and magnetic resonance imaging yield false negative results in respect of recurrent paraganglioma tissue. It is concluded that somatostatin receptor scintigraphy provides important information in patients with suspected paragangliomas of the head and neck region and has a strong impact on further

  13. The effects of somatostatin analogue therapy on pituitary tumor volume in patients with acromegaly. (United States)

    Colao, Annamaria; Auriemma, Renata S; Pivonello, Rosario


    In nearly all cases, acromegaly is caused by excess GH from a pituitary adenoma, resulting in elevated circulating levels of GH and, subsequently, IGF-1. Treatment goals are to eliminate morbidity and restore the increased mortality to normal rates. Therapeutic strategies aim to minimize tumor mass and normalize GH and IGF-1 levels. Somatostatin analogues are the medical treatment of choice in acromegaly, as first-line or post-surgical therapy, and have proven efficacy in pituitary tumor volume reduction (TVR). Here we review the effects of somatostatin analogue therapy on pituitary tumor volume in patients with acromegaly. TVR with somatostatin analogues may be mediated by direct anti-proliferative effects via activation of somatostatin receptors, or by indirect effects, such as angiogenesis inhibition, and is more pronounced when they are administered as first-line therapy. Various studies of first-line treatment with octreotide LAR have shown significant TVR in ≥73% of patients. First-line treatment with lanreotide Autogel has shown evidence of TVR, although more studies are needed. In a recent randomized, double-blind, 12-month trial in 358 medical-treatment-naïve acromegaly patients, significant TVR was achieved by 81% of patients administered pasireotide LAR and 77% administered octreotide LAR. Pre-operative somatostatin analogue therapy may also induce TVR and improve post-operative disease control compared with surgery alone. TVR is progressive with prolonged treatment, and decreased IGF-1 levels may be its best predictor, followed by age and degree of GH decrease. However, TVR does not always correlate with degree of biochemical control. Somatostatin analogues (first- or second-line treatment) are the mainstay of medical therapy and, as first-line medical therapy, are associated with significant pituitary TVR in most patients.

  14. Hydraulic Capacitor Analogy (United States)

    Baser, Mustafa


    Students have difficulties in physics because of the abstract nature of concepts and principles. One of the effective methods for overcoming students' difficulties is the use of analogies to visualize abstract concepts to promote conceptual understanding. According to Iding, analogies are consistent with the tenets of constructivist learning…

  15. Challenges in Using Analogies (United States)

    Lin, Shih-Yin; Singh, Chandralekha


    Learning physics requires understanding the applicability of fundamental principles in a variety of contexts that share deep features. One way to help students learn physics is via analogical reasoning. Students can be taught to make an analogy between situations that are more familiar or easier to understand and another situation where the same…

  16. Chroman-4-one and chromone based somatostatin β-turn mimetics. (United States)

    Fridén-Saxin, Maria; Seifert, Tina; Malo, Marcus; da Silva Andersson, Krystle; Pemberton, Nils; Dyrager, Christine; Friberg, Annika; Dahlén, Kristian; Wallén, Erik A A; Grøtli, Morten; Luthman, Kristina


    A scaffold approach has been used to develop somatostatin β-turn mimetics based on chroman-4-one and chromone ring systems. Such derivatives could adopt conformations resembling type II or type II' β-turns. Side chain equivalents of the crucial Trp8 and Lys9 in somatostatin were introduced in the 2- and 8-positions of the scaffolds using efficient reactions. Interestingly, this proof-of-concept study shows that 4 and 9 have Ki-values in the low μM range when evaluated for their affinity for the sst2 and sst4 receptors. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  17. Prolonged somatostatin therapy may cause down–regulation of SSTR–like GPCRs on Schistosoma mansoni

    Directory of Open Access Journals (Sweden)

    Eric Van Marck


    Full Text Available Background & objectives: Chemotherapy with praziquantel remains the only control measure to Schistosoma mansoni infections to date. The neuropeptide hormone somatostatin gives relief from gastrointestinal disturbances, liverpathology, and reduces egg production in S. mansoni infected mice, suggesting an interaction of somatostatin with the parasite rather than with the host alone. Using antibodies directed to epitopes of the seven somatostatin transmembrane receptors (SSTRs, the presence of SSTRs (or proteins that contain these epitopes was shown on both worm– and eggstages of S. mansoni. The present study was undertaken to investigate whether SSTRs on S. mansoni displayed homo/heterodimerisation properties as well as agonist induced down–regulation. Results: Somatostatin therapy was effective after two days of treatment with no further reduction in pathology after five days of therapy. Immunohistochemistry performed on parasite sections showed reactivity of the anti–SSTR antibodies to the tegument and internal parts of adult S. mansoni worms. SDS–PAGE–Western blotting identified protein bands of 70–100 and 200–250 kDa molecular weight. Upon carboxymethylation of the sulfhydryl groups of proteins in the worm lysate, a reduction in density of the protein band at 200–250 kDa and an increase in density of the protein band at 70–100 kDa were noted. This suggested that a substantial amount of the proteins detected on the blot are present as a homo/heterodimer. A protein microarray was used to investigate whether somatostatin therapy induced receptor down– or up–regulation on the adult worm of S. mansoni. Slides spotted with primary anti–SSTR antibody were exposed to lysates of worms collected from infected C3H mice that received none, two days or five days somatostatin treatment, followed by a secondary anti– SSTR antibody coupled to a fluorophore. Comparison of the different samples in terms of parasite dilution till when

  18. Positron emission tomography evaluation of somatostatin receptor targeted 64Cu-TATE-liposomes in a human neuroendocrine carcinoma mouse model. (United States)

    Petersen, Anncatrine L; Binderup, Tina; Jølck, Rasmus I; Rasmussen, Palle; Henriksen, Jonas R; Pfeifer, Andreas K; Kjær, Andreas; Andresen, Thomas L


    Targeted therapeutic and diagnostic nanocarriers functionalized with antibodies, peptides or other targeting ligands that recognize over-expressed receptors or antigens on tumor cells have potential in the diagnosis and therapy of cancer. Somatostatin receptors (SSTRs) are over-expressed in a variety of cancers, particularly neuroendocrine tumors (NETs) and can be targeted with somatostatin peptide analogs such as octreotate (TATE). In the present study we investigate liposomes that target SSTR in a NET xenograft mouse model (NCI-H727) by use of TATE. TATE was covalently attached to the distal end of DSPE-PEG(2000) on PEGylated liposomes with an encapsulated positron emitter (64)Cu that can be utilized for positron emission tomography (PET) imaging. The biodistribution and pharmacokinetics of the (64)Cu-loaded PEGylated liposomes with and without TATE was investigated and their ability to image NETs was evaluated using PET. Additionally, the liposome accumulation and imaging capability was compared with free radiolabelled TATE peptide administered as (64)Cu-DOTA-TATE. The presence of TATE on the liposomes resulted in a significantly faster initial blood clearance in comparison to control-liposomes without TATE. PEGylated liposomes with or without TATE accumulated at significantly higher quantities in NETs (5.1±0.3 and 5.8±0.2 %ID/g, respectively) than the free peptide (64)Cu-DOTA-TATE (1.4±0.3 %ID/g) 24 h post-injection. Importantly, (64)Cu-loaded PEGylated liposomes with TATE showed significantly higher tumor-to-muscle (T/M) ratio (12.7±1.0) than the control-liposomes without TATE (8.9±0.9) and the (64)Cu-DOTA-TATE free peptide (7.2±0.3). The higher T/M ratio of the PEGylated liposomes with TATE suggests some advantage of active targeting of NETs, although no absolute benefit in tumor accumulation over the non-targeted liposomes was observed. Collectively, these data showed that (64)Cu-loaded PEGylated liposomes with TATE conjugated to the surface could be

  19. Insulin Analogs: Impact on Treatment Success, Satisfaction, Quality of Life, and Adherence


    Hartman, Israel


    A growing body of medical research has demonstrated that intensive control of serum glucose levels can minimize the development of diabetes-related complications. Success with insulin management ultimately depends on how closely a given regimen can mimic normal physiologic insulin release patterns. The new insulin analogs, including the rapid-acting analogs (aspart, lispro, glulisine), the long-acting basal analogs (glargine, detemir), and the premixed insulin analog formulations (75% neutral...

  20. Long-term treatment of acromegaly with a long-acting analogue of somatostatin, octreotide. (United States)

    Page, M D; Millward, M E; Taylor, A; Preece, M; Hourihan, M; Hall, R; Scanlon, M F


    We have treated 16 acromegalic patients for up to 44 months with octreotide in varying doses. Growth hormone levels were suppressed in 14 patients with associated clinical improvement. IGF-1 levels were measured in 12 and fell into the normal range in 10. Prolactin was suppressed in six hyperprolactinaemic patients but was unaltered in normoprolactinaemic acromegalic patients. Post-prandial hyperglycaemia with impaired insulin secretion was noted in all patients, and one patient required oral hypoglycaemic agents. Octreotide did not affect thyroid function. CT scans from before and after six months of treatment demonstrated minimal tumour shrinkage in only two patients. Octreotide was well tolerated with no serious haematological or biochemical disturbance and no evidence of malabsorption. Two patients developed gallstones. Octreotide is effective in acromegaly. The development of gallstones is the only serious adverse event we have encountered.

  1. Expression of somatostatin receptors in human melanoma cell lines: effect of two different somatostatin analogues, octreotide and SOM230, on cell proliferation. (United States)

    Martinez-Alonso, M; Llecha, N; Mayorga, M E; Sorolla, A; Dolcet, X; Sanmartin, V; Abal, L; Casanova, J M; Baradad, M; Yeramian, A; Egido, R; Puig, S; Vilella, R; Matias-Guiu, X; Marti, R M


    Somatostatin analogues (SAs) are potential anticancer agents. This study was designed to investigate the expression of somatostatin receptors (SSTRs) in melanoma cells and the effect of two SAs on cell proliferation and viability. Eighteen primary and metastatic human cutaneous melanoma cell lines were treated with octreotide and SOM230. Expression of SSTR1, SSTR2, SSTR3 and SSTR5 was assessed by real-time polymerase chain reaction. Proliferation, viability and cell death were assessed using standard assays. Inhibition was modelled by mixed-effect regression. Melanoma cells expressed one or more SSTR. Both SAs inhibited proliferation of most melanoma cell lines, but inhibition was < 50%. Neither SA affected cell viability or induced cell death. The results suggest that melanoma cell lines express SSTRs. The SAs investigated, under the conditions used in this study, did not, however, significantly inhibit melanoma growth or induce cell death. Novel SAs, combination therapy with SAs and their anti-angiogenic properties should be further investigated.

  2. Troubleshooting analog circuits

    CERN Document Server

    Pease, Robert A


    Troubleshooting Analog Circuits is a guidebook for solving product or process related problems in analog circuits. The book also provides advice in selecting equipment, preventing problems, and general tips. The coverage of the book includes the philosophy of troubleshooting; the modes of failure of various components; and preventive measures. The text also deals with the active components of analog circuits, including diodes and rectifiers, optically coupled devices, solar cells, and batteries. The book will be of great use to both students and practitioners of electronics engineering. Other


    NARCIS (Netherlands)



    Thirty patients affected by insulin-dependent diabetes mellitus, without overt diabetic nephropathy, were randomly allocated to receive either octreotide (20 mug bolus followed by 10 mug.h-1) or vehicle intravenously over 2 hr. A similar infusion of octreotide with concomitant glucagon infusion (2 t

  4. Role of somatostatin receptor-2 in gentamicin-induced auditory hair cell loss in the Mammalian inner ear.

    Directory of Open Access Journals (Sweden)

    Yves Brand

    Full Text Available Hair cells and spiral ganglion neurons of the mammalian auditory system do not regenerate, and their loss leads to irreversible hearing loss. Aminoglycosides induce auditory hair cell death in vitro, and evidence suggests that phosphatidylinositol-3-kinase/Akt signaling opposes gentamicin toxicity via its downstream target, the protein kinase Akt. We previously demonstrated that somatostatin-a peptide with hormone/neurotransmitter properties-can protect hair cells from gentamicin-induced hair cell death in vitro, and that somatostatin receptors are expressed in the mammalian inner ear. However, it remains unknown how this protective effect is mediated. In the present study, we show a highly significant protective effect of octreotide (a drug that mimics and is more potent than somatostatin on gentamicin-induced hair cell death, and increased Akt phosphorylation in octreotide-treated organ of Corti explants in vitro. Moreover, we demonstrate that somatostatin receptor-1 knockout mice overexpress somatostatin receptor-2 in the organ of Corti, and are less susceptible to gentamicin-induced hair cell loss than wild-type or somatostatin-1/somatostatin-2 double-knockout mice. Finally, we show that octreotide affects auditory hair cells, enhances spiral ganglion neurite number, and decreases spiral ganglion neurite length.

  5. Comparison of integrated Chinese and Western medicine with and without somatostatin supplement in the treatment of severe acute pancreatitis

    Institute of Scientific and Technical Information of China (English)

    Qing Xia; Lin Yuan; Xiao-Nan Yang; Wen-Fu Tang; Jun-Ming Jiang


    AIM: To evaluate the therapeutic effect of the combined use of early short-term somatostatin and conventional integrated Chinese and Western medicine in treating severe acute pancreatitis.METHODS: Sixty patients with severe acute pancreatitis were divided at random into a somatostatin group and a basic treatment group. Both groups received integrated traditional Chinese and Western medicine without surgery.For patients in the somatostatin group, somatostatin was infused intravenously 250 μg/h for 72 h; other medications were the same as in the basic treatment group. In both groups, comparisons of therapeutic effectiveness were made in terms of morbidity of organic dysfunction and mortality rate, and severity of the disease according to serum levels of C-reaction protein, scores of acute physiology and chronic health evaluation (APACHE Ⅱ), and scores of Balthazar-CT.RESULTS: The indexes for C-reaction protein levels on the fourth and seventh days, and APACHE Ⅱ scores on the seventh day after treatment, were significantly improved in the somatostatin group than in the basic treatment group. The morbidity of organic dysfunction was lower in the somatostatin group than in the basic treatment group, although the difference was not statistically significant. There was no significant difference in mortality between the two groups.CONCLUSION: We conclude that combined traditional Chinese and Western medicines with an early short-term use of somatostatin can improve the condition of patients with severe acute pancreatitis.

  6. Urocortin3 mediates somatostatin-dependent negative feedback control of insulin secretion. (United States)

    van der Meulen, Talitha; Donaldson, Cynthia J; Cáceres, Elena; Hunter, Anna E; Cowing-Zitron, Christopher; Pound, Lynley D; Adams, Michael W; Zembrzycki, Andreas; Grove, Kevin L; Huising, Mark O


    The peptide hormone urocortin3 (Ucn3) is abundantly expressed by mature beta cells, yet its physiological role is unknown. Here we demonstrate that Ucn3 is stored and co-released with insulin and potentiates glucose-stimulated somatostatin secretion via cognate receptors on delta cells. Further, we found that islets lacking endogenous Ucn3 have fewer delta cells, reduced somatostatin content, impaired somatostatin secretion, and exaggerated insulin release, and that these defects are rectified by treatment with synthetic Ucn3 in vitro. Our observations indicate that the paracrine actions of Ucn3 activate a negative feedback loop that promotes somatostatin release to ensure the timely reduction of insulin secretion upon normalization of plasma glucose. Moreover, Ucn3 is markedly depleted from beta cells in mouse and macaque models of diabetes and in human diabetic islets. This suggests that Ucn3 is a key contributor to stable glycemic control, whose reduction during diabetes aggravates glycemic volatility and contributes to the pathophysiology of this disease.

  7. Somatostatin receptor biology in neuroendocrine and pituitary tumours: part 1--molecular pathways. (United States)

    Cakir, Mehtap; Dworakowska, Dorota; Grossman, Ashley


    Neuroendocrine tumours (NETs) may occur at many sites in the body although the majority occur within the gastroenteropancreatic axis. Non-gastroenteropancreatic NETs encompass phaeochromocytomas and paragangliomas, medullary thyroid carcinoma, anterior pituitary tumour, broncho-pulmonary NETs and parathyroid tumours. Like most endocrine tumours, NETs also express somatostatin (SST) receptors (subtypes 1-5) whose ligand SST is known to inhibit endocrine and exocrine secretions and have anti-tumour effects. In the light of this knowledge, the idea of using SST analogues in the treatment of NETs has become increasingly popular and new studies have centred upon the development of new SST analogues. We attempt to review SST receptor (SSTR) biology primarily in neuroendocrine tissues, focusing on pituitary tumours. A full data search was performed through PubMed over the years 2000-2009 with keywords 'somatostatin, molecular biology, somatostatin receptors, somatostatin signalling, NET, pituitary' and all relevant publications have been included, together with selected publications prior to that date. SSTR signalling in non-neuroendocrine solid tumours is beyond the scope of this review. SST is a potent anti-proliferative and anti-secretory agent for some NETs. The successful therapeutic use of SST analogues in the treatment of these tumours depends on a thorough understanding of the diverse effects of SSTR subtypes in different tissues and cell types. Further studies will focus on critical points of SSTR biology such as homo- and heterodimerization of SSTRs and the differences between post-receptor signalling pathways of SSTR subtypes.

  8. Somatostatin in the rat periventricular nucleus: sex differences and effect of gonadal steroids

    NARCIS (Netherlands)

    Vugt, van H.H.; Heijning, van de B.J.M.; Beek, van der E.M.


    In the rat, the sexual dimorphism in growth hormone release is driven by sex steroids, and is suggested to result mainly from differences in somatostatin (SOM) release patterns from the median eminence. We studied the effect of gonadal steroids on SOM peptide-containing cells in the periventricular

  9. Somatostatin adjunctive therapy for non-variceal upper gastrointestinal rebleeding after endoscopic therapy

    Institute of Scientific and Technical Information of China (English)

    Cheol Woong Choi; Dae Hwan Kang; Hyung Wook Kim; Su Bum Park; Kee Tae Park; Gwang Ha Kim; Geun Am Song; Mong Cho


    AIM: To evaluate the effect of pantoprazole with a somatostatin adjunct in patients with acute non-variceal upper gastrointestinal bleeding (NVUGIB).METHODS: We performed a retrospective analysis of a prospective database in a tertiary care university hospital. From October 2006 to October 2008, we enrolled 101 patients with NVUGIB that had a high-risk stigma on endoscopy. Within 24 h of hospital admission,all patients underwent endoscopic therapy. After successful endoscopic hemostasis, all patients received an 80-mg bolus of pantoprazole followed by continuous intravenous infusion (8 mg/h for 72 h). The somatostatin adjunct group (n = 49) also received a 250-μg bolus of somatostatin, followed by continuous infusion (250 μg/h for 72 h). Early rebleeding rates, disappearance of endoscopic stigma and risk factors associated with early rebleeding were examined.RESULTS: Early rebleeding rates were not significantly different between treatment groups (12.2% vs 14.3%, P = 0.766). Disappearance of endoscopic stigma on the second endoscopy was not significantly different between treatment groups (94.2% vs 95.9%, P = 0.696). Multivariate analysis showed that the complete Rockall score was a significant risk factor for early rebleeding (P = 0.044, OR: 9.080, 95% CI: 1.062-77.595).CONCLUSION: The adjunctive use of somatostatin was not superior to pantoprazole monotherapy after successful endoscopic hemostasis in patients with NVUGIB.

  10. Tissue-type plasminogen activator in somatostatin cells of rat pancreas and hypothalamus

    DEFF Research Database (Denmark)

    Kristensen, P; Larsson, L I; Danø, K;


    -PA, and immunoblotting analysis demonstrated one band with a similar electrophoretic mobility. No urokinase-type PA immunoreactivity was found in the rat endocrine pancreas. A granular t-PA immunoreactivity resembling that found in adjacent sections with somatostatin antiserum was found in the median eminence...

  11. Detection of meningioma metastasis to liver and lung using somatostatin receptor scintigraphy. (United States)

    Lanfranchi, Michael; Nikpoor, Nayer


    Extracranial meningioma metastasis is rare. We report a case of a 74-year-old Caucasian man with intracranial recurrence of atypical meningioma treated with a combination of surgical resection and gamma knife radiotherapy over a 4-year period. Somatostatin receptor scintigraphy using (111)In pentreotide for surveillance of tumor recurrence showed multiple pulmonary and hepatic metastases.

  12. Growth enhancement of rainbow trout (Oncorhynchus mykiss) by passive immunisation against somatostatin-14 (United States)

    Juvenile rainbow trout (Oncorhynchus mykiss) were passively immunised against somatostatin-14 (SS-14) using an antibody originating from egg laying chicken (Gallus domesticus). Fish were immunised weekly (0, 7, 14, 21, 28, 35 d) with chicken egg yolk derived immunoglobulin (IgY) against SS-14 (1:25 ...

  13. Interferon-γ inhibits ghrelin expression and secretion via a somatostatin-mediated mechanism

    Institute of Scientific and Technical Information of China (English)

    Jesper AB Strickertsson; Kristina BV Dφssing; Anna JM Aabakke; Hans-Olof Nilsson; Thomas VO Hansen; Ulrich Knigge; Andreas Kj(ae)r; Torkel Wadstr(o)m; Lennart Friis-Hansen


    AIM: To investigate if and how the proinflammatory cytokine interferon γ (IFNγ) affects ghrelin expression in mice. METHODS: The plasma concentration of ghrelin, and gastric ghrelin and somatostatin expression, were examined in wild-type mice and mice infected with Helicobacter pylori (H. pylori ). Furthermore, ghrelin expression was examined in two achlorhydric mouse models with varying degrees of gastritis due to bacterial overgrowth. To study the effect of IFNγ alone, mice were given a subcutaneous infusion of IFNγ for 7 d. Finally, the influence of IFNγ and somatostatin on the ghrelin promoter was characterized. RESULTS: H. pylori infection was associated with a 50% reduction in ghrelin expression and plasma concentration. Suppression of ghrelin expression was inversely correlated with gastric inflammation in achlorhdyric mouse models. Subcutaneous infusion of IFNγ suppressed fundic ghrelin mRNA expression and plasma ghrelin concentrations. Finally, we showed that the ghrelin promoter operates under the control of somatostatin but not under that of IFNγ. CONCLUSION: Gastric infection and inflammation is associated with increased IFNγ expression and reduced ghrelin expression. IFNγ does not directly control ghrelin expression but inhibits it indirectly via somatostatin.

  14. Cortistatin-17 and -14 exert the same endocrine activities as somatostatin in humans

    NARCIS (Netherlands)

    C. Gottero; E. Ghigo (Ezio); F. Broglio (Fabio); F. Prodam (Flavia); S. Destefanis; A. Benso; C. Gauna (Carlotta); E. Me (Elisa); L. Filtri (L.); F. Riganti (Fabrizio); A-J. van der Lely (Aart-Jan)


    textabstractCortistatin (CST) is a neuropeptide, which binds with high affinity all somatostatin (SS) receptor subtypes and shows high structural homology with SS itself. A receptor specific for CST only, i.e., not recognized by SS, has been recently described in agreement with data reporting that n

  15. Postsynaptic targets of somatostatin-immunoreactive interneurons in the rat hippocampus. (United States)

    Katona, I; Acsády, L; Freund, T F


    Two characteristic interneuron types in the hippocampus, the so-called hilar perforant path-associated cells in the dentate gyrus and stratum oriens/lacunosum-moleculare neurons in the CA3 and CA1 regions, were suggested to be involved in feedback circuits. In the present study, interneurons identical to these cell populations were visualized by somatostatin-immunostaining, then reconstructed, and processed for double-immunostaining and electron microscopy to establish their postsynaptic target selectivity. A combination of somatostatin-immunostaining with immunostaining for GABA or other interneuron markers revealed a quasi-random termination pattern. The vast majority of postsynaptic targets were GABA-negative dendritic shafts and spines of principal cells (76%), whereas other target elements contained GABA (8%). All of the examined neurochemically defined interneuron types (parvalbumin-, calretinin-, vasoactive intestinal polypeptide-, cholecystokinin-, substance P receptor-immunoreactive neurons) received innervation from somatostatin-positive boutons. Recent anatomical and electrophysiological data showed that the main excitatory inputs of somatostatin-positive interneurons originate from local principal cells. The present data revealed a massive GABAergic innervation of distal dendrites of local principal cells by these feedback driven neurons, which are proposed to control the efficacy and plasticity of entorhinal synaptic input as a function of local principal cell activity and synchrony.

  16. Effect of perioperative somatostatin administration of sphincteroplasty-induced increase of amylase. (United States)

    Roncoroni, L; De Bernardinis, M; Violi, V; Montanari, M; Peracchia, A


    Twenty patients undergoing sphincteroplasty for cholelithiasis were randomly divided into two groups of 10. The former (T) were treated with a 4-h somatostatin intravenous drip (250 micrograms/h), started at the beginning of operation, while the latter (C) made up the control group. Serum and urine amylase, amylase creatinine clearance ratio, and liver function tests were assessed for 2 days before surgery, after the operation and for a period of 5 postoperative days. Homogeneity between the two series was verified in experimental conditions. Statistical differences occurred postoperatively in amylase creatinine clearance ratio, which proved higher in C group, and gamma-GT, which was higher in T group. Short-term somatostatin administration proved effective in reducing the postoperative amylase creatinine clearance ratio, although more evident results are reported after long-term administration. Cholestasis or any serious impairment in liver function did not occur, suggesting the suitability of somatostatin use even in patients with jaundice. Since a relationship between postoperative amylase levels and risk of pancreatitis has not yet been proved, the value of somatostatin in the prevention of postoperative pancreatitis after sphincteroplasty needs to be further verified.

  17. Unique functional properties of somatostatin-expressing GABAergic neurons in mouse barrel cortex.

    NARCIS (Netherlands)

    Gentet, L.J.; Kremer, Y.; Taniguchi, H.; Huang, Z.J.; Staiger, J.F.; Petersen, C.C.H.


    Neocortical GABAergic neurons have diverse molecular, structural and electrophysiological features, but the functional correlates of this diversity are largely unknown. We found unique membrane potential dynamics of somatostatin-expressing (SOM) neurons in layer 2/3 of the primary somatosensory

  18. Challenges in Analogical Reasoning

    CERN Document Server

    Lin, Shih-Yin


    Learning physics requires understanding the applicability of fundamental principles in a variety of contexts that share deep features. One way to help students learn physics is via analogical reasoning. Students can be taught to make an analogy between situations that are more familiar or easier to understand and another situation where the same physics principle is involved but that is more difficult to handle. Here, we examine introductory physics students' ability to use analogies in solving problems involving Newton's second law. Students enrolled in an algebra-based introductory physics course were given a solved problem involving tension in a rope and were then asked to solve another problem for which the physics is very similar but involved a frictional force. They were asked to point out the similarities between the two problems and then use the analogy to solve the friction problem.

  19. TV Analog Station Transmitters (United States)

    Department of Homeland Security — This file is an extract from the Consolidated Database System (CDBS) licensed by the Media Bureau. It consists of Analog Television Stations (see Rule Part47 CFR...

  20. Analog multivariate counting analyzers

    CERN Document Server

    Nikitin, A V; Armstrong, T P


    Characterizing rates of occurrence of various features of a signal is of great importance in numerous types of physical measurements. Such signal features can be defined as certain discrete coincidence events, e.g. crossings of a signal with a given threshold, or occurrence of extrema of a certain amplitude. We describe measuring rates of such events by means of analog multivariate counting analyzers. Given a continuous scalar or multicomponent (vector) input signal, an analog counting analyzer outputs a continuous signal with the instantaneous magnitude equal to the rate of occurrence of certain coincidence events. The analog nature of the proposed analyzers allows us to reformulate many problems of the traditional counting measurements, and cast them in a form which is readily addressed by methods of differential calculus rather than by algebraic or logical means of digital signal processing. Analog counting analyzers can be easily implemented in discrete or integrated electronic circuits, do not suffer fro...

  1. Synthesis of Paclitaxel Analogs


    Xu, Zhibing


    Paclitaxel is one of the most successful anti-cancer drugs, particularly in the treatment of breast cancer and ovarian cancer. For the investigation of the interaction between paclitaxel and MD-2 protein, and development of new antagonists for lipopolysaccharide, several C10 A-nor-paclitaxel analogs have been synthesized and their biological activities have been evaluated. In order to reduce the myelosuppression effect of the paclitaxel, several C3â ² and C4 paclitaxel analogs have been synth...

  2. FGF growth factor analogs (United States)

    Zamora, Paul O [Gaithersburg, MD; Pena, Louis A [Poquott, NY; Lin, Xinhua [Plainview, NY; Takahashi, Kazuyuki [Germantown, MD


    The present invention provides a fibroblast growth factor heparin-binding analog of the formula: ##STR00001## where R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, X, Y and Z are as defined, pharmaceutical compositions, coating compositions and medical devices including the fibroblast growth factor heparin-binding analog of the foregoing formula, and methods and uses thereof.

  3. Analog circuits cookbook

    CERN Document Server

    Hickman, Ian


    Analog Circuits Cookbook presents articles about advanced circuit techniques, components and concepts, useful IC for analog signal processing in the audio range, direct digital synthesis, and ingenious video op-amp. The book also includes articles about amplitude measurements on RF signals, linear optical imager, power supplies and devices, and RF circuits and techniques. Professionals and students of electrical engineering will find the book informative and useful.

  4. An Optical Analog of a Black Holes

    CERN Document Server

    Royston, A; Royston, Andrew; Gass, Richard


    Using media with extremely low group velocities one can create an optical analog of a curved space-time. Leonhardt and Piwnicki have proposed that a vortex flow will act as an optical black hole. We show that although the Leonhardt - Piwnicki flow has an orbit of no return and an infinite red-shift surface, it is not a true black hole since it lacks a null hypersurface. However a radial flow will produce a true optical black hole that has a Hawking temperature and obeys the first law of black hole mechanics. By combining the Leonhardt - Piwnicki flow with a radial flow we obtain the analog of the Kerr black hole.

  5. Electrical Circuits and Water Analogies (United States)

    Smith, Frederick A.; Wilson, Jerry D.


    Briefly describes water analogies for electrical circuits and presents plans for the construction of apparatus to demonstrate these analogies. Demonstrations include series circuits, parallel circuits, and capacitors. (GS)

  6. Intracerebroventricular and intravenous administration of growth hormone secretagogue L-692,585, somatostatin, neuropeptide Y and galanin in pig: dose-dependent effects on growth hormone secretion. (United States)

    Cho, S-J; Lee, J-S; Mathias, E D; Chang, C; Hickey, G J; Lkhagvadorj, S; Anderson, L L


    Central regulation of growth hormone (GH) secretion by the GH secretagogue, L-692,585 (585), was determined in Yorkshire barrows (40-45kg BW) with intracerebroventricular (icv) stainless steel cannulas placed by stereotaxic coordinates and indwelling external jugular vein (iv) cannulas for injecting 585 or saline during 3h serial blood sampling. Dose-dependent effects of 585 were determined by icv injections of saline vehicle, 3, 10, and 30microg/kg BW by once daily increment. A switchback study of iv and icv 585 treatment determined central and peripheral regulation of GH secretion by the secretagogue at 30microg/kg BW. When administered icv, 585 increased GH concentration in a dose-dependent manner, with a return to baseline by 60min. GH secretion was attenuated by increased numbers of icv 585 injections (padministration of somatostatin (SRIF) decreased (padministration indicate that the GH secretagogue and neuropeptides act at the level of both porcine pituitary and hypothalamus.

  7. Digital and analog communication systems (United States)

    Shanmugam, K. S.


    The book presents an introductory treatment of digital and analog communication systems with emphasis on digital systems. Attention is given to the following topics: systems and signal analysis, random signal theory, information and channel capacity, baseband data transmission, analog signal transmission, noise in analog communication systems, digital carrier modulation schemes, error control coding, and the digital transmission of analog signals.

  8. Analogical Reasoning in Geometry Education (United States)

    Magdas, Ioana


    The analogical reasoning isn't used only in mathematics but also in everyday life. In this article we approach the analogical reasoning in Geometry Education. The novelty of this article is a classification of geometrical analogies by reasoning type and their exemplification. Our classification includes: analogies for understanding and setting a…

  9. Somatostatin and leu-enkephalin in the rat auditory brainstem during fetal and postnatal development. (United States)

    Kungel, M; Friauf, E


    A transient expression of the neuropeptide somatostatin has been described in several brain areas during early ontogeny and several opioid peptides, such as leu-enkephalin, have also been found in the brain at this stage in development. It is therefore believed that somatostatin and leu-enkephalin may play a role in neural maturation. The aim of the present study was to describe the spatiotemporal pattern of somatostatin and leu-enkephalin immunoreactivity in the auditory brainstem nuclei of the developing rat and to correlate it with other developmental events. In order to achieve this goal, we applied peroxidase-antiperoxidase immunocytochemistry to rat brains between embryonic day (E) 17 and adulthood. Somatostatin immunoreactivity (SIR) was found in all nuclei of the auditory brainstem, yet it was temporally restricted in most nuclei. SIR appeared prenatally and reached maximum levels around postnatal day (P) 7, when great numbers of immunoreactive neurons were present in the ventral cochlear nucleus (VCN) and in the lateral lemniscus. At that time relatively low numbers of cells were labeled in the dorsal cochlear nucleus, the lateral superior olive (LSO), and the inferior colliculus (IC). During the same period, when somata in the VCN were somatostatin-immunoreactive (SIR), a dense network of labeled fibers was also present in the LSO, the medial superior olive (MSO), and the medial nucleus of the trapezoid body (MNTB). As these nuclei receive direct input from VCN neurons, and as the distribution and morphology of the somatostatinergic fibers in the superior olivary complex (SOC) was like that of axons from VCN neurons, these findings suggest a transient somatostatinergic connection within the auditory system. Aside from the LSO, MSO, and MNTB, labeled fibers were found to a smaller extent in all other auditory brainstem nuclei. After P7, the SIR decreased and only a few immunoreactive elements were found in the adult auditory brainstem nuclei, indicating

  10. The Cortistatin Gene PSS2 Rather Than the Somatostatin Gene PSS1 Is Strongly Expressed in Developing Avian Autonomic Neurons


    Nishi, Rae; Stubbusch, Jutta; Hulce, Jonathan J.; Hruska, Martin; Pappas, Anthony; Bravo, Maria-Christina; Huber, Leslie P.; Bakondi, Benjamin; Soltys, John; Rohrer, Hermann


    Somatostatin and cortistatin are neuromodulators with divergent expression patterns and biological roles. Whereas expression and function of genes encoding somatostatin (PSS1) and the related peptide cortistatin (PSS2) have been studied in detail for the central nervous system (CNS) and immune system, relatively little is known about their expression patterns in the peripheral nervous system (PNS). We compare the expression patterns of PSS1 and PSS2 in chicken embryos. At E14, PSS1 is higher ...

  11. Positron emission tomography evaluation of somatostatin receptor targeted (64)Cu-TATE-liposomes in a human neuroendocrine carcinoma mouse model

    DEFF Research Database (Denmark)

    Petersen, Anncatrine Luisa; Binderup, Tina; Jølck, Rasmus Irming


    Targeted therapeutic and diagnostic nanocarriers functionalized with antibodies, peptides or other targeting ligands that recognize over-expressed receptors or antigens on tumor cells have potential in the diagnosis and therapy of cancer. Somatostatin receptors (SSTRs) are over-expressed in a var......Targeted therapeutic and diagnostic nanocarriers functionalized with antibodies, peptides or other targeting ligands that recognize over-expressed receptors or antigens on tumor cells have potential in the diagnosis and therapy of cancer. Somatostatin receptors (SSTRs) are over...

  12. 68Ga-DOTA-NOC PET/CT detects somatostatin receptors expression in von hippel-lindau cerebellar disease. (United States)

    Ambrosini, Valentina; Campana, Davide; Allegri, Vincenzo; Opocher, Giuseppe; Fanti, Stefano


    A case of Von-Hippel Lindau (VHL) disease has been studied using 68Ga-DOTA-NOC PET/CT. PET/CT demonstrated the presence of somatostatin receptors within 2 focal areas in the cerebellum corresponding to the lesions detected by MRI. Considering the heterogeneous lesions localizations in VHL disease, PET/CT may be a useful imaging modality for diagnosing lesions of central nervous system and neuroendocrine lesions and for direct demonstration of somatostatin receptors for targeted treatment.

  13. Somatostatin receptor scintigraphy in advanced renal cell carcinoma. Results of a phase II-trial of somatostatine analogue therapy in patients with advanced RCC

    Energy Technology Data Exchange (ETDEWEB)

    Freudenberg, L.S.; Goerges, R.; Stergar, H.; Bockisch, A. [Dept. of Nuclear Medicine, Univ. of Duisburg-Essen (Germany); Gauler, T.; Bauer, S. [Dept. of Internal Medicine (Cancer Research), Univ. of Duisburg-Essen (Germany); Antoch, G. [Dept. of Diagnostic and Interventional Radiology and Neuroradiology, Univ. of Duisburg-Essen (Germany); Schuette, J. [Dept. of Medical Oncology/Hematology, Marien-Hospital Duesseldorf (Germany)


    Aims: objective of this prospective study was to evaluate the role of somatostatin receptor scintigraphy (SRS) in advanced renal cell carcinoma (RCC) with respect to potential therapy with somatostatin analogue (SST-A) and to assess the response rate under therapy with SST-A. Patients, methods: 16 patients with documented progression of histologically confirmed advanced RCC were included. Planar whole-body SRS was performed 4, 24 and 48h post i.v. injection of 175-200 MBq {sup 111}In-pentetreoide. 5 and 25 h p.i. SPECT of thorax and abdomen were performed. Documentation of somatostatin receptor expression via SRS in > 50% of known tumour lesions was the criteria for treatment start with SST-A (Sandostatin LAR {sup registered} -Depot 30mg i.m. every four weeks). Results: in 9/16 of the patients SRS showed at least one metastasis with moderate (n = 5) or intense (n = 4) tracer uptake. Lesion-based SRS evaluation showed only 12.1% (20/165) of all metastases. Most false-negative lesions were located in the lungs. In too patients, the majority of the known metastases was SRS positive and these patients received SST-A therapy. The first radiographic evaluation after a two-month interval showed progressive disease in both patients. Conclusions: we conclude that SRS is of limited value in staging of advanced RCC. In our patients SST-A did not result in a growth control of RCC. Consequently, the use of SST-A in advanced RCC seems to be no relevant therapeutic option. (orig.)

  14. Effect of emergency operation combined with somatostatin therapy on inflammatory state and liver function levels in patients with acute cholecystitis

    Institute of Scientific and Technical Information of China (English)

    Shi-Zhong Li


    Objective:To study the effect of emergency operation combined with somatostatin therapy on inflammatory state and liver function levels in patients with acute cholecystitis.Methods:A total of 146 acute cholecystitis patients who accepted laparoscopic cholecystectomy in our hospital from May 2012 to October 2015 were selected as the research subjects and divided into somatostatin group and normal control group. Then the operation, perioperative energy metabolism as well as postoperative inflammatory state and liver function levels of the two groups were analyzed.Results:Operative field exposure of somatostatin group was clearer, local tissue edema and exudation were lighter and conversion rate to laparotomy was lower; perioperative REE of somatostatin group were significantly lower than those of normal control group; the very day after operation, numeration of leukocyte, neutrophil ratio as well as serum resistin, hypersensitive C-reactive protein and tumor necrosis factor-α, interleukin-6, total bilirubin, alkaline phosphatase, alanine aminotransferase and aspartate aminotransferase levels of somatostatin group were significantly lower than those of normal control group while prealbumin level was significantly higher than that of normal control group.Conclusions:Perioperative application of somatostatin can reduce the body's inflammatory response, local tissue edema and liver function injury. It is an ideal treatment for perioperative acute cholecystitis.

  15. Somatostatin receptors and their ligands in the human immune system

    NARCIS (Netherlands)

    V.A.S.H. Dalm (Virgil)


    textabstractMaintenance of homeostasis is essential for survival of the mammalian organism. For a long time it was believed that the different systems in the human body act independently from each other to achieve this goal. However, during the last decades it has become more evident that the differ

  16. Are Scientific Analogies Metaphors? (United States)


    psychospiritual processes. A more modern example of unclarified analogy is Freud’s (1973; reprinted from 1955) discussion of anal- eroticism , in which...299-304. Freud, S. On transformations of instinct as exemplified in anal eroticism . In J. Strachey (Ed.), The standard 37 edition of the complete

  17. Analogy, explanation, and proof. (United States)

    Hummel, John E; Licato, John; Bringsjord, Selmer


    People are habitual explanation generators. At its most mundane, our propensity to explain allows us to infer that we should not drink milk that smells sour; at the other extreme, it allows us to establish facts (e.g., theorems in mathematical logic) whose truth was not even known prior to the existence of the explanation (proof). What do the cognitive operations underlying the inference that the milk is sour have in common with the proof that, say, the square root of two is irrational? Our ability to generate explanations bears striking similarities to our ability to make analogies. Both reflect a capacity to generate inferences and generalizations that go beyond the featural similarities between a novel problem and familiar problems in terms of which the novel problem may be understood. However, a notable difference between analogy-making and explanation-generation is that the former is a process in which a single source situation is used to reason about a single target, whereas the latter often requires the reasoner to integrate multiple sources of knowledge. This seemingly small difference poses a challenge to the task of marshaling our understanding of analogical reasoning to understanding explanation. We describe a model of explanation, derived from a model of analogy, adapted to permit systematic violations of this one-to-one mapping constraint. Simulation results demonstrate that the resulting model can generate explanations for novel explananda and that, like the explanations generated by human reasoners, these explanations vary in their coherence.

  18. Quantum Analog Computing (United States)

    Zak, M.


    Quantum analog computing is based upon similarity between mathematical formalism of quantum mechanics and phenomena to be computed. It exploits a dynamical convergence of several competing phenomena to an attractor which can represent an externum of a function, an image, a solution to a system of ODE, or a stochastic process.

  19. Somatostatin Interneurons Control a Key Component of Mismatch Negativity in Mouse Visual Cortex

    Directory of Open Access Journals (Sweden)

    Jordan P. Hamm


    Full Text Available Patients with schizophrenia have deficient sensory processing, undermining how they perceive and relate to a changing environment. This impairment can be captured by the reduced mismatch negativity (MMN index, an electroencephalographic biomarker of psychosis. The biological factors contributing to MMN are unclear, though mouse research, in which genetic and optical methods could be applied, has given some insight. Using fast two-photon calcium imaging and multielectrode recordings in awake mice, we find that visual cortical circuits display adapted (decreased responses to repeated stimuli and amplified responses to a deviant stimulus, the key component of human MMN. Moreover, pharmacogenetic silencing of somatostatin-containing interneurons specifically eliminated this amplification, along with its associated theta/alpha-band response, leaving stimulus-specific adaption and related gamma-band modulations intact. Our results validate a mouse model of MMN and suggest that abnormalities in somatostatin-containing interneurons cause sensory deficits underlying MMN and schizophrenia.

  20. The potential value of somatostatin receptor scintigraphy in medullary thyroid carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Doerr, U.; Bihl, H. (Katharinenhospital, Stuttgart (Germany). Dept. of Nuclear Medicine); Frank-Raue, K.; Raue, F. (Heidelberg Univ. (Germany). Dept. of Internal Medicine); Sautter-Bihl, M.L.; Buhr, H.J. (Staedt. Klinikum, Karlsruhe (Germany). Dept. of Radiooncology and Nuclear Medicine); Guzman, G. (Katherinenhospital, Stuttgart (Germany). Dept. of Nuclear Medicine Inst. de Neurocirugia, Investigationes Cerebrales ' Dr Asenjo' Santiago (Chile). Dept. de Medicina Nuclear)


    In a prospective study, ten patients with recurrent medullary thyroid carcinoma (markedly elevated calcitonin levels) were investigated by means of somatostatin receptor scintigraphy (SRS) with [sup 111]In-pentetreotide. Scintigraphically, 30 sites of pathological uptake were found, mostly located in the neck and upper mediastinum. So far, 18 suspected tumour sites underwent histological examination and 14 of them could be verified as metastases of medullary thyroid carcinoma (MTC). The remaining four putative tumour lesions turned out to be false positive scintigraphic findings caused by chronic inflammation and somatostatin receptor positive tumours other than MTC. We conclude that SRS is a promising imaging modality for localization of MTC recurrence and may thus make a contribution to better management of this patient group. (Author).

  1. GRP-producing nerves control antral somatostatin and gastrin secretion in pigs

    DEFF Research Database (Denmark)

    Holst, J J; Orskov, C; Poulsen, Steen Seier


    of isolated perfused pig antrum with intact vagus nerve supply. Electrical stimulation of the vagus nerves at 4 Hz increased the antral release of GRP up to 10-fold and increased SS output 2- to 3-fold. Atropine at 10(-6) M had no effect on these responses. Intra-arterial GRP increased SS secretion...... the effects of vagus stimulation on gastrin and somatostatin output. Gastrin in concentrations up to 10(-7) M was without effect on SS secretion. We conclude that electrical stimulation of the vagus nerves increases antral SS gastrin secretion and that GRP is a likely transmitter.......By immunohistochemistry, nerve fibers containing gastrin-releasing polypeptide (GRP)-like immunoreactivity were identified close to the somatostatin (SS)-producing cells of the gastric antral mucosa. We, therefore, studied the possible role of GRP in the control of antral SS secretion by use...

  2. Somatostatin-immunoreactive nerve cell bodies and fibers in the medulla oblongata et spinalis. (United States)

    Forssmann, W G; Burnweit, C; Shehab, T; Triepel, J


    Complete serial sectioning of the medulla oblongata in monkey, cat, guinea pig, and japanese dancing mouse and incubation for somatostatin-immunoreaction was carried out. Numerous regions of the medulla oblongata such as the nucleus reticularis gigantocellularis, nucleus cuneatus et gracillis, nucleus raphe magnus, nucleus tractus solitarius, nucleus vestibularis, and parts of the oliva contain dense networks of somatostatin-immunoreactive nerve fibers. Cell bodies were seen in the nucleus reticularis medullae oblongatae. In the spinal cord the sections from each segment were analyzed, showing the highest concentrations of somatostatinergic fibers in the substantia gelantinosa of the columna dorsalis. Cell bodies were seen in the zona intermedia centralis, especially in the upper cervical segments. Many positive fibers were also seen in the entire zona intermedia and the columna ventralis. Especially prominent was the immunoreactivity in the zona intermediolateralis of the thoracic segments and the columna ventralis of the lower lumbar and sacral segments.

  3. Treatment of neuroendocrine tumours with radioactive labelled somatostatin analogues; Therapie neuroendokriner Tumoren mit radioaktiv markierten Somatostatinanaloga

    Energy Technology Data Exchange (ETDEWEB)

    Geisler, J.; Bartenstein, P.; Haug, Alexander R. [Ludwig-Maximilians-Univ., Muenchen (Germany). Klinik fuer Nuklearmedizin


    Therapy of neuroendocrine tumors (NET) using radiolabelled somatostatin receptors such as {sup 177}-Lu-DOTATATE or {sup 90}Y-DOTATOC is gaining more and more importance. Due to the over expression of somatostatin receptors in NET the tumor-to-background ratio is very favourable. A significant therapy response is achievable between 20% and up to 46% of treated patients with a median time to progression of up to 40 months. Furthermore, this kind of therapy is very beneficial in the case of hormonal active, functional NET in terms of symptom control. Also quality of life is significantly improved after therapy, even in non-responding patients. The most common side effects of this therapy are nausea, vomiting and transient hematologic toxicity. However, late serious side effects such as renal impairment or myelodysplastic syndrome are rare if renal protection is used during the course of therapy. (orig.)

  4. Somatostatin receptor biology in neuroendocrine and pituitary tumours: part 1 – molecular pathways (United States)

    Cakir, Mehtap; Dworakowska, Dorota; Grossman, Ashley


    Abstract Neuroendocrine tumours (NETs) may occur at many sites in the body although the majority occur within the gastroenteropancreatic axis. Non-gastroenteropancreatic NETs encompass phaeochromocytomas and paragangliomas, medullary thyroid carcinoma, anterior pituitary tumour, broncho-pulmonary NETs and parathyroid tumours. Like most endocrine tumours, NETs also express somatostatin (SST) receptors (subtypes 1–5) whose ligand SST is known to inhibit endocrine and exocrine secretions and have anti-tumour effects. In the light of this knowledge, the idea of using SST analogues in the treatment of NETs has become increasingly popular and new studies have centred upon the development of new SST analogues. We attempt to review SST receptor (SSTR) biology primarily in neuroendocrine tissues, focusing on pituitary tumours. A full data search was performed through PubMed over the years 2000–2009 with keywords ‘somatostatin, molecular biology, somatostatin receptors, somatostatin signalling, NET, pituitary’ and all relevant publications have been included, together with selected publications prior to that date. SSTR signalling in non-neuroendocrine solid tumours is beyond the scope of this review. SST is a potent anti-proliferative and anti-secretory agent for some NETs. The successful therapeutic use of SST analogues in the treatment of these tumours depends on a thorough understanding of the diverse effects of SSTR subtypes in different tissues and cell types. Further studies will focus on critical points of SSTR biology such as homo- and heterodimerization of SSTRs and the differences between post-receptor signalling pathways of SSTR subtypes. PMID:20629989

  5. Somatostatin receptor biology in neuroendocrine and pituitary tumours: part 1 – molecular pathways


    Cakir, Mehtap; Dworakowska, Dorota; Grossman, Ashley


    Abstract Neuroendocrine tumours (NETs) may occur at many sites in the body although the majority occur within the gastroenteropancreatic axis. Non-gastroenteropancreatic NETs encompass phaeochromocytomas and paragangliomas, medullary thyroid carcinoma, anterior pituitary tumour, broncho-pulmonary NETs and parathyroid tumours. Like most endocrine tumours, NETs also express somatostatin (SST) receptors (subtypes 1–5) whose ligand SST is known to inhibit endocrine and exocrine secretions and hav...

  6. Use of somatostatin analogue scintigraphy in the localization of recurrent medullary thyroid carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Berna, L.; Catafau, A.; Mari, C.; Flotats, A.; Martin, J.C.; Estorch, M.; Carrio, I. [Department of Nuclear Medicine, Hospital de la Santa Creu i Sant Pau, Barcelona (Spain); Chico, A.; Mato, E. [Department of Endocrinology, Hospital de la Santa Creu i Sant Pau, Barcelona (Spain); Matias-Guiu, X. [Department of Pathology, Hospital de la Santa Creu i Sant Pau, Barcelona (Spain); Alonso, C. [Department of Oncology, Hospital de la Santa Creu i Sant Pau, Barcelona (Spain); Mora, J.; Rodriguez-Espinosa, J. [Department of Biochemistry, Hospital de la Santa Creu i Sant Pau, Barcelona (Spain); Mauricio, D. [Department of Endocrinology, Hospital Parc Tauli, Sabadell (Spain)


    Detection of recurrence of medullary thyroid carcinoma (MTC) remains a diagnostic problem. Increased serum tumour marker levels frequently indicate recurrence while conventional imaging techniques (CIT) are non-diagnostic. In this study, we performed indium-111 octreotide scintigraphy and CIT in a series of 20 patients with MTC presenting with elevated serum tumour markers after surgery. {sup 111}In-octreotide whole-body studies detected 15 pathological uptake foci in 11 of the 20 patients studied and CIT detected 17 lesions in 11 of the 20 patients. Ten patients underwent reoperation, five of them with positive {sup 111}In-octreotide scintigraphy and CIT and two with positive isotopic exploration and negative CIT. Surgical findings demonstrated that the results of isotopic study and CIT had been false-positive for MTC in one case (sarcoidosis). The six patients with true-positive {sup 111}In-octreotide studies had significantly higher basal calcitonin (CT) and carcinoembryonic antigen (CEA) levels than the patients with negative isotopic studies. The expression of somatostatin receptor (SSTR) subtypes by PC-PCR could be investigated in four cases with a positive isotopic study. Among the three cases with a true-positive study, SSTR2, the SSTR subtype that preferentially binds to the somatostatin analogue octreotide, was detected in two, SSTR5 was demonstrated in the three, and SSTR3 was detected in one. No subtype of SSTR was detected in the case with a final diagnosis of sarcoidosis. We conclude that {sup 111}In-octreotide has limited sensitivity in detecting recurrence in patients with MTC, although its sensitivity may improve with high serum CT levels. This radionuclide imaging technique should be employed when conventional imaging techniques are negative or inconclusive or when the presence of somatostatin receptors may provide the basis for treatment with somatostatin analogues. (orig.) With 4 figs., 3 tabs., 29 refs.

  7. Effects of somatostatin and oral potassium administration on terbutaline-induced hypokalemia. (United States)

    Schnack, C; Podolsky, A; Watzke, H; Schernthaner, G; Burghuber, O C


    Terbutaline, a beta 2-adrenergic agonist, has been shown to cause hypokalemia and an increase of plasma glucose and serum insulin concentrations. We considered that terbutaline-induced hypokalemia may be due to the insulin-induced shift of potassium (K+) from the extracellular to the intracellular space. If so, then inhibition of insulin secretion by somatostatin would prevent terbutaline-induced hypokalemia. Further, we wondered whether oral potassium pretreatment could prevent terbutaline-induced hypokalemia. Therefore, 10 healthy volunteers (5 men, 5 women; mean age, 23 yr +/- 3 SD) received either sodium chloride (NaCl) or somatostatin intravenously together with 0.25 mg terbutaline subcutaneously in a double-blind crossover design. On a third test day, they received 39 mval of K+ powder orally before terbutaline injection in an open trial. Terbutaline caused a significant decrease of K+ (from 3.96 +/- 0.08 to 3.3 +/- 0.13 mmol/L +/- SEM; p less than 0.0005), accompanied by a significant increase in plasma glucose (from 83 +/- 3.6 to 101 +/- 4.4 mg/dl +/- SEM; p less than 0.01) and serum insulin concentrations (from 11.7 +/- 0.9 to 19.9 +/- 1.1 microU/ml +/- SEM; p less than 0.001), confirming earlier data. Somatostatin pretreatment inhibited the terbutaline-induced hypokalemia; the small fall of K+ (from 3.7 +/- 0.08 to 3.5 +/- 0.2 mmol/L) was no longer significant. Insulin secretion was completely blocked by somatostatin, leading to an even more pronounced increase of blood glucose. Hypokalemia after terbutaline injection was not prevented by oral potassium pretreatment. In summary, the present findings confirm that terbutaline-induced hypokalemia is associated with increased plasma glucose and insulin levels.(ABSTRACT TRUNCATED AT 250 WORDS)

  8. Epidrug-induced upregulation of functional somatostatin type 2 receptors in human pancreatic neuroendocrine tumor cells. (United States)

    Veenstra, Marije J; van Koetsveld, Peter M; Dogan, Fadime; Farrell, William E; Feelders, Richard A; Lamberts, Steven W J; de Herder, Wouter W; Vitale, Giovanni; Hofland, Leo J


    Somatostatin receptors are a pivotal target for treatment of pancreatic neuroendocrine tumors (pNET), either with somatostatin analogues (SSA) or radiolabeled SSA. The highest affinity target for the most commonly used SSA is the somatostatin receptor type 2 (sst2). An important factor that may complicate treatment efficacy, is the variable number of receptors expressed on pNETs. Gene expression is subject to complex regulation, in which epigenetics has a central role. In this study we explored the possible role of epigenetic modifications in the variations in sst2 expression levels in two human pNET cell lines, BON-1 and QGP-1. We found upregulation of sst2 mRNA after treatment with the epidrugs 5-aza-2'-deoxycytidine (5-aza-dC) and valproic acid (VPA), an increased uptake of radiolabeled octreotide, as well as increased sensitivity to the SSA octreotide in functional cAMP inhibition. At epigenetic level we observed low methylation levels of the sst2 gene promoter region irrespective of expression. Activating histone mark H3K9Ac can be regulated with epidrug treatment, with an angle of effect corresponding to the effect on mRNA expression. Repressive histone mark H3K27me3 is not regulated by either 5-aza-dC or VPA. We conclude that epidrug treatment, in particular with combined 5-aza-dC and VPA treatment, might hold promise for improving and adding to current SSA treatment strategies of patients with pNETs.


    Institute of Scientific and Technical Information of China (English)

    Jian Yin; Chang-bao Su; Zhi-qin Xu; Yi Yang; Wen-bin Ma; Wei Tao; Zhong Yang; Xue-wei Xia


    Objective To investigate whether somatostatin analog octreotide long acting release (LAR) shrinks growth hormone (GH) secreting adenomas, and improves the results of subsequent transsphenoidal surgery.Methods Seventeen previously untreated active acromegalic patients with pituitary adenomas were treated with LAR (30 mg intramuscular injection every 28 days) for 3 months prior to transsphenoidal surgery. Clinical reaction, mean GH secretion, and tumor volume were measured under basal conditions and after LAR treatment.Results Presurgical treatment improved acromegaly symptoms and induced a significant reduction of GH under the 5 ng/mL limit in microadenoma (P < 0.05), while only 18.2% (2/11) in macroadenoma. Meanwhile, tumor shrinkage occurred in 58.8% (10/17) patients, with 1 case in the microadenoma group. All marked shrinkage (> 25%) occurred in the macroadenoma group. Statistical analysis showed tumor shrinkage caused by LAR was greater in macroadenoma group than that in microadenoma group (P < 0.05). During operation, adenoma was soft in 15 cases, with the exception of 2cases in which the soft rumor was divided by fibrous septa, but all tumor removal was smooth.Conclusions A short term administration of preoperative LAR may induce a significant decrease in GH-secretion level and adenoma volume. Presurgical use of octreotide LAR improves surgical results especially in macroadenomas.

  10. The future of vitamin D analogs

    Directory of Open Access Journals (Sweden)

    Carlien eLeyssens


    Full Text Available The active form of vitamin D3, 1,25-dihydroxyvitamin D3, is a major regulator of bone and calcium homeostasis. In addition, this hormone also inhibits the proliferation and stimulates the differentiation of normal as well as malignant cells. Supraphysiological doses of 1,25-dihydroxyvitamin D3 are required to reduce cancer cell proliferation. However, these doses will lead in vivo to calcemic side effects such as hypercalcemia and hypercalciuria. During the last 25 years, many structural analogs of 1,25-dihydroxyvitamin D3 have been synthesized by the introduction of chemical modifications in the A-ring, central CD-ring region or side chain of 1,25-dihydroxyvitamin D3 in the hope to find molecules with a clear dissociation between the beneficial antiproliferative effects and adverse calcemic side effects. One example of such an analog with a good dissociation ratio is calcipotriol (DaivonexR, which is clinically used to treat the hyperproliferative skin disease psoriasis. Other vitamin D analogs were clinically approved for the treatment of osteoporosis or secondary hyperparathyroidism. No vitamin D analog is currently used in the clinic for the treatment of cancer although several analogs have been shown to be potent drugs in animal models of cancer. Omics studies as well as in vitro cell biological experiments unraveled basic mechanisms involved in the antineoplastic effects of vitamin D and its analogs. 1,25-dihydroxyvitamin D3 and analogs act in a cell type- and tissue-specific manner. Moreover, a blockade in the transition of the G0/1 towards S phase of the cell cycle, induction of apoptosis, inhibition of migration and invasion of tumor cells together with effects on angiogenesis and inflammation have been implicated in the pleiotropic effects of 1,25-dihydroxyvitamin D3 and its analogs. In this review we will give an overview of the action of vitamin D analogs in tumor cells and look forward how these compounds could be introduced in the

  11. Terrestrial Spaceflight Analogs: Antarctica (United States)

    Crucian, Brian


    Alterations in immune cell distribution and function, circadian misalignment, stress and latent viral reactivation appear to persist during Antarctic winterover at Concordia Station. Some of these changes are similar to those observed in Astronauts, either during or immediately following spaceflight. Others are unique to the Concordia analog. Based on some initial immune data and environmental conditions, Concordia winterover may be an appropriate analog for some flight-associated immune system changes and mission stress effects. An ongoing smaller control study at Neumayer III will address the influence of the hypoxic variable. Changes were observed in the peripheral blood leukocyte distribution consistent with immune mobilization, and similar to those observed during spaceflight. Alterations in cytokine production profiles were observed during winterover that are distinct from those observed during spaceflight, but potentially consistent with those observed during persistent hypobaric hypoxia. The reactivation of latent herpesviruses was observed during overwinter/isolation, that is consistently associated with dysregulation in immune function.

  12. Analogy Construction versus Analogy Solution, and Their Influence on Transfer (United States)

    Harpaz-Itay, Yifat; Kaniel, Shlomo; Ben-Amram, Einat


    This study compares transfer performed by subjects trained to solve verbal analogies, with transfer by subjects trained to construct them. The first group (n = 57) received instruction in a strategy to solve verbal analogies and the second group (n = 66) was trained in strategies for constructing such analogies. Before and after intervention, all…

  13. Analogy, Explanation, and Proof

    Directory of Open Access Journals (Sweden)

    John eHummel


    Full Text Available People are habitual explanation generators. At its most mundane, our propensity to explain allows us to infer that we should not drink milk that smells sour; at the other extreme, it allows us to establish facts (e.g., theorems in mathematical logic whose truth was not even known prior to the existence of the explanation (proof. What do the cognitive operations underlying the (inductive inference that the milk is sour have in common with the (deductive proof that, say, the square root of two is irrational? Our ability to generate explanations bears striking similarities to our ability to make analogies. Both reflect a capacity to generate inferences and generalizations that go beyond the featural similarities between a novel problem and familiar problems in terms of which the novel problem may be understood. However, a notable difference between analogy-making and explanation-generation is that the former is a process in which a single source situation is used to reason about a single target, whereas the latter often requires the reasoner to integrate multiple sources of knowledge. This small-seeming difference poses a challenge to the task of marshaling our understanding of analogical reasoning in the service of understanding explanation. We describe a model of explanation, derived from a model of analogy, adapted to permit systematic violations of this one-to-one mapping constraint. Simulation results demonstrate that the resulting model can generate explanations for novel explananda and that, like the explanations generated by human reasoners, these explanations vary in their coherence.

  14. Hyperpolarization of the Membrane Potential Caused by Somatostatin in Dissociated Human Pituitary Adenoma Cells that Secrete Growth Hormone (United States)

    Yamashita, Naohide; Shibuya, Naohiko; Ogata, Etsuro


    Membrane electrical properties and the response to somatostatin were examined in dissociated human pituitary adenoma cells that secrete growth hormone (GH). Under current clamp condition with a patch electrode, the resting potential was -52.4 ± 8.0 mV, and spontaneous action potentials were observed in 58% of the cells. Under voltage clamp condition an outward K+ current, a tetrodotoxin-sensitive Na+ current, and a Ca2+ current were observed. Cobalt ions suppressed the Ca2+ current. The threshold of Ca2+ current activation was about -60 mV. Somatostatin elicited a membrane hyperpolarization associated with increased membrane permeability in these cells. The reversal potential of somatostatin-induced hyperpolarization was -78.4 ± 4.3 mV in 6 mM K+ medium and -97.2 ± 6.4 mV in 3 mM K+ medium. These reversal potential values and a shift with the external K+ concentration indicated that membrane hyperpolarization was caused by increased permeability to K+. The hyperpolarized membrane potential induced by somatostatin was -63.6 ± 5.9 mV in the standard medium. This level was subthreshold for Ca2+ and Na+ currents and was sufficient to inhibit spontaneous action potentials. Hormone secretion was significantly suppressed by somatostatin and cobalt ions. Therefore, we suggest that Ca2+ entering the cell through voltage-dependent channels are playing an important role for GH secretion and that somatostatin suppresses GH secretion by blocking Ca2+ currents. Finally, we discuss other possibilities for the inhibitory effect of somatostatin on GH secretion.

  15. Melatonin influences somatostatin secretion from human pancreatic δ-cells via MT1 and MT2 receptors. (United States)

    Zibolka, Juliane; Mühlbauer, Eckhard; Peschke, Elmar


    Melatonin is an effector of the diurnal clock on pancreatic islets. The membrane receptor-transmitted inhibitory influence of melatonin on insulin secretion is well established and contrasts with the reported stimulation of glucagon release from α-cells. Virtually, nothing is known concerning the melatonin-mediated effects on islet δ-cells. Analysis of a human pancreatic δ-cell model, the cell line QGP-1, and the use of a somatostatin-specific radioimmunoassay showed that melatonin primarily has an inhibitory effect on somatostatin secretion in the physiological concentration range. In the pharmacological range, melatonin elicited slightly increased somatostatin release from δ-cells. Cyclic adenosine monophosphate (cAMP) is the major second messenger dose-dependently stimulating somatostatin secretion, in experiments employing the membrane-permeable 8-Br-cAMP. 8-Br-cyclic guanosine monophosphate proved to be of only minor relevance to somatostatin release. As the inhibitory effect of 1 nm melatonin was reversed after incubation of QGP-1 cells with the nonselective melatonin receptor antagonist luzindole, but not with the MT2-selective antagonist 4-P-PDOT (4-phenyl-2-propionamidotetraline), an involvement of the MT1 receptor can be assumed. Somatostatin release from the δ-cells at low glucose concentrations was significantly inhibited during co-incubation with 1 nm melatonin, an effect which was less pronounced at higher glucose levels. Transient expression experiments, overexpressing MT1, MT2, or a deletion variant as a control, indicated that the MT1 and not the MT2 receptor was the major transmitter of the inhibitory melatonin effect. These data point to a significant influence of melatonin on pancreatic δ-cells and on somatostatin release.

  16. A Transiting Jupiter Analog

    CERN Document Server

    Kipping, David M; Henze, Chris; Teachey, Alex; Isaacson, Howard T; Petigura, Erik A; Marcy, Geoffrey W; Buchhave, Lars A; Chen, Jingjing; Bryson, Steve T; Sandford, Emily


    Decadal-long radial velocity surveys have recently started to discover analogs to the most influential planet of our solar system, Jupiter. Detecting and characterizing these worlds is expected to shape our understanding of our uniqueness in the cosmos. Despite the great successes of recent transit surveys, Jupiter analogs represent a terra incognita, owing to the strong intrinsic bias of this method against long orbital periods. We here report on the first validated transiting Jupiter analog, Kepler-167e (KOI-490.02), discovered using Kepler archival photometry orbiting the K4-dwarf KIC-3239945. With a radius of $(0.91\\pm0.02)$ $R_{\\mathrm{Jup}}$, a low orbital eccentricity ($0.06_{-0.04}^{+0.10}$) and an equilibrium temperature of $(131\\pm3)$ K, Kepler-167e bears many of the basic hallmarks of Jupiter. Kepler-167e is accompanied by three Super-Earths on compact orbits, which we also validate, leaving a large cavity of transiting worlds around the habitable-zone. With two transits and continuous photometric ...

  17. Effect of treatment with depot somatostatin analogue octreotide on primary hyperparathyroidism (PHP) in multiple endocrine neoplasia type 1 (MEN1) patients. (United States)

    Faggiano, Antongiulio; Tavares, Lidice Brandao; Tauchmanova, Libuse; Milone, Francesco; Mansueto, Gelsomina; Ramundo, Valeria; De Caro, Maria Laura Del Basso; Lombardi, Gaetano; De Rosa, Gaetano; Colao, Annamaria


    In patients with multiple endocrine neoplasia type 1 (MEN1), expression of somatostatin receptor (SST) in parathyroid adenomas and effectiveness of therapy with somatostatin analogues on primary hyperparathyroidism (PHP) have been scarcely investigated. To evaluate the effects of depot long acting octreotide (OCT-LAR) in patients with MEN1-related PHP. Eight patients with a genetically confirmed MEN1, presenting both PHP and duodeno-pancreatic neuroendocrine tumours (NET), were enrolled. The initial treatment was OCT-LAR 30 mg every 4 weeks. This therapy was established to stabilize the duodeno-pancreatic NET before to perform parathyroidectomy for PHP. Before OCT-LAR therapy, a SST scintigraphy was performed in all patients. SST subtype 2A immunohistochemistry was performed on parathyroid tumour samples from three patients undergone parathyroidectomy after OCT-LAR therapy. Serum concentrations of PTH, calcium and phosphorus as well as the 24-h urine calcium : creatinine ratio and the renal threshold phosphate concentration were evaluated before and after OCT-LAR. After OCT-LAR therapy, hypercalcaemia and hypercalciuria normalized in 75% and 62.5% of patients, respectively, and serum phosphorus and renal threshold phosphate significantly increased. Serum PTH concentrations significantly decreased in all patients and normalized in two of them. SST subtype 2A immunostaining was found in all parathyroid adenomas investigated, while SST scintigraphy showed a positive parathyroid tumour uptake in three of eight patients (37.5%). Six months of OCT-LAR therapy controlled hypercalcaemia and hypercalciuria in two-thirds of patients with MEN1-related PHP. Direct OCT-LAR effects mediated by binding to SST expression on parathyroid tumour cells are likely the main mechanism to explain the activity of this compound on calcium and phosphorus abnormalities in MEN1 PHP.

  18. Inductive, Analogical, and Communicative Generalization

    Directory of Open Access Journals (Sweden)

    Adri Smaling


    Full Text Available Three forms of inductive generalization - statistical generalization, variation-based generalization and theory-carried generalization - are insufficient concerning case-to-case generalization, which is a form of analogical generalization. The quality of case-to-case generalization needs to be reinforced by setting up explicit analogical argumentation. To evaluate analogical argumentation six criteria are discussed. Good analogical reasoning is an indispensable support to forms of communicative generalization - receptive and responsive (participative generalization — as well as exemplary generalization.



    Haraguchi, Makoto


    This paper presents a mathematical theory of analogy, which should be a basis in developing analogical reasoning by a computer. The analogy is a partial identity between two sets of facts. In order to compare several analogies, we introduce an ordering of analogies, and we define two types of optimal analogies, maximal analogies and greatest ones. We show a condition under which the greatest analogy exists, and also present a top-down procedure to find the maximal analogies.

  20. Analogical scaffolding: Making meaning in physics through representation and analogy (United States)

    Podolefsky, Noah Solomon

    This work reviews the literature on analogy, introduces a new model of analogy, and presents a series of experiments that test and confirm the utility of this model to describe and predict student learning in physics with analogy. Pilot studies demonstrate that representations (e.g., diagrams) can play a key role in students' use of analogy. A new model of analogy, Analogical Scaffolding, is developed to explain these initial empirical results. This model will be described in detail, and then applied to describe and predict the outcomes of further experiments. Two large-scale (N>100) studies will demonstrate that: (1) students taught with analogies, according to the Analogical Scaffolding model, outperform students taught without analogies on pre-post assessments focused on electromagnetic waves; (2) the representational forms used to teach with analogy can play a significant role in student learning, with students in one treatment group outperforming students in other treatment groups by factors of two or three. It will be demonstrated that Analogical Scaffolding can be used to predict these results, as well as finer-grained results such as the types of distracters students choose in different treatment groups, and to describe and analyze student reasoning in interviews. Abstraction in physics is reconsidered using Analogical Scaffolding. An operational definition of abstraction is developed within the Analogical Scaffolding framework and employed to explain (a) why physicists consider some ideas more abstract than others in physics, and (b) how students conceptions of these ideas can be modeled. This new approach to abstraction suggests novel approaches to curriculum design in physics using Analogical Scaffolding.

  1. Effects of cysteamine on dopamine-mediated behaviors: evidence for dopamine-somatostatin interactions in the striatum

    Energy Technology Data Exchange (ETDEWEB)

    Martin-Iverson, M.T.; Radke, J.M.; Vincent, S.R.


    The effects of prior treatment with cysteamine, a drug which appears to deplete selectively the neuropeptide somatostatin, on apomorphine-induced stereotypy and amphetamine-induced locomotor activity and conditioned place preferences were investigated. Twelve hours following systemic cysteamine injections apomorphine-induced stereotypy was attenuated and striatal somatostatin levels were reduced by half. Systemic cysteamine also decreased the motor stimulant effects of amphetamine, without influencing the rewarding properties as determined by the conditioned place preference procedure. Direct injections of cysteamine into the nucleus accumbens also decreased the locomotor response to amphetamine, and produced a local reduction in somatostatin levels in the accumbens. Cysteamine did not appear to alter monoamine turnover in the striatum after either systemic or intra-accumbens injections. These results suggest that somatostatin in the nucleus accumbens and caudate-putamen modulates the motor, but not the reinforcing properties of dopaminergic drugs, possibly via an action postsynaptic to dopamine-releasing terminals. Furthermore, it is evident from these results that cysteamine is an important tool with which to study the central actions of somatostatin.

  2. ESD analog circuits and design

    CERN Document Server

    Voldman, Steven H


    A comprehensive and in-depth review of analog circuit layout, schematic architecture, device, power network and ESD design This book will provide a balanced overview of analog circuit design layout, analog circuit schematic development, architecture of chips, and ESD design.  It will start at an introductory level and will bring the reader right up to the state-of-the-art. Two critical design aspects for analog and power integrated circuits are combined. The first design aspect covers analog circuit design techniques to achieve the desired circuit performance. The second and main aspect pres

  3. Somatostatin Agonist Pasireotide Promotes a Physiological State Resembling Short-Day Acclimation in the Photoperiodic Male Siberian Hamster (Phodopus sungorus). (United States)

    Dumbell, R A; Scherbarth, F; Diedrich, V; Schmid, H A; Steinlechner, S; Barrett, P


    The timing of growth in seasonal mammals is inextricably linked to food availability. This is exemplified in the Siberian hamster (Phodopus sungorus), which uses the annual cycle of photoperiod to optimally programme energy expenditure in anticipation of seasonal fluctuations in food resources. During the autumn, energy expenditure is progressively minimised by physiological adaptations, including a 30% reduction in body mass, comprising a reduction in both fat and lean tissues. However, the mechanistic basis of this adaptation is still unexplained. We hypothesised that growth hormone (GH) was a likely candidate to underpin these reversible changes in body mass. Administration of pasireotide, a long-acting somatostatin receptor agonist developed for the treatment of acromegaly, to male hamsters under a long-day (LD) photoperiod produced a body weight loss. This comprised a reduction in lean and fat mass, including kidneys, testes and brown adipose tissue, typically found in short-day (SD) housed hamsters. Furthermore, when administered to hamsters switched from SD to LD, pasireotide retarded the body weight increase compared to vehicle-treated hamsters. Pasireotide did not alter photoperiod-mediated changes in hypothalamic energy balance gene expression but altered the expression of Srif mRNA expression in the periventricular nucleus and Ghrh mRNA expression in the arcuate nucleus consistent with a reduction in GH feedback and concurrent with reduced serum insulin-like growth factor-1. Conversely, GH treatment of SD hamsters increased body mass, which included increased mass of liver and kidneys. Together, these data indicate a role for the GH axis in the determination of seasonal body mass of the Siberian hamster.

  4. Albert Einstein, Analogizer Extraordinaire

    CERN Document Server

    CERN. Geneva


    Where does deep insight in physics come from? It is tempting to think that it comes from the purest and most precise of reasoning, following ironclad laws of thought that compel the clear mind completely rigidly. And yet the truth is quite otherwise. One finds, when one looks closely at any major discovery, that the greatest of physicists are, in some sense, the most crazily daring and irrational of all physicists. Albert Einstein exemplifies this thesis in spades. In this talk I will describe the key role, throughout Albert Einstein's fabulously creative life, played by wild guesses made by analogy lacking any basis whatsoever in pure reasoning. In particular, in this year of 2007, the centenary of 1907, I will describe how over the course of two years (1905 through 1907) of pondering, Einstein slowly came, via analogy, to understand the full, radical consequences of the equation that he had first discovered and published in 1905, arguably the most famous equation of all time: E = mc2.

  5. Analysis of transmission of novel polymorphisms in the somatostatin receptor 5 (SSTR5) gene in patients with autism

    DEFF Research Database (Denmark)

    Lauritsen, Marlene B; Nyegaard, Mette; Betancur, Catalina


    of chromosome abnormalities in individuals with autism. The somatostatin receptor 5 (SSTR5) gene is located on chromosome 16p13.3 and is thus a positional candidate gene for autism. SSTR5 may also be a functional candidate gene for autism because somatostatin inhibits growth hormone secretion, and increased...... growth hormone response has been reported in some individuals with autism. Moreover, the somatostatinergic system interacts with the dopaminergic system, which has been hypothesized to be involved in the etiology of autism; in particular, somatostatin secretion is regulated by dopamine, and the dopamine......Infantile autism is a pervasive developmental disorder with a strong genetic component. The mode of inheritance appears to be complex and no specific susceptibility genes have yet been identified. Chromosome 16p13.3 may contain a susceptibility gene based on findings from genome scans and reports...

  6. Somatostatin receptor 1 and 5 double knockout mice mimic neurochemical changes of Huntington's disease transgenic mice.

    Directory of Open Access Journals (Sweden)

    Padmesh S Rajput

    Full Text Available BACKGROUND: Selective degeneration of medium spiny neurons and preservation of medium sized aspiny interneurons in striatum has been implicated in excitotoxicity and pathophysiology of Huntington's disease (HD. However, the molecular mechanism for the selective sparing of medium sized aspiny neurons and vulnerability of projection neurons is still elusive. The pathological characteristic of HD is an extensive reduction of the striatal mass, affecting caudate putamen. Somatostatin (SST positive neurons are selectively spared in HD and Quinolinic acid/N-methyl-D-aspartic acid induced excitotoxicity, mimic the model of HD. SST plays neuroprotective role in excitotoxicity and the biological effects of SST are mediated by five somatostatin receptor subtypes (SSTR1-5. METHODS AND FINDINGS: To delineate subtype selective biological responses we have here investigated changes in SSTR1 and 5 double knockout mice brain and compared with HD transgenic mouse model (R6/2. Our study revealed significant loss of dopamine and cAMP regulated phosphoprotein of 32 kDa (DARPP-32 and comparable changes in SST, N-methyl-D-aspartic acid receptors subtypes, calbindin and brain nitric oxide synthase expression as well as in key signaling proteins including calpain, phospho-extracellular-signal-regulated kinases1/2, synapsin-IIa, protein kinase C-α and calcineurin in SSTR1/5(-/- and R6/2 mice. Conversely, the expression of somatostatin receptor subtypes, enkephalin and phosphatidylinositol 3-kinases were strain specific. SSTR1/5 appears to be important in regulating NMDARs, DARPP-32 and signaling molecules in similar fashion as seen in HD transgenic mice. CONCLUSIONS: This is the first comprehensive description of disease related changes upon ablation of G- protein coupled receptor gene. Our results indicate that SST and SSTRs might play an important role in regulation of neurodegeneration and targeting this pathway can provide a novel insight in understanding the

  7. Synthesis and evaluation of ligand targeting the somatostatin receptor for drug delivery to tumor cell

    Energy Technology Data Exchange (ETDEWEB)

    Lee, So Young; Hong, Young Don; Jung, Sung Hee; Choi, Sun Ju [Radioisotope Research Division, Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of)


    Most of targeted therapies block the action of certain enzymes, proteins, or other molecules involved in the growth and spread of cancer cells to produce its cytotoxic effect. Either small molecule drugs or monoclonal antibodies are mostly used in targeted therapies. Unfortunately, targeted therapy has a certain degree of unwanted side effect like other cytotoxicity inducing chemotherapies. To overcome and to reduce unwanted side effects during a cancer therapy, recently radiopeptide therapies has got the worlds' attraction for the tumor targeting modalities due to its beneficial effect on less side effect compared to cytotoxic chemotherapies. Among radiopeptide therapies, {sup 177}Lu-DOTATATE is a major modality as an effective one invented so far in treating neuroendocrine tumor (NET) and it has been in clinical trials at least one decade. Although it does have rather effective therapeutic effect on NET, it has less effective in rather large solid tumor. There are many ways to improve or increase therapeutic effect of radiopeptide are a finding the potent small molecules to target the tumor site selectively, or a labeling with radioisotope of emitting high energy, or an improving its biological half-life by introducing different moieties to increase lipophilicity. Present study was focus to increase a biological halflife of radio somatostatin which will target the somatostatin receptor by altering the bifunctional chelator (BFCA) by introducing lipophilic moiety to the somatostatin, which would make the labeled peptide stay longer in the tumor site and thus it can intensify the therapeutic effect on tumor cell itself and around tissues.

  8. Translational Advancement of Somatostatin Gene Delivery for Disease Modification and Cognitive Sparing in Intractable Epilepsy (United States)


    human clinical trials, and could provide a new, safe, and effective way to interfere with this evolution , associated loss of brain tissue from... brain . Our initial tests demonstrated that intracranial somatostatin gene delivery prevented the evolution to high-level seizures in 70% of rats...variables, effects on seizure­stimulated  brain  stem cell  division or differentiation, or obvious  brain  pathology.  Kindling increased new cell

  9. Hippocampal somatostatin receptors and modulation of adenylyl cyclase activity in histamine-treated rats


    Puebla Jiménez, Lilian; Rodríguez Martín, Eulalia; Arilla Ferreiro, Eduardo


    In the present study, the effects of an intracerebroventricular (i.c.v.) dose of histamine (0.1, 1.0 or 10.0 ¿g) on the hippocampal somatostatin (SS) receptor/effector system in Wistar rats were investigated. In view of the rapid onset of histamine action, the effects of histamine on the somatostatinergic system were studied 2 h after its administration. Hippocampal SS-like immunoreactivity (SSLI) levels were not modified by any of the histamine doses studied. SS-mediated inhibition of basal ...

  10. Plasma somatostatin increases during hypoglycaemia in insulin-dependent patients with and without B-cell function

    DEFF Research Database (Denmark)

    Madsbad, S; Hilsted, J; Krarup, T;


    Responses of somatostatin-like immunoreactivity (SLI) to hypoglycaemia were investigated in seven type 1 (insulin-dependent) patients with residual B-cell function, eight patients without B-cell function, and six healthy controls. A higher basal level of SLI was found in the group with B-cell...... function when compared with the group without B-cell function. The basal level in the normal subjects was in between the two diabetic groups. All the diabetics had a somatostatin response to hypoglycaemia which was independent of residual B-cell function and no different from that of normal subjects....

  11. Analysis of transmission of novel polymorphisms in the somatostatin receptor 5 (SSTR5) gene in patients with autism

    DEFF Research Database (Denmark)

    Lauritsen, Marlene B; Nyegaard, Mette; Betancur, Catalina


    of chromosome abnormalities in individuals with autism. The somatostatin receptor 5 (SSTR5) gene is located on chromosome 16p13.3 and is thus a positional candidate gene for autism. SSTR5 may also be a functional candidate gene for autism because somatostatin inhibits growth hormone secretion, and increased...... D2 receptor and the SSTR5 receptor interact to form a receptor complex with enhanced functional activity. In the present study, we tested whether the alleles of twelve new single nucleotide polymorphisms (SNPs) in the SSTR5 gene were preferentially transmitted, using the transmission disequilibrium...

  12. Feedback in analog circuits

    CERN Document Server

    Ochoa, Agustin


    This book describes a consistent and direct methodology to the analysis and design of analog circuits with particular application to circuits containing feedback. The analysis and design of circuits containing feedback is generally presented by either following a series of examples where each circuit is simplified through the use of insight or experience (someone else’s), or a complete nodal-matrix analysis generating lots of algebra. Neither of these approaches leads to gaining insight into the design process easily. The author develops a systematic approach to circuit analysis, the Driving Point Impedance and Signal Flow Graphs (DPI/SFG) method that does not require a-priori insight to the circuit being considered and results in factored analysis supporting the design function. This approach enables designers to account fully for loading and the bi-directional nature of elements both in the feedback path and in the amplifier itself, properties many times assumed negligible and ignored. Feedback circuits a...

  13. Vorticity in analog gravity (United States)

    Cropp, Bethan; Liberati, Stefano; Turcati, Rodrigo


    In the analog gravity framework, the acoustic disturbances in a moving fluid can be described by an equation of motion identical to a relativistic scalar massless field propagating in curved space-time. This description is possible only when the fluid under consideration is barotropic, inviscid, and irrotational. In this case, the propagation of the perturbations is governed by an acoustic metric that depends algebrically on the local speed of sound, density, and the background flow velocity, the latter assumed to be vorticity-free. In this work we provide a straightforward extension in order to go beyond the irrotational constraint. Using a charged—relativistic and nonrelativistic—Bose-Einstein condensate as a physical system, we show that in the low-momentum limit and performing the eikonal approximation we can derive a d’Alembertian equation of motion for the charged phonons where the emergent acoustic metric depends on flow velocity in the presence of vorticity.

  14. Loss of somatostatin receptor subtype 2 in prostate cancer is linked to an aggressive cancer phenotype, high tumor cell proliferation and predicts early metastatic and biochemical relapse.

    Directory of Open Access Journals (Sweden)

    Jan K Hennigs

    Full Text Available Somatostatin receptor subtype 2 (SSTR2 is the most frequently expressed SSTR subtype in normal human tissues. SSTR2 expression is differentially regulated in various tumor types and therapeutic somatostatin analogs binding to SSTR2 are in clinical use. In prostate cancers highly contradictory results in terms of SSTR2 expression and its consequences have been published over the past years. The aim of this study was to clarify prevalence and clinical significance of SSTR2 expression in prostate cancer. Therefore, quantitative immunohistochemistry (IHC using a tissue microarray containing samples from 3,261 prostate cancer patients with extensive clinical and molecular cancer characteristics and oncological follow-up data was performed. IHC data was compared to publicly available Gene Expression Omnibus datasets of human prostate cancer gene expression arrays. While membranous SSTR2 staining was always seen in normal prostate epithelium, SSTR2 staining was absent in more than half (56.1% of 2,195 interpretable prostate cancer samples. About 13% of all analyzed prostate cancers showed moderate to strong cytoplasmic and membranous SSTR2 staining. Staining intensities were inversely correlated with high Gleason grade, advanced pT category, high tumor cell proliferation (p<0.0001 each, high pre-operative PSA levels, (p = 0.0011 and positive surgical margins (p = 0.006. In silico analysis confirmed lower SSTR2 gene expression in prostate cancers vs. normal adjacent tissue (p = 0.0424, prostate cancer metastases vs. primary cancers (p = 0.0011 and recurrent vs. non-recurrent prostate cancers (p = 0.0438. PSA-free survival gradually declined with SSTR2 staining intensity (p<0.0001. SSTR2-negative cancers were more likely to develop metastases over time (p<0.05. In conclusion, most prostate cancers are indeed SSTR2-negative and loss of SSTR2 strongly predicts an unfavorable tumor phenotype and poor prognosis. Therefore, SSTR2

  15. Beginning analog electronics through projects

    CERN Document Server

    Singmin, Andrew


    Analog electronics is the simplest way to start a fun, informative, learning program. Beginning Analog Electronics Through Projects, Second Edition was written with the needs of beginning hobbyists and students in mind. This revision of Andrew Singmin's popular Beginning Electronics Through Projects provides practical exercises, building techniques, and ideas for useful electronics projects. Additionally, it features new material on analog and digital electronics, and new projects for troubleshooting test equipment.Published in the tradition of Beginning Electronics Through Projects an

  16. Mathematical problem solving by analogy. (United States)

    Novick, L R; Holyoak, K J


    We report the results of 2 experiments and a verbal protocol study examining the component processes of solving mathematical word problems by analogy. College students first studied a problem and its solution, which provided a potential source for analogical transfer. Then they attempted to solve several analogous problems. For some problems, subjects received one of a variety of hints designed to reduce or eliminate the difficulty of some of the major processes hypothesized to be involved in analogical transfer. Our studies yielded 4 major findings. First, the process of mapping the features of the source and target problems and the process of adapting the source solution procedure for use in solving the target problem were clearly distinguished: (a) Successful mapping was found to be insufficient for successful transfer and (b) adaptation was found to be a major source of transfer difficulty. Second, we obtained direct evidence that schema induction is a natural consequence of analogical transfer. The schema was found to co-exist with the problems from which it was induced, and both the schema and the individual problems facilitated later transfer. Third, for our multiple-solution problems, the relation between analogical transfer and solution accuracy was mediated by the degree of time pressure exerted for the test problems. Finally, mathematical expertise was a significant predictor of analogical transfer, but general analogical reasoning ability was not. The implications of the results for models of analogical transfer and for instruction were considered.

  17. [Analogies and analogy research in technical biology and bionics]. (United States)

    Nachtigall, Werner


    The procedural approaches of Technical Biology and Bionics are characterized, and analogy research is identified as their common basis. The actual creative aspect in bionical research lies in recognizing and exploiting technically oriented analogies underlying a specific biological prototype to indicate a specific technical application.

  18. Tc-99m-EDDA-HYNIC-TOC somatostatin receptor scintigraphy in patients with carcinoids

    Directory of Open Access Journals (Sweden)

    Vlajković Marina


    Full Text Available The aim of this paper is to determine the influence of Ki-67 proliferation index on somatostatin receptor scintigraphy (SSRS with Tc-99m-EDDA-HYNIC-TOC (Tc-99m-Tektrotyd somatostatin analogue in patients with carcinoid tumors. Sixty-one patients (31 female, 30 male; age range: 33-76 years were examined: 13 patients highly suspected of having a carcinoid, and 48 patients who had undergone the surgical removal of the tumor. Whole body SSRS at 4 h postinjection, spot scintigrams and SPECT of the selected regions were obtained for all patients. Tc-99m-Tektrotyd scintigraphy was classified as true positive in 26 out of 30 and true negative in 24 out of 28 patients. The sensitivity of Tc-99mTc-Tektrotyd scintigraphy was found to be as high as 94.74% in the group of patients with low mitotic index Ki67 (20%. The likelihood of Tc-99m-Tektrotyd scan being positive when a carcinoid is present was found to be inversely proportional to the value of Ki67 proliferation index. The results showed that Tc-99m-Tektrotyd SSRS is a sensitive method for diagnosing and staging patients with well-differentiated carcinoid tumors. However, in poorly differentiated tumors with high Ki67 proliferation index, additional analyses are necessary for precise staging.

  19. Development and characterization of lipid microparticles as a drug carrier for somatostatin. (United States)

    Reithmeier, H; Herrmann, J; Göpferich, A


    Somatostatin, a therapeutic peptide with a high therapeutical potential but a very short biological half-live was encapsulated within microparticles by a modified solvent evaporation method and a melt dispersion method without the use of organic solvent. As the use of synthetic polymer matrix materials often goes along with detrimental effects on incorporated peptides, we investigated the potential of physiological lipids such as glyceryl tripalmitate (Dynasan 116) as an alternative matrix material. The two preparation methods were evaluated with respect to surface topography, particle size distribution, encapsulation efficiency, in-vitro release behavior and modification of the resulting microparticles. Microparticles with a suitable particle size distribution for i.m. or s.c. injection could be prepared with both methods. The encapsulation efficiency of the peptide into glyceryl tripalmitate microparticles was substantially influenced by the preparation method and the physical state of the peptide to be incorporated. The melt dispersion technique and the incorporation of the drug as an aqueous solution gave the best results with actual drug loadings up to 9% and an encapsulation efficiency of approximately 90%. Microparticles prepared by the melt dispersion technique crystallized in the unstable alpha-modification. The peptide was released almost continuously over 10 days with no burst effect, 20-30% of the incorporated somatostatin was not released in the monitored time period.

  20. The evolution of vertebrate somatostatin receptors and their gene regions involves extensive chromosomal rearrangements

    Directory of Open Access Journals (Sweden)

    Ocampo Daza Daniel


    Full Text Available Abstract Background Somatostatin and its related neuroendocrine peptides have a wide variety of physiological functions that are mediated by five somatostatin receptors with gene names SSTR1-5 in mammals. To resolve their evolution in vertebrates we have investigated the SSTR genes and a large number of adjacent gene families by phylogeny and conserved synteny analyses in a broad range of vertebrate species. Results We find that the SSTRs form two families that belong to distinct paralogons. We observe not only chromosomal similarities reflecting the paralogy relationships between the SSTR-bearing chromosome regions, but also extensive rearrangements between these regions in teleost fish genomes, including fusions and translocations followed by reshuffling through intrachromosomal rearrangements. These events obscure the paralogy relationships but are still tractable thanks to the many genomes now available. We have identified a previously unrecognized SSTR subtype, SSTR6, previously misidentified as either SSTR1 or SSTR4. Conclusions Two ancestral SSTR-bearing chromosome regions were duplicated in the two basal vertebrate tetraploidizations (2R. One of these ancestral SSTR genes generated SSTR2, -3 and -5, the other gave rise to SSTR1, -4 and -6. Subsequently SSTR6 was lost in tetrapods and SSTR4 in teleosts. Our study shows that extensive chromosomal rearrangements have taken place between related chromosome regions in teleosts, but that these events can be resolved by investigating several distantly related species.

  1. Somatostatin receptor scintigraphy of a patient with a giant invasive prolactinoma

    Energy Technology Data Exchange (ETDEWEB)

    Meyer, P.; Bohnen, N.I.; Shapiro, B. [Michigan Univ., Ann Arbor, MI (United States). Dept. of Internal Medicine; Barkan, A.L. [Michigan Univ., Medical Center, Ann Arbor, MI (United States). Div. of Endocrinology and Metabolism


    A 41-year-old patient with a giant prolactinoma underwent In-111 pentetreotide (Octreotide) imaging showing very intense tracer uptake in the region of the anterior skull base. In contrast, there was no singificant response to Octreotide therapy. Prediction of clinical responsiveness to Octreotide therapy in patients with pituitary adenomas may depend on the presence of somatostatin receptor subtype 5. Pentetreotide does not avidly bind to this receptor subtype and therefore, cannot be used clinically to predict therapeutic Octreotide responsiveness in patients with large prolactinomas. (orig.) [Deutsch] Bei einem 41jaehrigen Patienten mit Makroprolaktinom wurde eine 111-Indium-Pentetreotid-(Octreotid-)Szintigraphie durchgefuehrt. Dabei zeigte sich eine sehr stark ausgepraegte Tracer-Aufnahme in der Region der vorderen Schaedelbasis. Im Gegensatz dazu fand sich keine signifikante Reaktion auf eine Octreotid-Therapie. Die Vorhersage einer klinischen Ansprechbarkeit auf eine Octreotid-Therapie bei Patienten mit Hypophysenadenomen haengt moeglicherweise vom Vorliegen des Somatostatin-Rezeptorsubtyps 5 ab. Pentetreotid zeigt keine starke Bindung an diesen Rezeptorsubtyp und kann daher bei Patienten mit Makroprolaktinomen klinisch nicht als Praediktor der therapeutischen Reaktion auf Octreotid eingesetzt werden. (orig.)


    Directory of Open Access Journals (Sweden)

    Paran Haim


    Full Text Available Background: Somatostatin has an inhibitory effect on the endocrine and exocrine secretions of the gut. It may have a beneficial effect in the conservative treatment of intestinal obstruction. The aim of the present study is to investigate the effect of octreotide in mechanical intestinal obstruction in rats. Method: Intestinal obstruction was induced in rats by ligation of a segment of the distal ileum. Animals were treated with the somatostatin analogue octreotide (n=16, or saline (n=16. Eight rats were operated but their intestine was not ligated (n=8 serving as sham controls. Forty eight hours after the operation, the animals were operated upon again and blood samples from the femoral vein were tested for electrolytes, urea, glucose, lactic acid, amylase, ph and bicarbonate. Portal vein blood samples were also obtained and tested for lactic acid and amylase. Results: Intestinal obstruction resulted, after 48 hours, in severe dilatation of bowel loops. A significant increase in plasma levels of urea, amylase and lactic acid was observed. Plasma pH decreased. In blood samples from the portal vein, a significant increase in lactic acid was observed, indicating metabolic acidosis, probably secondary to bowel ischemia. Octreotide treatment, resulted in less acidosis, with concomitant lower urea and lactic acid levels in the plasma and especially in the portal vein. Conclusion: Octreotide treatment may have a beneficial effect in the conservative treatment of selected cases of intestinal obstruction.

  3. Clinical utility of insulin and insulin analogs (United States)

    Sanlioglu, Ahter D.; Altunbas, Hasan Ali; Balci, Mustafa Kemal; Griffith, Thomas S.; Sanlioglu, Salih


    Diabetes is a pandemic disease characterized by autoimmune, genetic and metabolic abnormalities. While insulin deficiency manifested as hyperglycemia is a common sequel of both Type-1 and Type-2 diabetes (T1DM and T2DM), it does not result from a single genetic defect—rather insulin deficiency results from the functional loss of pancreatic β cells due to multifactorial mechanisms. Since pancreatic β cells of patients with T1DM are destroyed by autoimmune reaction, these patients require daily insulin injections. Insulin resistance followed by β cell dysfunction and β cell loss is the characteristics of T2DM. Therefore, most patients with T2DM will require insulin treatment due to eventual loss of insulin secretion. Despite the evidence of early insulin treatment lowering macrovascular (coronary artery disease, peripheral arterial disease and stroke) and microvascular (diabetic nephropathy, neuropathy and retinopathy) complications of T2DM, controversy exists among physicians on how to initiate and intensify insulin therapy. The slow acting nature of regular human insulin makes its use ineffective in counteracting postprandial hyperglycemia. Instead, recombinant insulin analogs have been generated with a variable degree of specificity and action. Due to the metabolic variability among individuals, optimum blood glucose management is a formidable task to accomplish despite the presence of novel insulin analogs. In this article, we present a recent update on insulin analog structure and function with an overview of the evidence on the various insulin regimens clinically used to treat diabetes. PMID:23584214

  4. Theory of analogous force on number sets (United States)

    Canessa, Enrique


    A general statistical thermodynamic theory that considers given sequences of x-integers to play the role of particles of known type in an isolated elastic system is proposed. By also considering some explicit discrete probability distributions px for natural numbers, we claim that they lead to a better understanding of probabilistic laws associated with number theory. Sequences of numbers are treated as the size measure of finite sets. By considering px to describe complex phenomena, the theory leads to derive a distinct analogous force fx on number sets proportional to (∂ px/∂ x) T at an analogous system temperature T. In particular, this leads to an understanding of the uneven distribution of integers of random sets in terms of analogous scale invariance and a screened inverse square force acting on the significant digits. The theory also allows to establish recursion relations to predict sequences of Fibonacci numbers and to give an answer to the interesting theoretical question of the appearance of the Benford's law in Fibonacci numbers. A possible relevance to prime numbers is also analyzed.

  5. Positons: slowly diminishing analogs of solitons

    CERN Document Server

    Matveev, V B


    The introduction to the theory of positons is presented. The positons are the remote-acting analogues of solitons and represent slowly diminishing and oscillating solitons of the nonlinear integrated equations of KdV type. The positon and soliton-positon solutions of the KdV equation were for the first time obtained and analyzed about 10 years ago and thereafter designed for a number of other models: mKdV, Toda chains, NSch, sn-Gordon equation and its lattice analog. By the proper selection of the scattering data the single positon and multipositon potentials are characterized by the remarkable property: the corresponding reflection coefficient is equal to zero and the transition coefficient is equal to one (the latter property, as it is known, has no place for the standard short-acting nonreflection potentials

  6. Analog regulation of metabolic demand

    Directory of Open Access Journals (Sweden)

    Muskhelishvili Georgi


    Full Text Available Abstract Background The 3D structure of the chromosome of the model organism Escherichia coli is one key component of its gene regulatory machinery. This type of regulation mediated by topological transitions of the chromosomal DNA can be thought of as an analog control, complementing the digital control, i.e. the network of regulation mediated by dedicated transcription factors. It is known that alterations in the superhelical density of chromosomal DNA lead to a rich pattern of differential expressed genes. Using a network approach, we analyze these expression changes for wild type E. coli and mutants lacking nucleoid associated proteins (NAPs from a metabolic and transcriptional regulatory network perspective. Results We find a significantly higher correspondence between gene expression and metabolism for the wild type expression changes compared to mutants in NAPs, indicating that supercoiling induces meaningful metabolic adjustments. As soon as the underlying regulatory machinery is impeded (as for the NAP mutants, this coherence between expression changes and the metabolic network is substantially reduced. This effect is even more pronounced, when we compute a wild type metabolic flux distribution using flux balance analysis and restrict our analysis to active reactions. Furthermore, we are able to show that the regulatory control exhibited by DNA supercoiling is not mediated by the transcriptional regulatory network (TRN, as the consistency of the expression changes with the TRN logic of activation and suppression is strongly reduced in the wild type in comparison to the mutants. Conclusions So far, the rich patterns of gene expression changes induced by alterations of the superhelical density of chromosomal DNA have been difficult to interpret. Here we characterize the effective networks formed by supercoiling-induced gene expression changes mapped onto reconstructions of E. coli's metabolic and transcriptional regulatory network. Our

  7. Natural analog studies: Licensing perspective

    Energy Technology Data Exchange (ETDEWEB)

    Bradbury, J.W. [Nuclear Regulatory Commission, Washington, DC (United States)


    This report describes the licensing perspective of the term {open_quotes}natural analog studies{close_quotes} as used in CFR Part 60. It describes the misunderstandings related to its definition which has become evident during discussions at the U.S Nuclear Regulatory Commission meetings and tries to clarify the appropriate applications of natural analog studies to aspects of repository site characterization.

  8. Conjecturing via Reconceived Classical Analogy (United States)

    Lee, Kyeong-Hwa; Sriraman, Bharath


    Analogical reasoning is believed to be an efficient means of problem solving and construction of knowledge during the search for and the analysis of new mathematical objects. However, there is growing concern that despite everyday usage, learners are unable to transfer analogical reasoning to learning situations. This study aims at facilitating…

  9. Musik som analogi og metafor

    DEFF Research Database (Denmark)


    Indeholder underkapitlerne: 2.5.1 Musik som analogi 2.5.2 Musik som metafor 2.5.3 Musikkens psykologiske funktioner - en taxonomi og metaforisk lytning til fire baroksatser......Indeholder underkapitlerne: 2.5.1 Musik som analogi 2.5.2 Musik som metafor 2.5.3 Musikkens psykologiske funktioner - en taxonomi og metaforisk lytning til fire baroksatser...

  10. Musik som analogi og metafor

    DEFF Research Database (Denmark)


    Indeholder underkapitlerne: 2.5.1 Musik som analogi 2.5.2 Musik som metafor 2.5.3 Musikkens psykologiske funktioner - en taxonomi og metaforisk lytning til fire baroksatser......Indeholder underkapitlerne: 2.5.1 Musik som analogi 2.5.2 Musik som metafor 2.5.3 Musikkens psykologiske funktioner - en taxonomi og metaforisk lytning til fire baroksatser...

  11. Radioiodinated somatostatin analogue RC-160: preparation, biological activity, in vivo application in rats and comparison with [sup 123]I-Tyr[sup 3]octreotide

    Energy Technology Data Exchange (ETDEWEB)

    Breeman, W.A.P. (Univ. Hospital Dijkzigt, Rotterdam (Netherlands). Dept. of Nuclear Medicine); Hofland, L.J. (Univ. Hospital Dijkzigt, Rotterdam (Netherlands). Dept. of Internal Medicine 3); Bakker, W.H. (Univ. Hospital Dijkzigt, Rotterdam (Netherlands). Dept. of Nuclear Medicine); Pluijm, M. van der (Univ. Hospital Dijkzigt, Rotterdam (Netherlands). Dept. of Nuclear Medicine); Koetsveld, P.M. van (Univ. Hospital Dijkzigt, Rotterdam (Netherlands). Dept. of Internal Medicine 3); Jong, M. de (Univ. Hospital Dijkzigt, Rotterdam (Netherlands). Dept. of Nuclear Medicine); Setyono-Han, B. (Dr. Daniel den Hoed Cancer Centre, Rotterdam (Netherlands)); Kwekkeboom, D.J. (Univ. Hospital Dijkzigt, Rotterdam (Netherlands). Dept. of Nuclear Medicine); Visser, T.J. (Univ. Hospital Dijkzigt, Rotterdam (Netherlands). Dept. of Internal Medicine 3); Lamberts, S.W.J. (Univ. Hospital Dijkzigt, Rotterdam (Netherlands). Dept. of Internal Medicine 3); Krenning, E.P. (Univ. Hospital Dijkzigt, Rotterd


    We have evaluated the potential usefulness of the radioiodinated octapeptide RC-160, a somatostatin analogue, which might serve as a radiopharmaceutical for th in vivo detection of somatostatin receptor-positive tumours. For this purpose, iodine-123 and iodine-125 labelled RC-160 was tested for biological activity and applied in vivo in rats bearing the transplantable rat pancreatic tumour CA20948, which expresses somatostatin receptors. Our group has recently described the in vivo visualization of such tumours in rats and in humans with the radioiodinated somatostatin analogue Tyr[sup 3]octreotide. Like [sup 123]I-Tyr[sup 3]octerotide, [sup 123]I-RC-160 showed uptake in and specific binding in vivo to somatostatin receptor-positive organs and tumours. However, blood radioactivity (bachground) was higher, resulting in a lower tumour to blood (background) ratio. We therefore conclude that in this animal model [sup 123]I-RC-160 has no advantage over [sup 123]I-Tyr[sup 3]octreotide as a radiopharmaceutical for the in vivo use as a somatostatin receptor imager, although, like [sup 123]I-Tyr[sup 3]octreotide, [sup 123]I-RC-160 shows specific binding to different somatostatin receptor-positive organs. (orig./MG)

  12. Effect of vasoactive intestinal polypeptide and somatostatin on secretion of epidermal growth factor and bicarbonate from Brunner's glands

    DEFF Research Database (Denmark)

    Poulsen, Steen Seier


    The effect of VIP and somatostatin on secretion of epidermal growth factor and bicarbonate from Brunner's glands was investigated in the rat. Vasoactive intestinal polypeptide infused in doses of 10 and 100 ng/kg/h significantly increased epidermal growth factor and bicarbonate output, but the co......The effect of VIP and somatostatin on secretion of epidermal growth factor and bicarbonate from Brunner's glands was investigated in the rat. Vasoactive intestinal polypeptide infused in doses of 10 and 100 ng/kg/h significantly increased epidermal growth factor and bicarbonate output......, but the concentrations did not change. Somatostatin infused at doses of 1, 10, 100 and 1000 ng/kg/h against a background of VIP 100 ng/kg/h inhibited in dose-dependent fashion the stimulated epidermal growth factor and bicarbonate outputs from rat Brunner's gland pouches. Also basal secretion was inhibited...... by somatostatin. Infusion of antisomatostatin serum stimulated Brunner's gland secretion. By immunohistochemical studies of rat duodena, it was found that epidermal growth factor, is almost exclusively present in the secretory cells of Brunner's glands. It is concluded that VIP stimulates secretion of epidermal...

  13. Long-term effects of cholinergic basal forebrain lesions on neuropeptide Y and somatostatin immunoreactivity in rat neocortex

    NARCIS (Netherlands)

    Gaykema, R.P.A.; Compaan, J.C.; Nyakas, C.; Horvath, E.; Luiten, P.G.M.


    The effect of cholinergic basal forebrain lesions on immunoreactivity to somatostatin (SOM-i) and neuropeptide-Y (NPY-i) was investigated in the rat parietal cortex, 16-18 months after multiple bilateral ibotenic acid injections in the nucleus basalis complex. As a result of the lesion, the choliner

  14. Guipi decoction effects on brain somatostatin levels and receptor mRNA expression in rats with spleen deficiency

    Institute of Scientific and Technical Information of China (English)

    Huinan Qian; Le Wang; Libo Shen; Xueqin Hu


    BACKGROUND:Somatostatin is abundant in the hypothalamus,cerebral cortex,limbic system,and mesencephalon.Somatostatin mRNA expression in the brain of rats with spleen deficiency is noticeably reduced,as well as attenuation of cognitive function. OBJECTIVE:To observe the interventional effect of Guipi decoction on somatostatin level and somatostatin receptor 1(SSTRI)mRNA expression in different encephalic regions of rats with spleen deficiency,and to compare the interventional effects of Guipi decoction,Chaihu Shugan powder,and Tianwang Buxin pellet. DESIGN:A randomized controlled observation. SETTING:Basic Medical College,Beijing University of Traditional Chinese Medicine.MATERIALS:Fifty adult Wistar male rats,of clean grade,weighing(160 ± 10)g,were provided by Beijing Weitong Lihua Laboratory Animal Technology Co.,Ltd.The protocol was performed in accordance with ethical guidelines for the use and care of animals.Somatostatin 1 polyclonal anti-rabbit antibody and SSTR1 in situ hybridization kit were provided by Department of Neuroanatomy,Shanghai Second Military Medical University of Chinese PLA.The drug for developing rat models of spleen deficiency was composed of Dahuang,Houpu and Zhishi,and prepared at 2:1:1.Guipi decoction,Chaihu Shugan powder,and Tianwang Buxin pellet recipes were made according to previous studies.METHODS:This study was performed at the Basic Medical College,Beijing University of Traditional Chinese Medicine from March 2002 to March 2005.The rats were randomly divided into 5 groups,with 10 rats in each group:normal,model,Guipi decoction,Chaihu Shugan powder,and Tianwang Buxin pelletgroups.Rat models of the latter 4 groups were developed by methods of purgation with bitter and cold nature drugs,improper diet,and overstrain.The rats received 7.5 g/kg of the drugs each morning and were fasted every other day,but were allowed free access to water at all times,The rats were forced to swim in 25℃ water until fatigued.Rats in the normal group

  15. Uptake Difference by Somatostatin Receptors in a Patient with Neuroendocrine Tumor: 99mTc-Octreotide Uptake in the Lung without Uptake in Liver Lesions

    Directory of Open Access Journals (Sweden)

    Elahe Pirayesh


    Full Text Available The diagnostic value of somatostatin receptor scintigraphy (SRS in detecting tumors has been assessed in a number of studies. We present a 30-year-old female with a history of eight months cough and left shoulder pain. Radiologic evaluation showed pulmonary mass and hepatic lesions, which were pathologically diagnosed as neuroendocrine carcinoma. 99mTc-octreotide scan demonstrated that the pulmonary lesion was positive for somatostatin receptor (SSTR, while the liver metastases were SSTR negative. The present case highlights the significance of a differential uptake pattern by somatostatin receptors in SRS in patients with neuroendocrine tumors.

  16. The role of somatostatin (octreotide) in the regulation of melatonin secretion in healthy volunteers and in patients with primary hypothyroidism. (United States)

    Wikner, J; Wetterberg, L; Röjdmark, S


    Somatostatin has been found in the pineal gland of several animal species, which suggests that it may be involved in the regulation of melatonin secretion. Whether somatostatin has regulatory influence on melatonin secretion in man has never been unequivocally shown. We studied the nocturnal melatonin secretion in 8 healthy volunteers, and 6 women with untreated primary hypothyroidism, a disease state that is associated with increased nocturnal secretion of melatonin. The participants were given subcutaneous injections at 18:00 h and 23:00 h of either saline or octreotide (Sandostatin; each injection 50 microg). During the nights when the healthy volunteers were given octreotide, melatonin secretion was similar to that recorded during administration of saline. Also the urinary excretion of melatonin was of similar magnitude at these two occasions. By contrast, the GH secretion was significantly lower the nights the healthy controls were given octreotide (GH AUC 22.6+/-5.4 mU/l x h during octreotide and 126.6+/-21.9 mU/l x h during saline; p<0.01). The patients with hypothyroidism also showed similar nocturnal melatonin secretion during octreotide and saline. Urinary excretion of melatonin also remained unchanged, as did GH secretion. The total nocturnal secretion of TSH was, however, significantly reduced by octreotide (TSH AUC 562+/-136 mU/l x h during octreotide and 851+/-185 mU/l x h during saline; p<0.05), thus suggesting that 100 microg of octreotide should be sufficient to inhibit also the pinealocytes if their function were regulated by somatostatin. Since exogenous somatostatin--in the form of octreotide--fails to influence nocturnal secretion and urinary excretion of melatonin in normal subjects and in patients with primary hypothyroidism, it is reasonable to assume that endogenous somatostatin may not be an important regulator of melatonin secretion in man.

  17. Effects of cysteamine administration on the in vivo incorporation of (/sup 35/S)cysteine into somatostatin-14, somatostatin-28, arginine vasopressin, and oxytocin in rat hypothalamus

    Energy Technology Data Exchange (ETDEWEB)

    Cameron, J.L.; Fernstrom, J.D.


    The effect of cysteamine injection on the in vivo incorporation of (/sup 35/S)cysteine into somatostatin-14 (SRIF-14), SRIF-28, arginine vasopressin (AVP), and oxytocin (OXT) in rat hypothalamus was studied. (/sup 35/S)Cysteine was injected into the third ventricle 1 h, 4 h, or 1 week after cysteamine (300 mg/kg, sc) injection; animals were killed 4 h later. The drug was found to substantially reduce immunoreactive SRIF levels, but not OXT or AVP, 4 h after its injection. Cysteamine also caused large reductions in label incorporation into SRIF-14, SRIF-28, and OXT 1 and 4 h after drug injection. However, (/sup 35/S)cysteine incorporation into AVP was increased substantially at these time points, while that into acid-precipitable protein was normal. One week after cysteamine injection, label incorporation into all hypothalamic peptides was normal. Cysteine specific activity was also measured after (/sup 35/S)cysteine injection and was found to be similar in treatment and control groups. The results suggest that cysteamine inhibits the syntheses of SRIF-14, SRIF-28, and OXT and stimulates that of AVP.

  18. Comprehensive evaluation of a somatostatin-based radiolabelled antagonist for diagnostic imaging and radionuclide therapy

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Xuejuan; Fani, Melpomeni [University Hospital Basel, Division of Radiological Chemistry, Basel (Switzerland); Schulz, Stefan [Jena University Hospital - Friedrich Schiller University Jena, Department of Pharmacology and Toxicology, Jena (Germany); Rivier, Jean [The Salk Institute for Biological Studies, The Clayton Foundation Laboratories for Peptide Biology, La Jolla, CA (United States); Reubi, Jean Claude [University of Bern, Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, Bern (Switzerland); Maecke, Helmut R. [University Hospital Basel, Division of Radiological Chemistry, Basel (Switzerland); University Hospital Freiburg, Department of Nuclear Medicine, Freiburg (Germany)


    Targeting of tumours positive for somatostatin receptors (sst) with radiolabelled peptides is of interest for tumour localization, staging, therapy follow-up and targeted radionuclide therapy. The peptides used clinically are exclusively agonists, but recently we have shown that the radiolabelled somatostatin-based antagonist {sup 111}In-DOTA-sst2-ANT may be preferable to agonists. However, a comprehensive study of this radiolabelled antagonist to determine its significance was lacking. The present report describes the evaluation of this novel antagonist labelled with {sup 111}In and {sup 177}Lu in three different tumour models. Radiopeptide binding, internalization and dissociation studies were performed using cells expressing HEK293-rsst{sub 2}. Biodistribution studies were performed in HEK293-rsst{sub 2}, HEK293-hsst{sub 2} and HEK293-rsst{sub 3} xenografted mice. Saturation binding analysis confirmed earlier IC{sub 50} data for {sup 111/nat}In-DOTA-sst2-ANT and showed similar affinity of {sup 177/nat}Lu-DOTA-sst2-ANT for the sst{sub 2}. Only low internalization was found in cell culture (6.68 {+-} 0.06 % at 4 h), which was not unexpected for an antagonist, and this could be further reduced by the addition of sucrose. No internalization was observed in HEK293 cells not expressing sst. Both results indicate that the internalization was specific. {sup 111}In-DOTA-sst2-ANT and {sup 177}Lu-DOTA-sst2-ANT were shown to target tumour xenografts expressing the rat and the human sst{sub 2} receptor with no differences in their uptake or pharmacokinetics. The uptake in rsst{sub 2} and hsst{sub 2} was high (about 30 %IA/g 4 h after injection) and surprisingly long-lasting (about 20-23 %IA/g 24 h after injection). Kidney uptake was blocked by approximately 50 % by lysine or Gelofusine. These results indicate that radiolabelled somatostatin-based antagonists may be superior to corresponding agonists. The long tumour retention time of {sup 177}Lu-DOTA-sst2-ANT indicates that

  19. Efficacy of a dopamine-somatostatin chimeric molecule, BIM-23A760, in the control of cell growth from primary cultures of human non-functioning pituitary adenomas: a multi-center study. (United States)

    Florio, Tullio; Barbieri, Federica; Spaziante, Renato; Zona, Gianluigi; Hofland, Leo J; van Koetsveld, Peter M; Feelders, Richard A; Stalla, Günter K; Theodoropoulou, Marily; Culler, Michael D; Dong, Jesse; Taylor, John E; Moreau, Jacques-Pierre; Saveanu, Alexandru; Gunz, Ginette; Dufour, Henry; Jaquet, Philippe


    Dopamine D2 and somatostatin receptors (sstrs) were reported to affect non-functioning pituitary adenoma (NFPA) proliferation in vitro. However, the reported results differ according to the experimental conditions used. We established an experimental protocol allowing reproducible evaluation of NFPA cell proliferation in vitro, to test and compare the antiproliferative effects of dopamine and somatostatin analogs (alone or in combination) with the activity of the dopamine-somatostatin chimeric molecule BIM-23A760. The protocol was utilized by four independent laboratories, studying 38 fibroblast-deprived NFPA cell cultures. Cells were characterized for GH, POMC, sstr1-sstr5, total dopamine D2 receptor (D2R) (in all cases), and D2 receptor long and short isoforms (in 15 out of 38 cases) mRNA expression and for alpha-subunit, LH, and FSH release. D2R, sstr3, and sstr2 mRNAs were consistently observed, with the dominant expression of D2R (2.9+/-2.6 copy/copy beta-glucuronidase; mean+/-s.e.m.), when compared with sstr3 and sstr2 (0.6+/-1.0 and 0.3+/-0.6 respectively). BIM-23A760, a molecule with high affinity for D2R and sstr2, significantly inhibited [3H]thymidine incorporation in 23 out of 38 (60%) NFPA cultures (EC50=1.2 pM and Emax=-33.6+/-3.7%). BIM-23A760 effects were similar to those induced by the selective D2R agonist cabergoline that showed a statistically significant inhibition in 18 out of 27 tumors (compared with a significant inhibition obtained in 17 out of 27 tumors using BIM-23A760, in the same subgroup of adenomas analyzed), while octreotide was effective in 13 out of 27 cases. In conclusion, superimposable data generated in four independent laboratories using a standardized protocol demonstrate that, in vitro, chimeric dopamine/sstr agonists are effective in inhibiting cell proliferation in two-thirds of NFPAs.

  20. Analog-to-digital conversion

    CERN Document Server

    Pelgrom, Marcel J M


    The design of an analog-to-digital converter or digital-to-analog converter is one of the most fascinating tasks in micro-electronics. In a converter the analog world with all its intricacies meets the realm of the formal digital abstraction. Both disciplines must be understood for an optimum conversion solution. In a converter also system challenges meet technology opportunities. Modern systems rely on analog-to-digital converters as an essential part of the complex chain to access the physical world. And processors need the ultimate performance of digital-to-analog converters to present the results of their complex algorithms. The same progress in CMOS technology that enables these VLSI digital systems creates new challenges for analog-to-digital converters: lower signal swings, less power and variability issues. Last but not least, the analog-to-digital converter must follow the cost reduction trend. These changing boundary conditions require micro-electronics engineers to consider their design choices for...

  1. Distributed Episodic and Analogical Reasoning (DEAR) (United States)


    ends analysis Carbonell 1983 Modeling of Analogy Making Structure Mapping Theory (SMT) Gentner 1984 Agent based approach to analogy making...Mapping Engine (SME) Forbus 1990 Learning by analogy with larger domains Prodigy/Analogy Veloso and Carbonell 1991 Analogical Retrieval Engine MAC/FAC

  2. Somatostatin receptors

    DEFF Research Database (Denmark)

    Møller, Lars Neisig; Stidsen, Carsten Enggaard; Hartmann, Bolette


    therefore been acknowledged to be a third endogenous ligand at SRIF receptors. This review goes through mechanisms of signal transduction, pharmacology, and anatomical distribution of SRIF receptors. Structurally, SRIF receptors belong to the superfamily of G protein-coupled (GPC) receptors, sharing....... The generation of knock-out (KO) mice, intended as a means to define the contributions made by individual receptor subtypes, necessarily marks but an approximation. Furthermore, we must now take into account the stunning complexity of receptor co-operation indicated by the observation of receptor homo......-peptides, receptor agonists and antagonists. Relatively long half lives, as compared to those of the endogenous ligands, have been paramount from the outset. Motivated by theoretical puzzles or the shortcomings of present-day diagnostics and therapy, investigators have also aimed to produce subtype...

  3. β-Arrestin 1 and 2 and G protein-coupled receptor kinase 2 expression in pituitary adenomas: role in the regulation of response to somatostatin analogue treatment in patients with acromegaly. (United States)

    Gatto, Federico; Feelders, Richard; van der Pas, Rob; Kros, Johan M; Dogan, Fadime; van Koetsveld, Peter M; van der Lelij, Aart-Jan; Neggers, Sebastian J C M M; Minuto, Francesco; de Herder, Wouter; Lamberts, Steven W J; Ferone, Diego; Hofland, Leo J


    Recent in vitro studies highlighted G protein-coupled receptor kinase (GRK)2 and β-arrestins as important players in driving somatostatin receptor (SSTR) desensitization and trafficking. Our aim was to characterize GRK2 and β-arrestins expression in different pituitary adenomas and to investigate their potential role in the response to somatostatin analog (SSA) treatment in GH-secreting adenomas (GHomas). We evaluated mRNA expression of multiple SSTRs, GRK2, β-arrestin 1, and β-arrestin 2 in 41 pituitary adenomas (31 GHomas, 6 nonfunctioning [NFPAs], and 4 prolactinomas [PRLomas]). Within the GHomas group, mRNA data were correlated with the in vivo response to an acute octreotide test and with the GH-lowering effect of SSA in cultured primary cells. β-Arrestin 1 expression was low in all 3 adenoma histotypes. However, its expression was significantly lower in GHomas and PRLomas, compared with NFPAs (P affect GRK2 and β-arrestin expression in GHomas or in cultured rat pituitary tumor GH3 cells. Noteworthy, β-arrestin 1 was significantly lower (P < .05) in tumors responsive to octreotide treatment in vitro, whereas GRK2 and SSTR subtype 2 were significantly higher (P < .05). Likewise, β-arrestin 1 levels were inversely correlated with the in vivo response to acute octreotide test (P = .001), whereas GRK2 and SSTR subtype 2 expression were positively correlated (P < .05). In conclusion, for the first time, we characterized GRK2, β-arrestin 1, and β-arrestin 2 expression in a representative number of pituitary adenomas. β-Arrestin 1 and GRK2 seem to have a role in modulating GH secretion during SSA treatment.

  4. Molecular modeling of fentanyl analogs

    Directory of Open Access Journals (Sweden)



    Full Text Available Fentanyl is a highly potent and clinically widely used narcotic analgesic. A large number of its analogs have been synthesized, some of which (sufentanil and alfentanyl are also in clinical use. Theoretical studies, in recent years, afforded a better understanding of the structure-activity relationships of this class of opiates and allowed insight into the molecular mechanism of the interactions of fentanyl analogs with their receptors. An overview of the current computational techniques for modeling fentanyl analogs, their receptors and ligand-receptor interactions is presented in this paper.

  5. Sulfonimidamide analogs of oncolytic sulfonylureas. (United States)

    Toth, J E; Grindey, G B; Ehlhardt, W J; Ray, J E; Boder, G B; Bewley, J R; Klingerman, K K; Gates, S B; Rinzel, S M; Schultz, R M; Weir, L C; Worzalla, J F


    A series of sulfonimidamide analogs of the oncolytic diarylsulfonylureas was synthesized and evaluated for (1) in vitro cytotoxicity against CEM cells, (2) in vivo antitumor activity against subaxillary implanted 6C3HED lymphosarcoma, and (3) metabolic breakdown to the o-sulfate of p-chloroaniline. The separated enantiomers of one sulfonimidamide analog displayed very different activities in the in vivo screening model. In general, several analogs demonstrated excellent growth inhibitory activity in the 6C3HED model when dosed orally or intraperitoneally. A correlative structure-activity relationship to the oncolytic sulfonylureas was not apparent.

  6. Serotonin- and Somatostatin-Positive Goblet Cell Carcinoid of the Duodenum

    Directory of Open Access Journals (Sweden)



    Full Text Available In the duodenum, mixed exocrine-endocrine tumors exhibiting both neuroendocrine and glandular differentiations [cf. appendiceal goblet cell carcinoids (GCCs] are rare. We present a Japanese case with a duodenal GCC that was found during pathologic examination of a gastrectomy specimen removed for gastric mucosal cancer. The tumor was widely distributed within both the first portion of the duodenum and the gastric antrum, although mucosal involvement was observed only in the duodenum. The tumor cells formed solid nests, trabeculae, or tubules, and some displayed a goblet cell appearance. They were immunoreactive against antibodies for both serotonin and somatostatin, and showed an argentaffin reaction (similar to a “midgut” enterochromaffin cell carcinoid. Ultra-structurally, the tumor cells had an amphicrine nature. Physicians encounter GCC in the duodenum only rarely, and its discovery may be incidental. Its diagnosis will be challenging and will require careful clinical and pathologic examinations.

  7. A gastric neuroendocrine carcinoma expressing somatostatin in a bearded dragon (Pogona vitticeps). (United States)

    Lyons, Jeremiah A; Newman, Shelley J; Greenacre, Cheryl B; Dunlap, John


    A metastatic gastric neuroendocrine carcinoma in a 2.5-year-old inland bearded dragon (Pogona vitticeps) with a chronic history of anorexia, weight loss, depression, and acute melena is described. Histologic examination of the gastric mass revealed a densely cellular tumor arranged in nests and occasional rosettes of hyperchromatic cells with oval to spindle-shaped nuclei and minimal cytoplasm; the tumor was supported by a moderate fibrovascular stroma. Similar cells invaded through the gastric mucosa, and there were multiple hepatic metastases. The neoplastic cells were weakly immunopositive for neuron-specific enolase and moderately positive for somatostatin but were negative for chromogranin AB and gastrin. Ultrastructural studies revealed scattered neurosecretory granules in the neoplastic cells, confirming the diagnosis of a neuroendocrine carcinoma.

  8. Disinhibition of somatostatin-positive GABAergic interneurons results in an anxiolytic and antidepressant-like brain state. (United States)

    Fuchs, T; Jefferson, S J; Hooper, A; Yee, P-Hp; Maguire, J; Luscher, B


    Major depressive disorder (MDD) is associated with reduced concentrations of γ-aminobutyric acid (GABA) that are normalized by antidepressant therapies. Moreover, depressive-like phenotypes of GABAA receptor mutant mice can be reversed by treatment with conventional antidepressants drugs, as well as by subanesthetic doses of ketamine. Thus GABAergic deficits may causally contribute to depressive disorders, while antidepressant therapies may enhance GABAergic synaptic transmission. Here we tested the hypothesis that sustained enhancement of GABAergic transmission alone is sufficient to elicit antidepressant-like behavior, using disinhibition of GABAergic interneurons. We focused on somatostatin-positive (SST(+)) GABAergic interneurons because of evidence that their function is compromised in MDD. To disinhibit SST(+) interneurons, we inactivated the γ2 subunit gene of GABAA receptors selectively in these neurons (SSTCre:γ2(f/f) mice). Loss of inhibitory synaptic input resulted in increased excitability of SST(+) interneurons. In turn, pyramidal cell targets of SST(+) neurons showed an increased frequency of spontaneous inhibitory postsynaptic currents. The behavior of SSTCre:γ2(f/f) mice mimicked the effects of anxiolytic and antidepressant drugs in a number of behavioral tests, without affecting performance in a spatial learning- and memory-dependent task. Finally, brain extracts of SSTCre:γ2(f/f) mice showed decreased phosphorylation of the eukaryotic elongation factor eEF2, reminiscent of the effects of ketamine. Importantly, these effects occurred without altered activity of the mammalian target of rapamycin pathway nor did they involve altered expression of SST. However, they were associated with reduced Ca(2+)/calmodulin-dependent auto-phosphorylation of eEF2 kinase, which controls the activity of eEF2 as its single target. Thus enhancing GABAergic inhibitory synaptic inputs from SST(+) interneurons to pyramidal cells and corresponding chronic reductions

  9. Intracellular Ca2+ signals in human-derived pancreatic somatostatin-secreting cells (QGP-1N). (United States)

    Squires, P E; Amiranoff, B; Dunne, M J


    Single-cell microfluorimetry techniques have been used to examine the effects of acetylcholine (0.1-100 microM) on the intracellular free calcium ion concentration ([Ca2+]i) in a human-derived pancreatic somatostatin-secreting cell line, QGP-1N. When applied to the bath solution, acetylcholine was found to evoke a marked and rapid increase in [Ca2+]i at all concentrations tested. These responses were either sustained, or associated with the generation of complex patterns of [Ca2+]i transients. Overall, the pattern of response was concentration related. In general, 0.1-10 microM acetylcholine initiated a series of repetitive oscillations in cytoplasmic Ca2+, whilst at higher concentrations the responses consisted of a rapid rise in [Ca2+]i followed by a smaller more sustained increase. Without external Ca2+, 100 microM acetylcholine caused only a transient rise in [Ca2+]i, whereas lower concentrations of the agonist were able to initiate, but not maintain, [Ca2+]i oscillations. Acetylcholine-evoked Ca2+ signals were abolished by atropine (1-10 microM), verapamil (100 microM) and caffeine (20 mM). Nifedipine failed to have any significant effect upon agonist-evoked increases in [Ca2+]i, whilst 50 mM KCl, used to depolarise the cell membrane, only elicited a transient increase in [Ca2+]i. Ryanodine (50-500 nM) and caffeine (1-20 mM) did not increase basal Ca2+ levels, but the Ca(2+)-ATPase inhibitors 2,5-di(tert-butyl)-hydroquinone (TBQ) and thapsigargin both elevated [Ca2+]i levels. These data demonstrate for the first time cytosolic Ca2+ signals in single isolated somatostatin-secreting cells of the pancreas. We have demonstrated that acetylcholine will evoke both Ca2+ influx and Ca2+ mobilisation, and we have partially addressed the subcellular mechanism responsible for these events.

  10. Neuropeptidomics of mouse hypothalamus after imipramine treatment reveal somatostatin as a potential mediator of antidepressant effects. (United States)

    Nilsson, Anna; Stroth, Nikolas; Zhang, Xiaoqun; Qi, Hongshi; Fälth, Maria; Sköld, Karl; Hoyer, Daniel; Andrén, Per E; Svenningsson, Per


    Excessive activation of the hypothalamic-pituitary-adrenal (HPA) axis has been associated with numerous diseases, including depression, and the tricyclic antidepressant imipramine has been shown to suppress activity of the HPA axis. Central hypothalamic control of the HPA axis is complex and involves a number of neuropeptides released from multiple hypothalamic subnuclei. The present study was therefore designed to determine the effects of imipramine administration on the mouse hypothalamus using a peptidomics approach. Among the factors found to be downregulated after acute (one day) or chronic (21 days) imipramine administration were peptides derived from secretogranin 1 (chromogranin B) as well as peptides derived from cerebellin precursors. In contrast, peptides SRIF-14 and SRIF-28 (1-11) derived from somatostatin (SRIF, somatotropin release inhibiting factor) were significantly upregulated by imipramine in the hypothalamus. Because diminished SRIF levels have long been known to occur in depression, a second part of the study investigated the roles of individual SRIF receptors in mediating potential antidepressant effects. SRA880, an antagonist of the somatostatin-1 autoreceptor (sst1) which positively modulates release of endogenous SRIF, was found to synergize with imipramine in causing antidepressant-like effects in the tail suspension test. Furthermore, chronic co-administration of SRA880 and imipramine synergistically increased BDNF mRNA expression in the cerebral cortex. Application of SRIF or L054264, an sst2 receptor agonist, but not L803807, an sst4 receptor agonist, increased phosphorylation of CaMKII and GluR1 in cerebrocortical slices. Our present experiments thus provide evidence for antidepressant-induced upregulation of SRIF in the brain, and strengthen the notion that augmented SRIF expression and signaling may counter depressive-like symptoms. This article is part of a Special Issue entitled 'Anxiety and Depression'.

  11. Altered Expression of Somatostatin Receptors in Pancreatic Islets from NOD Mice Cultured at Different Glucose Concentrations In Vitro and in Islets Transplanted to Diabetic NOD Mice In Vivo

    Directory of Open Access Journals (Sweden)

    Eva Ludvigsen


    Full Text Available Somatostatin acts via five receptors (sst1-5. We investigated if the changes in pancreatic islet sst expression in diabetic NOD mice compared to normoglycemic mice are a consequence of hyperglycemia or the ongoing immune reaction in the pancreas. Pancreatic islets were isolated from NOD mice precultured for 5 days and further cultured for 3 days at high or low glucose before examined. Islets were also isolated from NOD mice and transplanted to normal or diabetic mice in a number not sufficient to cure hyperglycemia. After three days, the transplants were removed and stained for sst1-5 and islet hormones. Overall, changes in sst islet cell expression were more common in islets cultured in high glucose concentration in vitro as compared to the islet transplantation in vivo to diabetic mice. The beta and PP cells exhibited more frequent changes in sst expression, while the alpha and delta cells were relatively unaffected by the high glucose condition. Our findings suggest that the glucose level may alter sst expressed in islets cells; however, immune mechanisms may counteract such changes in islet sst expression.

  12. Factors Affecting the Difficulty of Verbal Analogies. (United States)

    Roccas, Sonia; Moshinsky, Avital


    Examined factors affecting the difficulty of verbal analogies in a psychometric examination by characterizing 104 analogies using 5 defined attributes. Both knowledge and process attributes were found to contribute to the difficulty of verbal analogies assessed by 10 judges. (SLD)

  13. Solving a problem by analogy (United States)

    Easton, Don


    This note is a description of a student solution to a problem. I found the solution exciting because it exemplifies the kind of solution by analogy that Feynman describes in The Feynman Lectures on Physics.

  14. Analog CMOS contrastive Hebbian networks (United States)

    Schneider, Christian; Card, Howard


    CMOS VLSI circuits implementing an analog neural network with on-chip contrastive Hebbian learning and capacitive synaptic weight storage have been designed and fabricated. Weights are refreshed by periodic repetition of the training data. To evaluate circuit performance in a medium-sized system, these circuits were used to build a 132 synapse neural network. An adaptive neural system, such as the one described in this paper, can compensate for imperfections in the components from which it is constructed, and thus it is possible to build this type of system using simple, silicon area-efficient analog circuits. Because these analog VLSI circuits are far more compact than their digital counterparts, analog VLSI neural network implementations are potentially more efficient than digital ones.

  15. Verbal Analogies in the ITPA (United States)

    Levinson, Philip J.; Kunze, Luvern H.


    This study examined the extent to which the Auditory Association subtest of the revised Illinois Test of Psycholinguistic Abilities (ITPA) measures the ability of children to complete verbal analogies. (Author)

  16. Analog filters in nanometer CMOS

    CERN Document Server

    Uhrmann, Heimo; Zimmermann, Horst


    Starting from the basics of analog filters and the poor transistor characteristics in nanometer CMOS 10 high-performance analog filters developed by the authors in 120 nm and 65 nm CMOS are described extensively. Among them are gm-C filters, current-mode filters, and active filters for system-on-chip realization for Bluetooth, WCDMA, UWB, DVB-H, and LTE applications. For the active filters several operational amplifier designs are described. The book, furthermore, contains a review of the newest state of research on low-voltage low-power analog filters. To cover the topic of the book comprehensively, linearization issues and measurement methods for the characterization of advanced analog filters are introduced in addition. Numerous elaborate illustrations promote an easy comprehension. This book will be of value to engineers and researchers in industry as well as scientists and Ph.D students at universities. The book is also recommendable to graduate students specializing on nanoelectronics, microelectronics ...

  17. Privacy Act (United States)

    Learn about the Privacy Act of 1974, the Electronic Government Act of 2002, the Federal Information Security Management Act, and other information about the Environmental Protection Agency maintains its records.

  18. Analog electronic neural network circuits

    Energy Technology Data Exchange (ETDEWEB)

    Graf, H.P.; Jackel, L.D. (AT and T Bell Labs., Holmdel, NJ (USA))


    The large interconnectivity and moderate precision required in neural network models present new opportunities for analog computing. This paper discusses analog circuits for a variety of problems such as pattern matching, optimization, and learning. Most of the circuits build so far are relatively small, exploratory designs. The most mature circuits are those for template matching. Chips performing this function are now being applied to pattern recognition problems.

  19. Analog approach to mixed analog-digital circuit simulation (United States)

    Ogrodzki, Jan


    Logic simulation of digital circuits is a well explored research area. Most up-to-date CAD tools for digital circuits simulation use an event driven, selective trace algorithm and Hardware Description Languages (HDL), e.g. the VHDL. This techniques enable simulation of mixed circuits, as well, where an analog part is connected to the digital one through D/A and A/D converters. The event-driven mixed simulation applies a unified, digital-circuits dedicated method to both digital and analog subsystems. In recent years HDL techniques have been also applied to mixed domains, as e.g. in the VHDL-AMS. This paper presents an approach dual to the event-driven one, where an analog part together with a digital one and with converters is treated as the analog subsystem and is simulated by means of circuit simulation techniques. In our problem an analog solver used yields some numerical problems caused by nonlinearities of digital elements. Efficient methods for overriding these difficulties have been proposed.

  20. Glycine-extended gastrin enhances somatostatin release from cultured rabbit fundic D-cells [v1; ref status: indexed,

    Directory of Open Access Journals (Sweden)

    Ian LP Beales


    Full Text Available The role of the peptide hormone gastrin in stimulating gastric acid secretion is well established. Mature amidated gastrin is processed from larger peptide precursor forms. Increasingly these processing intermediates, such as glycine-extended gastrin (G-Gly and progastrin, have been shown to have biological activities of their own, often separate and complementary to gastrin. Although G-Gly is synthesized and secreted by gastric antral G-cells, the physiological functions of this putative mediator are unclear. Gastrin and cholecystokinin (CCK stimulate the secretion of somatostatin from gastric D-cells as part of the feedback control of gastric acid. In this study the effect of G-Gly and gastrin on the release of somatostatin from rabbit fundic D-cells was examined. D-cells were obtained by collagenase-EDTA digestion and elutriation and cultured for 48 hours. With a 2 hour exposure to the peptides, gastrin but not G-Gly stimulated somatostatin release. Treatment of D-cells for 24 hours with gastrin or G-Gly individually, significantly enhanced subsequent basal as well as CCK- and GLP-1-stimulated somatostatin release. Twenty four hours exposure to gastrin combined with G-Gly synergistically enhanced basal and agonist-stimulated somatostatin release and cellular somatostatin content. Gastrin and G-Gly may be important in the longer term regulation of D-cell function.

  1. SSERVI Analog Regolith Simulant Testbed Facility (United States)

    Minafra, Joseph; Schmidt, Gregory; Bailey, Brad; Gibbs, Kristina


    The Solar System Exploration Research Virtual Institute (SSERVI) at NASA's Ames Research Center in California's Silicon Valley was founded in 2013 to act as a virtual institute that provides interdisciplinary research centered on the goals of its supporting directorates: NASA Science Mission Directorate (SMD) and the Human Exploration & Operations Mission Directorate (HEOMD).Primary research goals of the Institute revolve around the integration of science and exploration to gain knowledge required for the future of human space exploration beyond low Earth orbit. SSERVI intends to leverage existing JSC1A regolith simulant resources into the creation of a regolith simulant testbed facility. The purpose of this testbed concept is to provide the planetary exploration community with a readily available capability to test hardware and conduct research in a large simulant environment.SSERVI's goals include supporting planetary researchers within NASA, other government agencies; private sector and hardware developers; competitors in focused prize design competitions; and academic sector researchers.SSERVI provides opportunities for research scientists and engineers to study the effects of regolith analog testbed research in the planetary exploration field. This capability is essential to help to understand the basic effects of continued long-term exposure to a simulated analog test environment.The current facility houses approximately eight tons of JSC-1A lunar regolith simulant in a test bin consisting of a 4 meter by 4 meter area, including dust mitigation and safety oversight.Facility hardware and environment testing scenarios could include, Lunar surface mobility, Dust exposure and mitigation, Regolith handling and excavation, Solar-like illumination, Lunar surface compaction profile, Lofted dust, Mechanical properties of lunar regolith, Surface features (i.e. grades and rocks)Numerous benefits vary from easy access to a controlled analog regolith simulant testbed, and

  2. Quantitative gene expression of somatostatin receptors and noradrenaline transporter underlying scintigraphic results in patients with neuroendocrine tumors

    DEFF Research Database (Denmark)

    Binderup, Tina; Knigge, Ulrich; Mellon Mogensen, Anne


    AIM: To measure, by a quantitative approach, the gene expression underlying the results of somatostatin receptor (sst) scintigraphy ((111)In-DTPA-octreotide) and noradrenaline transporter (NAT) scintigraphy ((123)I-MIBG) in patients with neuroendocrine (NE) tumors. METHODS: The gene expression...... of somatostatin receptors 1-5 (sst) and NAT was measured quantitatively by real-time PCR in a group of patients with NE tumors (n = 14) and compared to a group of patients with colorectal adenocarcinomas (n = 15). If available, scintigraphic results were compared with gene expression results (9 octreotide and 3...... in gene expression of sst(2) corresponded with scintigraphic results. Our data support that sst(2) is the best target for visualization of NE tumors, whereas NAT is only a useful target in a subpopulation of NE tumors. Comparison of scintigraphic results with quantitative gene expression may be used...

  3. Using Homology Modeling, Molecular Dynamics and Molecular Docking Techniques to Identify Inhibitor Binding Regions of Somatostatin Receptor 1

    Institute of Scientific and Technical Information of China (English)

    LAN Hai-nan; WANG Yue-xi; ZHENG Ming-zhu; HAN Wei-wei; ZHENG Xin


    The G protein coupled receptor(GPCR),one of the members in the superfamily,which consists of thousands of integral membrane proteins,exerts a wide variety of physiological functions and responses to a large portion of the drug targets.The 3D structure of somatostatin receptor 1(SSTR1) was modeled and refined by means of homology modeling and molecular dynamics simulation.This model was assessed by Verify-3D and Vadar,which confirmed the reliability of the refined model.The interaction between the inhibitor cysteamine,somatostatin(SST) and SSTRI was investigated by a molecular docking program,Affinity.The binding module not only showed the crucial residues involved in the interaction,but also provided important information about the interaction between SSTR1 on the one hand and ligands on the other,which might be the significant evidence for the structure-based design.

  4. All-optical analog comparator (United States)

    Li, Pu; Yi, Xiaogang; Liu, Xianglian; Zhao, Dongliang; Zhao, Yongpeng; Wang, Yuncai


    An analog comparator is one of the core units in all-optical analog-to-digital conversion (AO-ADC) systems, which digitizes different amplitude levels into two levels of logical ‘1’ or ‘0’ by comparing with a defined decision threshold. Although various outstanding photonic ADC approaches have been reported, almost all of them necessitate an electrical comparator to carry out this binarization. The use of an electrical comparator is in contradiction to the aim of developing all-optical devices. In this work, we propose a new concept of an all-optical analog comparator and numerically demonstrate an implementation based on a quarter-wavelength-shifted distributed feedback laser diode (QWS DFB-LD) with multiple quantum well (MQW) structures. Our results show that the all-optical comparator is very well suited for true AO-ADCs, enabling the whole digital conversion from an analog optical signal (continuous-time signal or discrete pulse signal) to a binary representation totally in the optical domain. In particular, this all-optical analog comparator possesses a low threshold power (several mW), high extinction ratio (up to 40 dB), fast operation rate (of the order of tens of Gb/s) and a step-like transfer function.

  5. Impaired excitability of somatostatin- and parvalbumin-expressing cortical interneurons in a mouse model of Dravet syndrome. (United States)

    Tai, Chao; Abe, Yasuyuki; Westenbroek, Ruth E; Scheuer, Todd; Catterall, William A


    Haploinsufficiency of the voltage-gated sodium channel NaV1.1 causes Dravet syndrome, an intractable developmental epilepsy syndrome with seizure onset in the first year of life. Specific heterozygous deletion of NaV1.1 in forebrain GABAergic-inhibitory neurons is sufficient to cause all the manifestations of Dravet syndrome in mice, but the physiological roles of specific subtypes of GABAergic interneurons in the cerebral cortex in this disease are unknown. Voltage-clamp studies of dissociated interneurons from cerebral cortex did not detect a significant effect of the Dravet syndrome mutation on sodium currents in cell bodies. However, current-clamp recordings of intact interneurons in layer V of neocortical slices from mice with haploinsufficiency in the gene encoding the NaV1.1 sodium channel, Scn1a, revealed substantial reduction of excitability in fast-spiking, parvalbumin-expressing interneurons and somatostatin-expressing interneurons. The threshold and rheobase for action potential generation were increased, the frequency of action potentials within trains was decreased, and action-potential firing within trains failed more frequently. Furthermore, the deficit in excitability of somatostatin-expressing interneurons caused significant reduction in frequency-dependent disynaptic inhibition between neighboring layer V pyramidal neurons mediated by somatostatin-expressing Martinotti cells, which would lead to substantial disinhibition of the output of cortical circuits. In contrast to these deficits in interneurons, pyramidal cells showed no differences in excitability. These results reveal that the two major subtypes of interneurons in layer V of the neocortex, parvalbumin-expressing and somatostatin-expressing, both have impaired excitability, resulting in disinhibition of the cortical network. These major functional deficits are likely to contribute synergistically to the pathophysiology of Dravet syndrome.

  6. Histamine H1-receptors modulate somatostatin receptors coupled to the inhibition of adenylyl cyclase in the rat frontoparietal cortex


    Puebla Jiménez, Lilian; Ocaña Fuentes, Aurelio; Arilla Ferreiro, Eduardo


    Since exogenous histamine has been previously shown to increase the somatostatin (SS) receptor-effector system in the rat frontoparietal cortex and both histamine H1-receptor agonists and SS modulate higher nervous activity and have anticonvulsive properties, it was of interest to determine the participation of the H1-histaminergic system in this response. The intracerebroventricular (i.c.v.) administration of the specific histamine H1-receptor agonist 2-pyridylethylamine (PEA) (10 ¿g) to rat...

  7. Functional aspects of the somatostatinergic system in the retina and the potential therapeutic role of somatostatin in retinal disease


    Casini, G.; Catalani, E.; M. Dal Monte; bagnoli, P


    The somatostatinergic system of the retina has been investigated in a variety of studies. A considerable amount of experimental evidence is available concerning the patterns of expression of somatostatin (SRIF) and its receptors in vertebrate retinas. However the functional roles of this peptidergic system in retinal physiology are far from being elucidated. Nonetheless, data have been provided concerning the regulatory action of SRIF on the excitability of...

  8. Effects of intra-gastric beta-casomorphin-7 on somatostatin and gastrin gene expression in rat gastric mucosa

    Institute of Scientific and Technical Information of China (English)

    Ya-Feng Zong; Wei-Hua Chen; Yuan-Shu Zhang; Si-Xiang Zou


    AIM: To investigate the in vivo effect of beta-casomorphin-7on the regulation of gastric somatostatin and gastrin messenger RNA in rat gastric mucosa.METHODS: Somatostatin and gastrin mRNA were quantified by RT-PCR and in situ hybridization (ISH)in 24 rats. The rats were divided into three treatment groups: basal diet + physiological saline (n = 8), basal diet + beta-casomorphin-7 (7.5 × 10-7 mol) (n = 8),and basal diet + poly-Gly-7 (containing equal mol of N with 7.5 x 10-7 mol beta-casomorphin-7) (n = 8).After oral administration for 30 days, rats were killed by exsanguinations.RESULTS: After intra-gastric administration of betacasomorphin-7 for 30 d, gastrin mRNA increased by 52.8% (P < 0.05, n = 8), and somatostatin mRNA levels decreased by 30.7% compared with the controls (P <0.01, n = 8). No significant differences in the expression of the two genes were observed in the poly-Gly-treated group, although gastrin mRNA expression was elevated by 35.6% as against the control group (P = 0.15, n =8). The long-term oral administration of a casomorphin solution significantly decreased the even gray of D-cells,but did not lower the number of D-cells both in the antrum and fundus. Interestingly, the number of G-cells increased in the antrum and fundus, but its average density was augmented only in the antrum.CONCLUSION: Beta-casomorphin-7 is capable of modulating gene expression of the regulatory peptides from G and D cells. Data from in situ hybridization studies indicate that beta-casomorphin-7 affects gastrin gene expression indirectly by means of the paracrine action of somatostatin, and depends on its intrinsic molecular function.

  9. Analog electronics for radiation detection

    CERN Document Server


    Analog Electronics for Radiation Detection showcases the latest advances in readout electronics for particle, or radiation, detectors. Featuring chapters written by international experts in their respective fields, this authoritative text: Defines the main design parameters of front-end circuitry developed in microelectronics technologies Explains the basis for the use of complementary metal oxide semiconductor (CMOS) image sensors for the detection of charged particles and other non-consumer applications Delivers an in-depth review of analog-to-digital converters (ADCs), evaluating the pros and cons of ADCs integrated at the pixel, column, and per-chip levels Describes incremental sigma delta ADCs, time-to-digital converter (TDC) architectures, and digital pulse-processing techniques complementary to analog processing Examines the fundamental parameters and front-end types associated with silicon photomultipliers used for single visible-light photon detection Discusses pixel sensors ...

  10. All-optical analog comparator


    Pu Li; Xiaogang Yi; Xianglian Liu; Dongliang Zhao; Yongpeng Zhao; Yuncai Wang


    An analog comparator is one of the core units in all-optical analog-to-digital conversion (AO-ADC) systems, which digitizes different amplitude levels into two levels of logical ‘1’ or ‘0’ by comparing with a defined decision threshold. Although various outstanding photonic ADC approaches have been reported, almost all of them necessitate an electrical comparator to carry out this binarization. The use of an electrical comparator is in contradiction to the aim of developing all-optical device...

  11. Role of Somatostatin-Positive Cortical Interneurons in the Generation of Sleep Slow Waves. (United States)

    Funk, Chadd M; Peelman, Kayla; Bellesi, Michele; Marshall, William; Cirelli, Chiara; Tononi, Giulio


    During non-rapid eye-movement (NREM) sleep, cortical and thalamic neurons oscillate every second or so between ON periods, characterized by membrane depolarization and wake-like tonic firing, and OFF periods, characterized by membrane hyperpolarization and neuronal silence. Cortical slow waves, the hallmark of NREM sleep, reflect near-synchronous OFF periods in cortical neurons. However, the mechanisms triggering such OFF periods are unclear, as there is little evidence for somatic inhibition. We studied cortical inhibitory interneurons that express somatostatin (SOM), because ∼70% of them are Martinotti cells that target diffusely layer I and can block excitatory transmission presynaptically, at glutamatergic terminals, and postsynaptically, at apical dendrites, without inhibiting the soma. In freely moving male mice, we show that SOM+ cells can fire immediately before slow waves and their optogenetic stimulation during ON periods of NREM sleep triggers long OFF periods. Next, we show that chemogenetic activation of SOM+ cells increases slow-wave activity (SWA), slope of individual slow waves, and NREM sleep duration; whereas their chemogenetic inhibition decreases SWA and slow-wave incidence without changing time spent in NREM sleep. By contrast, activation of parvalbumin+ (PV+) cells, the most numerous population of cortical inhibitory neurons, greatly decreases SWA and cortical firing, triggers short OFF periods in NREM sleep, and increases NREM sleep duration. Thus SOM+ cells, but not PV+ cells, are involved in the generation of sleep slow waves. Whether Martinotti cells are solely responsible for this effect, or are complemented by other classes of inhibitory neurons, remains to be investigated.SIGNIFICANCE STATEMENT Cortical slow waves are a defining feature of non-rapid eye-movement (NREM) sleep and are thought to be important for many of its restorative benefits. Yet, the mechanism by which cortical neurons abruptly and synchronously cease firing, the

  12. ACTS 2014

    DEFF Research Database (Denmark)

    Co-curator of ACTS 2014 together with Rasmus Holmboe, Judith Schwarzbart and Sanne Kofoed. ACTS is the Museum of Contemporary Art’s international bi-annual festival. ACTS was established in 2011 and, while the primary focus is on sound and performance art, it also looks toward socially oriented art...... various possibilities and public spaces as a stage. ACTS takes place in and around the museum and diverse locations in Roskilde city. ACTS is partly curated by the museum staff and partly by guest curators. ACTS 2014 is supported by Nordea-fonden and is a part of the project The Museum goes downtown....

  13. International Alligator Rivers Analog Project

    Energy Technology Data Exchange (ETDEWEB)

    Bichard, G.F.


    The Australian Nuclear Science and Technology Organization (ANSTO), the Japan Atomic Energy Research Institute, the Swedish Nuclear Power Inspectorate, the U.K. Department of the Environment, the US Nuclear Regulatory Commission (NRC), and the Power Reactor and Nuclear Fuel Development Corporation of Japan are participating under the aegis of the Nuclear Energy Agency in the International Alligator Rivers Analog Project. The project has a duration of 3 yr, starting in 1988. The project has grown out of a research program on uranium ore bodies as analogs of high-level waste (HLW) repositories undertaken by ANSTO supported by the NRC. A primary objective of the project is to develop an approach to radionuclide transport model validation that may be used by the participants to support assessments of the safety of radioactive waste repositories. The approach involves integrating mathematical and physical modeling with hydrological and geochemical field and laboratory investigations of the analog site. The Koongarra uranium ore body has been chosen as the analog site because it has a secondary ore body that has formed over the past million years as a result of leaching by groundwater flowing through fractures in the primary ore body.


    DEFF Research Database (Denmark)

    Gaunholt, Hans


    Theese lecture notes treats the fundamental theory and the most commonly used design methods for passive- active and digital filters with special emphasis on microelectronic realizations. The lecture notes covers 75% of the material taught in the course 49205 Analog and Digital Filters...

  15. Analog Input Data Acquisition Software (United States)

    Arens, Ellen


    DAQ Master Software allows users to easily set up a system to monitor up to five analog input channels and save the data after acquisition. This program was written in LabVIEW 8.0, and requires the LabVIEW runtime engine 8.0 to run the executable.

  16. Mathematical Analogy and Metaphorical Insight (United States)

    Zwicky, Jan


    How are we to understand the power of certain literary metaphors? The author argues that the apprehension of good metaphors is importantly similar to the apprehension of fruitful mathematical analogies: both involve a structural realignment of vision. The author then explores consequences of this claim, drawing conceptually significant parallels…

  17. Geometrical Analogies in Mathematics Lessons (United States)

    Eid, Wolfram


    A typical form of thinking to approach problem solutions humanly is thinking in analogous structures. Therefore school, especially mathematical lessons should help to form and to develop corresponding heuristic abilities of the pupils. In the contribution, a summary of possibilities of mathematics lessons regarding this shall particularly be…

  18. Schema Training in Analogical Reasoning. (United States)

    Robins, Shani; Mayer, Richard E.


    In 3 experiments, 93, 97, and 86 college students, respectively, learned how to solve 20 verbal analogy problems and took transfer and memory tests. Results are inconsistent with active responding theory and further indicate that schema induction is maximized when the schemas are made salient and the cognitive system is not overloaded. (SLD)


    DEFF Research Database (Denmark)

    Gaunholt, Hans


    Theese lecture notes treats the fundamental theory and the most commonly used design methods for passive- active and digital filters with special emphasis on microelectronic realizations. The lecture notes covers 75% of the material taught in the course 49205 Analog and Digital Filters...

  20. Paper Analogies Enhance Biology Teaching. (United States)

    Stencel, John E.


    Describes how to use paper analogies as models to illustrate various concepts in biology, human anatomy, and physiology classes. Models include biochemical paper models, protein papergrams, a paper model of early brain development, and a 3-D paper model of a eukaryotic cell. (AIM)

  1. Understanding & Teaching Genetics Using Analogies (United States)

    Woody, Scott; Himelblau, Ed


    We present a collection of analogies that are intended to help students better understand the foreign and often nuanced vocabulary of the genetics curriculum. Why is it called the "wild type"? What is the difference between a locus, a gene, and an allele? What is the functional (versus a rule-based) distinction between dominant and…

  2. Processes in Verbal Analogy Solution. (United States)

    Grudin, Jonathan


    Verbal analogy solution is more flexible than is suggested by either the standard process theory or Sternberg's theory. It was determined that subjects initially examine terms A and B; if this strategy is not successful, they examine the relationship between A and C. (Author/CP)

  3. Influence of Ganoderma lucidum spores on the levels of neuropeptide Y and somatostatin in brains of seizure rats

    Institute of Scientific and Technical Information of China (English)

    Kongli Zhu; Ming Lu; Shuqiu Wang; Shiling Zhang; Dixiang Sun


    BACKGROUND: Previous research has revealed that somatostatin can induce epilepsy, and that the levels of neuropeptide Y may increase and become more active in brain areas with epileptic seizures.OBJECTIVE: To observe the effect of Ganoderma lucidum spore powder on the neuropeptide Y and somatostatin content in the cerebral cortex and hippocampal regions of seizure rats induced by pentylenetetrazol (PTZ). Furthermore, to verify any effect of Ganoderma lucidum spore powder on inhibition of epileptic seizures.DESIGN, TIME AND SETTING: A randomized group animal study was performed in August 2007 in the School of Basic Medical Sciences, Jiamusi University (Jiamusi, Heilongjiang, China).MATERIALS: Thirty healthy, male, Wistar rats, aged 12 weeks and weighing 180-220g, were taken as the experimental animals. PTZ (Sigma Company, United States) was used to induce epilepsy. Ganoderma lucidum spores (Leyss, ex Fr variety) were purchased from Jiamusi City Wild Growing Case of the Ganoderma Lucidum (China). Rabbit anti-somatostatin antibodies and secondary antibodies were purchased from Wuhan Boster Company (China). Neuropeptide Y radioimmunoassay kit was purchased from Beijing Furui Biotechnology Company (China).METHODS: Thirty rats were randomly divided into three groups: a control group, an epilepsy model group and a Ganoderma lucidum spore-treated group. Each group contained 10 animals. Rats in the epilepsy model group were treated with intraperitoneal injections of PTZ and gastric perfusion of physiologic saline, In the Ganoderma lucidum spore-treated group, intraperitoneal injection of PTZ and gastric perfusion of Ganoderma lucidum spore powder were administered. The blank control group was only administered with the physiological saline by intraperitoneal injection and gastric perfusion.MAIN OUTCOME MEASURES: Immunohistochemical staining and radioimmunoassay methods were used to observe the changes of somatostatin and neuropeptide Y content in brain tissue of epileptic

  4. Safety and tolerability of pasireotide long-acting release in acromegaly-results from the acromegaly, open-label, multicenter, safety monitoring program for treating patients who have a need to receive medical therapy (ACCESS) study. (United States)

    Fleseriu, Maria; Rusch, Elisha; Geer, Eliza B


    Pasireotide long-acting release is a somatostatin analog that is indicated for treatment of patients with acromegaly. This analysis documents the safety of pasireotide long-acting release in patients with acromegaly enrolled in the ACCESS trial ( identifier: NCT01995734). ACCESS is an open-label, multicenter, single-arm, expanded-treatment protocol designed to provide patients access to pasireotide long-acting release pending regulatory approval. Patients received pasireotide long-acting release 40 mg administered intramuscularly every 28 days. The primary outcome was the proportion of patients having a treatment-emergent grade ≥3 or serious adverse event. Efficacy data were not collected. Forty-four adult patients with active acromegaly were enrolled in the study for an average of 37.6 weeks (range, 4-70 weeks). Twenty-five grade ≥3 treatment-emergent adverse events were reported in 11 patients (25.0 %), 3 of whom (27.3 %) experienced grade ≥3 hyperglycemia. In patients treated with pasireotide long-acting release for ≥3 months (n = 42), mean glycated hemoglobin and fasting plasma glucose levels increased significantly from 5.9 % and 100.4 mg/dL at baseline to 6.8 % and 135.9 mg/dL at 3 months, respectively. Ten patients (22.7 %) were treated with pasireotide long-acting release for ≥15 months, after which mean glycated hemoglobin and fasting plasma glucose levels were 6.3 % and 123 mg/dL, respectively. Twenty-one patients (48 %) initiated antidiabetic medication. Grade ≥3 adverse events (primary outcome) were reported in 25.0 % of acromegaly patients treated with pasireotide long-acting release in a clinical setting. Hyperglycemia-related adverse events were reported in 45.5 % of patients, but were typically manageable, supporting the role of pasireotide long-acting release as a safe treatment option for acromegaly patients.

  5. Crows spontaneously exhibit analogical reasoning. (United States)

    Smirnova, Anna; Zorina, Zoya; Obozova, Tanya; Wasserman, Edward


    Analogical reasoning is vital to advanced cognition and behavioral adaptation. Many theorists deem analogical thinking to be uniquely human and to be foundational to categorization, creative problem solving, and scientific discovery. Comparative psychologists have long been interested in the species generality of analogical reasoning, but they initially found it difficult to obtain empirical support for such thinking in nonhuman animals (for pioneering efforts, see [2, 3]). Researchers have since mustered considerable evidence and argument that relational matching-to-sample (RMTS) effectively captures the essence of analogy, in which the relevant logical arguments are presented visually. In RMTS, choice of test pair BB would be correct if the sample pair were AA, whereas choice of test pair EF would be correct if the sample pair were CD. Critically, no items in the correct test pair physically match items in the sample pair, thus demanding that only relational sameness or differentness is available to support accurate choice responding. Initial evidence suggested that only humans and apes can successfully learn RMTS with pairs of sample and test items; however, monkeys have subsequently done so. Here, we report that crows too exhibit relational matching behavior. Even more importantly, crows spontaneously display relational responding without ever having been trained on RMTS; they had only been trained on identity matching-to-sample (IMTS). Such robust and uninstructed relational matching behavior represents the most convincing evidence yet of analogical reasoning in a nonprimate species, as apes alone have spontaneously exhibited RMTS behavior after only IMTS training. Copyright © 2015 Elsevier Ltd. All rights reserved.

  6. Target-specific effects of somatostatin-expressing interneurons on neocortical visual processing. (United States)

    Cottam, James C H; Smith, Spencer L; Häusser, Michael


    A diverse array of interneuron types regulates activity in the mammalian neocortex. Two of the most abundant are the fast-spiking, parvalbumin-positive (PV(+)) interneurons, which target the axosomatic region of pyramidal cells, and the somatostatin-positive (SOM(+)) interneurons, which target the dendrites. Recent work has focused on the influence of PV(+) and SOM(+) interneurons on pyramidal cells. However, the connections among PV(+) and SOM(+) interneurons are poorly understood and could play an important role in cortical circuitry, since their interactions may alter the net influence on pyramidal cell output. We used an optogenetic approach to investigate the effect of SOM(+) interneurons on pyramidal cells and PV(+) interneurons during visual stimulation in mouse primary visual cortex. We find that SOM(+) interneuron activation suppresses PV(+) cell spiking at least twice as potently as pyramidal cell spiking during visual stimulation. This differential effect of SOM(+) cell stimulation is detectable even when only two to three SOM(+) cells are activated. Importantly, the remaining responses to oriented gratings in PV(+) cells are more orientation tuned and temporally modulated, suggesting that SOM(+) activity unmasks this tuning by suppressing untuned input. Our results highlight the importance of SOM(+) inhibition of PV(+) interneurons during sensory processing. This prominent competitive inhibition between interneuron types leads to a reconfiguration of inhibition along the somatodendritic axis of pyramidal cells, and enhances the orientation selectivity of PV(+) cells.

  7. Cortical plasticity induced by transplantation of embryonic somatostatin or parvalbumin interneurons. (United States)

    Tang, Yunshuo; Stryker, Michael P; Alvarez-Buylla, Arturo; Espinosa, Juan Sebastian


    GABAergic inhibition has been shown to play an important role in the opening of critical periods of brain plasticity. We recently have shown that transplantation of GABAergic precursors from the embryonic medial ganglionic eminence (MGE), the source of neocortical parvalbumin- (PV(+)) and somatostatin-expressing (SST(+)) interneurons, can induce a new period of ocular dominance plasticity (ODP) after the endogenous period has closed. Among the diverse subtypes of GABAergic interneurons PV(+) cells have been thought to play the crucial role in ODP. Here we have used MGE transplantation carrying a conditional allele of diphtheria toxin alpha subunit and cell-specific expression of Cre recombinase to deplete PV(+) or SST(+) interneurons selectively and to investigate the contributions of each of these types of interneurons to ODP. As expected, robust plasticity was observed in transplants containing PV(+) cells but in which the majority of SST(+) interneurons were depleted. Surprisingly, transplants in which the majority of PV(+) cells were depleted induced plasticity as effectively as those containing PV(+) cells. In contrast, depleting both cell types blocked induction of plasticity. These findings reveal that PV(+) cells do not play an exclusive role in ODP; SST(+) interneurons also can drive cortical plasticity and contribute to the reshaping of neural networks. The ability of both PV(+) and SST(+) interneurons to induce de novo cortical plasticity could help develop new therapeutic approaches for brain repair.

  8. The Developmental Patterns of Somatostatin Gene Expression in Gastric Tissue of Erhualian and Large White Pigs

    Institute of Scientific and Technical Information of China (English)

    XIA Dong; ZHAO Ru-qian; XU Qing-fu; XU Jin-xian; SHI Zi-gang; CHEN Jie


    In present study, the developmental patterns of somatostatin (SS) gene expression in gastrictissue were compared between Erhualian and Large White pigs. A semi-quantitative RT-PCR was applied todetermine the levels of SS mRNA. The results indicated that : (1) The gastric SS mRNA expression was high atbirth, followed by a significant decrease (P<0.05) at 3 days of age in both breeds of pigs; (2) From 3 to 30days of age, the expression of SS mRNA in gastric tissue exhibited remarkable up-regulation in both breeds,after which a strain difference in the developmental pattern was observed. In Erhualian pigs, SS mRNA ex-pression reached a peak at 90 days of age, declined thereafter towards 180 days of age. In Large White pigs,however, the expression of SS mRNA remained constant from 30 days of age onwards; (3) In general, Erhual-ian pigs expressed higher levels of SS mRNA in gastric tissue compared with Large White pigs at the same age.The strain difference was significant from birth to 90 days of age, but vanished at 120 and 180 days of age.The results suggest that the gastric expression of SS in the pig is regulated following an instinct timetable in astrain-specific manner, its relationship with the development of gastric function as well as its interactions withenvironmental factors are to be elucidated.

  9. Murine IgA-secreting plasmacytoma MOPC-315 expresses somatostatin receptors

    Energy Technology Data Exchange (ETDEWEB)

    Scicchitano, R.; Dazin, P.; Bienenstock, J.; Payan, D.G.; Stanisz, A.M.


    We have previously shown that some neuropeptides had a profound effect on in vitro Ig synthesis (especially IgA) and mitogen-driven murine lymphocyte proliferation. MOPC-315, an IgA-secreting plasmacytoma line, has been extensively used in studies of the regulation of IgA synthesis. In this report we show that the neuropeptide somatostatin (SOM) inhibits proliferation ((/sup 3/H)thymidine uptake) of MOPC-315 and also inhibits IgA synthesis in vitro. MOPC-315 cells bind both fluorescent SOM and (/sup 125/I)SOM specifically. On cytofluorimetric analysis, 68 +/- 6.8% (mean +/- SE, n = 7) of MOPC 315 cells labeled with fluorescent SOM and this staining was compatible by incubation with an excess of unlabeled peptide. Specific (/sup 125/I)SOM binding increased linearly with cell concentration, was rapid and achieved equilibrium after 20 min at 4 degrees C. It was temperature-dependent, readily reversible, and under equilibrium conditions demonstrated a dissociation constant of 1.6 +/- 0.7 nM (mean +/- SE, n = 5). Scatchard analysis showed that MOPC-315 cells had 40,733 +/- 16,050 (mean +/- SE) binding sites for SOM per cell. The characteristics of the interactions of SOM with MOPC-315 cells suggest a specific receptor-mediated mechanism whereby this neuropeptide may modulate lymphocyte function.

  10. The expression of somatostatin receptors in the hippocampus of pilocarpine-induced rat epilepsy model. (United States)

    Kwak, Sung-Eun; Kim, Ji-Eun; Choi, Hui-Chul; Song, Hong-Ki; Kim, Yeong-In; Jo, Seung-Mook; Kang, Tae-Cheon


    During the course of this study, we sought examine whether the expression of somatostatin receptors (SSTRs) is altered in the hippocampus following pilocarpine-induced status epilepticus (SE) in order to understand the role/function of SSTRs in the hippocampus after epileptogenic insults. SSTR1 and SSTR4 immunoreactivities were increased in the hippocampus at 1 week after SE. At 4 weeks after SE, SRIF1-family (SSTR 2A, SSTR2B, and SSTR5) immunoreactivity was increased only in neuropil. Both SSTR2A and 2B immunoreactivities were increased in CA2-3 pyramidal cells. However, SSTR3 and SSTR4 immunoreactivities were reduced in the CA1 pyramidal cells of epileptic rat due to neuronal loss. In addition, SSTR5 immunoreactivity was reduced in CA2 pyramidal cells and various interneurons. Both SSTR2B and SSTR4 immunoreactivities were increased within microglia following SE. Our findings suggest that increases in neuron-glial SSTR expressions may be closely related to the enhanced inhibition of the dentate gyrus and regulation of reactive microgliosis in the hippocampus of a pilocarpine model of temporal lobe epilepsy.

  11. Parallel secretion of pancreastatin and somatostatin from human pancreastatin producing cell line (QGP-1N). (United States)

    Funakoshi, A; Tateishi, K; Kitayama, N; Jimi, A; Matsuoka, Y; Kono, A


    In this investigation we studied pancreastatin (PST) secretion from a human PST producing cell line (QGP-1N) in response to various secretagogues. Immunocytochemical study revealed the immunoreactivity of PST and somatostatin (SMT) in the same cells of a monolayer culture. Ki-ras DNA point mutation on codon 12 was found. Carbachol stimulated secretion of PST and SMT and intracellular Ca2+ mobilization in the range of 10(-6)-10(-4) M. The secretion and Ca2+ mobilization were inhibited by atropine, a muscarinic receptor antagonist. Phorbol ester and calcium ionophore (A23187) stimulated secretion of PST and SMT. The removal of extracellular calcium suppressed both secretions throughout stimulation with 10(-5) M carbachol. Fluoride, a well-known activator of guanine nucleotide binding (G) protein, stimulated intracellular Ca2+ mobilization and secretion of PST and SMT in a dose-dependent manner in the range of 5-40 mM. Also, 10(-5) M carbachol and 20 mM fluoride stimulated inositol 1,4,5-triphosphate production. However, cholecystokinin and gastrin-releasing peptide did not stimulate Ca2+ mobilization or secretion of the two peptides. These results suggest that secretion of PST and SMT from QGP-1N cells is regulated mainly by acetylcholine in a parallel fashion through muscarinic receptors coupled to the activation of polyphosphoinositide breakdown by a G-protein and that increases in intracellular Ca2+ and protein kinase C play an important role in stimulus-secretion coupling.

  12. Enhancement Effect of CpG DNA on the Somatostatin DNA Vaccine in Mice

    Institute of Scientific and Technical Information of China (English)

    XUE Chun-lin; MAO Da-gan; YANG Li-guo; CHENG Bao


    To study the immune effect of CpGDNA on somatostatin (SS) DNA vaccine, the 20-day-old experimental mice were immunized with 20 μg SS eukaryotic expression plasmid pES/2SS with different adjuvants in equal dose, such as the synthetic CpG-ODN, the pE-CpG plasmid, E. coli DNA and the crude liposome. A booster was given two weeks later. The results showed that the body weight gain of female mice in the SS immunized group was higher than that of the control (P<0.05). The levels of antibodies against SS, IgG2a/IgG1, spleen lymphocyte proliferation activity and the concentrations of GH and IGF- Ⅰ in the DNA vaccine groups combined with CpGDNA were significantly increased compared to that of the group immunized with DNA vaccine alone. All these suggested the recombinant SS expression plasmid can stimulate animals to produce antibodies against SS, and CpGDNA adjuvant can enhance the immune effect of DNA vaccine against SS and influence the concentration of GH and IGF- Ⅰ.

  13. Somatostatin expression in human hair follicles and its potential role in immune privilege. (United States)

    Breitkopf, Trisia; Lo, Blanche K K; Leung, Gigi; Wang, Eddy; Yu, Mei; Carr, Nicholas; Zloty, David; Cowan, Bryce; Shapiro, Jerry; McElwee, Kevin J


    Immune privilege (IP) is believed to exist in the anagen hair follicle (HF). Studies have shown that downregulation of major histocompatibility complex Class I occurs and immunosuppressive factors are expressed in the HF bulb and bulge. However, demonstration and quantification of functional IP in HF cells are required. We examined the middle (sheath) and lower (bulb) portions of the human HF using quantitative real-time RT-PCR (qPCR), immunohistology, ELISA, in vitro coculture with peripheral blood mononuclear cells (PBMCs), and flow cytometry. We found that HF cells, relative to non-follicular epidermal cells, failed to promote allogeneic PBMC proliferation and CD4(+) and CD8(+) IFNγ production. By qPCR, we found significant downregulation of Class I and Class II HLA alleles in both the bulb and sheath, and upregulation of multiple immunoregulatory genes. It is noteworthy that somatostatin (SST) was significantly upregulated relative to epidermis. By immunohistochemistry, SST was most strongly expressed in the HF outer root sheath, and, by ELISA, cultured sheath cells secreted SST. PBMCs, cultured with stimulatory allogeneic epidermal cells and SST, secreted significantly less IFNγ than controls. Addition of SST antagonists to PBMCs cocultured with allogeneic HF cells increased IFNγ secretion. The data identify SST as a secretory factor potentially contributing to the HF IP repertoire.

  14. Peripheral nervous system assessment in acromegaly patients under somatostatin analogue therapy. (United States)

    Alibas, H; Gogas Yavuz, D; Kahraman Koytak, P; Uygur, M; Tanridag, T; Uluc, K


    Acromegaly is known to affect peripheral nervous system (PNS) causing carpal tunnel syndrome (CTS) and polyneuropathy. The frequency of these disorders and the evaluation methods vary among studies. In the present study, we aimed to examine PNS of acromegaly patients under somatostatin analogue (SSA) therapy. Forty-eight acromegaly patients (26 F/22 M, 45.58 ± 11.6 years) under SSA treatment and 44 healthy controls (25 F/19 M, 47.46 ± 8.7 years) were assessed by symptom questionnaires, neurologic examination and electrophysiological studies. 87.5 % of the acromegaly patients had at least one abnormal finding regarding PNS. With the incorporation of palm-wrist median nerve conduction velocity method, we detected CTS in 50 % of patients. Polyneuropathy was less frequent (29.2 %). Both conditions were independent from the coexisting diabetes mellitus (p = 0.22 for CTS, p = 0.71 for polyneuropathy). Polyneuropathy but not CTS was more common among biochemically uncontrolled acromegaly patients rather than those under control (p = 0.03; p = 0.68, respectively). Our findings emphasize the high prevalence of peripheral nervous system involvement in acromegaly patients under SSA therapy and importance of neurological evaluation of these patients. Early diagnosis and treatment of the disease may reduce the PNS involvement.

  15. Somatostatin receptor-1 induces cell cycle arrest and inhibits tumor growth in pancreatic cancer. (United States)

    Li, Min; Wang, Xiaochi; Li, Wei; Li, Fei; Yang, Hui; Wang, Hao; Brunicardi, F Charles; Chen, Changyi; Yao, Qizhi; Fisher, William E


    Functional somatostatin receptors (SSTR) are lost in human pancreatic cancer. Transfection of SSTR-1 inhibited pancreatic cancer cell proliferation in vitro. We hypothesize that stable transfection of SSTR-1 may inhibit pancreatic cancer growth in vivo possibly through cell cycle arrest. In this study, we examined the expression of SSTR-1 mRNA in human pancreatic cancer tissue specimens, and investigated the effect of SSTR-1 overexpression on cell proliferation, cell cycle, and tumor growth in a subcutaneous nude mouse model. We found that SSTR-1 mRNA was downregulated in the majority of pancreatic cancer tissue specimens. Transfection of SSTR-1 caused cell cycle arrest at the G(0)/G(1) growth phase, with a corresponding decline of cells in the S (mitotic) phase. The overexpression of SSTR-1 significantly inhibited subcutaneous tumor size by 71% and 43% (n = 5, P < 0.05, Student's t-test), and inhibited tumor weight by 69% and 47% (n = 5, P < 0.05, Student's t-test), in Panc-SSTR-1 and MIA-SSTR-1 groups, respectively, indicating the potent inhibitory effect of SSTR-1 on pancreatic cancer growth. Our data demonstrate that overexpression of SSTR-1 significantly inhibits pancreatic cancer growth possibly through cell cycle arrest. This study suggests that gene therapy with SSTR-1 may be a potential adjuvant treatment for pancreatic cancer.

  16. Is prophylactic somatostatin effective to prevent post-endoscopic retrograde cholangiopancreatography pancreatitis or hyperamylasemia? A randomized, placebo-controlled pilot trial

    Institute of Scientific and Technical Information of China (English)

    WANG Zi-kai; YANG Yun-sheng; CAI Feng-chun; WANG Yong-hua; SHI Xiao-lin; DING Chen; LI Wen


    Background Effects of prophylactic somatostatin on post-endoscopic retrograde cholangiopancreatography (ERCP)pancreatitis (PEP) and hyperamylasemia remain inconclusive.This study aimed to examine whether high-dose,long-term continuous infusion of somatostatin can reduce the incidence of PEP and post-ERCP hyperamylasemia.Methods This was a randomized,placebo-controlled pilot trial.One hundred and twenty-four patients scheduled for ERCP from December 2008 to May 2010 randomly received one of the following three interventions:pre-ERCP somatostatin (0.5 mg/h for 24 hours,starting 1 hour prior to ERCP; n=36),post-ERCP somatostatin (0.5 mg/h for 24 hours,starting 1 hour after ERCP; n=47),or placebo (saline for 24 hours,starting 1 hour prior to ERCP; n=41).Serum amylase and lipase concentrations were measured 1 to 3 hours prior to ERCP and 6,24,and 48 hours after ERCP.Results The three groups did not differ in age,gender,medical history,or ERCP procedure (catheterization using contrast or guidewire,pancreatic duct visualization,procedure time,or procedure type).The rate of PEP was 13.7% (17/124)in the overall study sample and 16.7% (6/36),10.6% (5/47),and 14.6% (6/41) in the pre-ERCP somatostatin,postERCP somatostatin,and placebo groups,respectively (P=0.715).The rate of post-ERCP hyperamylasemia was 19.4% (7/36),21.3% (10/47),and 46.3% (19/41) in the pre-ERCP somatostatin,post-ERCP somatostatin,and placebo groups,respectively (P=0.011).Conclusions High-dose,long-term continuous infusion (0.5 mg/h for 24 hours) of somatostatin,performed as either a pre-or post-ERCP,can reduce the incidence of hyperamylasemia,but not PEP.

  17. Analog circuit design art, science and personalities

    CERN Document Server

    Williams, Jim


    This book is far more than just another tutorial or reference guide - it's a tour through the world of analog design, combining theory and applications with the philosophies behind the design process. Readers will learn how leading analog circuit designers approach problems and how they think about solutions to those problems. They'll also learn about the `analog way' - a broad, flexible method of thinking about analog design tasks.A comprehensive and useful guide to analog theory and applications. Covers visualizing the operation of analog circuits. Looks at how to rap

  18. Interaction between phosphoinositide turnover system and cyclic AMP pathway for the secretion of pancreastatin and somatostatin from QGP-1N cells. (United States)

    Tateishi, K; Funakoshi, A; Kitayama, N; Matsuoka, Y


    It is found that secretion of pancreastatin and somatostatin from QGP-1N cells is regulated through muscarinic receptor-mediated activation of phosphatidylinositide hydrolysis system. In this report, whether the cAMP pathway interacts with the phosphoinositide turnover system for the secretion of pancreastatin and somatostatin from QGP-1N cells through muscarinic receptors was studied. Stimulation of QGP-1N cells with carbachol increased intracellular cAMP levels. The carbachol-induced increase in cAMP levels was inhibited by atropine. Calcium ionophore (A23187) and phorbol 12-myristate 13-acetate increased cAMP synthesis. Dibutyryl cAMP, forskolin and theophylline stimulated secretion of pancreastatin and somatostatin. When either dibutyryl cAMP, forskolin or theophylline was added in culture medium with A23187, phorbol ester or carbachol, a synergistic effect was found on pancreastatin and somatostatin secretion. These results suggest that interaction between the phosphoinositide turnover system and the cAMP pathway occurs in QGP-1N cells through muscarinic receptor stimulation for the secretion of pancreastatin and somatostatin.

  19. The influence of ovarian factors on the somatostatin-growth hormone system during the postnatal growth and sexual development in lambs. (United States)

    Wańkowska, Marta; Polkowska, Jolanta; Misztal, Tomasz; Romanowicz, Katarzyna


    The aim of the study was to elucidate the effects of ovarian hormones on somatostatin in the hypothalamic neurons and growth hormone (GH) secretion during the postnatal growth and development of sheep. The study was performed on 9-week-old (infantile) lambs that were ovary-intact (OVI) or ovariectomized (OVX) at 39 days of age, and on 16-week-old (juvenile) lambs that were OVI or OVX at 88 days of age. Hormones in neurons and somatotropic cells were assayed with immunohistochemistry and radioimmunoassay. Following ovariectomy, immunoreactive somatostatin was more abundant (p0.05) between OVI and OVX lambs. In conclusion, ovarian factors may inhibit the GH secretion in infantile lambs but enhance the GH secretion in juvenile lambs. Transition to puberty, as related to the growth rate, appears to be due mainly to change in gonadal influence on the somatostatin neurosecretion. A stimulation of somatostatin output in the median eminence by gonadal factors in infancy is followed by a stimulation of somatostatin accumulation after infancy. Thus, ovarian factors modulate mechanisms within the somatotropic system of lambs to synchronize the somatic growth with sexual development.

  20. Synaptic dynamics in analog VLSI. (United States)

    Bartolozzi, Chiara; Indiveri, Giacomo


    Synapses are crucial elements for computation and information transfer in both real and artificial neural systems. Recent experimental findings and theoretical models of pulse-based neural networks suggest that synaptic dynamics can play a crucial role for learning neural codes and encoding spatiotemporal spike patterns. Within the context of hardware implementations of pulse-based neural networks, several analog VLSI circuits modeling synaptic functionality have been proposed. We present an overview of previously proposed circuits and describe a novel analog VLSI synaptic circuit suitable for integration in large VLSI spike-based neural systems. The circuit proposed is based on a computational model that fits the real postsynaptic currents with exponentials. We present experimental data showing how the circuit exhibits realistic dynamics and show how it can be connected to additional modules for implementing a wide range of synaptic properties.

  1. Holism and nonseparability by analogy (United States)

    Arageorgis, Aristidis


    This paper explores the issues of holism and nonseparability in relativistic quantum field theory (QFT) by focusing on an analog of the typical model featuring in many discussions of holism and nonseparability in nonrelativistic quantum mechanics. It is argued that the quantum field theoretic model does exhibit holism in a metaphysical sense and that there are plausible grounds to view QFT holistic in an epistemological sense. However, the complexities arising from the fact that quantum fields have infinite degrees of freedom prohibit the exploitation of the elaborated analogy toward demonstrating that the QFT model exhibits the kind of state nonseparability familiar from ordinary quantum mechanics. Still, it is argued that the QFT model does satisfy a rather weak epistemological criterion for state nonseparability.

  2. Analog-to-digital conversion

    CERN Document Server

    Pelgrom, Marcel


    This textbook is appropriate for use in graduate-level curricula in analog-to-digital conversion, as well as for practicing engineers in need of a state-of-the-art reference on data converters. It discusses various analog-to-digital conversion principles, including sampling, quantization, reference generation, nyquist architectures and sigma-delta modulation. This book presents an overview of the state of the art in this field and focuses on issues of optimizing accuracy and speed, while reducing the power level. This new, third edition emphasizes novel calibration concepts, the specific requirements of new systems, the consequences of 22-nm technology and the need for a more statistical approach to accuracy. Pedagogical enhancements to this edition include additional, new exercises, solved examples to introduce all key, new concepts and warnings, remarks and hints, from a practitioner’s perspective, wherever appropriate. Considerable background information and practical tips, from designing a PCB, to lay-o...

  3. Mechanical Analogies of Fractional Elements

    Institute of Scientific and Technical Information of China (English)

    HU Kai-Xin; ZHU Ke-Qin


    A Fractional element model describes a special kind of viscoelastic material.Its stress is proportional to the fractional-order derivative of strain. Physically the mechanical analogies of fractional elements can be represented by spring-dashpot fractal networks. We introduce a constitutive operator in the constitutive equations of viscoelastic materials.To derive constitutive operators for spring-dashpot fractal networks, we use Heaviside operational calculus, which provides explicit answers not otherwise obtainable simply.Then the series-parallel formulas for the constitutive operator are derived. Using these formulas, a constitutive equation of fractional element with 1/2-order derivative is obtained.Finally we find the way to derive the constitutive equations with other fractional-order derivatives and their mechanical analogies.

  4. Endogenous somatostatin is critical in regulating the acute effects of L-arginine on growth hormone and insulin release in mice. (United States)

    Córdoba-Chacón, Jose; Gahete, Manuel D; Pozo-Salas, Ana I; Castaño, Justo P; Kineman, Rhonda D; Luque, Raul M


    l-arginine (l-Arg) rapidly stimulates GH and insulin release in vivo. It has been hypothesized that l-Arg stimulates GH release by lowering hypothalamic somatostatin (SST) tone. l-Arg may also act directly at the pituitary to stimulate GH release. Moreover, l-Arg has a direct stimulatory effect on β-cells, which is thought to be blunted by the release of SST from pancreatic δ-cells. To confirm the role of endogenous SST on l-Arg-induced GH and insulin release, wild-type (WT) and SST-knockout (SST-KO) mice were injected with l-Arg (ip; 0.8 g/kg), and pre-/post-injection GH, insulin, and glucose levels were measured. In WT mice, l-Arg evoked a 6-fold increase in circulating GH. However, there was only a modest increase in GH levels in WT pituitary cell cultures treated with l-Arg. In contrast, l-Arg failed to increase GH in SST-KO beyond their already elevated levels. These results further support the hypothesis that the primary mechanism by which l-Arg acutely increases GH in vivo is by lowering hypothalamic SST input to the pituitary and not via direct pituitary effects. Additionally, l-Arg induced a clear first-phase insulin secretion in WT mice, but not in SST-KO. However, SST-KO, but not WT mice, displayed a robust and sustained second-phase insulin release. These results further support a role for endogenous SST in regulating l-Arg-mediated insulin release.

  5. Low Power CMOS Analog Multiplier

    Directory of Open Access Journals (Sweden)

    Shipra Sachan


    Full Text Available In this paper Low power low voltage CMOS analog multiplier circuit is proposed. It is based on flipped voltage follower. It consists of four voltage adders and a multiplier core. The circuit is analyzed and designed in 0.18um CMOS process model and simulation results have shown that, under single 0.9V supply voltage, and it consumes only 31.8µW quiescent power and 110MHZ bandwidth.

  6. A global analog of Cheshire charge

    CERN Document Server

    McGraw, P


    It is shown that a model with a spontaneously broken global symmetry can support defects analogous to Alice strings, and a process analogous to Cheshire charge exchange can take place. A possible realization in superfluid He-3 is pointed out.

  7. Investigating visual analogies for visual insight problems


    Corina Sas; Eric Luchian; Linden Ball


    Much research has focused on the impact of analogies in insight problem solving, but less work has investigated how the visual analogies for insight are actually constructed. Thus, it appears that in the search for their facilitative impact on the incubation effect, the understanding of what makes good visual analogies has somehow been lost. This paper presents preliminary work of constructing a set of 6 visual analogies and evaluating their impact on solving the visual problem of eight coins...

  8. Distribution of growth hormone-like immunoreactive cells and somatostatin receptors in the nervous system and Hatschek's pit of amphioxus, Branchiostoma belcheri

    Institute of Scientific and Technical Information of China (English)


    Using immunohistochemical method and double staining technique, the localization of growth hormone (GH) and somatostatin receptors in the nervous system and Hatschek's pit of amphioxus has been investigated. The results showed that the growth hormone-like nerve cells and endocrine cells as well as three subtypes-of somatostatin receptors exist in the nervous system and Hatschek's pit, and GH-like nerve cells and endocrine cells co-exist with three subtypes of somatostatin receptors in the brain vesicle and Hatschek's pit. It is suggested that a primitive control system of inhibitory growth hormone secretion in Hatschek's pit could have been developed in amphioxus, as in vertebrates. The present study provides new evidence for the endocrinology and the evolution of Hatschek's pit.

  9. Hegel, Analogy, and Extraterrestrial Life (United States)

    Ross, Joseph T.

    Georg Wilhelm Friedrich Hegel rejected the possibility of life outside of the Earth, according to several scholars of extraterrestrial life. Their position is that the solar system and specifically the planet Earth is the unique place in the cosmos where life, intelligence, and rationality can be. The present study offers a very different interpretation of Hegel's statements about the place of life on Earth by suggesting that, although Hegel did not believe that there were other solar systems where rationality is present, he did in fact suggest that planets in general, not the Earth exclusively, have life and possibly also intelligent inhabitants. Analogical syllogisms are superficial, according to Hegel, insofar as they try to conclude that there is life on the Moon even though there is no evidence of water or air on that body. Similar analogical arguments for life on the Sun made by Johann Elert Bode and William Herschel were considered by Hegel to be equally superficial. Analogical arguments were also used by astronomers and philosophers to suggest that life could be found on other planets in our solar system. Hegel offers no critique of analogical arguments for life on other planets, and in fact Hegel believed that life would be found on other planets. Planets, after all, have meteorological processes and therefore are "living" according to his philosophical account, unlike the Moon, Sun, and comets. Whereas William Herschel was already finding great similarities between the Sun and the stars and had extended these similarities to the property of having planets or being themselves inhabitable worlds, Hegel rejected this analogy. The Sun and stars have some properties in common, but for Hegel one cannot conclude from these similarities to the necessity that stars have planets. Hegel's arguments against the presence of life in the solar system were not directed against other planets, but rather against the Sun and Moon, both of which he said have a different

  10. Somatostatin receptor scintigraphy to predict the clinical evolution and therapeutic response of thyroid-associated ophthalmopathy

    Energy Technology Data Exchange (ETDEWEB)

    Nocaudie, M.; Bailliez, A.; Itti, E. [Centre Hospitalier Regional et Universitaire, Lille (France). Service Central de Medecine Nucleaire et Imagerie Fonctionnelle; Bauters, C.; Wemeau, J.L. [Clinique d`Endocrinologie, Centre Hospitalier Regional et Universitaire de Lille (France); Marchandise, X.


    Management of thyroid-associated ophthalmopathy remains a topic of controversy. Immunosuppressive treatments have to be applied at peak disease activity and before criteria of severity develop. Expression of somatostatin receptors on activated lymphocytes allows scintigraphic imaging with indium-111 pentetreotide. We conducted a prospective study with 17 patients who presented severe ophthalmopathy (11 Graves` disease, four Hashimoto`s thyroiditis, two isolated in appearance: Means` syndrome). Each patient underwent hormonal (free T{sub 3} and TSH) and immunological (TBII) assessment, an orbital computed tomography scan or magnetic resonance imaging, a visual functional examination and {sup 111}In-pentetreotide orbital scintigraphy before undergoing treatment by steroids and/or radiotherapy, independently of scintigraphic results. At 4 and 24 h after the intravenous injection of 111 MBq of {sup 111}In-pentetreotide, planar imaging centred on the head and neck (anterior and both lateral views) was carried out. Retrobulbar uptake was assessed by visual semi-quantitative analysis (score given by two independent trained observers) and by quantitative analyses (regions of interest, orbit/brain uptake indices). Patients were ophthalmologically followed up for 6 months and then classified as improved or not. Visual semi-quantitative analysis of 4-h/24-h planar images was correlated with the ophthalmological evolution ({chi}{sup 2} test, P<0.01). All ten patients in whom scintigraphy was considered positive were clinically improved at 6 months, and of the seven patients in whom scintigraphy was negative, six were not improved. Nevertheless, objective quantitative analysis did not succeed in confirming these results. We conclude that {sup 111}In-pentetreotide scintigraphy requires further developments, including quantitative single-photon emission tomographic acquisition, if its role as a guide to therapeutic strategy in thyroid-associated ophthalmopathy is to be confirmed

  11. Somatostatin analogues increase AIP expression in somatotropinomas, irrespective of Gsp mutations. (United States)

    Jaffrain-Rea, Marie-Lise; Rotondi, Sandra; Turchi, Annarita; Occhi, Gianluca; Barlier, Anne; Peverelli, Erika; Rostomyan, Lilya; Defilles, Céline; Angelini, Mariolina; Oliva, Maria-Antonietta; Ceccato, Filippo; Maiorani, Orlando; Daly, Adrian F; Esposito, Vincenzo; Buttarelli, Francesca; Figarella-Branger, Dominique; Giangaspero, Felice; Spada, Anna; Scaroni, Carla; Alesse, Edoardo; Beckers, Albert


    Germline aryl hydrocarbon receptor interacting protein (AIP) gene mutations confer a predisposition to pituitary adenoma (PA), predominantly GH-secreting (GH-PA). As recent data suggest a role for AIP in the pathogenesis of sporadic GH-PA and their response to somatostatin analogues (SSA), the expression of AIP and its partner, aryl hydrocarbon receptor (AHR), was determined by semiquantitative immunohistochemistry scoring in 62 sporadic GH-PA (37 treated with SSA preoperatively). The influence of Gsp status was studied in a subset of tumours (n=39, 14 Gsp(+)) and six GH-PA were available for primary cultures. AIP and AHR were detected in most cases, with a positive correlation between AIP and cytoplasmic AHR (P=0.012). Low AIP expression was significantly more frequent in untreated vs SSA-treated tumours (44.0 vs 20.5%, P=0.016). AHR expression or localisation did not differ between the two groups. Similarly, in vitro octreotide induced a median twofold increase in AIP expression (range 1.2-13.9, P=0.027) in GH-PA. In SSA-treated tumours, the AIP score was significantly higher in the presence of preoperative IGF1 decrease or tumour shrinkage (P=0.008 and P=0.014 respectively). In untreated tumours, low AIP expression was significantly associated with invasiveness (P=0.028) and suprasellar extension (P=0.019). The only effect of Gsp status was a significantly lower nuclear AHR score in Gsp(+) vs Gsp(-) tumours (P=0.025), irrespective of SSA. In conclusion, AIP is involved in the aggressiveness of sporadic GH-PA, regardless of Gsp status, and AIP up-regulation in SSA-treated tumours is associated with a better preoperative response, with no clear role for AHR.

  12. [Bronchial carcinoid tumor and scintigraphy of somatostatin receptors: detection of bone metastasis]. (United States)

    Banzo, J; Abós, M D; Prats, E; García, F; Freile, E; Razola, P; Escalera, T


    Surgery is the treatment of choice for bronchial carcinoid tumor (BCT), whenever the staging is adequate. There is little information about the capability of the somatostatin receptor scintigraphy (SRS) to detect bone metastases in the carcinoid tumor. This work has aimed to evaluate retrospectively the diagnostic accuracy of the SRS in the detection of bone metastases in BCT. Based on their clinical indication, the patients were classified into two different groups: Group A (n = 4), staging of a known BCT; and Group B (n = 6), treatment control. The SRS results could be correlated with the CT results in all 4 patients from the group A, and in one patient from the group B, and the SRS results were compared with the clinical follow up during at least one year in the other 5 patients. The SRS scan detected the 4 BCT from the group A; in 2 of them the patient staging was superior when the SRS was used than with the CT, whereas the scan overestimated the tumor stage (BCT + sarcoidosis) in another patient. During the clinical course, one of these patients developed bone and liver metastases. The SRS was normal in 5 asymptomatic patients from group B, whereas the scan showed disseminated metastatic disease (liver, bone, spleen and lymph nodes) in another patient. In the 2 patients with bone metastases, the total number of bone metastases detected by the bone scan was 12, and by the SRS 8. The four lesions that were not detected by SRS were located in the ribs (n = 3) and 12-D (n = 1). The capability of the SRS to detect bone metastases makes it more useful in BCT staging. Over the next few years, the role of the bone scan and SRS in the detection of bone metastases in carcinoid tumors needs to be established.

  13. Gallium-68 DOTATOC PET/CT in vivo characterization of somatostatin receptor expression in the prostate. (United States)

    Todorović-Tirnanić, Mila V; Gajić, Milan M; Obradović, Vladimir B; Baum, Richard P


    The aim was to investigate somatostatin receptor (sstr) expression in normal prostate by determining the maximum standardized uptake value (SUVmax) of (68)Ga-DOTATOC PET/CT in neuroendocrine tumor (NET) patients, without NET involvement of the prostate gland, for establishing the reference standard. Sixty-four NET patients underwent (68)Ga-DOTATOC PET/CT. SUVmax of the prostate gland, normal liver, testes, and gluteus muscles were evaluated. The prostate gland size was measured. Statistical analysis was performed using dedicated software (SPSS13). Mean/median (68)Ga-DOTATOC SUVmax values were as follows: normal prostate 2.6 ± 0.0, slightly enlarged prostate 4.2 ± 1.6, prostatic hypertrophy 4.9 ± 1.6, prostatic hyperplasia 5.0 ± 1.5, prostate cancer 9.5 ± 2.1, normal liver 7.3 ± 1.8, testes 1.8 ± 0.5, and gluteus 1.0 ± 0.2. The normal prostate gland had three times less sstr expression than normal liver tissue. Strong correlation was found between patient age and sstr expression in prostate/prostate size. No significant difference existed in sstr expression between prostatic hypertrophy and hyperplasia. Much higher sstr expression was found in prostatic cancer compared with normal prostate. (68)Ga-DOTATOC PET/CT defines the baseline sstr uptake in prostate not affected by NET (significantly lower than in the liver). Higher values were established in prostatic hyperplasia and hypertrophy. Only concomitant prostate cancer was associated with higher SUVmax in comparison with non-neoplastic liver.

  14. K(+) channel expression distinguishes subpopulations of parvalbumin- and somatostatin-containing neocortical interneurons. (United States)

    Chow, A; Erisir, A; Farb, C; Nadal, M S; Ozaita, A; Lau, D; Welker, E; Rudy, B


    Kv3.1 and Kv3.2 K(+) channel proteins form similar voltage-gated K(+) channels with unusual properties, including fast activation at voltages positive to -10 mV and very fast deactivation rates. These properties are thought to facilitate sustained high-frequency firing. Kv3.1 subunits are specifically found in fast-spiking, parvalbumin (PV)-containing cortical interneurons, and recent studies have provided support for a crucial role in the generation of the fast-spiking phenotype. Kv3.2 mRNAs are also found in a small subset of neocortical neurons, although the distribution of these neurons is different. We raised antibodies directed against Kv3.2 proteins and used dual-labeling methods to identify the neocortical neurons expressing Kv3.2 proteins and to determine their subcellular localization. Kv3.2 proteins are prominently expressed in patches in somatic and proximal dendritic membrane as well as in axons and presynaptic terminals of GABAergic interneurons. Kv3.2 subunits are found in all PV-containing neurons in deep cortical layers where they probably form heteromultimeric channels with Kv3.1 subunits. In contrast, in superficial layer PV-positive neurons Kv3.2 immunoreactivity is low, but Kv3.1 is still prominently expressed. Because Kv3.1 and Kv3.2 channels are differentially modulated by protein kinases, these results raise the possibility that the fast-spiking properties of superficial- and deep-layer PV neurons are differentially regulated by neuromodulators. Interestingly, Kv3. 2 but not Kv3.1 proteins are also prominent in a subset of seemingly non-fast-spiking, somatostatin- and calbindin-containing interneurons, suggesting that the Kv3.1-Kv3.2 current type can have functions other than facilitating high-frequency firing.

  15. Renal response to intravenous somatostatin in insulin-dependent diabetic patients and normal subjects

    Energy Technology Data Exchange (ETDEWEB)

    Vora, J.; Owens, D.R.; Luzio, S.; Atiea, J.; Ryder, R.; Hayes, T.M.


    The acute effects of iv somatostatin (SRIH; 100 micrograms/h) on the urinary flow (Uvol), effective renal plasma flow (RPF), and glomerular filtration rate (GFR) were compared with those of a control infusion of 0.15 M NaCl in nine insulin-dependent diabetic (IDD) patients of less than 10 yr disease duration and six normal subjects (NS). RPF and GFR were measured using a standard primed constant isotope infusion of (/sup 125/I)iodohippurate and (51Cr)chromium EDTA. Uvol, RPF, and GFR were measured during 20-min clearance periods. During the NaCl infusion mean Uvol, RPF, and GFR were 14.1 +/- 0.2 (+/- SEM), 708 +/- 4, and 150 +/- 1 mL/min in the IDD group and 12.7 +/- 0.4, 568 +/- 5, and 110 +/- 2 mL/min in the NS group, respectively. In the IDD patients Uvol, RPF, and GFR decreased from 16.6 +/- 1.8, 670 +/- 30, 146 +/- 4 mL/min pre-SRIH to 9.2 +/- 1, 553 +/- 25 (P less than 0.001), and 130 +/- 5 mL/min, respectively, at 120 min during the SRIH infusion. Similarly, in the NS group mean Uvol, RPF, and GFR were 14.2 +/- 0.6, 552 +/- 15, and 112 +/- 5 mL/min pre-SRIH and decreased to 7.4 +/- 0.6, 422 +/- 7, and 93 +/- 3 mL/min, respectively, after 120 min of the SRIH infusion. SRIH, therefore, had a profound effect on renal function in both IDD patients and NS, resulting in a reduction in RPF, GFR, and, as a consequence, Uvol.

  16. Attitudes and preferences in patients with acromegaly on long-term treatment with somatostatin analogues

    Directory of Open Access Journals (Sweden)

    Cecilia Follin


    Full Text Available Introduction: Patients with acromegaly can be treated with surgery, medical therapy and/or radiation therapy. For the patients not being cured with surgery, treatment with somatostatin analogues (SSAs is the primary therapy. SSA can be taken by self- or partner-administered injections in addition to being given by a nurse at a clinic. The aim was to assess if patients with acromegaly prefer self-injections and to investigate their attitudes towards long-term medical therapy. Method: All patients in the southern medical region of Sweden with a diagnosis of acromegaly and treated with SSA were eligible for the study (n = 24. The study is based on a questionnaire asking about the patients’ attitudes and preferences for injections with SSA, including their attitudes towards self-injection with SSA. Results: The patients’ (23 included median age was 68.5 years and the patients had been treated with SSA for 13 (1–38 years. One patient was currently self-injecting. All of the other patients were receiving injections from a nurse at a clinic. Three patients preferred self-injections, one preferred partner injections and 19 patients did not prefer self- or partner injections. The most frequent arguments to not preferring self-injections were ‘feeling more secure with an educated nurse’ and ‘preferring regular contact with a specialised nurse’. Conclusion: Patients with acromegaly prefer regular contact with the endocrine team to the independence offered by self-injections. These findings might mirror the patients’ desires for continuity and safety. We need to address patients’ concerns regarding injections with SSA and support them in their choices.

  17. Multiparametric PET imaging in thyroid malignancy characterizing tumour heterogeneity: somatostatin receptors and glucose metabolism

    Energy Technology Data Exchange (ETDEWEB)

    Traub-Weidinger, Tatjana [Medical University of Vienna, Division of Nuclear Medicine, Department of Biomedical Imaging and Image-guided Therapy, Vienna (Austria); Medical University of Innsbruck, Department of Nuclear Medicine, Innsbruck (Austria); Putzer, Daniel; Bale, Reto [Medical University of Innsbruck, Department of Radiology, Innsbruck (Austria); Guggenberg, Elisabeth von; Dobrozemsky, Georg; Nilica, Bernhard; Kendler, Dorota; Virgolini, Irene Johanna [Medical University of Innsbruck, Department of Nuclear Medicine, Innsbruck (Austria)


    Radiolabelled somatostatin (SST) analogues have proven useful in diagnosing tumours positive for SST receptor (SSTR). As different subtypes of SSTR are expressed on the tumour cell surface, the choice of appropriate therapeutic SST analogue is crucial. We evaluated the SSTR status of thyroid cancer patients who had signs of progressive disease comparing different SSTR ligands for PET imaging to evaluate possible further therapeutic options. PET with {sup 68}Ga-radiolabelled SSTR ligands DOTA lanreotide (DOTA-LAN), DOTA-Tyr{sup 3} octreotide (DOTA-TOC) and {sup 18}F-FDG was performed in 31 patients with thyroid cancer (TC). These 31 patients comprised 18 with radioiodine non-avid differentiated TC (DTC) including 6 papillary TC (PTC), 8 follicular TC (FTC) and 4 oxyphilic TC (oxyTC), 5 with anaplastic TC (ATC), and 8 with medullary TC (MTC). The PET results were compared in a region-based evaluation. All patients underwent a PET study with {sup 68}Ga-DOTA-LAN, 28 patients with {sup 68}Ga-DOTA-TOC and 28 patients with {sup 18}F-FDG. A lack of SSTR expression was found in 13 of the 31 patients (42 %) with negative results with both SSTR tracers in 12 patients. Ambiguous results with both SSTR tracers were observed in one patient. High tracer uptake in SSTR PET images was seen in seven DTC patients (39 %; two PTC, three FTC, two oxyTC), in four ATC patients (80 %) and in six MTC patients (75 %). Lesions showing aerobic glycolysis on {sup 18}F-FDG PET were found in 24 of 28 patients (86 %) with corresponding positive results with {sup 68}Ga-DOTA-LAN in 35 % and with {sup 68}Ga-DOTA-TOC in 29 %. The heterogeneous SSTR profile of TC tumour lesions needs to be evaluated using different SSTR PET tracers to characterize more closely the SSTR subtype affinities in patients with progressive TC in order to further stratify therapy with SSTR therapeutics. (orig.)

  18. Topography of somatostatin gene expression relative to molecular progenitor domains during ontogeny of the mouse hypothalamus

    Directory of Open Access Journals (Sweden)

    Nicanor eMorales-Delgado


    Full Text Available The hypothalamus comprises alar, basal and floor plate developmental compartments. Recent molecular data support a rostro-caudal subdivision into rostral (terminal and caudal (peduncular halves. In this context, the distribution of neuronal populations expressing somatostatin (Sst mRNA was analyzed in the developing mouse hypothalamus, comparing with the expression pattern of the genes Orthopedia (Otp, Distal-less 5 (Dlx5, Sonic Hedgehog (Shh and Nk2 homeobox 1 (Nkx2.1. At embryonic day 10.5 (E10.5, Sst mRNA was first detectable in the anterobasal nucleus, a Nkx2.1-, Shh- and Otp- positive basal domain. By E13.5, nascent Sst expression was also related to two additional Otp-positive domains within the alar plate and one in the basal plate. In the alar plate, Sst-positive cells were observed in rostral and caudal ventral subdomains of the Otp-positive paraventricular complex. An additional basal Sst-expressing cell group was found within a longitudinal Otp-positive periretromamillary band that separates the retromamillary area from tuberal areas. Apart of subsequent growth of these initial populations, at E13.5 and E15.5 some Sst-positive derivatives migrate tangentially into neighboring regions. A subset of cells produced at the anterobasal nucleus disperses ventralwards into the shell of the ventromedial hypothalamic nucleus and the arcuate nucleus. Cells from the rostroventral paraventricular subdomain reach the suboptic nucleus, whereas a caudal contingent migrates radially into lateral paraventricular, perifornical and entopeduncular nuclei. Our data provide a topologic map of molecularly-defined progenitor areas originating a specific neuron type during early hypothalamic development. Identification of four main separate sources helps to understand causally its complex adult organization.

  19. Diversity and overlap of Parvalbumin and Somatostatin expressing interneurons in mouse presubiculum

    Directory of Open Access Journals (Sweden)

    Mérie eNassar


    Full Text Available The presubiculum, located between hippocampus and entorhinal cortex, plays a fundamental role in representing spatial information, notably head direction. Little is known about GABAergic interneurons of this region. Here, we used three transgenic mouse lines, Pvalb-Cre, Sst-Cre and X98, to examine distinct interneurons labeled with tdTomato or green fluorescent protein. The distribution of interneurons in presubicular lamina for each animal line was compared to that in the GAD67-GFP knock-in animal line. Labelling was specific in the Pvalb-Cre line with 87% of labeled interneurons immunopositive for (PV. Immunostaining for somatostatin (SOM revealed good specificity in the X98 line with 89% of fluorescent cells, but a lesser specificity in Sst-Cre animals where only 71% of labeled cells were immunopositive. A minority of ~ 6% of interneurons co-expressed PV and SOM in the presubiculum of Sst-Cre animals. The electrophysiological and morphological properties of fluorescent interneurons from Pvalb-Cre, Sst-Cre and X98 mice differed. Distinct physiological groups of presubicular interneurons were resolved by unsupervised cluster analysis of parameters describing passive properties, firing patterns and AP shapes. One group consisted of SOM-positive, Martinotti type neurons with a low firing threshold (cluster 1. Fast spiking basket cells, mainly from the Pvalb-Cre line, formed a distinct group (cluster 3. Another group (cluster 2 contained interneurons of intermediate electrical properties and basket-cell like morphologies. These labeled neurons were recorded from both Sst-Cre and Pvalb-Cre animals. Thus, our results reveal a wide variation in anatomical and physiological properties for these interneurons, a real overlap of interneurons immuno-positive for both PV and SOM as well as an off-target recombination in the Sst-Cre line, possibly linked to maternal cre inheritance.

  20. Diversity and overlap of parvalbumin and somatostatin expressing interneurons in mouse presubiculum. (United States)

    Nassar, Mérie; Simonnet, Jean; Lofredi, Roxanne; Cohen, Ivan; Savary, Etienne; Yanagawa, Yuchio; Miles, Richard; Fricker, Desdemona


    The presubiculum, located between hippocampus and entorhinal cortex, plays a fundamental role in representing spatial information, notably head direction. Little is known about GABAergic interneurons of this region. Here, we used three transgenic mouse lines, Pvalb-Cre, Sst-Cre, and X98, to examine distinct interneurons labeled with tdTomato or green fluorescent protein. The distribution of interneurons in presubicular lamina for each animal line was compared to that in the GAD67-GFP knock-in animal line. Labeling was specific in the Pvalb-Cre line with 87% of labeled interneurons immunopositive for parvalbumin (PV). Immunostaining for somatostatin (SOM) revealed good specificity in the X98 line with 89% of fluorescent cells, but a lesser specificity in Sst-Cre animals where only 71% of labeled cells were immunopositive. A minority of ∼6% of interneurons co-expressed PV and SOM in the presubiculum of Sst-Cre animals. The electrophysiological and morphological properties of fluorescent interneurons from Pvalb-Cre, Sst-Cre, and X98 mice differed. Distinct physiological groups of presubicular interneurons were resolved by unsupervised cluster analysis of parameters describing passive properties, firing patterns and AP shapes. One group consisted of SOM-positive, Martinotti type neurons with a low firing threshold (cluster 1). Fast spiking basket cells, mainly from the Pvalb-Cre line, formed a distinct group (cluster 3). Another group (cluster 2) contained interneurons of intermediate electrical properties and basket-cell like morphologies. These labeled neurons were recorded from both Sst-Cre and Pvalb-Cre animals. Thus, our results reveal a wide variation in anatomical and physiological properties for these interneurons, a real overlap of interneurons immuno-positive for both PV and SOM as well as an off-target recombination in the Sst-Cre line, possibly linked to maternal cre inheritance.

  1. Biokinetics and imaging with the somatostatin receptor PET radioligand {sup 68}Ga-DOTATOC: preliminary data

    Energy Technology Data Exchange (ETDEWEB)

    Hofmann, M.; Boerner, A.R.; Weckesser, E.; Oei, M.L.; Meyer, G.J.; Knapp, W.H. [Dept. of Nuclear Medicine, Hannover University Medical School (Germany); Maecke, H.; Heppeler, A. [Dept. of Radiology, Kantonspittal, Basel (Switzerland); Schoeffski, P. [Dept. of Haematology and Oncology, Hannover University Medical School (Germany); Schumacher, J.; Henze, M. [German Cancer Research Centre, Heidelberg (Germany)


    Somatostatin (SMS) scintigraphy is widely used for the detection and staging of neuroendocrine tumours. Because of its superior imaging properties, there is growing interest in the use of positron emission tomography (PET) technology for SMS scintigraphy. This study addressed the production of gallium-68 DOTATOC, its biokinetics and its clinical performance in detecting SMS-positive tumours and metastases. A preparation protocol was developed, yielding 40% overall incorporation of {sup 68}Ga into the peptide (DOTATOC). After column filtration, the radiochemical purity exceeded 98%. Eight patients with histologically verified carcinoid tumours were injected with 80-250 MBq of this tracer. PET acquisition was initiated immediately after administration and carried out until 3 h post injection. Images were quantitated using standardised uptake values and target to non-target ratios. Prior to {sup 68}Ga-DOTATOC PET, all patients underwent indium-111 octreotide planar and single-photon emission tomographic (SPET) imaging. Arterial activity elimination was bi-exponential, with half-lives of 2.0 ({+-}0.3) min and 48 ({+-}7) min. No radioactive metabolites were detected within 4 h in serum. Maximal tumour activity accumulation was reached 70{+-}20 min post injection. Kidney uptake averaged <50% compared with spleen uptake. Of 40 lesions predefined by computed tomography and/or magnetic resonance imaging, {sup 68}Ga-DOTATOC PET identified 100%, whereas {sup 111}In-octreotide planar and SPET imaging identified only 85%. Tumour to non-tumour ratios ranged from >3:1 for liver ({sup 111}In-octreotide: 1.5:1) to 100:1 for CNS ({sup 111}In-octreotide: 10:1). With {sup 68}Ga-DOTATOC >30% additional lesions were detected. It is concluded that PET using {sup 68}Ga-DOTATOC results in high tumour to non-tumour contrast and low kidney accumulation and yields higher detection rates as compared with {sup 111}In-octreotide scintigraphy. (orig.)

  2. Radial and tangential migration of telencephalic somatostatin neurons originated from the mouse diagonal area. (United States)

    Puelles, Luis; Morales-Delgado, N; Merchán, P; Castro-Robles, B; Martínez-de-la-Torre, M; Díaz, C; Ferran, J L


    The telencephalic subpallium is the source of various GABAergic interneuron cohorts that invade the pallium via tangential migration. Based on genoarchitectonic studies, the subpallium has been subdivided into four major domains: striatum, pallidum, diagonal area and preoptic area (Puelles et al. 2013; Allen Developing Mouse Brain Atlas), and a larger set of molecularly distinct progenitor areas (Flames et al. 2007). Fate mapping, genetic lineage-tracing studies, and other approaches have suggested that each subpallial subdivision produces specific sorts of inhibitory interneurons, distinguished by differential peptidic content, which are distributed tangentially to pallial and subpallial target territories (e.g., olfactory bulb, isocortex, hippocampus, pallial and subpallial amygdala, striatum, pallidum, septum). In this report, we map descriptively the early differentiation and apparent migratory dispersion of mouse subpallial somatostatin-expressing (Sst) cells from E10.5 onward, comparing their topography with the expression patterns of the genes Dlx5, Gbx2, Lhx7-8, Nkx2.1, Nkx5.1 (Hmx3), and Shh, which variously label parts of the subpallium. Whereas some experimental results suggest that Sst cells are pallidal, our data reveal that many, if not most, telencephalic Sst cells derive from de diagonal area (Dg). Sst-positive cells initially only present at the embryonic Dg selectively populate radially the medial part of the bed nucleus striae terminalis (from paraseptal to amygdaloid regions) and part of the central amygdala; they also invade tangentially the striatum, while eschewing the globus pallidum and the preoptic area, and integrate within most cortical and nuclear pallial areas between E10.5 and E16.5.

  3. Biokinetics and imaging with the somatostatin receptor PET radioligand (68)Ga-DOTATOC: preliminary data. (United States)

    Hofmann, M; Maecke, H; Börner, R; Weckesser, E; Schöffski, P; Oei, L; Schumacher, J; Henze, M; Heppeler, A; Meyer, J; Knapp, H


    Somatostatin (SMS) scintigraphy is widely used for the detection and staging of neuroendocrine tumours. Because of its superior imaging properties, there is growing interest in the use of positron emission tomography (PET) technology for SMS scintigraphy. This study addressed the production of gallium-68 DOTATOC, its biokinetics and its clinical performance in detecting SMS-positive tumours and metastases. A preparation protocol was developed, yielding 40% overall incorporation of (68)Ga into the peptide (DOTATOC). After column filtration, the radiochemical purity exceeded 98%. Eight patients with histologically verified carcinoid tumours were injected with 80-250 MBq of this tracer. PET acquisition was initiated immediately after administration and carried out until 3 h post injection. Images were quantitated using standardised uptake values and target to non-target ratios. Prior to (68)Ga-DOTATOC PET, all patients underwent indium-111 octreotide planar and single-photon emission tomographic (SPET) imaging. Arterial activity elimination was bi-exponential, with half-lives of 2.0 (+/-0.3) min and 48 (+/-7) min. No radioactive metabolites were detected within 4 h in serum. Maximal tumour activity accumulation was reached 70+/-20 min post injection. Kidney uptake averaged 68)Ga-DOTATOC PET identified 100%, whereas (111)In-octreotide planar and SPET imaging identified only 85%. Tumour to non-tumour ratios ranged from >3:1 for liver ((111)In-octreotide: 1.5:1) to 100:1 for CNS ((111)In-octreotide: 10:1). With (68)Ga-DOTATOC >30% additional lesions were detected. It is concluded that PET using (68)Ga-DOTATOC results in high tumour to non-tumour contrast and low kidney accumulation and yields higher detection rates as compared with (111)In-octreotide scintigraphy.

  4. Tumor-associated macrophages in glioblastoma multiforme-a suitable target for somatostatin receptor-based imaging and therapy?

    Directory of Open Access Journals (Sweden)

    Constantin Lapa

    Full Text Available Glioblastoma multiforme (GBM is the most common primary brain tumor in adults. Tumor-associated macrophages (TAM have been shown to promote malignant growth and to correlate with poor prognosis. [1,4,7,10-tetraazacyclododecane-NN',N″,N'″-tetraacetic acid]-d-Phe1,Tyr3-octreotate (DOTATATE labeled with Gallium-68 selectively binds to somatostatin receptor 2A (SSTR2A which is specifically expressed and up-regulated in activated macrophages. On the other hand, the role of SSTR2A expression on the cell surface of glioma cells has not been fully elucidated yet. The aim of this study was to non-invasively assess SSTR2A expression of both glioma cells as well as macrophages in GBM.15 samples of patient-derived GBM were stained immunohistochemically for macrophage infiltration (CD68, proliferative activity (Ki67 as well as expression of SSTR2A. Anti-CD45 staining was performed to distinguish between resident microglia and tumor-infiltrating macrophages. In a subcohort, positron emission tomography (PET imaging using 68Ga-DOTATATE was performed and the semiquantitatively evaluated tracer uptake was compared to the results of immunohistochemistry.The amount of microglia/macrophages ranged from 50% in the tumor samples with the vast majority being resident microglial cells. A strong SSTR2A immunostaining was observed in endothelial cells of proliferating vessels, in neurons and neuropile. Only faint immunostaining was identified on isolated microglial and tumor cells. Somatostatin receptor imaging revealed areas of increased tracer accumulation in every patient. However, retention of the tracer did not correlate with immunohistochemical staining patterns.SSTR2A seems not to be overexpressed in GBM samples tested, neither on the cell surface of resident microglia or infiltrating macrophages, nor on the surface of tumor cells. These data suggest that somatostatin receptor directed imaging and treatment strategies are less promising in GBM.

  5. Analogical Reasoning: A Review of the Literature. (United States)

    Dawis, Rene V.; Siojo, Luis T.

    The mathematical and philosophical origins of "analogy" are described and their influence on the thinking of intelligence theorists is traced. Theories of intelligence and cognition bearing on analogical reasoning are examined, specifically those of Spearman, Thorndike, Guilford and Piaget. The analogy test item is shown to be a paradigm…

  6. Reasoning by Analogy in Constructing Mathematical Ideas. (United States)

    English, Lyn D.

    A powerful way of understanding something new is by analogy with something already known. An analogy is defined as a mapping from one structure, which is already known (the base or source), to another structure that is to be inferred or discovered (the target). The research community has given considerable attention to analogical reasoning in the…

  7. Discovery of substituted (4-phenyl-1H-imidazol-2-yl)methanamine as potent somatostatin receptor 3 agonists. (United States)

    Lai, Zhong; He, Shuwen; Sherer, Edward C; Wu, Zhicai; Yu, Yang; Ball, Richard; Hong, Qingmei; Yang, David X; Guo, Liangqing; Li, Derun; Tuang, Quang; Chicchi, Gary G; Trusca, Dorina; Tsao, Kwei-Lan; Zhou, Yun-Ping; Howard, Andrew D; Nargund, Ravi P; Hagmann, William K


    We report SAR studies on a novel non-peptidic somatostatin receptor 3 (SSTR3) agonist lead series derived from (4-phenyl-1H-imidazol-2-yl)methanamine. This effort led to the discovery of a highly potent low molecular weight SSTR3 agonist 5c (EC50=5.2 nM, MW=359). The results from molecular overlays of 5c onto the L-129 structure indicate good alignment, and two main differences of the proposed overlays of the antagonist MK-4256 onto the conformation of 5c lead to inversion of antagonism to agonism. Copyright © 2015 Elsevier Ltd. All rights reserved.

  8. Differential sensitivity of growth hormone-releasing hormone and somatostatin release from perifused mouse hypothalamic fragments in response to glucose deficiency. (United States)

    Sato, M; Frohman, L A


    The effects of glucose deficiency on growth hormone (GH)-releasing hormone (GRH) and somatostatin (SRIH) release from mouse hypothalamic fragments were investigated using an in vitro perifusion system. Fragments were perifused with Krebs-Ringer bicarbonate solution (KRB) containing 5.6 mM glucose for 3 h followed by reduced glucose concentrations in KRB for the next 2 h. GRH release was simulated by 0.7-2.8 mM glucose in an inverse concentration-dependent manner. In contrast, SRIH release was not stimulated by glucose at concentrations of 2.8 and 1.4 mM; only at 0.7 mM was there a modest stimulation of SRIH release that was comparable to the effect of 2.8 mM glucose on GRH release. The maximal stimulation of GRH and SRIH release by 0.7 mM glucose was 221 and 150%, respectively, of controls. Glucose concentrations of 11.2 and 22.4 mM inhibited GRH release but did not alter SRIH release. The glucose analog 2-deoxy-D-glucose (2-DG; 5.6-39.2 mM) also stimulated GRH release in a dose-dependent manner, and SRIH release was less sensitive to 2-DG than was GRH. The maximal stimulation of GRH and SRIH release by 39.2 mM 2-DG was 190 and 147%, respectively, of controls. Increases in GRH and SRIH release stimulated by 30 mM KCl 1 h after exposure to low glucose or 2-DG were not significantly different from those after exposure to 5.6 mM glucose. However, the SRIH response to K(+)-induced depolarization was much greater than that of GRH. The glucose intermediate pyruvate (4.9 and 9.8 mM) partially inhibited both GRH and SRIH release induced by 0.7 mM glucose.(ABSTRACT TRUNCATED AT 250 WORDS)

  9. Are all analogies created equal? Prefrontal cortical functioning may predict types of analogical reasoning. (United States)

    Chrysikou, Evangelia G; Thompson-Schill, Sharon L


    Abstract The proposed theory can account for analogies based on learned relationships between elements in the source and target domains. However, its explanatory power regarding the discovery of new relationships during analogical reasoning is limited. We offer an alternative perspective for the role of PFC in analogical thought that may better address different types of analogical mappings.

  10. Analog and mixed-signal electronics

    CERN Document Server

    Stephan, Karl


    A practical guide to analog and mixed-signal electronics, with an emphasis on design problems and applications This book provides an in-depth coverage of essential analog and mixed-signal topics such as power amplifiers, active filters, noise and dynamic range, analog-to-digital and digital-to-analog conversion techniques, phase-locked loops, and switching power supplies. Readers will learn the basics of linear systems, types of nonlinearities and their effects, op-amp circuits, the high-gain analog filter-amplifier, and signal generation. The author uses system design examples to motivate

  11. Analog circuit design art, science, and personalities

    CERN Document Server

    Williams, Jim


    Analog Circuit Design: Art, Science, and Personalities discusses the many approaches and styles in the practice of analog circuit design. The book is written in an informal yet informative manner, making it easily understandable to those new in the field. The selection covers the definition, history, current practice, and future direction of analog design; the practice proper; and the styles in analog circuit design. The book also includes the problems usually encountered in analog circuit design; approach to feedback loop design; and other different techniques and applications. The text is

  12. Practical analog electronics for technicians

    CERN Document Server

    Kimber, W A


    'Practical Analog Electronics for Technicians' not only provides an accessible introduction to electronics, but also supplies all the problems and practical activities needed to gain hands-on knowledge and experience. This emphasis on practice is surprisingly unusual in electronics texts, and has already gained Will Kimber popularity through the companion volume, 'Practical Digital Electronics for Technicians'. Written to cover the Advanced GNVQ optional unit in electronics, this book is also ideal for BTEC National, A-level electronics and City & Guilds courses. Together with 'Practical Digit

  13. Transfer Between Analogies: How Solving One Analogy Problem Helps to Solve Another


    Keane, Mark T.


    This paper deals with transfer between analogies; with what people acquire from one analogy problem-solving episode that can be re-applied to a subsequent analogy, problem-solving episode. This issue must be resolved if we are to understand the nature of expertise and the appropriate use of analogy in education. There are two main explanations of what subjects acquire from an analogy problem-solving episode. The schema-induction hypothesis maintains that subjects acquire an abs...

  14. Analogies between optical and quantum mechanical angular momentum (United States)

    Nienhuis, Gerard


    The insight that a beam of light can carry orbital angular momentum (AM) in its propagation direction came up in 1992 as a surprise. Nevertheless, the existence of momentum and AM of an electromagnetic field has been well known since the days of Maxwell. We compare the expressions for densities of AM in general three-dimensional modes and in paraxial modes. Despite their classical nature, these expressions have a suggestive quantum mechanical appearance, in terms of linear operators acting on mode functions. In addition, paraxial wave optics has several analogies with real quantum mechanics, both with the wave function of a free quantum particle and with a quantum harmonic oscillator. We discuss how these analogies can be applied. This article is part of the themed issue 'Optical orbital angular momentum'.

  15. Analog-to-digital conversion

    CERN Document Server

    Pelgrom, Marcel J. M


    This textbook is appropriate for use in graduate-level curricula in analog to digital conversion, as well as for practicing engineers in need of a state-of-the-art reference on data converters.  It discusses various analog-to-digital conversion principles, including sampling, quantization, reference generation, nyquist architectures and sigma-delta modulation.  This book presents an overview of the state-of-the-art in this field and focuses on issues of optimizing accuracy and speed, while reducing the power level. This new, second edition emphasizes novel calibration concepts, the specific requirements of new systems, the consequences of 45-nm technology and the need for a more statistical approach to accuracy.  Pedagogical enhancements to this edition include more than twice the exercises available in the first edition, solved examples to introduce all key, new concepts and warnings, remarks and hints, from a practitioner’s perspective, wherever appropriate.  Considerable background information and pr...

  16. Reliability of analog quantum simulation

    Energy Technology Data Exchange (ETDEWEB)

    Sarovar, Mohan [Sandia National Laboratories, Digital and Quantum Information Systems, Livermore, CA (United States); Zhang, Jun; Zeng, Lishan [Shanghai Jiao Tong University, Joint Institute of UMich-SJTU, Key Laboratory of System Control and Information Processing (MOE), Shanghai (China)


    Analog quantum simulators (AQS) will likely be the first nontrivial application of quantum technology for predictive simulation. However, there remain questions regarding the degree of confidence that can be placed in the results of AQS since they do not naturally incorporate error correction. Specifically, how do we know whether an analog simulation of a quantum model will produce predictions that agree with the ideal model in the presence of inevitable imperfections? At the same time there is a widely held expectation that certain quantum simulation questions will be robust to errors and perturbations in the underlying hardware. Resolving these two points of view is a critical step in making the most of this promising technology. In this work we formalize the notion of AQS reliability by determining sensitivity of AQS outputs to underlying parameters, and formulate conditions for robust simulation. Our approach naturally reveals the importance of model symmetries in dictating the robust properties. To demonstrate the approach, we characterize the robust features of a variety of quantum many-body models. (orig.)

  17. Somatostatin and opioid receptors do not regulate proliferation or apoptosis of the human multiple myeloma U266 cells

    Directory of Open Access Journals (Sweden)

    Allouche Stéphane


    Full Text Available Abstract Background opioid and somatostatin receptors (SSTRs that can assemble as heterodimer were individually reported to modulate malignant cell proliferation and to favour apoptosis. Materials and methods: SSTRs and opioid receptors expression were examined by RT-PCR, western-blot and binding assays, cell proliferation was studied by XTT assay and propidium iodide (PI staining and apoptosis by annexin V-PI labelling. Results almost all human malignant haematological cell lines studied here expressed the five SSTRs. Further experiments were conducted on the human U266 multiple myeloma cells, which express also μ-opioid receptors (MOP-R. XTT assays and cell cycle studies provide no evidence for a significant effect upon opioid or somatostatin receptors stimulation. Furthermore, neither direct effect nor potentiation of the Fas-receptor pathway was detected on apoptosis after these treatments. Conclusion these data suggest that SSTRs or opioid receptors expression is not a guaranty for an anti-tumoral action in U266 cell line.

  18. Parvalbumin, somatostatin and cholecystokinin as chemical markers for specific GABAergic interneuron types in the rat frontal cortex. (United States)

    Kawaguchi, Yasuo; Kondo, Satoru


    It remains to be clarified how many classes of GABAergic nonpyramidal cells exist in the cortical circuit. We have divided GABA cells in the rat frontal cortex into 3 groups, based on their firing characteristics: fast-spiking (FS) cells, late-spiking (LS) cells, and non-FS cells. Expression of calcium-binding proteins and peptides could be shown in separate groups of GABA cells in layers II/III and V of the frontal cortex: (1) parvalbumin cells, (2) somatostatin cells, (3) calretinin and/or vasoactive intestinal polypeptide (VIP) cells [partially positive for cholecystokinin (CCK)] and (4) large CCK cells (almost negative for VIP/calretinin). Combining the physiological and chemical properties of morphologically diverse nonpyramidal cells allows division into several groups, including FS basket cells containing parvalbumin, non-FS somatostatin Martinotti cells with ascending axonal arbors, and non-FS large basket cells positive for CCK. These subtypes show characteristic spatial distributions of axon collaterals and the innervation tendency of postsynaptic elements. With synchronized activity induced by cortical excitatory or inhibitory circuits, firing patterns were also found to differ. Subtype-selective occurrence of electrical coupling, finding for potassium channel Kv3.1 proteins, and cholinergic and serotonergic modulation supports our tentative classification. To clarify the functional architecture in the frontal cortex, it is important to reveal the connectional characteristics of GABA cell subtypes and determine whether they are similar to those in other cortical regions.

  19. Relationship between expression of somatostatin receptors subtype 2 mRNA and estrogen and progesterone receptors in breast cancer

    Institute of Scientific and Technical Information of China (English)

    曾希志; 姚榛祥


    Objectives To observe the expression of somatostatin receptor subtype 2 (SSTR2) mRNA, and investigate the relationship between the expression of SSTR2 mRNA and the expressions of estrogen and progesterone receptors (ERs and PRs) in benign and malignant breast tissues.Methods Samples from a total of 23 breast carcinomas, 16 mammary hyperplasias, and 9 mammary fibroadenomas were analyzed. SSTR2 mRNA expression was examined by in situ hybridization using multiphase oligoprobes. ER and PR expressions were detected by immunohistochemical staining. A computerized image analysis system was utilized to estimate the relative content of SSTR2 mRNA.Results The rate of expression (87.0%) and relative content (0.47) of SSTR2 mRNA in breast cancer were higher than those in benign breast tissue (64%,0.26) (P<0.05). SSTR2 mRNA expression was closely correlated with ER and PR expressions in breast cancer (P<0.05). SSTR2 mRNA was also positively correlated with ER expression in benign breast tissues.Conclusions SSTR2 mRNA expression is higher or in benign breast tissues than in malignant ones. There is a significant positive correlation between SSTR2 mRNA and ER and PR expressions. Combined antiestrogen and somatostatin analogue in treatment of ER-positive breast cancers should be further investigated.

  20. Regulation of oxidative stress and somatostatin, cholecystokinin, apelin gene expressions by ghrelin in stomach of newborn diabetic rats. (United States)

    Coskun, Zeynep Mine; Sacan, Ozlem; Karatug, Ayse; Turk, Neslihan; Yanardag, Refiye; Bolkent, Sehnaz; Bolkent, Sema


    The aim of the study was to determine whether ghrelin treatment has a protective effect on gene expression and biochemical changes in the stomach of newborn streptozotocin (STZ) induced diabetic rats. In this study, four groups of Wistar rats were used: control, ghrelin control, diabetic and diabetic+ghrelin. The rats were sacrificed after four weeks of treatment for diabetes. The gene expressions of: somatostatin, cholecystokinin, apelin and the altered active caspase-3, active caspase-8, proliferating cell nuclear antigen, were investigated in the pyloric region of the stomach and antioxidant parameters were measured in all the stomach. Although ghrelin treatment to diabetic rats lowered the stomach lipid peroxidation levels, the stomach glutathione levels were increased. Exogenous ghrelin caused an increased activities of stomach catalase, superoxide dismutase, glutathione reductase and glutathione peroxidase in diabetic rats. Numbers of somatostatin, cholecystokinin and proliferating cell nuclear antigen immunoreactive cells decreased in the diabetic+ghrelin group compared to the diabetic group. Apelin mRNA expressions were remarkably less in the diabetic+ghrelin rats than in diabetic rats. The results may indicate that ghrelin treatment has a protective effect to some extent on the diabetic rats. This protection is possibly accomplished through the antioxidant activity of ghrelin observed in type 2 diabetes. Consequently exogenous ghrelin may be a candidate for therapeutic treatment of diabetes. Copyright © 2013 Elsevier GmbH. All rights reserved.

  1. NMDAR hypofunction and somatostatin-expressing GABAergic interneurons and receptors: A newly identified correlation and its effects in schizophrenia

    Directory of Open Access Journals (Sweden)

    Fatemah Alherz


    Full Text Available This review investigates the association between N-methyl-d-Aspartate receptor (NMDAR hypofunction and somatostatin-expressing GABAergic interneurons (SST+ and how it contributes to the cognitive deficits observed in schizophrenia (SZ. This is based on evidence that NMDAR antagonists caused symptoms resembling SZ in healthy individuals. NMDAR hypofunction in GABAergic interneurons results in the modulation of the cortical network oscillation, particularly in the gamma range (30–80 Hz. These gamma-band oscillation (GBO abnormalities were found to lead to the cognitive deficits observed in the disorder. Postmortem mRNA studies have shown that SST decreased more significantly than any other biomarker in schizophrenic subjects. The functional role of Somatostatin (SST in the aetiology of SZ can be studied through its receptors. Genetic knockout studies in animal models in Huntington's disease (HD have shown that a specific SST receptor, SSTR2, is increased along with the increased NMDAR activity, with opposing patterns observed in SZ. A direct correlation between SSTR and NMDAR is hence inferred in this review with the hope of finding a potential new therapeutic target for the treatment of SZ and related neurological conditions.

  2. A structure-activity-relationship (SAR) study of somatostatin receptor-binding peptides radiolabeled with Tc-99m

    Energy Technology Data Exchange (ETDEWEB)

    Lister-James, J.; McBride, W.J.; Moyer, B.R. [Diatech, Inc, Londonderry, NH (United States)] [and others


    Somatostatin receptor (SSTR)-expressing tumors can be detected with high accuracy using In-111-[DTPA]octreotide. We sought a high-affinity SSTR-binding peptide labeled with the preferred radioisotope Tc-99m. We have prepared over 120 SSTR-binding peptides each containing a (N{sub 3}S or N{sub 2}S{sub 2}) chelator for Tc-99m in a SAR study in which peptide structure was systematically altered to optimize SSTR-binding affinity, in vivo rumor uptake and favorable biodistribution and pharmacokinetics. The HPLC-purified (>90% purity), chelator-containing peptides were characterized by FAB/ESMS and assayed in vitro for SSTR binding affinity by a competition assay (I-125 somatostatin-14 tracer and AR42J rat pancreatic tumor cell membranes). The oxo-rhenium complexes of the peptides were prepared by ligand exchange, characterized by FAB or ESMS and assayed for SSTR binding affinity as surrogates for the Tc-99m complexes. The Tc-99m complexes of peptides giving high-affinity oxo-rhenium complexes were also prepared by ligand exchange with specific activities of approx 300 mCi/mmol and examined in vivo for biodistribution and tumor uptake characteristics in CA20948 tumor-bearing rats.

  3. The production of somatostatin interneurons in the olfactory bulb is regulated by the transcription factor sp8.

    Directory of Open Access Journals (Sweden)

    Xuhua Jiang

    Full Text Available Somatostatin (Som, one of the most concentrated neuropeptides in the brain, is highly expressed in the olfactory bulb (OB. However, the temporal profile by which OB somatostatin-expressing (Som+ interneurons are produced and the molecular mechanisms controlling this profile are totally unknown. In the present study, we found that all the Som+ interneurons in the mouse external plexiform layer (EPL and the rat glomerular layer (GL express the transcription factor Sp8.Using the 5-bromo-2'-deoxyuridine (BrdU birth dating method, combined with immunostaining, we showed that the generation of Som+ interneurons in the mouse and rat OB is confined to the later embryonic and earlier postnatal stages. Within the mouse OB, the production of Som+ interneurons is maximal during late embryogenesis and decreases after birth, whereas the generation of Som+ interneurons is low during embryogenesis and increases gradually after birth in the rat OB. Interestingly, genetic ablation of Sp8 by cre/loxP-based recombination severely reduces the number of Som+ interneurons in the EPL of the mouse OB. Taken together, these results suggest that Sp8 is required for the normal production of Som+ interneurons in the EPL of the mouse OB.

  4. Hippocampal somatostatin receptors and modulation of adenylyl cyclase activity in histamine-treated rats. (United States)

    Puebla, L; Rodríguez-Martín, E; Arilla, E


    In the present study, the effects of an intracerebroventricular (i.c.v.) dose of histamine (0.1, 1.0 or 10.0 micrograms) on the hippocampal somatostatin (SS) receptor/effector system in Wistar rats were investigated. In view of the rapid onset of histamine action, the effects of histamine on the somatostatinergic system were studied 2 h after its administration. Hippocampal SS-like immunoreactivity (SSLI) levels were not modified by any of the histamine doses studied. SS-mediated inhibition of basal and forskolin (FK)-stimulated adenylyl cyclase (AC) activity was markedly increased in hippocampal membranes from rats treated with 10 micrograms of histamine (23% +/- 1% vs. 17% +/- 1% and 37% +/- 2% vs. 23% +/- 1%, respectively). In contrast, neither the basal nor the FK-stimulated enzyme activities were affected by histamine administration. The functional activity of the hippocampal guanine-nucleotide binding inhibitory protein (Gi protein), as assessed by the capacity of the stable GTP analogue 5'-guanylylimidodiphosphate (Gpp[NH]p) to inhibit FK-stimulated AC activity, was not modified by histamine administration. These data suggest that the increased response of the enzyme to SS was not related to an increased functional activity of Gi proteins. In fact, the increased AC response to SS in hippocampal membranes from histamine (10 micrograms)-treated rats was associated with quantitative changes in the SS receptors. Equilibrium binding data obtained with [125I]Tyr11-SS indicate an increase in the number with specific SS receptors (541 +/- 24 vs. 365 +/- 16 fmol/mg protein, P histamine (10 micrograms)-treated rats as compared to control animals. With the aim of determining if these changes were related to histamine binding to its specific receptor sites, the histaminergic H1 and H2 receptor antagonists mepyramine and cimetidine, respectively, were administered 1 h before histamine injection. The pretreatment with mepyramine or cimetidine induced an increase in the

  5. Gene transfer of somatostatin receptor type 2 by intratumoral injection inhibits established pancreatic carcinoma xenografts

    Institute of Scientific and Technical Information of China (English)

    Zhi-Yong Du; Ren-Yi Qin; Wei Xia; Rui Tian; Manoj Kumar


    AIM: To investigate the therapeutic effect of somatostatin receptor type 2 (SSTR2) gene transfection on pancreatic carcinoma xenograftsin vivo in experimental cancers.METHODS: Human pancreatic cancer cell line Panc-1 was inoculated subcutaneously into the back of nude mice. When tumor nodules were grown as large as about 5 mm×5 mm days after inoculation, the mice were randomly divided into 3 groups (6 mice in each group). Group Ⅰ served as untreated control group. Group Ⅱ received an intratumoral injection of a combination of human cytomegalovirus promoter-6C (pCMV-6C) and lipofectamine 2000. Group Ⅲ received an intratumoral injection of a combination of pCMV-6C-SSTR2 and lipofectamine 2000. The rate of tumor growth was compared among these three groups. The expression of SSTR2 in these tumors was detected by immunohistochemistry and Western-blot. Apoptosis index (AI) in these tumors was examined by using TUNEL in situ.RESULTS: Intratumoral injection of a combination of pCMV-6C-SSTR2 and lipofectamine 2000 resulted in the expression of SSTR2 protein. The tumor size and weight in group Ⅲ (0.318±0.098 cm3, and 0.523±0.090 g,respectively) were significantly lower than those in group Ⅰ (2.058±0.176 cm3, and 1.412±0.146 g, respectively) and group Ⅱ (2.025±0.163 cm3, and 1.365±0.116 g, respectively)(P<0.05) The AI in group Ⅲ (1.47±0.13%) was significantly higher than that in group Ⅰ (0.56±0.09%) and group Ⅱ (0.57±0.11%) (P<0.05). But there were no significant differences between groups Ⅰ and Ⅱ.CONCLUSION: Our data demonstrate that re-expression of SSTR2 gene has antitumor effects on experimental pancreatic cancer. Restoration of SSTR2 gene expression through gene transfer in vivo might be a potential gene therapy strategy for human pancreatic cancer.

  6. Balancing Acts (United States)

    ... Past Issues Special Section: Focus on Communication Balancing Acts Past Issues / Fall 2008 Table of Contents For ... scientific research on hearing, balance, smell, taste, voice, speech, and language—common elements in how we perceive ...

  7. Assessment of inflammatory mediator, intestinal flora and Fas/FasL expression in patients with acute pancreatitis after lactulose combined with somatostatin therapy

    Institute of Scientific and Technical Information of China (English)

    Bing-Li Zheng; Jie Peng; Aihemaitibaikere


    Objective:To study the effect of lactulose combined with somatostatin therapy on inflammatory mediator, intestinal flora and Fas/FasL expression in patients with acute pancreatitis.Methods:A total of 56 patients with acute pancreatitis treated in our hospital between May 2013 and October 2015 were randomly divided into group A and group B, group A received lactulose, somatostatin combined with conventional therapy and group B received somatostatin combined with conventional therapy. Three days after treatment, the levels of inflammatory mediators, sFas and sFasL in serum, the expression of Fas and FasL in peripheral blood as well as the copy number of intestinal flora in feces tissue were determined. Results:Three days after treatment, IL-1β, IL-6, IL-8, IL-10, IL-18, sFas and sFasL content in serum of group A were significantly lower than those of group B,FasandFasL mRNA content and protein content in peripheral blood were significantly lower than those of group B, lactobacillus, bifidobacterium and bacteroides content in feces tissue were significantly higher than those of group B, and Escherichia coli, enterococcus and proteus content in feces tissue were significantly lower than those of group B.Conclusions:Lactulose combined with somatostatin treatment of acute pancreatitis can improve the intestinal mucosal barrier function, correct intestinal flora disturbance, relieve inflammation and inhibit the immunosuppression mediated by Fas/FasL.

  8. Does somatostatin have a role in the regulation of cortisol secretion in primary pigmented nodular adrenocortical disease (PPNAD)? A clinical and in vitro investigation

    NARCIS (Netherlands)

    Z. Bram (Zakariae); P. Xekouki (Paraskevi); E. Louiset (Estelle); M. Keil (Mark); D. Avgeropoulos (Dimitrios); C. Giatzakis (Christoforos); M. Nesterova (Maria); N. Sinaii (Ninet); L.J. Hofland (Leo); R. Cherqaoui (Rabia); H. Lefebvre (Hervé); C.A. Stratakis (Constantine)


    textabstractContext: Somatostatin (SST) receptors (SSTRs) are expressed in a number of tissues, including the adrenal cortex, but their role in cortisol secretion has not been well characterized. Objectives: The objective of the study was to investigate the expression of SSTRs in the adrenal cortex

  9. Does somatostatin have a role in the regulation of cortisol secretion in primary pigmented nodular adrenocortical disease (PPNAD)? A clinical and in vitro investigation

    NARCIS (Netherlands)

    Z. Bram (Zakariae); P. Xekouki (Paraskevi); E. Louiset (Estelle); M. Keil (Mark); D. Avgeropoulos (Dimitrios); C. Giatzakis (Christoforos); M. Nesterova (Maria); N. Sinaii (Ninet); L.J. Hofland (Leo); R. Cherqaoui (Rabia); H. Lefebvre (Hervé); C.A. Stratakis (Constantine)


    textabstractContext: Somatostatin (SST) receptors (SSTRs) are expressed in a number of tissues, including the adrenal cortex, but their role in cortisol secretion has not been well characterized. Objectives: The objective of the study was to investigate the expression of SSTRs in the adrenal cortex

  10. Type 1 and 2 gastric carcinoid tumors: long-term follow-up of the efficacy of treatment with a slow-release somatostatin analogue. (United States)

    Manfredi, Sylvain; Pagenault, Mael; de Lajarte-Thirouard, Anne-Sophie; Bretagne, Jean-François


    Little is known about the long-term results of treating gastric carcinoid tumors with a slow-release somatostatin analogue. We report three patients with type 1 and 2 gastric carcinoid tumors who were treated in the above mentioned way and followed for 27-50 months. In all cases, alternative endoscopic or surgical management was considered but deemed inappropriate. Treatment with a slow-release somatostatin analogue was begun in light of a favorable recent report. The result was regression or complete disappearance of macroscopic fundal tumors. No side-effects were reported and, most notably, none of the patients developed gallstones. This small study may help define the optimal duration, dose, and administration interval of the treatment. Slow-release somatostatin analogue is a safe and efficacious treatment for type 1 and 2 gastric carcinoid tumors, and can be used when tumors are growing rapidly. Slow-release somatostatin analogue represents an alternative to repeated endoscopic treatment or high-risk surgery.

  11. Centrally Applied Somatostatin Inhibits the Estrogen-Induced Luteinizing Hormone Surge via Hypothalamic Gonadotropin-Releasing Hormone Cell Activation in Female Rats

    NARCIS (Netherlands)

    Vugt, van H.H.; Swarts, J.J.M.; Heijning, van de H.J.M.; Beek, van der E.M.


    Overexpression of growth hormone (GH) as well as GH-deficiency dramatically impairs reproductive function. Decreased reproductive function as a result of altered GH release is, at least partially, due to changes at the hypothalamic-pituitary level. We hypothesize that hypothalamic somatostatin (SOM)

  12. Effect of calcitonin gene-related peptide (CGRP) on motility and on the release of substance P, neurokinin A, somatostatin and gastrin in the isolated perfused porcine antrum

    DEFF Research Database (Denmark)

    Rasmussen, T N; Schmidt, P; Poulsen, S S


    release. The effect of pCGRP was unaffected by the addition of the nonpeptide antagonists for the NK-1 (CP-99994) and NK-2 receptors (SR48968), both at 10(-6) mol L(-1), whereas atropine (10(-6) mol L(-1)) completely abolished the motor effect of pCGRP. The release of somatostatin was significantly...

  13. Capsaicin in adult frogs: effects on nociceptive responses to cutaneous stimuli and on nervous tissue concentrations of immunoreactive substance P, somatostatin and cholecystokinin. (United States)

    Chéry-Croze, S; Godinot, F; Jourdan, G; Bernard, C; Chayvialle, J A


    Adult frogs (Rana esculenta) were given subcutaneous injections of 10, 20, 30, 50 and 100 mg/kg capsaicin in sequential order over 5 days, or the vehicle only. The nociceptive thresholds to electrical, thermal and chemical stimuli were measured before, and 1, 5 and 24 h after each injection. Capsaicin was followed by a dose-related reduction of nociceptive responses to all stimuli, but these effects lasted for only 1-5 h after the given injection. Water/acetic extracts of undivided brains and spinal cords were prepared at the corresponding time periods for the radioimmunoassay of peptides. Spinal cord concentrations of immunoreactive substance P were essentially unaffected by capsaicin, while those of immunoreactive somatostatin were significantly increased after the second for fourth injections (20, 30 and 50 mg/kg) of capsaicin. Brain extracts showed an increase of somatostatin and substance P concentrations after the dose of 50 mg/kg. In an additional experiment, immunoreactive substance P, somatostatin and cholecystokinin were measured in tissue samples taken at 2 and 10 min, and 1, 5 and 24 h after a single dose of either 50 mg/kg capsaicin or the vehicle. The only significant effect of capsaicin was an increase of immunoreactive somatostatin concentration in brain homogenates at 5 h, while the vehicle in itself elicited major variations of all three peptides in spinal cord and/or brain. These results indicate that capsaicin reduces the nociceptive responses to cutaneous stimuli in adult frogs.(ABSTRACT TRUNCATED AT 250 WORDS)

  14. 17-beta-estradiol-dependent regulation of somatostatin receptor subtype expression in the 7315b prolactin secreting rat pituitary tumor in vitro and in vivo

    NARCIS (Netherlands)

    H.A. Visser-Wisselaar (Heleen); C.J. van Uffelen; P.M. van Koetsveld (Peter); E.G. Lichtenauer-Kaligis; A.M. Waaijers (Annet); P. Uitterlinden (Piet); D.M. Mooy; S.W.J. Lamberts (Steven); L.J. Hofland (Leo)


    textabstractIn the present study, we have investigated the role of estrogens in the regulation of somatostatin receptor subtype (sst) expression in 7315b PRL-secreting rat pituitary tumor cells in vitro and in vivo. sst were undetectable in freshly dispersed cells of the transplant

  15. Analog computing by Brewster effect. (United States)

    Youssefi, Amir; Zangeneh-Nejad, Farzad; Abdollahramezani, Sajjad; Khavasi, Amin


    Optical computing has emerged as a promising candidate for real-time and parallel continuous data processing. Motivated by recent progresses in metamaterial-based analog computing [Science343, 160 (2014)SCIEAS0036-807510.1126/science.1242818], we theoretically investigate the realization of two-dimensional complex mathematical operations using rotated configurations, recently reported in [Opt. Lett.39, 1278 (2014)OPLEDP0146-959210.1364/OL.39.001278]. Breaking the reflection symmetry, such configurations could realize both even and odd Green's functions associated with spatial operators. Based on such an appealing theory and by using the Brewster effect, we demonstrate realization of a first-order differentiator. Such an efficient wave-based computation method not only circumvents the major potential drawbacks of metamaterials, but also offers the most compact possible device compared to conventional bulky lens-based optical signal and data processors.

  16. Priming analogical reasoning with false memories. (United States)

    Howe, Mark L; Garner, Sarah R; Threadgold, Emma; Ball, Linden J


    Like true memories, false memories are capable of priming answers to insight-based problems. Recent research has attempted to extend this paradigm to more advanced problem-solving tasks, including those involving verbal analogical reasoning. However, these experiments are constrained inasmuch as problem solutions could be generated via spreading activation mechanisms (much like false memories themselves) rather than using complex reasoning processes. In three experiments we examined false memory priming of complex analogical reasoning tasks in the absence of simple semantic associations. In Experiment 1, we demonstrated the robustness of false memory priming in analogical reasoning when backward associative strength among the problem terms was eliminated. In Experiments 2a and 2b, we extended these findings by demonstrating priming on newly created homonym analogies that can only be solved by inhibiting semantic associations within the analogy. Overall, the findings of the present experiments provide evidence that the efficacy of false memory priming extends to complex analogical reasoning problems.


    Directory of Open Access Journals (Sweden)

    O. V. Dvornikov


    Full Text Available Problems of specialized analog integrated circuit design for sensor equipments are considered. It is offered to produce of radiation hardened analog IC on structured chips for economic efficiency at small production volume. The approach to analog IC design is described, including recommendations for choice of: types and quantities of structured chip analogue components; active and passive components; schematic decisions of analogue components with programmed parameters and small sensitivity to radiation. 

  18. Design and Analysis of Reconfigurable Analog System (United States)


    34010010" �" �" �" �" �" �" �±" N3 N2 N± P1 P2 P3 * Current sources $RR = 1; *Ramp Rate (slope of the...2008/12/12/31e83bac-500f-4182- acca -4d360295fd9c.pdf, Analog Devices, Analog Dialogue 39-06, June 2005. [15] D. A. Johns, K. Martin "Analog Integrated

  19. Fermilab accelerator control system: Analog monitoring facilities

    Energy Technology Data Exchange (ETDEWEB)

    Seino, K.; Anderson, L.; Smedinghoff, J.


    Thousands of analog signals are monitored in different areas of the Fermilab accelerator complex. For general purposes, analog signals are sent over coaxial or twinaxial cables with varying lengths, collected at fan-in boxes and digitized with 12 bit multiplexed ADCs. For higher resolution requirements, analog signals are digitized at sources and are serially sent to the control system. This paper surveys ADC subsystems that are used with the accelerator control systems and discusses practical problems and solutions, and it describes how analog data are presented on the console system.

  20. Robust hyperchaotic synchronization via analog transmission line (United States)

    Sadoudi, S.; Tanougast, C.


    In this paper, a novel experimental chaotic synchronization technique via analog transmission is discussed. We demonstrate through Field-Programmable Gate Array (FPGA) implementation design the robust synchronization of two embedded hyperchaotic Lorenz generators interconnected with an analog transmission line. The basic idea of this work consists in combining a numerical generation of chaos and transmitting it with an analog signal. The numerical chaos allows to overcome the callback parameter mismatch problem and the analog transmission offers robust data security. As application, this technique can be applied to all families of chaotic systems including time-delayed chaotic systems.

  1. Expert analogy use in a naturalistic setting (United States)

    Kretz, Donald R.; Krawczyk, Daniel C.


    The use of analogy is an important component of human cognition. The type of analogy we produce and communicate depends heavily on a number of factors, such as the setting, the level of domain expertise present, and the speaker's goal or intent. In this observational study, we recorded economics experts during scientific discussion and examined the categorical distance and structural depth of the analogies they produced. We also sought to characterize the purpose of the analogies that were generated. Our results supported previous conclusions about the infrequency of superficial similarity in subject-generated analogs, but also showed that distance and depth characteristics were more evenly balanced than in previous observational studies. This finding was likely due to the nature of the goals of the participants, as well as the broader nature of their expertise. An analysis of analogical purpose indicated that the generation of concrete source examples of more general target concepts was most prevalent. We also noted frequent instances of analogies intended to form visual images of source concepts. Other common purposes for analogies were the addition of colorful speech, inclusion (i.e., subsumption) of a target into a source concept, or differentiation between source and target concepts. We found no association between depth and either of the other two characteristics, but our findings suggest a relationship between purpose and distance; i.e., that visual imagery typically entailed an outside-domain source whereas exemplification was most frequently accomplished using within-domain analogies. Overall, we observed a rich and diverse set of spontaneously produced analogical comparisons. The high degree of expertise within the observed group along with the richly comparative nature of the economics discipline likely contributed to this analogical abundance. PMID:25505437

  2. The Parvalbumin/Somatostatin Ratio Is Increased in Pten Mutant Mice and by Human PTEN ASD Alleles

    Directory of Open Access Journals (Sweden)

    Daniel Vogt


    Full Text Available Mutations in the phosphatase PTEN are strongly implicated in autism spectrum disorder (ASD. Here, we investigate the function of Pten in cortical GABAergic neurons using conditional mutagenesis in mice. Loss of Pten results in a preferential loss of SST+ interneurons, which increases the ratio of parvalbumin/somatostatin (PV/SST interneurons, ectopic PV+ projections in layer I, and inhibition onto glutamatergic cortical neurons. Pten mutant mice exhibit deficits in social behavior and changes in electroencephalogram (EEG power. Using medial ganglionic eminence (MGE transplantation, we test for cell-autonomous functional differences between human PTEN wild-type (WT and ASD alleles. The PTEN ASD alleles are hypomorphic in regulating cell size and the PV/SST ratio in comparison to WT PTEN. This MGE transplantation/complementation assay is efficient and is generally applicable for functional testing of ASD alleles in vivo.

  3. A Mechanical Analogy for the Photoelectric Effect (United States)

    Kovacevic, Milan S.; Djordjevich, Alexandar


    Analogy is a potent tool in the teacher's repertoire. It has been particularly well recognized in the teaching of science. However, careful planning is required for its effective application to prevent documented drawbacks when analogies are stretched too far. Befitting the occasion of the World Year of Physics commemorating Albert Einstein's 1905…

  4. An Analog Computer for Electronic Engineering Education (United States)

    Fitch, A. L.; Iu, H. H. C.; Lu, D. D. C.


    This paper describes a compact analog computer and proposes its use in electronic engineering teaching laboratories to develop student understanding of applications in analog electronics, electronic components, engineering mathematics, control engineering, safe laboratory and workshop practices, circuit construction, testing, and maintenance. The…

  5. An Analog Computer for Electronic Engineering Education (United States)

    Fitch, A. L.; Iu, H. H. C.; Lu, D. D. C.


    This paper describes a compact analog computer and proposes its use in electronic engineering teaching laboratories to develop student understanding of applications in analog electronics, electronic components, engineering mathematics, control engineering, safe laboratory and workshop practices, circuit construction, testing, and maintenance. The…

  6. Analogies in high school Brazilian chemistry textbooks

    Directory of Open Access Journals (Sweden)

    Rosária Justi


    Full Text Available This paper presents and discusses an analysis of the analogies presented by Brazilian chemistry textbooks for the medium level. The main aim of the analysis is to discuss whether such analogies can be said good teaching models. From the results, some aspects concerning with teachers' role are discussed. Finally, some new research questions are emphasised.


    Directory of Open Access Journals (Sweden)

    Nyoto Suseno


    Full Text Available The research of any where founded majority students have common difficulties in abstract physics concept. The result of observation, lecturers have problem  in teaching implementation of abstract concepts on physics learning. The objective of this research is to find out the ways how to overcome this problem. The research place of  physics education programs and senior high school. The data are colected by quetionere, observation and interview. The lecturer behavior to making out this case is use of analogy to make concrete a abstract concept. This action is true, because the analogies are dynamic tools that facilitate understanding, rather than representations of the correct and static explanations. Using analogies not only promoted profound understanding of abstract concept, but also helped students overcome their misconceptions. However used analogy in teaching not yet planed with seriousness, analogy used spontanously with the result that less optimal. By planing and selecting right analogy, the role of analogy can be achieved the optimal result. Therefore, it is important to maping analogies of abstract consepts on physics learning.

  8. Response Generation Norms for Verbal Analogies. (United States)

    Ingram, Albert; Pellegrino, James W.

    Normative data were collected for the generation of responses to 150 incomplete verbal analogies. Two types of normative data are provided: (a) the probabilities associated with each response produced for each analogy base and (b) the probabilities that initial responses represented the appropriate semantic relationship, with a division of…

  9. Analogies in biology textbooks in zoology teaching

    Directory of Open Access Journals (Sweden)

    Saulo Cézar Seiffert Santos


    Full Text Available The biologic structures of living creatures are of difficult understanding for students, because they are usually unknown by those, in needs of strategic didactics in order to facilitate the student understanding. There are several strategies and methods for teaching, such as, analogies, metaphors, descriptions, among others. In this article we aim to identify, assess and classify the analogies used in the Higher School Biology textbooks, commonly used in Public State Schools of Manaus – AM, related to the zoology theme. The methodological procedure includes: a analysis of the whole zoological content of the most used textbooks in the public state network of Amazonas throughout the year; b three didactic textbooks have been specifically analyzed in order to specify the class taxon of “Fish” for the comparison of possible variations of types and quantities of analogies. The adopted classification of analogies was of Curtis & Reigeluth (1984 and the model of enriching analysis was according to the TWA Glynn model (Harrison & Treagust, 1993. It has been concluded that the use of analogies is greater in the content of invertebrates than that of vertebrates. Most Analogies are presented in a simple and direct manner, comparing structures, concrete to concrete, and of verbal mediation, almost nothing is presented in a diverse and heuristic manner of Zoology content on the LD. The development of limits of comparison and reflexion about the analogies was rare, only the presentation of the analogue and the target of analogy occurred.

  10. Verbal Analogical Reasoning in Children and Adolescents. (United States)

    Nippold, Marilyn A.


    Verbal analogical reasoning tasks are described as potentially valuable in the assessment and management of subtle linguistic defects less easily detected by standardized language tests. Semantic and structural factors that should be considered in the development of verbal analogies as test items are cited, as well as adaptations for nonreaders.…

  11. The Multidimensionality of Verbal Analogy Items (United States)

    Ullstadius, Eva; Carlstedt, Berit; Gustafsson, Jan-Eric


    The influence of general and verbal ability on each of 72 verbal analogy test items were investigated with new factor analytical techniques. The analogy items together with the Computerized Swedish Enlistment Battery (CAT-SEB) were given randomly to two samples of 18-year-old male conscripts (n = 8566 and n = 5289). Thirty-two of the 72 items had…

  12. Antibacterial and Antibiofilm Activities of Makaluvamine Analogs

    Directory of Open Access Journals (Sweden)

    Bhavitavya Nijampatnam


    Full Text Available Streptococcus mutans is a key etiological agent in the formation of dental caries. The major virulence factor is its ability to form biofilms. Inhibition of S. mutans biofilms offers therapeutic prospects for the treatment and the prevention of dental caries. In this study, 14 analogs of makaluvamine, a marine alkaloid, were evaluated for their antibacterial activity against S. mutans and for their ability to inhibit S. mutans biofilm formation. All analogs contained the tricyclic pyrroloiminoquinone core of makaluvamines. The structural variations of the analogs are on the amino substituents at the 7-position of the ring and the inclusion of a tosyl group on the pyrrole ring N of the makaluvamine core. The makaluvamine analogs displayed biofilm inhibition with IC50 values ranging from 0.4 μM to 88 μM. Further, the observed bactericidal activity of the majority of the analogs was found to be consistent with the anti-biofilm activity, leading to the conclusion that the anti-biofilm activity of these analogs stems from their ability to kill S. mutans. However, three of the most potent N-tosyl analogs showed biofilm IC50 values at least an order of magnitude lower than that of bactericidal activity, indicating that the biofilm activity of these analogs is more selective and perhaps independent of bactericidal activity.

  13. Novel Analog For Muscle Deconditioning (United States)

    Ploutz-Snyder, Lori; Ryder, Jeff; Buxton, Roxanne; Redd. Elizabeth; Scott-Pandorf, Melissa; Hackney, Kyle; Fiedler, James; Ploutz-Snyder, Robert; Bloomberg, Jacob


    Existing models (such as bed rest) of muscle deconditioning are cumbersome and expensive. We propose a new model utilizing a weighted suit to manipulate strength, power, or endurance (function) relative to body weight (BW). Methods: 20 subjects performed 7 occupational astronaut tasks while wearing a suit weighted with 0-120% of BW. Models of the full relationship between muscle function/BW and task completion time were developed using fractional polynomial regression and verified by the addition of pre-and postflightastronaut performance data for the same tasks. Splineregression was used to identify muscle function thresholds below which task performance was impaired. Results: Thresholds of performance decline were identified for each task. Seated egress & walk (most difficult task) showed thresholds of leg press (LP) isometric peak force/BW of 18 N/kg, LP power/BW of 18 W/kg, LP work/BW of 79 J/kg, isokineticknee extension (KE)/BW of 6 Nm/kg, and KE torque/BW of 1.9 Nm/kg.Conclusions: Laboratory manipulation of relative strength has promise as an appropriate analog for spaceflight-induced loss of muscle function, for predicting occupational task performance and establishing operationally relevant strength thresholds.

  14. Uncertainty Relations for Analog Signals

    CERN Document Server

    Eldar, Yonina C


    In the past several years there has been a surge of research investigating various aspects of sparse representations and compressed sensing. Most of this work has focused on the finite-dimensional setting in which the goal is to decompose a finite-length vector into a given finite dictionary. Underlying many of these results is the conceptual notion of an uncertainty principle: a signal cannot be sparsely represented in two different bases. Here, we extend these ideas and results to the analog, infinite-dimensional setting by considering signals that lie in a finitely-generated shift-invariant (SI) space. This class of signals is rich enough to include many interesting special cases such as multiband signals and splines. By adapting the notion of coherence defined for finite dictionaries to infinite SI representations, we develop an uncertainty principle similar in spirit to its finite counterpart. We demonstrate tightness of our bound by considering a bandlimited low-pass comb that achieves the uncertainty p...

  15. Compressed Sensing of Analog Signals

    CERN Document Server

    Eldar, Yonina C


    A traditional assumption underlying most data converters is that the signal should be sampled at a rate which exceeds twice the highest frequency. This statement is based on a worst-case scenario in which the signal occupies the entire available bandwidth. In practice, many signals posses a sparse structure so that a large part of the bandwidth is not exploited. In this paper, we consider a framework for utilizing this sparsity in order to sample such analog signals at a low rate. More specifically, we consider continuous-time signals that lie in a shift-invariant (SI) space generated by m kernels, so that any signal in the space can be expressed as an infinite linear combination of the shifted kernels. If the period of the underlying SI space is equal to T, then such signals can be perfectly reconstructed from samples at a rate of m/T. Here we treat the case in which only k out of the m generators are active, meaning that the signal actually lies in a lower dimensional space spanned by k generators. However,...

  16. An optical analog signal transmitter

    Energy Technology Data Exchange (ETDEWEB)

    Fudzita, K.; Itida, T.; Tanaka, Kh.


    An optical laser analog signal transmitter employing an amplitude modulated subcarrier is patented; this transmitter performs stable and high quality transmission of information signals over great distances. A feature of the proposed transmitter is a special transmitter operational mode in which the light emission reflected off the connection point to the fiber optic conduit is sent back to the laser diode in a transient period. As a result, the critical mode of the generated emission is not influenced by the reflected signal. The transmitter consists of a laser diode with biasing near the cutoff point, an amplitude modulator with a subcarrier frequency oscillator, a section of flexible fiber-optic cable of length L, which connects the laser diode to the primary optical fiber conduit, and the connector itself. The subcarrier frequency may vary over wide ranges to establish the necessary correlation between the length of the light conduit section L and the return propagation time of the reflected light signal from the connection point to the laser diode. The difference between the lasing time of the light signal and the return time to the laser diode of the signal reflected off the connector is determined by the relation tau equals 2nL/c - mtauc, where L is the length of the connecting section; n is the refractivity of the optical fiber; c is the velocity of light; tauc is the period of the high frequency subcarrier signal; and m is an integer.

  17. Role of high mobility group box-1 and protection of growth hormone and somatostatin in severe acute pancreatitis

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Y.F. [Department of Surgery, Huashan Hospital, Fudan University, Shanghai (China); Wu, M. [Department of Surgery, Jinshan Pavilion Forest Hospital, Shanghai (China); Ma, B.J.; Cai, D.A.; Yin, B.B. [Department of Surgery, Huashan Hospital, Fudan University, Shanghai (China)


    In this study, we investigated the potential role of high-mobility group box 1 (HMGB1) in severe acute pancreatitis (SAP) and the effects of growth hormone (G) and somatostatin (S) in SAP rats. The rats were randomly divided into 6 groups of 20 each: sham-operated, SAP, SAP+saline, SAP+G, SAP+S and SAP+G+S. Ileum and pancreas tissues of rats in each group were evaluated histologically. HMGB1 mRNA expression was measured by reverse transcription-PCR. Levels of circulating TNF-α, IL-1, IL-6, and endotoxin were also measured. In the SAP group, interstitial congestion and edema, inflammatory cell infiltration, and interstitial hemorrhage occurred in ileum and pancreas tissues. The levels of HMGB1, TNF-α, IL-1, IL-6 and endotoxin were significantly up-regulated in the SAP group compared with those in the sham-operated group, and the 7-day survival rate was 0%. In the SAP+G and SAP+S groups, the inflammatory response of the morphological structures was alleviated, the levels of HMGB1, TNF-α, IL-1, IL-6, and endotoxin were significantly decreased compared with those in the SAP group, and the survival rate was increased. Moreover, in the SAP+G+S group, all histological scores were significantly improved and the survival rate was significantly higher compared with the SAP group. In conclusion, HMGB1 might participate in pancreas and ileum injury in SAP. Growth hormone and somatostatin might play a therapeutic role in the inflammatory response of SAP.

  18. Physiological Uptake in the Pancreatic Head on Somatostatin Receptor Scintigraphy Using [111In-DTPA]Octreotide: Incidence and Mechanism. (United States)

    Brabander, Tessa; Teunissen, Jaap; Kwekkeboom, Dik


    Physiological uptake in the uncinate process or pancreatic head has been described with Ga-labeled PET tracers for somatostatin receptor imaging. In-DTPA-octreotide is the only registered radiopharmaceutical for the imaging of neuroendocrine tumors. We studied the uptake in this region of the pancreatic head on somatostatin receptor scintigraphy (SRS) using In-DTPA-octreotide in a large group of patients. Furthermore, known physiological and clinical characteristics are discussed in an attempt to elucidate this phenomenon. Four hundred seven patients underwent SRS using In-DTPA-octreotide in our department in 2014. After excluding patients with a known malignancy in or close to the pancreas, as well as all scans without SPECT/CT of the upper abdomen, we reviewed 178 scans in total. The uptake was graded on a 4-point scale that correlates the uptake in the pancreatic head to physiological uptake in the liver. Uptake in the region of the pancreatic head, including the uncinate process, was seen in 46 (26%) of 178 patients on SPECT/CT and in 12 patients (7%) on planar imaging. On SPECT/CT, uptake was lower than the liver in 26 patients (15%), equal to the liver in 17 patients (10%), and higher than the liver in 3 patients (2%). In patients with diabetes mellitus (DM), the incidence of uptake in the pancreatic head was 50% on SPECT/CT. Physiological uptake in the pancreatic head is seen on SPECT/CT with In-DTPA-octreotide in 26% of patients, and the incidence is doubled in patients with DM. Previous case reports showed uptake in the pancreatic head due to histologically proven pancreatic polypeptide (PP) cell hyperplasia. Also, patients with DM have elevated serum PP concentrations, which is likely due to PP cell hyperplasia. Because 90% of PP cells are present in the pancreatic head, PP cell hyperplasia is the most likely explanation for visualization of the pancreatic head on SRS in a substantial number of patients.

  19. An evaluation of the effects of somatostatin analogue therapy in non-functioning pituitary adenomas in comparison to acromegaly. (United States)

    Zawada, Natalia Bożena; Kunert-Radek, Jolanta; Pawlikowski, Marek; Pisarek, Hanna; Radek, Maciej


    Non-functioning pituitary adenomas (NFPA) are often diagnosed late as invasive macroadenomas. The surgical resection is usually incomplete and about 50% of patients require additional surgery. Recent data suggest that somatostatin analogues (SSA), so important in the pharmacotherapy of acromegaly, can also be effective in the management of NFPA. We analysed data of patients who had been treated up to 10 years previously with SSA: 40 with acromegaly (23 - primary, 17 - recurrent tumours) and 22 with NFPA (4 - primary, 18 - recurrent tumours). Hormonal profile, dynamics of tumour size change, ophthalmic syndromes, somatostatin receptor (SSTR) scintigraphy, and immunohistochemistry of SSTR subtypes of operated tumours as well as side effects were investigated. Biochemical cure of acromegaly was achieved in 57.5% of patients, while reduction of tumour size was observed in 37% of patients and it was more frequent in not-operated cases. Regarding NFPA, stabilisation of tumour size was noticed in 68% of patients. Tumour shrinkage was reported in 9% of cases, but in 23% of the study group the adenoma size increased with indication for reoperation. The efficacy of SSA in NFPA is much lower in comparison to their well-established effects in the treatment of acromegaly. Stabilisation of tumour size, which is observed in the majority of NFPA, is significantly more frequent in comparison to the natural history of untreated NFPA and our previous studies as well. Analysis of SSTR subtypes is an argument in favour of introduction of novel broad-spectrum SSA that may be more effective in the treatment of NFPA. Referring to acromegaly, adenoma size decrease was reported more frequently in primary therapy. Considering recurrent tumours better outcomes were achieved in patients who were pre-treated with SSA before planned surgery. (Endokrynol Pol 2016; 67 (3): 292-298).

  20. A novel lanreotide-encoded micelle system targets paclitaxel to the tumors with overexpression of somatostatin receptors. (United States)

    Zheng, Nan; Dai, Wenbing; Du, Wenwen; Zhang, Haoran; Lei, Liandi; Zhang, Hua; Wang, Xueqing; Wang, Jiancheng; Zhang, Xuan; Gao, Jinming; Zhang, Qiang


    Many tumor cells specifically overexpress somatostatin receptors, in particular, subtype 2 (SSTR2). Lanreotide, a somatostatin analogue with high affinity for SSTR2, can be exploited as a ligand for tumor targeted therapy. In this study, lanreotide was first conjugated to poly(ethylene glycol)-b-poly(ε-caprolactone) (PEG-b-PCL) copolymer, and the active targeting micelles with paclitaxel (lanreotide-PM-PTX) or fluorescent agent were constructed and characterized with various analytical methods. Lanreotide-PM-PTX micelles were spherical in shape with a hydrodynamic diameter of 43.2 ± 0.4 nm, high drug encapsulation (87.1 ± 2.8%) and slow drug release rate. Two cancer cell lines (human lung cancer H446 and human breast cancer MCF-7 cells) with different expression levels of SSTR2 were used in this study. As observed by flow cytometry, confocal microscopy and cytotoxicity studies, lanreotide-encoded PEG-b-PCL micelles demonstrated more specific cell uptake and cytotoxicity in SSTR2-positive tumor cells via a receptor-mediated mechanism over the passive targeting micelles. The active targeting micelles showed higher accumulation in tumor tissue and tumor cells in tumor-bearing mice in vivo by near-infrared fluorescence (NIRF) imaging, high-performance liquid chromatography and confocal microscopy, respectively. Furthermore, treatment with lanreotide-PM-PTX micelles resulted in stronger tumor inhibition, increased life span and enhanced tumor cell apoptosis in SSTR2-overexpressing tumor model in athymic nude mice. The in vivo efficacy test with both H446 and MCF-7 tumor models further demonstrated the involvement of receptor-mediated interaction. Finally, the active targeting micelles exhibited less body weight loss, lower hemolysis and lower myelosuppression, as compared with the control groups. In conclusion, lanreotide can serve as an effective homing peptide, and the lanreotide-modified PEG-b-PCL micelles hold considerable promise in the treatment of SSTR2

  1. Demonstrative and non-demonstrative reasoning by analogy


    Ippoliti, Emiliano


    The paper analizes a set of issues related to analogy and analogical reasoning, namely: 1) The problem of analogy and its duplicity; 2) The role of analogy in demonstrative reasoning; 3) The role of analogy in non-demonstrative reasoning; 4) The limits of analogy; 5) The convergence, particularly in multiple analogical reasoning, of these two apparently distinct aspects and its methodological and philosophical consequences. The paper, using example from number theory, argues for an heuristc c...

  2. Growth hormone secretion from chicken adenohypophyseal cells in primary culture: effects of human pancreatic growth hormone-releasing factor, thyrotropin-releasing hormone, and somatostatin on growth hormone release. (United States)

    Perez, F M; Malamed, S; Scanes, C G


    A primary culture of chicken adenohypophyseal cells has been developed to study the regulation of growth hormone (GH) secretion. Following collagenase dispersion, cells were exposed for 2 hr to vehicle (control) or test agents. Human pancreatic (tumor) growth hormone-releasing factor (hpGRF) and rat hypothalamic growth hormone-releasing factor stimulated GH release to similar levels. GH release was increased by the presence of dibutyryl cyclic AMP. Thyrotropin-releasing hormone (TRH) alone did not influence GH release; however, TRH plus hpGRF together exerted a synergistic (greater than additive) effect, increasing GH release by 100 to 300% over the sum of the values for each secretagogue acting alone. These relationships between TRH and hpGRF were further examined in cultured cells exposed to secretagogues for two consecutive 2-hr incubations. TRH pretreatment enhanced subsequent hpGRF-stimulated GH release by about 80% over that obtained if no secretagogue was present during the first incubation. In other experiments, somatostatin (SRIF) alone did not alter GH secretion. However, SRIF reduced hpGRF-stimulated GH release to levels found in controls. Furthermore, GH release stimulated by the presence of both TRH and hpGRF was lowered to control values by SRIF. The results of these studies demonstrate that a primary culture of chicken adenohypophyseal cells is a useful model for the study of GH secretion. Indeed, these results suggest that TRH and hpGRF regulate GH secretion by mechanisms which are not identical.

  3. Computational approaches to analogical reasoning current trends

    CERN Document Server

    Richard, Gilles


    Analogical reasoning is known as a powerful mode for drawing plausible conclusions and solving problems. It has been the topic of a huge number of works by philosophers, anthropologists, linguists, psychologists, and computer scientists. As such, it has been early studied in artificial intelligence, with a particular renewal of interest in the last decade. The present volume provides a structured view of current research trends on computational approaches to analogical reasoning. It starts with an overview of the field, with an extensive bibliography. The 14 collected contributions cover a large scope of issues. First, the use of analogical proportions and analogies is explained and discussed in various natural language processing problems, as well as in automated deduction. Then, different formal frameworks for handling analogies are presented, dealing with case-based reasoning, heuristic-driven theory projection, commonsense reasoning about incomplete rule bases, logical proportions induced by similarity an...

  4. Photonic analog-to-digital converter via asynchronous oversampling (United States)

    Carver, Spencer; Reeves, Erin; Siahmakoun, Azad; Granieri, Sergio


    This paper presents a hybrid opto-electronic asynchronous delta-sigma modulator, implemented in the form of a fiber-optic Analog-to-Digital converter (ADC). This architecture was chosen for its independence of an external clock and ease of demodulation through a single low-pass filter stage. The fiber-optic prototype consists of an input laser (wavelength λ1) which is modulated with an input RF signal, a high-speed comparator circuit working as bi-stable quantizer, and a fiber-optic loop that includes a SOA and a band-pass filter that act as a leaky integrator. The fiber-optic loop acts as a fiber-ring resonator (FRR), and defines the resonance wavelength λ2 of the system. The gain within this loop is modified through cross-gain modulation (XGM) by the input wavelength λ1, and thus achieves the desired modulation effect. The proposed architecture has been constructed and characterized at a sampling rate of 15.4 MS/s processing input analog signals in the range of dc-3 MHz with a signal-to-noise ratio of 36 dB and an effective number of bits of 5.7.

  5. Synthesis and biological activities of some human gastrin analogs. (United States)

    Lima-Leite, A C; Fulcrand, P; Galleyrand, J C; Berge, G; Aumelas, A; Bali, J P; Castel, J; Martinez, J


    The synthesis of analogs of the C-terminal tridecapeptide of gastrin is described. These pseudopeptide analogs were obtained either by replacing the C-terminal phenylalanine amide with 2-phenylethylalcohol or with 2-phenylethylamine, or by replacing the peptide bond between Trp and Leu, or between Leu and Asp with an aminomethylene (CH2NH). The ability of these compounds to stimulate gastric acid secretion in anesthetized rats and to inhibit binding of labeled CCK-8 to isolated cells from rabbit fundic mucosa was tested. [desPhe13, Leu11]-HG-12-I-beta-phenylethylester 33, [desPhe13, Leu11]-HG-12-II-beta-phenylethylester 38, [desPhe13, Leu11]-HG-12-I-beta-phenylethylamide 32, and [desPhe13, Leu11]-HG-12-II-beta-phenylethylamide 37 acted as gastrin receptor antagonists, while [Trp10-psi(CH2NH)-Leu11]-HG-13-I 31 and [Trp10-psi(CH2NH)-Leu11]-HG-13-II 36 acted as agonists. Unexpectedly, [Leu11-psi(CH2NH)-Asp12]-HG-13-I 30 and [Leu11-psi (CH2NH)-Asp12]-HG-13-II 35 were almost devoid of affinity for the gastrin receptor.

  6. An Analog Earth Climate Model (United States)

    Varekamp, J. C.


    The earth climate is broadly governed by the radiative power of the sun as well as the heat retention and convective cooling of the atmosphere. I have constructed an analog earth model for an undergraduate climate class that simulates mean climate using these three parameters. The ‘earth’ is a hollow, black, bronze sphere (4 cm diameter) mounted on a thin insulated rod, and illuminated by two opposite optic fibers, with light focused on the sphere by a set of lenses. The sphere is encased in a large double-walled aluminum cylinder (34 cm diameter by 26 cm high) with separate water cooling jackets at the top, bottom, and sides. The cylinder can be filled with a gas of choice at a variety of pressures or can be run in vacuum. The exterior is cladded with insulation, and the temperature of the sphere, atmosphere and walls is monitored with thermocouples. The temperature and waterflow of the three cooling jackets can be monitored to establish the energy output of the whole system; the energy input is the energy yield of the two optic fibers. A small IR transmissive lens at the top provides the opportunity to hook up the fiber of a hyper spectrometer to monitor the emission spectrum of the black ‘earth’ sphere. A pressure gauge and gas inlet-outlet system for flushing of the cell completes it. The heat yield of the cooling water at the top is the sum of the radiative and convective components, whereas the bottom jacket only carries off the radiative heat of the sphere. Undergraduate E&ES students at Wesleyan University have run experiments with dry air, pure CO2, N2 and Ar at 1 atmosphere, and a low vacuum run was accomplished to calibrate the energy input. For each experiment, the lights are flipped on, the temperature acquisition routine is activated, and the sphere starts to warm up until an equilibrium temperature has been reached. The lights are then flipped off and the cooling sequence towards ambient is registered. The energy input is constant for a given

  7. Activation of Muscarinic Acetylcholine Receptor Subtype 4 is Essential for Cholinergic Stimulation of Gastric Acid Secretion - Relation To D Cell/Somatostatin -

    Directory of Open Access Journals (Sweden)

    Koji Takeuchi


    Full Text Available AbstractBackground/Aim: Muscarinic acetylcholine receptors exist in five subtypes (M1~M5, and they are widely expressed in various tissues to mediate diverse autonomic functions, including gastric secretion. In the present study, we demonstrated, using M1~M5 KO mice, the importance of M4 receptors in carbachol (CCh stimulation of acid secretion and investigated how the secretion is modulated by the activation of M4 receptors. Methods: C57BL/6J mice of wild-type (WT and M1-M5 KO were used. Under urethane anesthesia, acid secretion was measured in the stomach equipped with an acute fistula. CCh (30 µg/kg was given s.c. to stimulate acid secretion. Atropine or octreotide (a somatostatin analogue was given s.c. 20 min before the administration of CCh. CYN154806 (a somatostatin SST2 receptor antagonist was given i.p. 20 min before the administration of octreotide or CCh. Results: CCh caused an increase of acid secretion in WT mice, and the effect was totally inhibited by prior administration of atropine. The effect of CCh was similarly observed in the animals lacking M1, M2 or M5 receptors but significantly decreased in M3 or M4 KO mice. CYN154806, the SST2 receptor antagonist, dose-dependently and significantly reversed the decreased acid response to CCh in M4 but not M3 KO mice. Octreotide, the somatostatin analogue, inhibited the secretion of acid under CCh-stimulated conditions in WT mice. The immunohistochemical study showed the localization of M4 receptors on D cells in the stomach. Serum somatostatin levels in M4 KO mice were higher than WT mice under basal conditions, while those in WT mice were significantly decreased in response to CCh. Conclusions: These results suggest that under cholinergic stimulation the acid secretion is directly mediated by M3 receptors and indirectly modified by M4 receptors. It is assumed that the activation of M4 receptors inhibits the release of somatostatin from D cells and minimizes the acid inhibitory effect

  8. Namibian Analogs To Titan Dunes (United States)

    Wall, Stephen D.; Lopes, R.; Kirk, R.; Stofan, E.; Farr, T.; Van der Ploeg, P.; Lorenz, R.; Radebaugh, J.


    Titan's equatorial dunes, observed in Cassini SAR, have been described as longitudinal, similar to longitudinal dunes in the Namib sand sea in southern Africa. Their "Y” junctions and the way they divert around topography are used as evidence of equatorial wind flow direction. In two instances of such diversion they exhibit overlying or crosshatched patterns in two distinct directions that have been interpreted as a transition to transverse dunes. Here we describe field observations of the Namibian dunes and these comparisons, we present images of the dunes from terrestrial SAR missions, and we discuss implications to both the Titan dunes and the wind regime that created them. Selected portions of the Namibian dunes resemble Titan's dunes in peak-to-peak distance and length. They are morphologically similar to Titan, and specific superficial analogs are common, but they also differ. For example, when Titan dunes encounter topography they either terminate abruptly, "climb” the upslope, or divert around; only the latter behavior is seen in remote sensing images of Namibia. Namib linear dunes do transition to transverse as they divert, but at considerably smaller wavelength, while at Titan the wavelengths are of the same scale. Crosshatching of similar-wavelength dunes does occur in Namibia, but not near obstacles. Many additional aeolian features that are seen at Namibia such as star dunes, serpentine ridges and scours have not been detected on Titan, although they might be below the Cassini SAR's 300-m resolution. These similarities and differences allow us to explore mechanisms of Titan dune formation, in some cases giving us clues as to what larger scale evidence to look for in SAR images. Viewed at similar resolution, they provide interesting comparisons with the Titan dunes, both in likeness and differences. A part of this work was carried out at JPL under contract with NASA.

  9. Advances in Analog Circuit Design 2015

    CERN Document Server

    Baschirotto, Andrea; Harpe, Pieter


    This book is based on the 18 tutorials presented during the 24th workshop on Advances in Analog Circuit Design. Expert designers present readers with information about a variety of topics at the frontier of analog circuit design, including low-power and energy-efficient analog electronics, with specific contributions focusing on the design of efficient sensor interfaces and low-power RF systems. This book serves as a valuable reference to the state-of-the-art, for anyone involved in analog circuit research and development. ·         Provides a state-of-the-art reference in analog circuit design, written by experts from industry and academia; ·         Presents material in a tutorial-based format; ·         Includes coverage of high-performance analog-to-digital and digital to analog converters, integrated circuit design in scaled technologies, and time-domain signal processing.

  10. Analogies: Explanatory Tools in Web-Based Science Instruction (United States)

    Glynn, Shawn M.; Taasoobshirazi, Gita; Fowler, Shawn


    This article helps designers of Web-based science instruction construct analogies that are as effective as those used in classrooms by exemplary science teachers. First, the authors explain what analogies are, how analogies foster learning, and what form analogies should take. Second, they discuss science teachers' use of analogies. Third, they…

  11. Multifocal Head and Neck Paraganglioma Evaluated with Different PET Tracers: Comparison Between Fluorine-18-Fluorodeoxyglucose Between Fluorine-18-Fluorodeoxyglucose and Gallium-68-Somatostatin Receptor PET/CT

    Energy Technology Data Exchange (ETDEWEB)

    Castaldi, Paola; Rufini, Vittoria [Catholic Univ. of the Sacred Heart, Rome (Italy); Treglia, G. [Oncology Institute of Southern Switzerland, Bellinzona (Switzerland)


    We report the case of a 46-year-old woman with a succinate dehydrogenase subtype D (SDHD) gene mutation and multifocal head and neck paraganglioma evaluated with fluorine-18-fluorodeoxyglucose and gallium-68-somatostatin receptor positron emission tomography/computed tomography (PET/CT). Gallium-68-somatostatin receptor PET/CT correctly assessed the extent of the disease in this patient, detecting additional lesions compared with fluorine-18-fluorodeoxyglucose PET/CT and influencing the patient management. A 46-year-old woman was referred to our centre for surveillance of a gastrointestinal stromal tumour (GIST). The patient underwent fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (F-18-FDG-PET/CT), which demonstrated a focal area of increased radiopharmaceutical uptake corresponding to a lesion located between the right carotid vessels (yellow arrow; Fig. 1a). This F-18-FDG-PET/CT finding was suspicious for a paraganglioma of the neck. The patient underwent further examinations, including biochemical and genetic tests and a somatostatin receptor PET/CT using somatostatin analogues labelled with gallium-68 (Ga-68-DOTANOC-PET/CT). Laboratory data were suspicious for a non-functioning neuroendocrine tumour. Increased serum chromogranin A value and normal values of plasmatic and urinary catecholamines and their metabolites were found. The patient had no symptoms of a functioning tumour. Genetic tests demonstrated the presence of a succinate dehydrogenase subtype D (SDHD) gene mutation, which is associated with head and neck paragangliomas. Surprisingly, Ga-68-DOTANOC-PET/CT (Fig. 1b) showed multiple bilateral areas of increased radiopharmaceutical uptake in the head and neck region, corresponding to bilateral neuroendocrine lesions and suggesting the presence of bilateral paragangliomas (yellow arrows) with small cervical lymph nodal metastases with short axis less than 1 cm of diameter (red arrows). Physiological radiopharmaceutical

  12. Analog to Digital Conversion in Physical Measurements

    CERN Document Server

    Kapitaniak, T; Feudel, U; Grebogi, C


    There exist measuring devices where an analog input is converted into a digital output. Such converters can have a nonlinear internal dynamics. We show how measurements with such converting devices can be understood using concepts from symbolic dynamics. Our approach is based on a nonlinear one-to-one mapping between the analog input and the digital output of the device. We analyze the Bernoulli shift and the tent map which are realized in specific analog/digital converters. Furthermore, we discuss the sources of errors that are inevitable in physical realizations of such systems and suggest methods for error reduction.

  13. A computational model of analogical reasoning

    Institute of Scientific and Technical Information of China (English)

    李波; 赵沁平


    A computational model of analogical reasoning is presented, which divides analogical reasoning process into four subprocesses, i.e. reminding, elaboration, matching and transfer. For each subprocess, its role and the principles it follows are given. The model is discussed in detail, including salient feature-based reminding, relevance-directed elaboration, an improved matching model and a transfer model. And the advantages of this model are summarized based on the results of BHARS, which is an analogical reasoning system implemented by this model.

  14. Analogies in science education: contributions and challenges

    Directory of Open Access Journals (Sweden)

    Maria da Conceição Duarte


    Full Text Available An analogy is a comparison between domains of knowledge that have similarities at the levels of characteristics and relationships. Several authors highlight the importance of this tool in the teaching and learning of difficult scientific concepts. Nevertheless, some problems associated to the use of analogies have been found. This paper aims at contributing to a better understanding of the use of analogies in science education, by means of a review of the state of art regarding this matter. It will take into account its contribution to science education as well as the challenges to further research

  15. Pertussis toxin non-sensitive G protein mediates cholinergic stimulation for secretion of pancreastatin and somatostatin from QGP-1N cells. (United States)

    Funakoshi, A; Tateishi, K; Tsuru, M; Kono, A


    To clarify the possible role of a guanine nucleotide-binding protein (G-protein) in the signal transducing system activated by carbachol, actions of carbachol on human pancreastatin producing cell line (QGP-1N) were compared with those of fluoride, a well-known activator of stimulatory (Gs) or inhibitory (Gi) G protein. 10(-5) M of carbachol as well as 20 mM of NaF stimulated secretion of pancreastatin and somatostatin and intracellular Ca2+ mobilization. These secretion and Ca2+ mobilization were not modified by pertussis toxin, an inhibitor of Gi protein. These results suggest that pancreastatin and somatostatin secretions from QGP-1N are regulated by acetylcholine through a muscarinic receptor coupled to the activation of polyphosphoinositide breakdown by a G protein, which appears to be fluoride sensitive but is other than a Gi-like protein.

  16. A graphene oxide-based fluorescent biosensor for the analysis of peptide-receptor interactions and imaging in somatostatin receptor subtype 2 overexpressed tumor cells. (United States)

    Bianying, Feng; Linjie, Guo; Lihua, Wang; Fan, Li; Jianxin, Lu; Jimin, Gao; Chunhai, Fan; Qing, Huang


    Analysis of peptide-receptor interactions provides insights for understanding functions of proteins in cells. In this work, we report the development of a fluorescent biosensor for the analysis of peptide-receptor interactions using graphene oxide (GO) and fluorescein isothiocyanate (FITC)-labeled octreotide (FOC). Octreotide is a synthesized cyclic peptide with somatostatin-like bioactivity that has been clinically employed. FOC exhibits high adsorption affinity for GO, and its binding results in efficient fluorescence quenching of FITC. Interestingly, the specific binding of the antibody anti-octreotide (AOC) with FOC competitively releases FOC from the GO surface, leading to the recovery of fluorescence. By using this GO-based fluorescent platform, we can detect AOC with a low detection limit of 2 ng/mL. As a step further, we employ this GO-FOC biosensor to image somatostatin receptor subtype 2 overexpressed AR42J tumor cells, which demonstrates high promise for molecular imaging in cancer diagnosis.

  17. Identifying Solar Analogs in the Kepler Field (United States)

    Buzasi, Derek L.; Lezcano, Andrew; Preston, Heather L.


    Since human beings live on a planet orbiting a G2 V star, to us perhaps the most intrinsically interesting category of stars about which planets have been discovered is solar analogs. While Kepler has observed more than 26000 targets which have effective temperatures within 100K of the Sun, many of these are not true solar analogs due to activity, surface gravity, metallicity, or other considerations. Here we combine ground-based measurements of effective temperature and metallicity with data on rotational periods and surface gravities derived from 16 quarters of Kepler observations to produce a near-complete sample of solar analogs in the Kepler field. We then compare the statistical distribution of stellar physical parameters, including activity level, for subsets of solar analogs consisting of KOIs and those with no detected exoplanets. Finally, we produce a list of potential solar twins in the Kepler field.

  18. Use of analogy in learning scientific concepts. (United States)

    Donnelly, C M; McDaniel, M A


    Four experiments compared learning of scientific concepts as expressed in either traditional literal form or through an analogy. Comprehension of basic-level details and inferential implications was measured through multiple-choice testing. In Experiment 1, literal or analogical renditions were presented in textual form only. In Experiment 2, text was accompanied by a dynamic video. In Experiment 3, the video and text literal rendition was compared with a text-only analogical rendition. In Experiment 4, subjects read only about a familiar domain. Subjects consistently answered basic-level questions most accurately when concepts were expressed literally, but answered inferential questions most accurately when concepts were expressed analogically. Analysis of individual differences (Experiment 2) indicated that this interaction strongly characterized the conceptual learning of science novices. The results are discussed within the framework of schema induction.

  19. Efficient Image Transmission Through Analog Error Correction

    CERN Document Server

    Liu, Yang; Li,; Xie, Kai


    This paper presents a new paradigm for image transmission through analog error correction codes. Conventional schemes rely on digitizing images through quantization (which inevitably causes significant bandwidth expansion) and transmitting binary bit-streams through digital error correction codes (which do not automatically differentiate the different levels of significance among the bits). To strike a better overall performance in terms of transmission efficiency and quality, we propose to use a single analog error correction code in lieu of digital quantization, digital code and digital modulation. The key is to get analog coding right. We show that this can be achieved by cleverly exploiting an elegant "butterfly" property of chaotic systems. Specifically, we demonstrate a tail-biting triple-branch baker's map code and its maximum-likelihood decoding algorithm. Simulations show that the proposed analog code can actually outperform digital turbo code, one of the best codes known to date. The results and fin...

  20. Synthesis and Biological Activity of Philanthotoxin Analogs

    Institute of Scientific and Technical Information of China (English)

    Yong An ZHANG; Ke Zhong LIU; Deng Yuan WANG; Yu Zhu WANG; Liang Jian QU; Chang Jin ZHU


    The synthesis of four analogs of philanthotoxin is described. The preliminary bioassay showed that these compounds all had good insecticidal activities, and the compound 6a had the best killing effect.

  1. Gastroenteropancreatic Neuroendocrine Tumors: Standardizing Therapy Monitoring with 68Ga-DOTATOC PET/CT Using the Example of Somatostatin Receptor Radionuclide Therapy


    Wolfgang Luboldt; Holger Hartmann; Bärbel Wiedemann; Klaus Zöphel; Hans-Joachim Luboldt


    The purpose of this study was to standardize therapy monitoring of hepatic metastases from gastroenteropancreatic neuroendocrine tumors (GEP-NETs) during the course of somatostatin receptor radionuclide therapy (SRRT). In 21 consecutive patients with nonresectable hepatic metastases of GEP-NETs, chromogranin A (CgA) and 68Ga-DOTATOC PET/CT were compared before and after the last SRRT. On 68Ga-DOTATOC PET/CT, the maximum standard uptake values (SUVmax) of normal liver and hepatic metastases we...

  2. Somatostatin receptor scintigraphy - a case report and review of the literature; Cintilografia de receptores de somatostatina - relato de um caso e revisao da literatura

    Energy Technology Data Exchange (ETDEWEB)

    Yamaga, Lilian Yuri Itaya; Belfer, Aron J.; Segal, Amisa [Unidade Radiologica Paulista, Sao Paulo, SP (Brazil)


    The authors report a case of carcinoid tumor, diagnosed in a 75-year-old male patient, confirmed by laparotomy and anatomo-pathological study. The patient was examined by somatostatin receptor scintigraphy with In-pentetreotide, and correlation was performed with I-MIBG and CT scan. A review of current literature about this new tracer for detection of carcinoid tumor is presented. (author) 6 refs., 6 figs.

  3. Molecular imaging with {sup 68}Ga-SSTR PET/CT and correlation to immunohistochemistry of somatostatin receptors in neuroendocrine tumours

    Energy Technology Data Exchange (ETDEWEB)

    Kaemmerer, Daniel; Haugvik, Sven-Petter; Hommann, Merten [Zentralklinik Bad Berka GmbH, Department of General and Visceral Surgery, Bad Berka (Germany); Peter, Luisa; Lupp, Amelie; Schulz, Stefan [University of Jena, Department of Pharmacology and Toxicology, Jena (Germany); Saenger, Joerg [Laboratory of Pathology and Cytology, Bad Berka (Germany); Prasad, Vikas; Kulkarni, Harshad; Baum, Richard Paul [Zentralklinik Bad Berka, Department of Nuclear Medicine and Center for PET, Bad Berka (Germany)


    Somatostatin receptors (SSTR) are known for an overexpression in gastroenteropancreatic neuroendocrine tumours (GEP-NET). The aim of the present study was to find out if the receptor density predicted by the semi-quantitative parameters generated from the static positron emission tomography (PET/CT) correlated with the in vitro immunohistochemistry using a novel rabbit monoclonal anti-SSTR2A antibody (clone UMB-1) for specific SSTR2A immunohistochemistry and polyclonal antibodies for SSTR1 and 3-5. Overall 14 surgical specimens generated from 34 histologically documented GEP-NET patients were correlated with the preoperative {sup 68}Ga-DOTA-NOC PET/CT. Quantitative assessment of the receptor density was done using the immunoreactive score (IRS) of Remmele and Stegner; the additional 4-point IRS classification for immunohistochemistry and standardized uptake values (SUV{sub max} and SUV{sub mean}) were used for PET/CT. The IRS for SSTR2A and SSTR5 correlated highly significant with the SUV{sub max} on the PET/CT (p < 0.001; p < 0.05) and the IRS for SSTR2A with the SUV{sub mean} (p < 0.013). The level of SSTR2A score correlated significantly with chromogranin A staining and indirectly to the tumour grading. The highly significant correlation between SSTR2A and SSTR5 and the SUV{sub max} on the {sup 68}Ga-DOTA-NOC PET/CT scans is concordant with the affinity profile of {sup 68}Ga-DOTA-NOC to the SSTR subtypes and demonstrates the excellent qualification of somatostatin analogues in the diagnostics of NET. This study correlating somatostatin receptor imaging using {sup 68}Ga-DOTA-NOC PET/CT with immunohistochemically analysed SSTR also underlines the approval of therapy using somatostatin analogues, follow-up imaging as well as radionuclide therapy. (orig.)

  4. The Structure of Analogical Models in Science. (United States)


    analogies cannot. 8. A Freudian defense might claim that the theory merely reflects the illogic of the unconscious. But a theory about an initial comparison. To illustrate the points, analogies of historical importance are analyzed. Although the focus is on theory , some empirical...feature-list theory , the structure-mapping approach makes a strong distinction between objects and their attributes, on the one hand, and relationships, on

  5. Learning Domain Theories via Analogical Transfer (United States)


    Shive & Weber 1982). In the linear kinematics section of the textbook used for this study ( Giancoli 1991), there are eight worked out analogous to the dynamics of linear motion” (p. 197, Giancoli 1991). This is common practice in textbooks, and analogies between domains form the...and Worked Solution All problems and worked solutions used in this work were taken from the same physics textbook ( Giancoli 1991). Problems are

  6. Synthetic heparin-binding growth factor analogs (United States)

    Pena, Louis A.; Zamora, Paul; Lin, Xinhua; Glass, John D.


    The invention provides synthetic heparin-binding growth factor analogs having at least one peptide chain that binds a heparin-binding growth factor receptor, covalently bound to a hydrophobic linker, which is in turn covalently bound to a non-signaling peptide that includes a heparin-binding domain. The synthetic heparin-binding growth factor analogs are useful as soluble biologics or as surface coatings for medical devices.

  7. Analogical Learning and Automated Rule Constructions

    Institute of Scientific and Technical Information of China (English)



    This paper describes some experiments of analogical learning and automated rule construction.The present investigation focuses on knowledge acquisition,learning by analyogy,and knowledge retention.The developed system initially learns from scratch,gradually acquires knowledge from its environment through trial-and-error interaction,incrementally augments its knowledge base,and analogically solves new tasks in a more efficient and direct manner.

  8. Analogy betwen dislocation creep and relativistic cosmology


    J.A. Montemayor-Aldrete; J.D. Muñoz-Andrade; Mendoza-Allende, A.; Montemayor-Varela, A.


    A formal, physical analogy between plastic deformation, mainly dislocation creep, and Relativistic Cosmology is presented. The physical analogy between eight expressions for dislocation creep and Relativistic Cosmology have been obtained. By comparing the mathematical expressions and by using a physical analysis, two new equations have been obtained for dislocation creep. Also, four new expressions have been obtained for Relativistic Cosmology. From these four new equations, one may determine...

  9. Analog baseband circuits for sensor systems



    This thesis is composed of six publications and an overview of the research topic, which also summarizes the work. The research presented in this thesis focuses on research into analog baseband circuits for sensor systems. The research is divided into three different topics: the integration of analog baseband circuits into a radio receiver for sensor applications; the integration of an ΔΣ modulator A/D converter into a GSM/WCDMA radio receiver for mobile phones, and the integration of algorit...

  10. Automated Integrated Analog Filter Design Issues



    An analysis of modern automated integrated analog circuits design methods and their use in integrated filter design is done. Current modern analog circuits automated tools are based on optimization algorithms and/or new circuit generation methods. Most automated integrated filter design methods are only suited to gmC and switched current filter topologies. Here, an algorithm for an active RC integrated filter design is proposed, that can be used in automated filter designs. The algorithm is t...

  11. The analogy between stereo depth and brightness. (United States)

    Brookes, A; Stevens, K A


    Apparent depth in stereograms exhibits various simultaneous-contrast and induction effects analogous to those reported in the luminance domain. This behavior suggests that stereo depth, like brightness, is reconstructed, ie recovered from higher-order spatial derivatives or differences of the original signal. The extent to which depth is analogous to brightness is examined. There are similarities in terms of contrast effects but dissimilarities in terms of the lateral inhibition effects traditionally attributed to underlying spatial-differentiation operators.

  12. Protein Structure Prediction with Visuospatial Analogy (United States)

    Davies, Jim; Glasgow, Janice; Kuo, Tony

    We show that visuospatial representations and reasoning techniques can be used as a similarity metric for analogical protein structure prediction. Our system retrieves pairs of α-helices based on contact map similarity, then transfers and adapts the structure information to an unknown helix pair, showing that similar protein contact maps predict similar 3D protein structure. The success of this method provides support for the notion that changing representations can enable similarity metrics in analogy.

  13. AMiBA Wideband Analog Correlator

    CERN Document Server

    Li, Chao-Te; Wilson, Warwick; Lin, Kai-Yang; Chen, Ming-Tang; Ho, P T P; Chen, Chung-Cheng; Han, Chih-Chiang; Oshiro, Peter; Martin-Cocher, Pierre; Chang, Chia-Hao; Chang, Shu-Hao; Altamirano, Pablo; Jiang, Homin; Chiueh, Tzi-Dar; Lien, Chun-Hsien; Wang, Huei; Wei, Ray-Ming; Yang, Chia-Hsiang; Peterson, Jeffrey B; Chang, Su-Wei; Huang, Yau-De; Hwang, Yuh-Jing; Kesteven, Michael; Koch, Patrick; Liu, Guo-Chin; Nishioka, Hiroaki; Umetsu, Keiichi; Wei, Tashun; Wu, Jiun-Huei Proty


    A wideband analog correlator has been constructed for the Yuan-Tseh Lee Array for Microwave Background Anisotropy. Lag correlators using analog multipliers provide large bandwidth and moderate frequency resolution. Broadband IF distribution, backend signal processing and control are described. Operating conditions for optimum sensitivity and linearity are discussed. From observations, a large effective bandwidth of around 10 GHz has been shown to provide sufficient sensitivity for detecting cosmic microwave background variations.

  14. HAPS, a Handy Analog Programming System

    DEFF Research Database (Denmark)

    Højberg, Kristian Søe


    HAPS (Hybrid Analog Programming System) is an analog compiler that can be run on a minicomputer in an interactive mode. Essentially HAPS is written in FORTRAN. The equations to be programmed for an ana log computer are read in by using a FORTRAN-like notation. The input must contain maximum...... and emphasizes the limitations HAPS puts on equation structure, types of computing circuit, scaling, and static testing....

  15. Bipolar disorder type 1 and schizophrenia are accompanied by decreased density of parvalbumin- and somatostatin-positive interneurons in the parahippocampal region. (United States)

    Wang, Alice Y; Lohmann, Kathryn M; Yang, C Kevin; Zimmerman, Eric I; Pantazopoulos, Harry; Herring, Nicole; Berretta, Sabina; Heckers, Stephan; Konradi, Christine


    GABAergic interneurons synchronize network activities and monitor information flow. Post-mortem studies have reported decreased densities of cortical interneurons in schizophrenia (SZ) and bipolar disorder (BPD). The entorhinal cortex (EC) and the adjacent subicular regions are a hub for integration of hippocampal and cortical information, a process that is disrupted in SZ. Here we contrast and compare the density of interneuron populations in the caudal EC and subicular regions in BPD type I (BPD-I), SZ, and normal control (NC) subjects. Post-mortem human parahippocampal specimens of 13 BPD-I, 11 SZ and 17 NC subjects were used to examine the numerical density of parvalbumin-, somatostatin- or calbindin-positive interneurons. We observed a reduction in the numerical density of parvalbumin- and somatostatin-positive interneurons in the caudal EC and parasubiculum in BPD-I and SZ, but no change in the subiculum. Calbindin-positive interneuron densities were normal in all brain areas examined. The profile of decreased density was strikingly similar in BPD-I and SZ. Our results demonstrate a specific reduction of parvalbumin- and somatostatin-positive interneurons in the parahippocampal region in BPD-I and SZ, likely disrupting synchronization and integration of cortico-hippocampal circuits.

  16. Enhanced bilateral somatostatin receptor expression in mediastinal lymph nodes (``chimney sign``) in occult metastatic medullary thyroid cancer: a typical site of tumour manifestation?

    Energy Technology Data Exchange (ETDEWEB)

    Behr, T.M. [Department of Nuclear Medicine, Georg-August-University of Goettingen (Germany); Gratz, S. [Department of Nuclear Medicine, Georg-August-University of Goettingen (Germany); Markus, P.M. [Department of Surgery (General and Endocrine Surgery), Georg-August-University of Goettingen (Germany); Dunn, R.M. [Garden State Cancer Center at the Center for Molecular Medicine and Immunology, Belleville (United States); Huefner, M. [Department of Internal Medicine (Endocrinology), Georg-August-University of Goettingen (Germany); Becker, H. [Department of Surgery (General and Endocrine Surgery), Georg-August-University of Goettingen (Germany); Becker, W. [Department of Nuclear Medicine, Georg-August-University of Goettingen (Germany)


    In medullary thyroid cancer (MTC), post-surgically elevated plasma calcitonin and/or carcinoembryonic antigen levels frequently indicate persisting metastatic disease, although conventional diagnostic procedures fail to localize the responsible lesions (occult disease). Somatostatin analogues have been used successfully in disease localization, but recently concerns have been raised that increased thoracic uptake of indium-111 pentetreotide in patients with previous external beam irradiation may represent a false-positive finding, caused by post-irradiation pulmonary fibrosis. We recently examined seven patients with metastatic MTC by somatostatin receptor scintigraphy (six with occult and one with established disease). In four patients, all of whom had stable or slowly rising tumour marker levels over several years, a chimney-like bilateral mediastinal uptake of indium-111 pentetreotide was found. In two patients with persisting hypercalcitonaemia immediately after primary surgery, supraclavicular lymph node metastases were identified as the responsible lesions. None of these seven patients had prior external beam radiation therapy. In two cases, histological confirmation was obtained. In one patient, disease progression could be shown during follow-up. These data suggest that bilateral mediastinal lymph node involvement is a typical site of disease in slowly progressing occult metastatic MTC; the ``chimney sign`` may represent a typical finding with somatostatin analogues in such cases. Therefore, we believe that even in the case of prior external beam irradiation, mediastinal uptake of octreotide might represent metastatic MTC rather than radiation fibrosis. (orig.). With 2 figs., 1 tab.

  17. Blunted ACTH and cortisol responses to systemic injection of corticotropin-releasing hormone (CRH) in fibromyalgia: role of somatostatin and CRH-binding protein. (United States)

    Riedel, Walter; Schlapp, Ulrike; Leck, Stefanie; Netter, Petra; Neeck, Gunther


    Thirteen female patients suffering from fibromyalgia (FM) and thirteen female age-matched controls were intravenously injected with a bolus dose of 100 microg corticotropin-releasing hormone (CRH), and the evoked secretion pattern of ACTH, cortisol, somatostatin, and growth hormone (GH) was followed up for two hours, together with the plasma levels of CRH. The increases of ACTH and cortisol following CRH were not significantly different between controls and FM patients. The increase of plasma CRH following its injection was significantly higher in FM patients and lasted about 45 min, paralleled by an increase of somatostatin with a similar time course. Basal GH levels were significantly lower in FM patients. GH increased in FM patients 90 min after injection of CRH, coincident with decreasing CRH and somatostatin levels, while GH levels in controls rather decreased with the lowest values occurring 90 min after CRH. The results support the concept that the hormonal secretion pattern frequently observed in FM patients is primarily caused by CRH, possibly as a response to chronic pain and stress. The elevated levels of CRH in the circulation of FM patients suggest elevated levels of CRH-binding protein, which could explain why the levels of ACTH and cortisol between controls and FM following CRH do not differ.

  18. Analog modelling of obduction processes (United States)

    Agard, P.; Zuo, X.; Funiciello, F.; Bellahsen, N.; Faccenna, C.; Savva, D.


    Obduction corresponds to one of plate tectonics oddities, whereby dense, oceanic rocks (ophiolites) are presumably 'thrust' on top of light, continental ones, as for the short-lived, almost synchronous Peri-Arabic obduction (which took place along thousands of km from Turkey to Oman in c. 5-10 Ma). Analog modelling experiments were performed to study the mechanisms of obduction initiation and test various triggering hypotheses (i.e., plate acceleration, slab hitting the 660 km discontinuity, ridge subduction; Agard et al., 2007). The experimental setup comprises (1) an upper mantle, modelled as a low-viscosity transparent Newtonian glucose syrup filling a rigid Plexiglas tank and (2) high-viscosity silicone plates (Rhodrosil Gomme with PDMS iron fillers to reproduce densities of continental or oceanic plates), located at the centre of the tank above the syrup to simulate the subducting and the overriding plates - and avoid friction on the sides of the tank. Convergence is simulated by pushing on a piston at one end of the model with velocities comparable to those of plate tectonics (i.e., in the range 1-10 cm/yr). The reference set-up includes, from one end to the other (~60 cm): (i) the piston, (ii) a continental margin containing a transition zone to the adjacent oceanic plate, (iii) a weakness zone with variable resistance and dip (W), (iv) an oceanic plate - with or without a spreading ridge, (v) a subduction zone (S) dipping away from the piston and (vi) an upper, active continental margin, below which the oceanic plate is being subducted at the start of the experiment (as is known to have been the case in Oman). Several configurations were tested and over thirty different parametric tests were performed. Special emphasis was placed on comparing different types of weakness zone (W) and the extent of mechanical coupling across them, particularly when plates were accelerated. Displacements, together with along-strike and across-strike internal deformation in all

  19. Development of analogical problem-solving skill. (United States)

    Holyoak, K J; Junn, E N; Billman, D O


    3 experiments were performed to assess children's ability to solve a problem by analogy to a superficially dissimilar situation. Preschoolers and fifth and sixth graders were asked to solve a problem that allowed multiple solutions. Some subjects were first read a story that included an analogous problem and its solution. When the mapping between the relations involved in the corresponding solutions was relatively simple, and the corresponding instruments were perceptually and functionally similar, even preschoolers were able to use the analogy to derive a solution to the transfer problem (Experiment 1). Furthermore, salient similarity of the instruments was neither sufficient (Experiment 2) nor necessary (Experiment 3) for success by preschool subjects. When the story analog mapped well onto the transfer problem, 4-year-olds were often able to generate a solution that required transformation of an object with little perceptual or semantic similarity to the instrument used in the base analog (Experiment 3). The older children used analogies in a manner qualitatively similar to that observed in comparable studies with adults (Experiment 1), whereas the younger children exhibited different limitations.

  20. Comparative analysis of the anti-chikungunya virus activity of novel bryostatin analogs confirms the existence of a PKC-independent mechanism. (United States)

    Abdelnabi, Rana; Staveness, Daryl; Near, Katherine E; Wender, Paul A; Delang, Leen; Neyts, Johan; Leyssen, Pieter


    Previously, we reported that salicylate-based analogs of bryostatin protect cells from chikungunya virus (CHIKV)-induced cell death. Interestingly, 'capping' the hydroxyl group at C26 of a lead bryostatin analog, a position known to be crucial for binding to and modulation of protein kinase C (PKC), did not abrogate the anti-CHIKV activity of the scaffold, putatively indicating the involvement of a pathway independent of PKC. The work detailed in this study demonstrates that salicylate-derived analog 1 and two capped analogs (2 and 3) are not merely cytoprotective compounds, but act as selective and specific inhibitors of CHIKV replication. Further, a detailed comparative analysis of the effect of the non-capped versus the two capped analogs revealed that compound 1 acts both at early and late stages in the chikungunya virus replication cycle, while the capped analogs only interfere with a later stage process. Co-dosing with the PKC inhibitors sotrastaurin and Gö6976 counteracts the antiviral activity of compound 1 without affecting that of capped analogs 2 and 3, providing further evidence that the latter elicit their anti-CHIKV activity independently of PKC. Remarkably, treatment of CHIKV-infected cells with a combination of compound 1 and a capped analog resulted in a pronounced synergistic antiviral effect. Thus, these salicylate-based bryostatin analogs can inhibit CHIKV replication through a novel, yet still elusive, non-PKC dependent pathway. Copyright © 2016 Elsevier Inc. All rights reserved.