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Sample records for calcitonin

  1. Calcitonin

    Science.gov (United States)

    ... Factor Antibody Iron Iron Tests JAK2 Mutation Kidney Stone Analysis Kidney Stone Risk Panel KRAS Mutation Lactate Lactate Dehydrogenase (LD) ... or breathing Persistent cough not associated with a cold A recent study also recommended measuring calcitonin before ...

  2. Oral calcitonin

    Directory of Open Access Journals (Sweden)

    Hamdy RC

    2012-09-01

    Full Text Available Ronald C Hamdy,1,2 Dane N Daley11Osteoporosis Center, College of Medicine, East Tennessee State University, 2Veterans Affairs Medical Center, Johnson City, TN, USAAbstract: Calcitonin is a hormone secreted by the C-cells of the thyroid gland in response to elevations of the plasma calcium level. It reduces bone resorption by inhibiting mature active osteoclasts and increases renal calcium excretion. It is used in the management of postmenopausal osteoporosis, Paget's disease of bone, and malignancy-associated hypercalcemia. Synthetic and recombinant calcitonin preparations are available; both have similar pharmacokinetic and pharmacodynamic profiles. As calcitonin is a peptide, the traditional method of administration has been parenteral or intranasal. This hinders its clinical use: adherence with therapy is notoriously low, and withdrawal from clinical trials has been problematic. An oral formulation would be more attractive, practical, and convenient to patients. In addition to its effect on active osteoclasts and renal tubules, calcitonin has an analgesic action, possibly mediated through β-endorphins and the central modulation of pain perception. It also exerts a protective action on cartilage and may be useful in the management of osteoarthritis and possibly rheumatoid arthritis. Oral formulations of calcitonin have been developed using different techniques. The most studied involves drug-delivery carriers such as Eligen® 8-(N-2hydroxy-5-chloro-benzoyl-amino-caprylic acid (5-CNAC (Emisphere Technologies, Cedar Knolls, NJ. Several factors affect the bioavailability and efficacy of orally administered calcitonin, including amount of water used to take the tablet, time of day the tablet is taken, and proximity to intake of a meal. Preliminary results looked promising. Unfortunately, in two Phase III studies, oral calcitonin (0.8 mg with 200 mg 5-CNAC, once a day for postmenopausal osteoporosis and twice a day for osteoarthritis failed to

  3. Calcitonin blood test

    Science.gov (United States)

    ... page: //medlineplus.gov/ency/article/003699.htm Calcitonin blood test To use the sharing features on this page, please enable JavaScript. The calcitonin blood test measures the level of the hormone calcitonin in ...

  4. Calcitonin Salmon Nasal Spray

    Science.gov (United States)

    ... bottle and turn to tighten. Then take the plastic cover off of the top of the spray unit. ... room temperature in an upright position. Replace the plastic cover to keep the nozzle clean. Opened calcitonin salmon ...

  5. Effects of salmon calcitonin and calcitonin gene related peptide ...

    African Journals Online (AJOL)

    The aim of this investigation was to examine and compare the effects of calcitonin gene related peptide (CGRP) and salmon calcitonin (sCT) on gastric lesions and mucosal barrier components such as mucus and phospholipids in rats exposed to cold + restraint stress (CRS). Twenty-eight Wistar albino rats (150 – 200 g) ...

  6. Calcitonin secretion in normal human subjects

    Energy Technology Data Exchange (ETDEWEB)

    Parthemore, J.G.; Deftos, L.J.

    1978-07-01

    A sensitive RIA for human calcitonin has been developed which can detect 1 to 2 pg hormone. This procedure permits the measurement of the low concentrations of calcitonin in the unextracted plasma of normal human subjects. In 55 normal adults, mean plasma calcitonin was 24 pg/ml with an SD of +-18 pg/ml, an SE of +-2 pg/ml, and a range of less than 10 to 75 pg/ml. There were no discernible age or sex differences in basal hormone concentration. Infusions of calcium, pentagastrin, and glucagon stimulated plasma calcitonin, whereas food and oral calcium did not. The stimulatory effect of pentagastrin was greater in males than in females. These data demonstrate that the low concentration of calcitonin in humans can be stimulated by several secretagogues and suggest that females may have decreased calcitonin reserve.

  7. 21 CFR 862.1140 - Calcitonin test system.

    Science.gov (United States)

    2010-04-01

    ...) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems § 862... measure the thyroid hormone calcitonin (thyrocalcitonin) levels in plasma and serum. Calcitonin...

  8. Calcitonin

    Science.gov (United States)

    ... 2010). Clinical Chemistry: Theory, Analysis, Correlation , 5th Edition: Mosby, Inc. p 626. Mayo Clinic Interpretive Handbook. Test ... Edition]. Pagana, Kathleen D. & Pagana, Timothy J. (2001). Mosby's Diagnostic and Laboratory Test Reference 5th Edition: Mosby, ...

  9. High serum calcitonin levels in heroin addicts.

    Science.gov (United States)

    Tagliaro, F; Capra, F; Dorizzi, R; Luisetto, G; Accordini, A; Renda, E; Parolin, A

    1984-08-01

    An involvement of calcitonin in the mechanism of pain perception has recently been hypothesized. In order to collect information about the relationship between this hormone and well known analgesic substances such as opioids, we have studied the serum levels of calcitonin in a group of heroin addicts, finding higher average concentrations than in normal subjects of matched age and sex. In these addicts there were no severe signs of impaired renal or hepatic function, or alterations of the serum levels of calcium and phosphate. So we think that opioids, in a direct or indirect way, can stimulate the secretion of calcitonin.

  10. Calcitonin receptor expression in medullary thyroid carcinoma.

    Science.gov (United States)

    Cappagli, Virginia; Potes, Catarina Soares; Ferreira, Luciana Bueno; Tavares, Catarina; Eloy, Catarina; Elisei, Rossella; Sobrinho-Simões, Manuel; Wookey, Peter J; Soares, Paula

    2017-01-01

    Calcitonin expression is a well-established marker for medullary thyroid carcinoma (MTC); yet the role of calcitonin receptor (CTR), its seven-transmembrane G-protein coupled receptor, remains to be established in C-cells derived thyroid tumors. The aim of this work was to investigate CTR expression in MTC and to correlate such expression with clinicopathological features in order to evaluate its possible role as a prognostic indicator of disease aggressiveness and outcome. Calcitonin receptor expression was analyzed in a series of 75 MTCs by immunohistochemistry, and by qPCR mRNA quantification in specimens from four patients. Statistical tests were used to evaluate the correlation between CTR expression and the clinicopathological and molecular characteristics of patients and tumors. Calcitonin receptor expression was detected in 62 out of 75 samples (82.7%), whereas 13 of the 75 samples (17.3%) were completely negative. CTR expression was significantly associated with expression of cytoplasmatic phosphatase and tensin homologue deleted on chromosome 10 and osteopontin, as well as with wild type RET/RAS genes and absence of tumor stroma, suggesting that CTR expression do not associate with clinicopathological signs of worse prognosis. Calcitonin receptor expression appears to be associated in MTC with more differentiated status of the neoplastic cells.

  11. Serotonin, calcitonin and calcitonin gene-related peptide in acute pancreatitis

    DEFF Research Database (Denmark)

    Wahlstrøm, Kirsten Lykke; Novovic, Srdan; Ersbøll, Annette Kjær

    2017-01-01

    with alcohol- or gallstone-induced AP were included over a 15-month period. Patients were treated according to a standardized algorithm and monitored for organ specific morbidity and mortality. Organ functions and blood samples were assessed on days 0, 1, 2 and 14 after hospital admission. Twenty healthy......OBJECTIVE: The aim of this study was to investigate plasma levels of serotonin, calcitonin and calcitonin gene-related peptide (CGRP) in the course of acute pancreatitis (AP) taking organ failure, etiology and severity into consideration. MATERIAL AND METHODS: Sixty consecutive patients...

  12. [Hormones and osteoporosis update. Calcitonin, CGRP and bone].

    Science.gov (United States)

    Ozono, Keiichi

    2009-07-01

    Calcitonin is the hormone secreted from parafollicular cells in the thyroid and inhibits osteoclast activity, leading to reduced bone resorption and low levels of serum calcium. Calcitonin is approved to use for osteoporosis and hypercalcemia. However, its effect on the prevention of bone fracture is still controversial, although bone mineral content is apparently improved. The same gene, CALCA, encodes another active peptide, calcitonin gene related peptide (CGRP). CGRP has been reported to promote bone formation based on the high bone mass phenotype of CALCA - deficient mouse.

  13. Calcitonin gene-related peptide and pain

    DEFF Research Database (Denmark)

    Schou, Wendy Sophie; Ashina, Sait; Amin, Faisal Mohammad

    2017-01-01

    BACKGROUND: Calcitonin gene-related peptide (CGRP) is widely distributed in nociceptive pathways in human peripheral and central nervous system and its receptors are also expressed in pain pathways. CGRP is involved in migraine pathophysiology but its role in non-headache pain has not been...... to date have investigated the efficacy of monoclonal antibodies against CGRP receptor in non-headache pain conditions. CONCLUSION: The present review revealed the association between measured CGRP levels and somatic, visceral, neuropathic and inflammatory pain. These data suggest that CGRP may act...... clarified. METHODS: We performed a systematic literature search on PubMed, Embase and ClinicalTrials.gov for articles on CGRP and non-headache pain covering human studies including experimental studies and randomized clinical trials. RESULTS: The literature search identified 375 citations of which 50...

  14. Serum levels of calcitonin in Cushing's syndrome.

    Science.gov (United States)

    Luisetto, G; Mantero, F; Boscaro, M; Tizian, L; Zangari, M; Ziliotto, D

    1986-06-01

    Serum levels of calcitonin (CT) were studied in 21 patients with Cushing's syndrome (CS), 18 females and 3 males aging from 16 to 59 years, and in 70 age and sex matched normal subjects. Patients with CS showed CT values significantly lower than those found in controls (9.9 +/- 5.0 pg/ml vs. 15.9 +/- 6.3 pg/ml, mean +/- SD; p less than 0.01), while no difference was observed in total serum calcium and phosphate and calcium corrected for albumin. No correlation between CT and serum calcium and phosphate, serum cortisol and urinary free cortisol was found. It is possible that low CT levels are involved in the pathogenesis of bone loss observed in CS.

  15. Calcitonin-like diuretic hormones in insects.

    Science.gov (United States)

    Zandawala, Meet

    2012-10-01

    Insect neuropeptides control various biological processes including growth, development, homeostasis and reproduction. The calcitonin-like diuretic hormone (CT/DH) is one such neuropeptide that has been shown to affect salt and water transport by Malpighian tubules of several insects. With an increase in the number of sequenced insect genomes, CT/DHs have been predicted in several insect species, making it easier to characterize the gene encoding this hormone and determine its function in the species in question. This mini review summarizes the current knowledge on insect CT/DHs, focusing on mRNA and peptide structures, distribution patterns, physiological roles, and receptors in insects. Copyright © 2012 Elsevier Ltd. All rights reserved.

  16. Calcitonin gene related peptide and its functions

    Directory of Open Access Journals (Sweden)

    Karimian M

    1998-07-01

    Full Text Available Calcitonin Gene Related Peptide (CGRP was first reported in 1982. This peptide contains 37 amino acids which could be found in Alpha and Beta forms. CGRP shows diversity both in its receptors and biological effects and up to now four different types of receptors have been reported. It can act like a neurotransmitter, local hormone and neuromodulator. They have a variety of effects on different organs such as a potent effect on vasodilation and smooth muscle relaxation. Ability of CGRP for induction of protein extravasation from blood vessels was uncertain. In this study intra-articular infusion of 10^-6 M CGRP to the rat knee joint induced significant protein extravasation into the rat knee joint space. The amount of protein was detected by modified Iawata method which could detect amount of protein between 5-500 mg/L. Higher and lower concentrations failed to induce protein extravasation. Failure in higher concentration was likely due to significant fall in blood pressure. In the presence of an arterial hypotension induced by an ? adenoreceptor antagonist, 10^-6 M of CGRP failed to produce protein extravasation. This effect of CGRP was a specific active effect and not a passive effect due to its potent vasodilation effect, as similar vasodilatory response induced by a ?-adrenoreceptor agonist failed to induce protein extravasation. There is more than 50% of sensory neurons which contain CGRP and they are spread in all over the body and joints, therefore CGRP induced protein extravasation can potentiate inflammation in different organs.

  17. Salmon calcitonin: conformational changes and stabilizer effects

    Directory of Open Access Journals (Sweden)

    Shan-Yang Lin

    2015-11-01

    Full Text Available The therapeutic activity of peptides or protein drugs is highly dependent on their conformational structure. The protein structure is flexible and responds to external conditions, which may compromise the protein's native conformation and influence its physical and chemical stability. The physical and chemical stability of peptides or protein drugs are important characteristics of biopharmaceutical products. Calcitonin (CT is a polypeptide hormone that participates in diverse physiological functions in humans; therefore, it is a potentially useful protein for investigations of different aspects of pharmacology and drug delivery systems. Of the different types of CT available for clinical use, salmon CT (sCT is one of the most potent. In this review article, the commercially available sCT was selected as a suitable peptide candidate for the discussion of its stability and conformational changes in the aqueous and solid states using Fourier transform infrared (FTIR spectroscopic analysis under different external conditions, including pH, temperature, drying method, and added excipients. Particularly, excipients that have been optimized as stabilizers of sCT in aqueous solution and as lyophilized and spray-dried drug formulations are also discussed.

  18. Calcitonin Receptor Plays a Physiological Role to Protect Against Hypercalcemia in Mice

    OpenAIRE

    Davey, Rachel A; Turner, Andrew G.; McManus, Julie F; Chiu, WS Maria; Tjahyono, Francisca; Moore, Alison J; Gerald J. Atkins; Anderson, Paul H.; Ma, Cathy; Glatt, Vaida; MacLean, Helen E.; Vincent, Cristina; Bouxsein, Mary,; Morris, Howard A.; Findlay, David M.

    2008-01-01

    It is well established that calcitonin is a potent inhibitor of bone resorption; however, a physiological role for calcitonin acting through its cognate receptor, the calcitonin receptor (CTR), has not been identified. Data from previous genetically modified animal models have recognized a possible role for calcitonin and the CTR in controlling bone formation; however, interpretation of these data are complicated, in part because of their mixed genetic background. Therefore, to elucidate the ...

  19. Calcitonin gene-related peptide antagonism and cluster headache

    DEFF Research Database (Denmark)

    Ashina, Håkan; Newman, Lawrence; Ashina, Sait

    2017-01-01

    Calcitonin gene-related peptide (CGRP) is a key signaling molecule involved in migraine pathophysiology. Efficacy of CGRP monoclonal antibodies and antagonists in migraine treatment has fueled an increasing interest in the prospect of treating cluster headache (CH) with CGRP antagonism. The exact...... role of CGRP and its mechanism of action in CH have not been fully clarified. A search for original studies and randomized controlled trials (RCTs) published in English was performed in PubMed and in ClinicalTrials.gov . The search term used was "cluster headache and calcitonin gene related peptide......" and "primary headaches and calcitonin gene related peptide." Reference lists of identified articles were also searched for additional relevant papers. Human experimental studies have reported elevated plasma CGRP levels during both spontaneous and glyceryl trinitrate-induced cluster attacks. CGRP may play...

  20. [Calcitonin as an alternative treatment for root resorption].

    Science.gov (United States)

    Pierce, A; Berg, J O; Lindskog, S

    1989-01-01

    Inflammatory root resorption is a common finding following trauma and will cause eventual destruction of the tooth root if left untreated. This study examined the effects of intrapulpal application of calcitonin, a hormone known to inhibit osteoclastic bone resorption, on experimental inflammatory root resorption induced in monkeys. Results were histologically evaluated using a morphometric technique and revealed that calcitonin was an effective medicament for the treatment of inflammatory root resorption. It was concluded that this hormone could be a useful therapeutic adjunct in difficult cases of external root resorption.

  1. [Prevention of recurrence of Sudeck's disease with calcitonin].

    Science.gov (United States)

    Kissling, R O; Bloesch, A C; Sager, M; Dambacher, M A; Schreiber, A

    1991-01-01

    In patients suffering from, or with a history of, reflex sympathetic dystrophy (RSD), there is always a risk of exacerbation or reactivation of this disease after surgery or trauma. The use of calcitonin in the treatment of this type of disorder is well established. Starting in 1984, 18 patients with clinical symptoms of RSD or a history of this disease were given daily prophylactic treatment with salmon calcitonin (100 IU subcutaneously or as a spray). Ten of the patients underwent orthopaedic surgery and 8 received conservative treatment following trauma. The mean duration of prophylactic treatment was 4 days before and 23 days after surgery or trauma. Only one recurrence was observed (3 per cent). For comparison, a retrospective analysis of a group with the same inclusion criteria who underwent surgery or received conservative treatment after trauma, without prophylactic administration of calcitonin showed a recurrence of the underlying disease 28 per cent of the cases. It is therefore possible to recommend prophylactic administration of calcitonin, to patients with a history of RSD who are about to undergo orthopaedic surgery or conservative treatment following trauma.

  2. Calcitonin gene-related peptide, neurokinin A and substance P

    DEFF Research Database (Denmark)

    Pedersen-Bjergaard, U; Nielsen, L B; Jensen, Kai

    1991-01-01

    Calcitonin gene-related peptide (CGRP) was injected alone and in combination with substance P (SP) or neurokinin A (NKA) into the forearm skin and temporal muscle of human volunteers. In the skin, 50 pmol of CGRP induced a wheal response and a delayed erythema. No pain was recorded. No interaction...

  3. Calcitonin serum levels in different pituitary diseases. A preliminary report.

    Science.gov (United States)

    Ziliotto, D; Luisetto, G; Cecchini, M; Gastaldo, M; Francia, G; Padovan, L; Heynen, G

    1980-01-01

    The calcitonin (CT) concentration has been determined in the serum of 17 patients with different pituitary diseases. More or less elevated levels were found in 7 of them. No definite correlation has been observed between the immunoreactive CT and the different pituitary hormones.

  4. Bone repair in rats treated with sodic diclofenac and calcitonin.

    Science.gov (United States)

    Sassioto, Maria Cristina Pita; Inouye, Celso Massaschi; Aydos, Ricardo Dutra; Figueiredo, Arthur Silveira de

    2006-01-01

    To investigate clinical and histologically the bone repair in treated animals with calcitonin and sodic diclofenac. Ninety-six femoral defects were created in forty-eight animals distributed in four groups (n=24): either left untreated, treated with the sodic diclofenac or calcitonin or both. Follow-up was 7, 14 and 21 days. Histological sections stained by haematoxylin-eosin was observed under light microscopy (100X) and quantitatively scored for their trabecular formation. The groups and subgroups were compared being used the Kruskall-Wallis test. Smaller trabecular formation was observed in the animals of the group II and larger trabecular formation in the animals of the group III. Was found significant differences in the comparison between all the groups (Kruskall-Wallis, p sodic diclofenac and accelerated by the calcitonina, when used separately. The associated use of calcitonina and sodic diclofenac didn't show to be the best therapeutic option in the treatment of bone defects surgically created.

  5. Calcitonin gene-related peptide and migraine with aura

    DEFF Research Database (Denmark)

    Hansen, Jakob M; Ashina, Messoud

    2014-01-01

    BACKGROUND: Calcitonin gene-related peptide (CGRP) is a key molecule in migraine pathophysiology. Most studies have focused on CGRP in relation to migraine without aura (MO). About one-third of migraine patients have attacks with aura (MA), and this is a systematic review of the current literature...... of CGRP in MA is less studied than in MO. Further studies of the importance of CGRP for auras and migraine are needed....

  6. Identification of the calcitonin receptor in osteoarthritic chondrocytes

    Directory of Open Access Journals (Sweden)

    Christensen Tjorbjoern

    2011-10-01

    Full Text Available Abstract Background Preclinical and clinical studies have shown that salmon calcitonin has cartilage protective effects in joint degenerative diseases, such as osteoarthritis (OA. However, the presence of the calcitonin receptor (CTR in articular cartilage chondrocytes is yet to be identified. In this study, we sought to further investigate the expression of the CTR in naïve human OA articular chondrocytes to gain further confirmation of the existents of the CTR in articular cartilage. Methods Total RNA was purified from primary chondrocytes from articular cartilage biopsies from four OA patients undergoing total knee replacement. High quality cDNA was produced using a dedicated reverse transcription polymerase chain reaction (RT-PCR protocol. From this a nested PCR assay amplifying the full coding region of the CTR mRNA was completed. Western blotting and immunohistochemistry were used to characterize CTR protein on protein level in chondrocytes. Results The full coding transcript of the CTR isoform 2 was identified in all four individuals. DNA sequencing revealed a number of allelic variants of the gene including two potentially novel polymorphisms: a frame shift mutation, +473del, producing a shorter form of the receptor protein, and a single nucleotide polymorphism in the 3' non coding region of the transcript, +1443 C>T. A 53 kDa protein band, consistent with non-glycosylated CTR isoform 2, was detected in chondrocytes with a similar size to that expressed in osteoclasts. Moreover the CTR was identified in the plasma membrane and the chondrocyte lacuna of both primary chondrocytes and OA cartilage section. Conclusions Human OA articular cartilage chondrocytes do indeed express the CTR, which makes the articular a pharmacological target of salmon calcitonin. In addition, the results support previous findings suggesting that calcitonin has a direct anabolic effect on articular cartilage.

  7. Calcitonin Gene-Related Peptide: Physiology and Pathophysiology

    Science.gov (United States)

    Russell, F. A.; King, R.; Smillie, S.-J.; Kodji, X.; Brain, S. D.

    2014-01-01

    Calcitonin gene-related peptide (CGRP) is a 37-amino acid neuropeptide. Discovered 30 years ago, it is produced as a consequence of alternative RNA processing of the calcitonin gene. CGRP has two major forms (α and β). It belongs to a group of peptides that all act on an unusual receptor family. These receptors consist of calcitonin receptor-like receptor (CLR) linked to an essential receptor activity modifying protein (RAMP) that is necessary for full functionality. CGRP is a highly potent vasodilator and, partly as a consequence, possesses protective mechanisms that are important for physiological and pathological conditions involving the cardiovascular system and wound healing. CGRP is primarily released from sensory nerves and thus is implicated in pain pathways. The proven ability of CGRP antagonists to alleviate migraine has been of most interest in terms of drug development, and knowledge to date concerning this potential therapeutic area is discussed. Other areas covered, where there is less information known on CGRP, include arthritis, skin conditions, diabetes, and obesity. It is concluded that CGRP is an important peptide in mammalian biology, but it is too early at present to know if new medicines for disease treatment will emerge from our knowledge concerning this molecule. PMID:25287861

  8. Circulating parathyroid hormone and calcitonin in rats after spaceflight

    Science.gov (United States)

    Arnaud, Sara B.; Fung, Paul; Popova, Irina A.; Morey-Holton, Emily R.; Grindeland, Richard E.

    1992-01-01

    Parathyroid hormone and calcithonin, two major calcium-regulating hormones, were measured in the plasma of five experimental groups of rats to evaluate postflight calcium homeostasis after the 14-day Cosmos 2044 flight. Parathyroid hormone values were slightly higher in the flight animals (F) than in the appropriate cage and diet controls (S) (44 +/- 21 vs 21 +/- 4 pg/ml, P less than 0.05), but they were the same as in the vivarium controls (V), which had different housing and feeding schedules. The difference in F and V (22 +/- 11 vs 49 +/- 16 pg/ml, P less than 0.05) was most likely due to failure of circulating calcitonin in F to show the normal age-dependent increase which was demonstrated in age-matched controls in a separate experiment. Basal values for parathyroid hormone and calcitonin were unchanged after 2 wk of hindlimb suspension, a flight simulation model, in age-matched and younger rats. From a time course experiment serum calcium was higher and parathyroid hormone lower after 4 wk than in ambulatory controls. Postflight circulating levels of parathyroid hormone appear to reflect disturbances in calcium homeostasis from impaired renal function of undetermined cause, whereas levels of calcitonin reflect depression of a normal growth process.

  9. Effects of salmon calcitonin on fracture healing in ovariectomized rats.

    Science.gov (United States)

    Li, Xiaolin; Luo, Xinle; Yu, Nansheng; Zeng, Bingfang

    2007-01-01

    To explore the effects of salmon calcitonin on the healing process of osteoporotic fractures in ovariectomized rats. We performed this study in The First Affiliated Hospital of Guangzhou Medical College, Guangzhou, China, during the period March 2002 to December 2004. We used 120 female adult Wistar rats in this experiment, among which 90 underwent ovariectomy (OVX) and the other 30 had sham-operation. All rats had their left tibias fractured 3 months later. The 90 OVX rats were randomly divided into 3 groups with 30 in each, while the 30 sham-operated rats served as control group. After the fracture the rats had subcutaneous injection of normal saline, salmon calcitonin and estrogen, respectively. X-ray film, histological examination, bone mineral density (BMD) measurement and biomechanics testing were carried out to evaluate the fracture healing. Compared with OVX rats treated with normal saline, the rats with salmon calcitonin had significantly higher BMD values in the left tibia, higher max torque, shear stress of the left tibia 8 weeks after fracture (pbiomechanical properties and improve the process of fracture healing in fractured osteoporotic bone.

  10. Investigation of the direct effects of salmon calcitonin on human osteoarthritic chondrocytes

    Directory of Open Access Journals (Sweden)

    Pedersen Christian

    2010-04-01

    Full Text Available Abstract Background Calcitonin has been demonstrated to have chondroprotective effects under pre-clinical settings. It is debated whether this effect is mediated through subchondral-bone, directly on cartilage or both in combination. We investigated possible direct effects of salmon calcitonin on proteoglycans and collagen-type-II synthesis in osteoarthritic (OA cartilage. Methods Human OA cartilage explants were cultured with salmon calcitonin [100 pM-100 nM]. Direct effects of calcitonin on articular cartilage were evaluated by 1 measurement of proteoglycan synthesis by incorporation of radioactive labeled 35SO4 [5 μCi] 2 quantification of collagen-type-II formation by pro-peptides of collagen type II (PIINP ELISA, 3 QPCR expression of the calcitonin receptor in OA chondrocytes using four individual primer pairs, 4 activation of the cAMP signaling pathway by EIA and, 5 investigations of metabolic activity by AlamarBlue. Results QPCR analysis and subsequent sequencing confirmed expression of the calcitonin receptor in human chondrocytes. All doses of salmon calcitonin significantly elevated cAMP levels (P 35SO4 incorporation, with a 96% maximal induction at 10 nM (P Conclusion Calcitonin treatment increased proteoglycan and collagen synthesis in human OA cartilage. In addition to its well-established effect on subchondral bone, calcitonin may prove beneficial to the management of joint diseases through direct effects on chondrocytes.

  11. Preoperative calcitonin levels are predictive of tumor size and postoperative calcitonin normalization in medullary thyroid carcinoma. Groupe d'Etudes des Tumeurs a Calcitonine (GETC).

    Science.gov (United States)

    Cohen, R; Campos, J M; Salaün, C; Heshmati, H M; Kraimps, J L; Proye, C; Sarfati, E; Henry, J F; Niccoli-Sire, P; Modigliani, E

    2000-02-01

    Medullary thyroid carcinoma (MTC) is a calcitonin (CT)-secreting endocrine tumor. Although plasma CT level is a specific and sensitive marker of MTC, its preoperative usefulness in predicting tumor size and postoperative CT normalization has not been documented. From a nationwide database set up by the French CT Tumor Study Group, 226 MTC patients were selected according to the following criteria: preoperative CT level determination by an immunoradiometric assay (normal value, normalization was ascertained by negative response of CT to pentagastrin stimulation (forms (15.0 vs. 7.0 mm, P forms. Furthermore, preoperative CT levels under 50 pg/mL appeared to be predictive of postoperative CT normalization (44 of 45 patients). However, higher CT levels did not mean absence of postoperative CT normalization (50 of 120 patients). We conclude that low preoperative CT levels are predictive of tumor size and postoperative CT normalization.

  12. Anti-hyperalgesic effects of calcitonin on neuropathic pain interacting with its peripheral receptors

    Directory of Open Access Journals (Sweden)

    Ito Akitoshi

    2012-06-01

    Full Text Available Abstract Background The polypeptide hormone calcitonin is clinically well known for its ability to relieve neuropathic pain such as spinal canal stenosis, diabetic neuropathy and complex regional pain syndrome. Mechanisms for its analgesic effect, however, remain unclear. Here we investigated the mechanism of anti-hyperalgesic action of calcitonin in a neuropathic pain model in rats. Results Subcutaneous injection of elcatonin, a synthetic derivative of eel calcitonin, relieved hyperalgesia induced by chronic constriction injury (CCI. Real-time reverse transcriptase-polymerase chain reaction analysis revealed that the CCI provoked the upregulation of tetrodotoxin (TTX-sensitive Nav.1.3 mRNA and downregulation of TTX-resistant Nav1.8 and Nav1.9 mRNA on the ipsilateral dorsal root ganglion (DRG, which would consequently increase the excitability of peripheral nerves. These changes were reversed by elcatonin. In addition, the gene expression of the calcitonin receptor and binding site of 125I-calcitonin was increased at the constricted peripheral nerve tissue but not at the DRG. The anti-hyperalgesic effect and normalization of sodium channel mRNA by elcatonin was parallel to the change of the calcitonin receptor expression. Elcatonin, however, did not affect the sensitivity of nociception or gene expression of sodium channel, while it suppressed calcitonin receptor mRNA under normal conditions. Conclusions These results suggest that the anti-hyperalgesic action of calcitonin on CCI rats could be attributable to the normalization of the sodium channel expression, which might be exerted by an unknown signal produced at the peripheral nerve tissue but not by DRG neurons through the activation of the calcitonin receptor. Calcitonin signals were silent in the normal condition and nerve injury may be one of triggers for conversion of a silent to an active signal.

  13. Calcitonin directly attenuates collagen type II degradation by inhibition of matrix metalloproteinase expression and activity in articular chondrocytes

    DEFF Research Database (Denmark)

    Sondergaard, B C; Wulf, H; Henriksen, K

    2006-01-01

    -dependently increased cAMP levels in isolated chondrocytes. Explants cultured with TNF-alpha and OSM showed a 100-fold increase in CTX-II release compared to vehicle-treated controls (Pconcentration-dependently inhibited by calcitonin, 65% protection.......0001-1 microM]. In vivo, cartilage degradation was investigated in ovariectomized (OVX) rats administered with oral calcitonin [2 mg/kg calcitonin] for 9 weeks. RESULTS: The calcitonin receptor was identified in articular chondrocytes by immunohistochemistry and RT-PCR. Calcitonin concentration...

  14. Medullary thyroid carcinoma and duodenal calcitonin-secreting neuroendocrine tumour: more than coincidence?

    Science.gov (United States)

    Huguet, I; Lamas, C; Vera, R; Lomas, A; Quilez, R P; Grossman, A; Botella, F

    2013-01-01

    Summary Neuroendocrine tumours (NETs) are a heterogeneous group of neoplasms whose management can be problematic. In many cases, multiple tumours may occur in the same patient or his or her family, and some of these have now been defined genetically, although in other cases the underlying gene or genes involved remain unclear. We describe a patient, a 63-year-old female, who was diagnosed with a medullary thyroid carcinoma (MTC), which was confirmed pathologically after thyroidectomy, but whose circulating calcitonin levels remained elevated after thyroidectomy with no evidence of metastatic disease. Subsequently, an entirely separate and discrete duodenal NET was identified; this was 2.8 cm in diameter and was removed at partial duodenectomy. The tumour stained immunohistochemically for calcitonin, and its removal led to persistent normalisation of the circulating calcitonin levels. There was no germline mutation of the RET oncogene. This is the first identification of a duodenal NET secreting calcitonin and also the first demonstration of a second tumour secreting calcitonin in a patient with MTC. We suggest that where calcitonin levels remain high after removal of a MTC a search for other NETs should be conducted. Learning points NETs are a complex and heterogeneous group of related neoplasms, and multiple tumours may occur in the same patient.Calcitonin can be produced ectopically by several tumours outside the thyroid.Persistently elevated calcitonin levels after removal of a MTC may not necessarily indicate persisting or metastatic disease from the tumour.The real prevalence of calcitonin-producing NETs may be underestimated, as serum determination is only recommended in the diagnosis of pancreatic NETs. PMID:24616764

  15. Involvement of calcitonin gene-related peptide in migraine

    DEFF Research Database (Denmark)

    Lassen, L H; Jacobsen, V B; Haderslev, P A

    2008-01-01

    mug/min) or placebo for 20 min was studied in 12 patients with migraine without aura outside attacks. Xenon-133 inhalation SPECT-determined regional cerebral blood flow (rCBF) and transcranial Doppler (TCD)-determined blood velocity (V (mean)) in the middle cerebral artery (MCA), as well as the heart......Calcitonin gene-related peptide (CGRP)-containing nerves are closely associated with cranial blood vessels. CGRP is the most potent vasodilator known in isolated cerebral blood vessels. CGRP can induce migraine attacks, and two selective CGRP receptor antagonists are effective in the treatment...... of migraine attacks. It is therefore important to investigate its mechanism of action in patients with migraine. We here investigate the effects of intravenous human alpha-CGRP (halphaCGRP) on intracranial hemodynamics. In a double-blind, cross-over study, the effect of intravenous infusion of halphaCGRP (2...

  16. Calcitonin Forms Oligomeric Pore-Like Structures in Lipid Membranes

    Science.gov (United States)

    Diociaiuti, Marco; Polzi, Laura Zanetti; Valvo, Luisa; Malchiodi-Albedi, Fiorella; Bombelli, Cecilia; Gaudiano, Maria Cristina

    2006-01-01

    Calcitonin is a polypeptidic hormone involved in calcium metabolism in the bone. It belongs to the amyloid protein family, which is characterized by the common propensity to aggregate acquiring a β-sheet conformation and include proteins associated with important neurodegenerative diseases. Here we show for the first time, to our knowledge, by transmission electron microscopy (TEM) that salmon-calcitonin (sCT) forms annular oligomers similar to those observed for β-amyloid and α-sinuclein (Alzheimer's and Parkinson's diseases). We also investigated the interaction between sCT and model membranes, such as liposomes, with particular attention to the effect induced by lipid “rafts” made of cholesterol and GM1. We observed, by TEM immunogold labeling of sCT, that protein binding is favored by the presence of rafts. In addition, we found by TEM that sCT oligomers inserted in the membrane have the characteristic pore-like morphology of the amyloid proteins. Circular dichroism experiments revealed an increase in β-content in sCT secondary structure when the protein was reconstituted in rafts mimicking liposomes. Finally, we showed, by spectrofluorimetry experiments, that the presence of sCT allowed Ca2+ entry in rafts mimicking liposomes loaded with the Ca2+-specific fluorophore Fluo-4. This demonstrates that sCT oligomers have ion-channel activity. Our results are in good agreement with recent electrophysiological studies reporting that sCT forms Ca2+-permeable ion channels in planar model membranes. It has been proposed that, beyond the well-known interaction of the monomer with the specific receptor, the formation of Ca2+ channels due to sCT oligomers could represent an extra source of Ca2+ entry in osteoblasts. Structural and functional data reported here support this hypothesis. PMID:16940475

  17. [Effect of calcitonin, somatostatin and cimetidine on stress ulcer in rats].

    Science.gov (United States)

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

    1978-05-01

    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.

  18. Calcitonin in the treatment of Paget’s disease of bone

    OpenAIRE

    Mallia, Carmel;

    1989-01-01

    A retrospective survey at the request of Pharmacy & Therapeutics Committee, St. Luke’s Hospital was undertaken to evaluate prescribing habits of calcitonin in Paget’s disease of bone, as well as to assess its effectiveness.

  19. Positive effect of calcitonin on the seizures induced by pentylenetetrazole in rats.

    Science.gov (United States)

    Aksoy, Durdane; Solmaz, Volkan; Erbas, Oytun

    2014-03-01

    There are many difficulties involved with the treatment of epilepsy, and these problems have driven the search for new agents to control epileptic seizures. Calcitonin is a peptide hormone that has been well studied and shown to have a positive effect on neuropathic and chronic pain. The mechanism by which calcitonin affects these pain syndromes is thought to be similar to the effect of antiepileptic drugs, such as pregabalin, gabapentin and carbamazepine. In this study, we aim to investigate the effects of calcitonin on seizures induced by pentylenetetrazole (PTZ) in rats. The rats were divided into four groups. The first group was the control group, and the rats were given no medications. The second group was given saline+PTZ. The third group was given 50IU/kg calcitonin+PTZ, and the fourth group was given 100IU/kg calcitonin+PTZ. EEG traces, Racine's convulsion stages and the time of onset of the first myoclonic jerk were compared between the groups. Between the groups, there were significant differences in the Racine's convulsion stages, the onset of the 'first myoclonic jerk', and the rate of the spikes in the EEG traces. The differences were more pronounced in the 100IU/kg calcitonin-treated group (p<0.001). It has been stated that calcitonin relieves pain via regulating voltage-gated Ca(2+) and/or Na(+) channels. Calcitonin has a positive effect on convulsions in epileptic rats, possibly using the same mechanisms as is used in the treatment of neuropathic and chronic pain. Copyright © 2014 Elsevier B.V. All rights reserved.

  20. Low-Level Laser Therapy and Calcitonin in Bone Repair: Densitometric Analysis

    Directory of Open Access Journals (Sweden)

    Tatiana Pinto Ribeiro

    2012-01-01

    Full Text Available The aim of this work was to evaluate the association of low-level laser therapy (LLLT, 830 nm and calcitonin in bone repair considering that bone healing remains a challenge to health professionals. Calcitonin has antiosteoclastic action and LLLT is a treatment that uses low-level lasers or light-emitting diodes to alter cellular function. Both are used to improve bone healing. Densitometry is a clinical noninvasive valuable tool used to evaluate bone mineral density (BMD. Sixty male rats were submitted to bone defect with a trephine bur, randomly divided into four groups of 15 animals each: control (C; synthetic salmon calcitonin (Ca; LLLT (La; LLLT combined with calcitonin (LaCa. Animals from Ca and LaCa received 2 UI/Kg synthetic salmon calcitonin intramuscularly on alternate days after surgery. Animals from groups La and LaCa were treated with infrared LLLT (830 nm, 10 mW, 20 J/cm2, 6 s, contact mode. Five animals from each group were euthanized 7, 14, and 21 days after surgery and bone defects were analyzed by densitometry. Statistical analysis showed a significant difference in BMD values in LaCa group at 7 and 21 days (=0,005. The results of the densitometric study showed that LLLT (830 nm combined with calcitonin improved bone repair.

  1. False positive results using calcitonin as a screening method for medullary thyroid carcinoma

    Science.gov (United States)

    Batista, Rafael Loch; Toscanini, Andrea Cecilia; Brandão, Lenine Garcia; Cunha-Neto, Malebranche Berardo C.

    2013-01-01

    The role of serum calcitonin as part of the evaluation of thyroid nodules has been widely discussed in literature. However there still is no consensus of measurement of calcitonin in the initial evaluation of a patient with thyroid nodule. Problems concerning cost-benefit, lab methods, false positive and low prevalence of medullary thyroid carcinoma (MTC) are factors that limit this approach. We have illustrated two cases where serum calcitonin was used in the evaluation of thyroid nodule and rates proved to be high. A stimulation test was performed, using calcium as secretagogue, and calcitonin hyper-stimulation was confirmed, but anatomopathologic examination did not evidence medullar neoplasia. Anatomopathologic diagnosis detected Hashimoto thyroiditis in one case and adenomatous goiter plus an occult papillary thyroid carcinoma in the other one. Recommendation for routine use of serum calcitonin in the initial diagnostic evaluation of a thyroid nodule, followed by a confirming stimulation test if basal serum calcitonin is showed to be high, is the most currently recommended approach, but questions concerning cost-benefit and possibility of diagnosis error make the validity of this recommendation discussible. PMID:23869316

  2. False positive results using calcitonin as a screening method for medullary thyroid carcinoma

    Directory of Open Access Journals (Sweden)

    Rafael Loch Batista

    2013-01-01

    Full Text Available The role of serum calcitonin as part of the evaluation of thyroid nodules has been widely discussed in literature. However there still is no consensus of measurement of calcitonin in the initial evaluation of a patient with thyroid nodule. Problems concerning cost-benefit, lab methods, false positive and low prevalence of medullary thyroid carcinoma (MTC are factors that limit this approach. We have illustrated two cases where serum calcitonin was used in the evaluation of thyroid nodule and rates proved to be high. A stimulation test was performed, using calcium as secretagogue, and calcitonin hyper-stimulation was confirmed, but anatomopathologic examination did not evidence medullar neoplasia. Anatomopathologic diagnosis detected Hashimoto thyroiditis in one case and adenomatous goiter plus an occult papillary thyroid carcinoma in the other one. Recommendation for routine use of serum calcitonin in the initial diagnostic evaluation of a thyroid nodule, followed by a confirming stimulation test if basal serum calcitonin is showed to be high, is the most currently recommended approach, but questions concerning cost-benefit and possibility of diagnosis error make the validity of this recommendation discussible.

  3. Ureteral relaxation through calcitonin gene-related peptide release from sensory nerve terminals by hypotonic solution.

    Science.gov (United States)

    Materazzi, Serena; Minocci, Daiana; De Siena, Gaetano; Benemei, Silvia; Nassini, Romina

    2015-09-01

    To evaluate the influence of hypotonic solutions on ureteral relaxation mediated by the release of calcitonin gene-related peptide from intramural sensory nerve endings. Urine osmolarity of Sprague-Dawley rats drinking water low in salt content (Fiuggi water) or a reference water for 7 days was measured. Release of calcitonin gene-related peptide-like immunoreactivity from slices of rat ureter and urinary bladder by hypotonic solutions was assessed by an immunometric assay. The mechanism through which hypotonic solutions inhibit neurokinin A-induced phasic contractions of isolated rat ureters was evaluated by organ bath studies. A 7-day consumption of Fiuggi water in rats reduced urine osmolarity by ~40%. Exposure to hypotonic solutions released calcitonin gene-related peptide-like immunoreactivity from slices of rat ureter. This response was abated in a calcium-free medium, after capsaicin desensitization, and in the presence of the unselective transient receptor potential channel antagonist, ruthenium red. Exposure of isolated rat ureteral preparations to a hypotonic solution inhibited neurokinin A-evoked phasic contraction. This response was attenuated by capsaicin desensitization and in the presence of the calcitonin gene-related peptide receptor antagonist, calcitonin gene-related peptide8-37 . Transient receptor potential vanilloid 1 or transient receptor potential vanilloid 4 antagonists did not affect the neurogenic and calcitonin gene-related peptide-dependent relaxation. Present data show that hypotonic solution evokes calcitonin gene-related peptide release from capsaicin-sensitive intramural sensory nerves, thus inhibiting ureteral contractility, through a transient receptor potential-dependent mechanism. However, this mechanism does not involve transient receptor potential vanilloid 1 or transient receptor potential vanilloid 4. Future studies with appropriate in vivo models should investigate the hypothesis that hypostenuric urine diffusing into the

  4. Calcitonin Gene-Related Peptide in Tension-Type Headache

    Directory of Open Access Journals (Sweden)

    M. Ashina

    2002-01-01

    Full Text Available In the last 10 years there has been increasing interest in the role of calcitonin gene-related peptide (CGRP in primary headaches. Tension-type headache is one of the most common and important types of primary headaches, and ongoing nociception from myofascial tissues may play an important role in the pathophysiology of this disorder. CGRP sensory fibers are preferentially located in the walls of arteries, and nerve fibers containing CGRP accompany small blood vessels in human cranial muscles. It is well established that nociception may lead to release of CGRP from sensory nerve endings and from central terminals of sensory afferents into the spinal cord. It has also been shown that density of CGRP fibers around arteries is increased in persistently inflamed muscle. These findings indicate that ongoing activity in sensory neurons in the cranial muscles may be reflected in changes of plasma levels of neuropeptides in patients with chronic tension-type headache. To explore the possible role of CGRP in tension-type headache, plasma levels of CGRP were measured in patients with chronic tension-type headache. This study showed that plasma levels of CGRP are normal in patients and unrelated to headache state. However, the findings of normal plasma levels of CGRP do not exclude the possibility that abnormalities of this neuropeptide at the neuronal or peripheral (pericranial muscles levels play a role in the pathophysiology of tension-type headache. Investigation of CGRP in other compartments with new sensitive methods of analysis is necessary to clarify its role in tension-type headache.

  5. Calcitonin as Biomarker for the Medullary Thyroid Carcinoma.

    Science.gov (United States)

    Bae, Yoon Ju; Schaab, Michael; Kratzsch, Juergen

    2015-01-01

    Calcitonin (CTN) is a polypeptide hormone consisting of 32 amino acids with a disulfide bridge between position 1 and 7 that is mainly produced by the C-cells of thyroid gland. The measurement of CTN concentrations in blood reflects C-cell activity and is performed in general by immunoassay methods. However, there are analytical, physiological, pharmacological, and pathological factors that can influence results of serum CTN values. Due to the influence of these factors, there is a high variability in assay-dependent cutoffs used to discriminate between MTC, C-cell hyperplasia (CCH), and the absence of the pathological impairment of C-cells. There is a lot of evidence that the measurement of serum CTN concentrations in patients with thyroid nodules can lead to an earlier diagnosis of MTC or CCH than the exclusive use of imaging procedures and/or fine-needle aspiration cytology. Basal CTN concentrations higher than 60-100 pg/mL are highly indicative for the diagnosis MTC. In the range between cutoff and 60 pg/mL CTN, both MTC and HCC may be a relevant diagnosis. PCT and CTN appear to have a comparable diagnostic capability to diagnose MTCs. However, "positive" PCT values of more than 50 pg/mL may be reached also in subclinical infections and will lead, therefore, to an overdiagnosis of the tumor. Pentagastrin- or calcium-stimulated serum CTN concentrations higher than cutoff values might improve diagnostics of MTC, but the non-availability of the first and the lacking of relevant cutoff values for the second tool favors the use of only basal values currently.

  6. Oral salmon calcitonin attenuates hyperglycaemia and preserves pancreatic beta-cell area and function in Zucker diabetic fatty rats

    DEFF Research Database (Denmark)

    Feigh, M; Andreassen, K V; Neutzsky-Wulff, A V

    2012-01-01

    Oral salmon calcitonin (sCT), a dual-action amylin and calcitonin receptor agonist, improved glucose homeostasis in diet-induced obese rats. Here, we have evaluated the anti-diabetic efficacy of oral sCT using parameters of glycaemic control and beta-cell morphology in male Zucker diabetic fatty...... (ZDF) rats, a model of type 2 diabetes....

  7. Skeletal blood flow in Paget's disease of bone and its response to calcitonin therapy.

    Science.gov (United States)

    Wootton, R; Reeve, J; Spellacy, E; Tellez-Yudilevich, M

    1978-01-01

    1. Blood flow to the skeleton was measured by the 18F clearance method of Wooton, Reeve & Veall (1976) in 24 patients with untreated Paget's disease. In every patient but one, resting skeletal blood flow was increased. There was a significant positive correlation between skeletal blood flow and serum alkaline phosphatase and between skeletal blood flow and urinary total hydroxyproline excretion. 2. Fourteen patients were re-studied after they had received short-term (7 days or less) or long-term (7 weeks or more) calcitonin. Skeletal blood flow, alkaline phosphatase and urinary hydroxy-proline excretion fell towards normal in every case. There was some evidence from the short-term studies that calcitonin produced a more rapid fall in skeletal blood flow than in alkaline phosphatase. 3. Glomerular filtration rate appeared to increase transiently in response to calcitonin.

  8. A phase 3 trial of the efficacy and safety of oral recombinant calcitonin: the Oral Calcitonin in Postmenopausal Osteoporosis (ORACAL) trial.

    Science.gov (United States)

    Binkley, Neil; Bolognese, Michael; Sidorowicz-Bialynicka, Anna; Vally, Tasneem; Trout, Richard; Miller, Colin; Buben, Christine E; Gilligan, James P; Krause, David S

    2012-08-01

    The Oral Calcitonin in Postmenopausal Osteoporosis (ORACAL) study was a randomized, double-blind, double-dummy, active- and placebo-controlled, multiple-dose, phase 3 study to assess the efficacy and safety of oral recombinant calcitonin for treatment of postmenopausal osteoporosis. A total of 565 women age 46 to 86 (mean 66.5) years were randomized (4:3:2) to receive oral recombinant salmon calcitonin (rsCT) tablets (0.2  mg/d) plus placebo nasal spray, synthetic salmon calcitonin (ssCT) nasal spray (200 IU/d) plus placebo tablets, or placebo (placebo tablets plus placebo nasal spray), respectively for 48 weeks. All women received calcium (≥1000  mg/d) and vitamin D (800 IU/d). Women randomized to oral rsCT had a mean ± SD percent increase from baseline in lumbar spine bone mineral density (BMD) (1.5% ± 3.2%) that was greater than those randomized to ssCT nasal spray (0.78% ± 2.9%) or placebo (0.5% ± 3.2%). Lumbar spine BMD change in those receiving nasal calcitonin did not differ from placebo. Oral rsCT treatment also resulted in greater improvements in trochanteric and total proximal femur BMD than ssCT nasal spray. Reductions in bone resorption markers with oral rsCT were greater than those observed in ssCT nasal spray or placebo recipients. Approximately 80% of subjects in each treatment group experienced an adverse event, the majority of which were mild or moderate in intensity. Gastrointestinal system adverse events were reported by nearly one-half of women in all treatment groups and were the principal reason for premature withdrawals. Less than 10% of women experienced a serious adverse event and no deaths occurred. Overall, oral rsCT was superior to nasal ssCT and placebo for increasing BMD and reducing bone turnover. Oral rsCT was safe and as well tolerated as ssCT nasal spray or placebo. Oral calcitonin may provide an additional treatment alternative for women with postmenopausal osteoporosis. Copyright © 2012 American Society

  9. An immunohistochemical study of the antinociceptive effect of calcitonin in ovariectomized rats

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    Sekiguchi Miho

    2008-12-01

    Full Text Available Abstract Background Calcitonin is used as a treatment to reduce the blood calcium concentration in hypercalcemia and to improve bone mass in osteoporosis. An analgesic effect of calcitonin has been observed and reported in clinical situations. Ovariectomaized (OVX rats exhibit the same hormonal changes as observed in humans with osteoporosis and are an animal model of postmenopousal osteoporosis. The aim of this study to investigate antinociceptive effect of calcitonin in OVX rats using the immunohistochemical study. Methods We assessed the antinociceptive effects of calcitonin in an ovariectomized (OVX rat model, which exhibit osteoporosis and hyperalgesia, using the immunohistochemical method. Fifteen rats were ovariectomized bilaterally, and ten rats were received the same surgery expected for ovariectomy as a sham model. We used five groups: the OVX-CT (n = 5, the sham-CT (n = 5, and the OVX-CT-pcpa (n = 5 groups recieved calcitonin (CT: 4 U/kg/day, while OVX-vehi (n = 5 and the sham-vehi (n = 5 groups received vehicle subcutaneously 5 times a week for 4 weeks. The OVX-CT-pcpa-group was given traperitoneal injection of p-chlorophenylalanine (pcpa; an inhibitor of serotonin biosynthesis (100 mg/kg/day in the last 3 days of calcitonon injection. Two hours after 5% formalin (0.05 ml subcutaneously into the hind paw, the L5 spinal cord were removed and the number of Fos-immunoreactive (ir neurons were evaluated using the Mann-Whitney-U test. Results The numbers of Fos-ir neurons in the OVX-CT and sham-CT groups were significantly less than in the OVX-vehi and sham-vehi groups, respectively (p = 0.0090, p = 0.0090. The number of Fos-ir neurons in the OVX-CT-pcpa-group was significantly more than that of the OVX-CT-group (p = 0.0283, which means pcpa inhibits calcitonin induced reduction of c-Fos production. Conclusion The results in this study demonstrated that 1 the increase of c-Fos might be related to hyperalgesia in OVX-rats. 2 Calcitonin has

  10. Association of Basal and Calcium-stimulated Calcitonin Levels with Pathological Findings After Total Thyroidectomy.

    Science.gov (United States)

    Papadakis, Georgios; Keramidas, Ioannis; Triantafillou, Eleni; Kanouta, Fotini; Pappa, Theodora; Kaltzidou, Victoria; Tertipi, Athanasia; Iordanidou, Lydia; Trivizaki, Erasmia; Vecchini, Gino; Villiotou, Vassiliki; Pappas, Anastasios

    2015-07-01

    Medullary thyroid carcinoma (MTC) originates from thyroid C-cells and is a calcitonin-secreting tumor. Calcitonin is also elevated in C-cell hyperplasia (CCH). The objective of the study was to determine the optimal basal (bCT) and peak stimulated calcitonin (psCT) cut-off value for differentiating MTC from CCH, and to examine the histological findings of thyroidectomy in patients with maximum psCT >100 pg/ml. Fifty-five patients had a maximum calcium-psCT >100 pg/ml and underwent total thyroidectomy. A total of 20 patients were diagnosed with MTC and the remaining 35 with CCH. A bCT level >17.4 pg/ml and psCT level >452 pg/ml demonstrated the best sensitivity and positive predictive value for differenting MTC from CCH. The overlap of calcitonin levels between MTC and CCH reduces the accuracy of the calcium stimulation test. Remarkably, an appreciable number of patients with psCT levels >100 pg/ml harbor differentiated thyroid carcinoma of follicular origin. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  11. Calcitonin gingival crevicular fluid levels and pain discomfort during early orthodontic tooth movement in young patients.

    Science.gov (United States)

    Alarcón, José Antonio; Linde, Dolores; Barbieri, Germán; Solano, Patricia; Caba, Octavio; Rios-Lugo, María Judith; Sanz, Mariano; Martin, Conchita

    2013-06-01

    To investigate the previously unreported presence of calcitonin (CT) levels in gingival crevicular fluid (GCF), its variations during initial orthodontic tooth movement in both tension and compression sites, and its possible association with the experienced dental pain. Fifteen children (mean age: 12.6 years) requiring orthodontic closure of the upper midline diastema were included. We collected GCF from the compression and tension sites of the upper right central incisor (experimental) and first bicuspid (control), before and after (1h, 24h, 7d, 15d) beginning of treatment. Calcitonin levels were determined by Western blot. Pain intensity was assessed using a visual analogue scale. Calcitonin levels were higher in the compression site versus the control site at 7d (p=0.014). Intragroup comparisons showed an increment of CT between 1h and 7d (680.81±1672.60pg/30s, p=0.010) in the compression site. No significant changes were found in the tension and control sites. Calcitonin levels and pain intensity were negatively associated during the period from 24h to 15d (r=-0.54, p=0.05). CT levels in the GCF significantly increased in the compression site after the short term after application of orthodontic forces. These changes were negatively associated with the perceived patient's dental pain during the period from 24h to 15d. Copyright © 2012 Elsevier Ltd. All rights reserved.

  12. Effect of calcium carbonate combined with calcitonin on hypercalcemia in hemodialysis patients.

    Science.gov (United States)

    Wei, Yong; Kong, Xiang Lei; Li, Wen Bin; Wang, Zun Song

    2014-12-01

    This short-term study assessed the efficacy and safety of calcium carbonate combined with calcitonin in the treatment of hypercalcemia in hemodialysis patients. Patients (n=64) on hemodialysis for chronic kidney disease for more than 6 months were included based on total serum calcium more than 10.5 mg/dL. All patients were randomized (1:1) to receive calcium carbonate combined with calcitonin (Group I) or lanthanum carbonate (Group II) for 12 weeks. Blood levels of calcium, phosphorus and intact parathyroid hormone (iPTH) were measured every month, bone mass density (BMD) and coronary artery calcium scores (CACS) were measured at 3 months. During the study period, serum calcium decreased from 10.72 ± 0.39 to 10.09 ± 0.28 mg/dL (P Calcium carbonate combined with calcitonin and lanthanum carbonate were equally effective in the suppression of hypercalcemia in hemodialysis patients. There were no serious treatment-related adverse events in treatment with calcium carbonate combined with calcitonin. © 2014 The Authors. Therapeutic Apheresis and Dialysis © 2014 International Society for Apheresis.

  13. Relation of calcitonin gene-related peptide to systemic vasodilatation and central hypovolaemia in cirrhosis

    DEFF Research Database (Denmark)

    Møller, Søren; Bendtsen, Flemming; Schifter, S

    1996-01-01

    BACKGROUND: The aetiology of the reduced systemic vascular resistance and abnormal 'filling' of the vascular bed in cirrhosis is still obscure. As increased concentrations of the potent vasodilator calcitonin gene-related peptide (CGRP) have recently been reported in cirrhosis, we related CGRP......-central blood volume (P abnormal distribution of the blood volume, which may lead to abnormal sodium and water handling....

  14. Effect of the calcitonin gene-related peptide (CGRP) receptor antagonist telcagepant in human cranial arteries

    NARCIS (Netherlands)

    L. Edvinsson (Lars); K.Y. Chan (Kayi); S. Eftekhari; E. Nilsson (Elisabeth); R. de Vries (René); H. Säveland (Hans); C.M.F. Dirven (Clemens); A.H.J. Danser (Jan)

    2010-01-01

    textabstractIntroduction: Calcitonin gene-related peptide (CGRP) is a neuronal messenger in intracranial sensory nerves and is considered to play a significant role in migraine pathophysiology. Materials and methods: We investigated the effect of the CGRP receptor antagonist, telcagepant, on

  15. Impact of congenital calcitonin deficiency due to dysgenetic hypothyroidism on bone mineral density

    Directory of Open Access Journals (Sweden)

    Daripa M.

    2004-01-01

    Full Text Available The objective of the present study was to determine the effect of chronic calcitonin deficiency on bone mass development. The results of 11 patients with thyroid dysgenesis (TD were compared to those of 17 normal individuals (C and of 9 patients with other forms of hypothyroidism (OH: 4 with hypothyroidism due to inborn errors of thyroid hormone synthesis and 5 with Hashimoto's thyroiditis. The subjects received an intravenous calcium stimulus and blood was collected for the determination of ionized calcium (Ca2+, calcitonin, and intact parathyroid hormone. Bone mineral density (BMD was determined by dual-energy X-ray absorptiometry. After calcium administration the levels of Ca2+ in the two groups of hypothyroidism were significantly higher than in the normal control group (10 min after starting calcium infusion: C = 1.29 ± 0.08 vs TD = 1.34 ± 0.03 vs OH = 1.34 ± 0.02 mmol/l; P < 0.05, and only the TD group showed no calcitonin response (5 min after starting calcium infusion: C = 27.9 ± 5.8 vs TD = 6.6 ± 0.3 vs OH = 43.0 ± 13.4 ng/l. BMD values did not differ significantly between groups (L2-L4: C = 1.116 ± 0.02 vs TD = 1.109 ± 0.03 vs OH = 1.050 ± 0.04 g/cm². These results indicate that early deficiency of calcitonin secretion has no detrimental effect on bone mass development. Furthermore, the increased calcitonin secretion observed in patients with inborn errors of thyroid hormone biosynthesis does not confer any advantage in terms of BMD.

  16. Calcitonin Gene-Related Peptide (Cgrp, Adrenomedullin (Am, Amylin, And Calcitonin (Ct Receptors And Overlapping Biological Actions

    Directory of Open Access Journals (Sweden)

    J.A. Fischer

    2001-01-01

    Full Text Available CGRP, AM, amylin, and CT have in common N-terminal 6-7 amino acid ring structures linked by disulfide bridges and amidated C-termini required for biological activity. For the related bioactive peptides, receptor-binding sites linked to cAMP stimulation and to a lesser extent to the phospholipase C signaling pathway have been identified in tissue specific manner. The highest density of CGRP receptors has been recognized in the cerebellum and the spinal cord. There photoaffinity-labeled N-glycosylated 60,000 and 54,000 Mr proteins are converted to 46,000 and 41,000 Mr components following endoglycosidase F/N-glycosidase F treatment. The same proteins were specifically labeled with [125I]-hCGRP-I(1-37 and -(8-37. Some cross-reaction between the CGRP receptor and AM was evident whereas amylin and CT were only recognized at over 10-7 M. A different AM receptor localized predominantly in the lung recognized CGRP at low, and amylin and calcitonin at equally high concentrations. CT receptor binding sites have been identified in osteoclasts and in the periventricular region of the brain. They cross-reacted with amylin at low concentrations and with CGRP and AM at over 10-7 M. Amylin receptor binding sites cross-reacting with salmon CT and CGRP but not with hCT and adrenomedullin to any great extent were originally described by Sexton in the nucleus accumbens and may represent a second CGRP receptor. The structure of a CT receptor was elucidated by the group of Goldring in 1991 through molecular cloning, and of a 60% homologous human CT receptor-like receptor (CRLR shortly thereafter here. The latter was an orphan receptor until the discovery of the receptor-activity-modifying proteins (RAMP by Foord which upon coexpression yield a CGRP receptor with RAMP1 and an AM receptor with RAMP2. Coexpression of the hCT receptor isotype 2 revealed a CGRP/amylin receptor with RAMP1 and an amylin receptor isotype with RAMP3. The CRLR/RAMP1 receptor antagonized by

  17. Calcitonin gene-related peptide induced migraine attacks in patients with and without familial aggregation of migraine

    DEFF Research Database (Denmark)

    Guo, Song; Christensen, Anne Francke; Liu, Marie Louise

    2017-01-01

    BACKGROUND: Calcitonin gene-related peptide provokes migraine attacks in 65% of patients with migraine without aura. Whether aggregation of migraine in first-degree relatives (family load) or a high number of risk-conferring single nucleotide polymorphisms contributes to migraine susceptibility...... to calcitonin gene-related peptide infusion in migraine patients is unknown. We hypothesized that genetic enrichment plays a role in triggering of migraine and, therefore, migraine without aura patients with high family load would report more migraine attacks after calcitonin gene-related peptide infusion than...... patients with low family load. METHODS: We allocated 40 previously genotyped migraine without aura patients to receive intravenous infusion of 1.5 µg/min calcitonin gene-related peptide and recorded migraine attacks including headache characteristics and associated symptoms. Information of familial...

  18. Calcitonin gene-related peptide induced migraine attacks in patients with and without familial aggregation of migraine.

    Science.gov (United States)

    Guo, Song; Christensen, Anne Francke; Liu, Marie Louise; Janjooa, Benjamin Naveed; Olesen, Jes; Ashina, Messoud

    2017-02-01

    Background Calcitonin gene-related peptide provokes migraine attacks in 65% of patients with migraine without aura. Whether aggregation of migraine in first-degree relatives (family load) or a high number of risk-conferring single nucleotide polymorphisms contributes to migraine susceptibility to calcitonin gene-related peptide infusion in migraine patients is unknown. We hypothesized that genetic enrichment plays a role in triggering of migraine and, therefore, migraine without aura patients with high family load would report more migraine attacks after calcitonin gene-related peptide infusion than patients with low family load. Methods We allocated 40 previously genotyped migraine without aura patients to receive intravenous infusion of 1.5 µg/min calcitonin gene-related peptide and recorded migraine attacks including headache characteristics and associated symptoms. Information of familial aggregation was obtained by telephone interview of first-degree relatives using a validated semi-structured questionnaire. Results Calcitonin gene-related peptide infusion induced a migraine-like attack in 75% (12 out of 16) of patients with high family load compared to 52% (12 out of 23) with low family load ( P = 0.150). In addition, we found that the migraine response after calcitonin gene-related peptide was not associated with specific or a high number of risk-conferring single nucleotide polymorphisms of migraine without aura. Conclusion We found no statistical association between familial aggregation of migraine and hypersensitivity to calcitonin gene-related peptide infusion in migraine without aura patients. We also demonstrated that the currently known single nucleotide polymorphisms conferring risk of migraine without aura have no additive effect on calcitonin gene-related peptide induced migraine-like attacks.

  19. Associations of Osteocalcin, Osteoprotegerin, and Calcitonin with Inflammation Biomarkers in Atherosclerotic Plaques of Coronary Arteries.

    Science.gov (United States)

    Polonskaya, Ya V; Kashtanova, E V; Murashov, I S; Volkov, A M; Kurguzov, A V; Chernyavsky, A M; Ragino, Yu I

    2017-04-01

    We studied associations of osteocalcin, osteoprotegerin, and calcitonin with markers of inflammation in atherosclerotic plaques in coronary arteries and assessed the influence of these biomolecules on calcification of atherosclerotic plaques. The initial stage of calcification of atherosclerotic plaques is characterized by activation of inflammatory processes, which is seen from increased levels of proinflammatory biomarkers (IL-6, IL 8, TNF-α, and IL-1β). Progressive calcification of atherosclerotic plaques is accompanied by insignificant accumulation of calcitonin and osteoprotegerin. The exception is osteocalcin, its concentration significantly increased during calcification. The results suggest that severe vascular calcification can be regarded as non-specific marker of atherosclerosis. Instability of atherosclerotic plaques is associated with higher level of calcification.

  20. Effect of antibodies to calcitonin on the pharmacokinetics and the pharmacodynamics of the hormone.

    Science.gov (United States)

    Tagliaro, F; Dorizzi, R; Luisetto, G

    1995-01-01

    Calcitonin pharmacokinetics and pharmacodynamics were studied in two groups of patients with postmenopausal osteoporosis, who, treated for one year with intranasal Asu1.7-eel calcitonin (eCT), had (Ab+) and had not (Ab-) developed a specific immune response to the drug. The treatment consisted of daily intranasal administrations of eCT (80 IU/die) with 1 g supplemental calcium. Eight women who had developed specific antibodies and 5 who had not, were given 50 IU of CT i.m., in order to assess the pharmacokinetics and pharmacodynamics of the drug. The rise of serum levels of the hormone was significantly greater in Ab+ than in Ab- patients. At the end of the study, no significant differences in mineral bone loss between the two groups were found. In conclusion, the presence of antibodies to eCT does not represent a negative event in the therapy of osteoporosis, but significantly affects the pharmacokinetics of the drug.

  1. Quantitative Structure-Activity Relationships and Docking Studies of Calcitonin Gene-Related Peptide Antagonists

    DEFF Research Database (Denmark)

    Jenssen, Håvard; Mehrabian, Mohadeseh; Kyani, Anahita

    2012-01-01

    of calcitonin gene-related peptide antagonists was performed using a panel of physicochemical descriptors. The computational studies evaluated different variable selection techniques and demonstrated shuffling stepwise multiple linear regression to be superior over genetic algorithm-multiple linear regression....... The linear quantitative structure-activity relationship model revealed better statistical parameters of cross-validation in comparison with the non-linear support vector regression technique. Implementing only five peptide descriptors into this linear quantitative structure-activity relationship model...

  2. Use of calcitonin in recalcitrant phantom limb pain complicated by heterotopic ossification.

    Science.gov (United States)

    Viana, Ricardo; Payne, Michael W C

    2015-01-01

    Phantom limb pain (PLP) is a common complication after amputation, affecting up to 80% of the amputee population. However, only 5% to 10% of amputees have severe PLP impacting daily function. The present report details the management of severe, treatment-resistant PLP in a 72-year-old man with a traumatic left transradial amputation and a comorbid complication of heterotopic ossification (HO). To describe a case of PLP with HO and the possible role of calcitonin in the treatment of both conditions. A systematic review of the literature regarding the management of PLP. Seventeen articles that directly addressed PLP were identified; 11 were randomized controlled trials. All involved small samples and follow-up ranged from 6 h to one year, with the majority limited to six weeks. In the present case, medication management was limited by side effects, lack of response and the patient's desire to avoid long-term medication. Investigations revealed HO, which was suspected to envelop the median nerve in the proximal forearm. After several unsuccessful medication trials, the literature was reviewed in search of common variables between HO formation and persistent PLP. Ultimately, the biochemical effects associated with nerve injury were identified to be a possible factor in both HO and PLP development. Calcitonin's proposed mechanisms of action may help to manage HO and PLP at multiple stages of disease development and maintenance. In the present case, a four-week trial of intranasal calcitonin was successful, with pain control lasting at least 18 months. The present case report provided a review of the current literature in PLP pharmacological management and the current understanding of the etiology of PLP and HO, as well as how the two may coexist. It also provided an opportunity to discuss the proposed mechanisms of action of calcitonin in the management of PLP and HO.

  3. Calcitonin gene-related peptide does not cause migraine attacks in patients with familial hemiplegic migraine

    DEFF Research Database (Denmark)

    Hansen, Jakob M; Thomsen, Lise L; Olesen, Jes

    2011-01-01

    Calcitonin gene-related peptide (CGRP) is a key molecule in migraine pathogenesis. Intravenous CGRP triggers migraine-like attacks in patients with migraine with aura and without aura. In contrast, patients with familial hemiplegic migraine (FHM) with known mutations did not report more migraine......-like attacks compared to controls. Whether CGRP triggers migraine-like attacks in FHM patients without known mutations is unknown....

  4. Comparison of Calcitonin and Pamidronate Treatments in Children with Osteogenesis Imperfecta

    Directory of Open Access Journals (Sweden)

    Neslihan Onenli Mungan

    2013-08-01

    Full Text Available Purpose: The main objective of this study was to compare the treatments of calcitonin and pamidronate by clinical, biochemical, and radiological findings in children with osteogenesis imperfecta and evaluate the efficiency of pamidronate treatment. Patients and methods: A total of 12 patients, aged 41±38 (1-120 months were studied. Group 1 was consisted of six patients who had received intranasal calcitonin at a dosage of 4-6 U/kg three times a week before switching to pamidronate treatment. Group 2 was also consisted of six patients who had received only pamidronate infusion at a dosage of 0.5-2 mg/kg every two months. Results: Annual fracture rates decreased from 2.72 ± 0.80 to 0.40 ± 0.70 (p0.05, and from -3.08 ± -0.61 to -2.29 ± -0.56 in pamidronate group. The difference between the Z-scores of bone mineral density after calcitonin and pamidronate treatments was statistically significant (p<0.05. The Z-scores of pre (-3.44 ± -0.96 and post (-2.47 ± -0.60 pamidronate treatments of whole 12 patients were significantly different (p<0.001. Conclusion: Pamidronate was significantly more effective in reducing pain, annual fracture rate, and increasing bone mineral density and mobility than calcitonin without any severe adverse effects even in the neonatal period and severe forms of osteogenesis imperfecta. [Cukurova Med J 2013; 38(4.000: 667-674

  5. [Calcifediol and calcitonin in the therapy of rheumatoid arthritis. A short-term controlled study].

    Science.gov (United States)

    Dottori, L; D'Ottavio, D; Brundisini, B

    1982-11-10

    A short-term study (30 days) has been carried out on 45 patients suffering from rheumatoid arthritis with radiologically verified osteoporosis and definite pain symptomatology. The patients were divided at random into three groups (A, B, C) of 15 each. Group A was given basic therapy (calcium, dichlrophenac, nor-androstenolone) with addition of calcifediol. Group B received basic therapy plus calcitonine in paraphysiological doses. Group C was treated with basic therapy only (highly effective on its own). Observation and treatment were brief but able to provide useful indications regarding the implementation of longer courses of treatment (3-6 months). At the end of treatment, results were submitted to biometric control. With the aid of statistics it can thus be stated that alkaline phosphatase and hydroxyprolinuria fall in group B (basic treatment + calcitonine) and this suggests that the treatment causes some improvement in the exchangeable bone calcium pool. The values of these parameters also fall with the addition of calcifediol to basic therapy, but this fall is not very high. Pain symptomatology is also favourably affected, and to a statistically significant extent, by the three treatments: group A patients (basic + calcifediol) show greater improvement compared with straightforward basic therapy, but the best results are encountered in group B, treated with an association of basic and calcitonine. No side-effects were observed.

  6. Calcitonin gene-related peptide antagonism and cluster headache: an emerging new treatment.

    Science.gov (United States)

    Ashina, Håkan; Newman, Lawrence; Ashina, Sait

    2017-08-30

    Calcitonin gene-related peptide (CGRP) is a key signaling molecule involved in migraine pathophysiology. Efficacy of CGRP monoclonal antibodies and antagonists in migraine treatment has fueled an increasing interest in the prospect of treating cluster headache (CH) with CGRP antagonism. The exact role of CGRP and its mechanism of action in CH have not been fully clarified. A search for original studies and randomized controlled trials (RCTs) published in English was performed in PubMed and in ClinicalTrials.gov . The search term used was "cluster headache and calcitonin gene related peptide" and "primary headaches and calcitonin gene related peptide." Reference lists of identified articles were also searched for additional relevant papers. Human experimental studies have reported elevated plasma CGRP levels during both spontaneous and glyceryl trinitrate-induced cluster attacks. CGRP may play an important role in cluster headache pathophysiology. More refined human studies are warranted with regard to assay validation and using larger sample sizes. The results from RCTs may reveal the therapeutic potential of CGRP monoclonal antibodies and antagonists for cluster headache treatment.

  7. Heat hyperalgesia and mechanical hypersensitivity induced by calcitonin gene-related peptide in a mouse model of neurofibromatosis.

    Directory of Open Access Journals (Sweden)

    Stephanie White

    Full Text Available This study examined whether mice with a deficiency of neurofibromin, a Ras GTPase activating protein, exhibit a nociceptive phenotype and probed a possible contribution by calcitonin gene-related peptide. In the absence of inflammation, Nf1+/- mice (B6.129S6 Nf1/J and wild type littermates responded comparably to heat or mechanical stimuli, except for a subtle enhanced mechanical sensitivity in female Nf1+/- mice. Nociceptive phenotype was also examined after inflammation induced by capsaicin and formalin, which release endogenous calcitonin gene-related peptide. Intraplantar injection of capsaicin evoked comparable heat hyperalgesia and mechanical hypersensitivity in Nf1+/- and wild type mice of both genders. Formalin injection caused a similar duration of licking in male Nf1+/- and wild type mice. Female Nf1+/- mice licked less than wild type mice, but displayed other nociceptive behaviors. In contrast, intraplantar injection of CGRP caused greater heat hyperalgesia in Nf1+/- mice of both genders compared to wild type mice. Male Nf1+/- mice also exhibited greater mechanical hypersensitivity; however, female Nf1+/- mice exhibited less mechanical hypersensitivity than their wild type littermates. Transcripts for calcitonin gene-related peptide were similar in the dorsal root ganglia of both genotypes and genders. Transcripts for receptor activity-modifying protein-1, which is rate-limiting for the calcitonin gene-related peptide receptor, in the spinal cord were comparable for both genotypes and genders. The increased responsiveness to intraplantar calcitonin gene-related peptide suggests that the peripheral actions of calcitonin gene-related peptide are enhanced as a result of the neurofibromin deficit. The analgesic efficacy of calcitonin gene-related peptide receptor antagonists may therefore merit investigation in neurofibromatosis patients.

  8. Heat hyperalgesia and mechanical hypersensitivity induced by calcitonin gene-related peptide in a mouse model of neurofibromatosis.

    Science.gov (United States)

    White, Stephanie; Marquez de Prado, Blanca; Russo, Andrew F; Hammond, Donna L

    2014-01-01

    This study examined whether mice with a deficiency of neurofibromin, a Ras GTPase activating protein, exhibit a nociceptive phenotype and probed a possible contribution by calcitonin gene-related peptide. In the absence of inflammation, Nf1+/- mice (B6.129S6 Nf1/J) and wild type littermates responded comparably to heat or mechanical stimuli, except for a subtle enhanced mechanical sensitivity in female Nf1+/- mice. Nociceptive phenotype was also examined after inflammation induced by capsaicin and formalin, which release endogenous calcitonin gene-related peptide. Intraplantar injection of capsaicin evoked comparable heat hyperalgesia and mechanical hypersensitivity in Nf1+/- and wild type mice of both genders. Formalin injection caused a similar duration of licking in male Nf1+/- and wild type mice. Female Nf1+/- mice licked less than wild type mice, but displayed other nociceptive behaviors. In contrast, intraplantar injection of CGRP caused greater heat hyperalgesia in Nf1+/- mice of both genders compared to wild type mice. Male Nf1+/- mice also exhibited greater mechanical hypersensitivity; however, female Nf1+/- mice exhibited less mechanical hypersensitivity than their wild type littermates. Transcripts for calcitonin gene-related peptide were similar in the dorsal root ganglia of both genotypes and genders. Transcripts for receptor activity-modifying protein-1, which is rate-limiting for the calcitonin gene-related peptide receptor, in the spinal cord were comparable for both genotypes and genders. The increased responsiveness to intraplantar calcitonin gene-related peptide suggests that the peripheral actions of calcitonin gene-related peptide are enhanced as a result of the neurofibromin deficit. The analgesic efficacy of calcitonin gene-related peptide receptor antagonists may therefore merit investigation in neurofibromatosis patients.

  9. Physiological studies in heterozygous calcium sensing receptor (CaSR gene-ablated mice confirm that the CaSR regulates calcitonin release in vivo

    Directory of Open Access Journals (Sweden)

    Kovacs Christopher S

    2004-04-01

    Full Text Available Abstract Background The calcium sensing receptor (CaSR regulates serum calcium by suppressing secretion of parathyroid hormone; it also regulates renal tubular calcium excretion. Inactivating mutations of CaSR raise serum calcium and reduce urine calcium excretion. Thyroid C-cells (which make calcitonin express CaSR and may, therefore, be regulated by it. Since calcium stimulates release of calcitonin, the higher blood calcium caused by inactivation of CaSR should increase serum calcitonin, unless CaSR mutations alter the responsiveness of calcitonin to calcium. To demonstrate regulatory effects of CaSR on calcitonin release, we studied calcitonin responsiveness to calcium in normal and CaSR heterozygous-ablated (Casr+/- mice. Casr+/- mice have hypercalcemia and hypocalciuria, and live normal life spans. Each mouse received either 500 μl of normal saline or one of two doses of elemental calcium (500 μmol/kg or 5 mmol/kg by intraperitoneal injection. Ionized calcium was measured at baseline and 10 minutes, and serum calcitonin was measured on the 10 minute sample. Results At baseline, Casr+/- mice had a higher blood calcium, and in response to the two doses of elemental calcium, had greater increments and peak levels of ionized calcium than their wild type littermates. Despite significantly higher ionized calcium levels, the calcitonin levels of Casr+/- mice were consistently lower than wild type at any ionized calcium level, indicating that the dose-response curve of calcitonin to increases in ionized calcium had been significantly blunted or shifted to the right in Casr+/- mice. Conclusions These results confirm that the CaSR is a physiological regulator of calcitonin; therefore, in response to increases in ionized calcium, the CaSR inhibits parathyroid hormone secretion and stimulates calcitonin secretion.

  10. Cellular uptake but low permeation of human calcitonin-derived cell penetrating peptides and Tat(47-57) through well-differentiated epithelial models

    DEFF Research Database (Denmark)

    Tréhin, Rachel; Krauss, Ulrike; Beck-Sickinger, Annette G

    2004-01-01

    To investigate whether cell penetrating peptides (CPP) derived from human calcitonin (hCT) possess, in addition to cellular uptake, the capacity to deliver their cargo through epithelial barriers.......To investigate whether cell penetrating peptides (CPP) derived from human calcitonin (hCT) possess, in addition to cellular uptake, the capacity to deliver their cargo through epithelial barriers....

  11. Treatment of aneurysmal bone cysts by percutaneous CT-guided injection of calcitonin and steroid

    Energy Technology Data Exchange (ETDEWEB)

    Chang, Connie Y.; Kattapuram, Susan V.; Huang, Ambrose J.; Simeone, F.J.; Torriani, Martin; Bredella, Miriam A. [Massachusetts General Hospital, Department of Radiology Division of Musculoskeletal Imaging and Intervention, Boston, MA (United States)

    2017-01-15

    To determine the efficacy and safety of percutaneous calcitonin and steroid injection in the treatment of aneurysmal bone cysts (ABCs). Our study was IRB-approved and HIPAA-compliant. We reviewed pre- and post-procedural imaging studies and medical records of all CT-guided percutaneous injections of ABCs with calcitonin and steroid performed at our institution between 2003 and 2015. Treatment success based on imaging was categorized as substantial (51-100 %), partial (1-50 %), or none (0 %) by comparing radiographs of the lesion before and after treatment. Our study group comprised 9 patients (7 female, 2 male; mean age 19 ± 5 (range 12-25) years). ABCs were located in the pubis (n = 3), femur (n = 2), and humerus/scapula/ilium/sacrum (n = 1 for each). One patient did not have any clinical or imaging follow-up. For the other 8 patients, clinical and imaging follow-up ranged from 1 to 93 months (mean 16 ± 29 months). One patient had two injections, and 1 patient had three injections. Six out of eight patients (75 %) had complete symptomatic relief and 2 patients (25 %) had partial symptomatic relief after initial injection. Imaging follow-up revealed substantial imaging response in 4 out of 8 patients (50 %). There was a partial imaging response in 2 patients (25 %) and no imaging response in 2 out of 8 patients (25 %), and all 4 of these patients had local recurrence. There were no complications. Percutaneous CT-guided injection of ABCs with calcitonin and steroid is a safe and effective treatment. Lack of imaging response may necessitate more aggressive treatment to minimize local recurrence. (orig.)

  12. Calcitonin gene-related peptide triggers migraine-like attacks in patients with migraine with aura

    DEFF Research Database (Denmark)

    Hansen, Jakob Møller; Hauge, Anne Werner; Olesen, J.

    2010-01-01

    Calcitonin gene-related peptide (CGRP) is a key molecule in migraine pathogenesis. Intravenous CGRP infusion triggers delayed migraine-like attacks in patients with migraine without aura (MO). In contrast to patients with MO, in prior studies patients with familial hemiplegic migraine (FHM) did...... not report more migraine-like attacks compared to controls. Whether CGRP triggers migraine in patients with typical (non-hemiplegic) migraine with aura is (MA) unknown. In the present study we examined the migraine inducing effect of CGRP infusion in patients suffering from MA and healthy controls....

  13. Calcitonin gene-related peptide (CGRP receptors are important to maintain cerebrovascular reactivity in chronic hypertension.

    Directory of Open Access Journals (Sweden)

    Zhenghui Wang

    Full Text Available Cerebral blood flow autoregulation (CA shifts to higher blood pressures in chronic hypertensive patients, which increases their risk for brain damage. Although cerebral vascular smooth muscle cells express the potent vasodilatatory peptides calcitonin gene-related peptide (CGRP and adrenomedullin (AM and their receptors (calcitonin receptor-like receptor (Calclr, receptor-modifying proteins (RAMP 1 and 2, their contribution to CA during chronic hypertension is poorly understood. Here we report that chronic (10 weeks hypertensive (one-kidney-one-clip-method mice overexpressing the Calclr in smooth muscle cells (CLR-tg, which increases the natural sensitivity of the brain vasculature to CGRP and AM show significantly better blood pressure drop-induced cerebrovascular reactivity than wt controls. Compared to sham mice, this was paralleled by increased cerebral CGRP-binding sites (receptor autoradiography, significantly in CLR-tg but not wt mice. AM-binding sites remained unchanged. Whereas hypertension did not alter RAMP-1 expression (droplet digital (dd PCR in either mouse line, RAMP-2 expression dropped significantly in both mouse lines by about 65%. Moreover, in wt only Calclr expression was reduced by about 70% parallel to an increase of smooth muscle actin (Acta2 expression. Thus, chronic hypertension induces a stoichiometric shift between CGRP and AM receptors in favor of the CGRP receptor. However, the parallel reduction of Calclr expression observed in wt mice but not CLR-tg mice appears to be a key mechanism in chronic hypertension impairing cerebrovascular reactivity.

  14. Long-term treatment of osteogenesis imperfects tarda in adults with salmon calcitonin and calcium

    Energy Technology Data Exchange (ETDEWEB)

    Zanzi, I.; Wallach, S.; Ellis, K.J.; Aloia, J.F.; Atkins, H.L.; Cohn, S.H.

    1976-02-01

    Three postmenopausal women with osteogenesis imperfecta (O.I.) tarda were treated with daily salmon calcitonin (sCT) and calcium supplements for 12 to 33 months. Total body calcium (TBCa) measured by total body neutron activation analysis revealed a marked deficit exceeding that of severely osteoporotic women. In one patient a rapid loss of TBCa of 5 percent at five months of treatment was partially reversed after twelve months of treatment. In eight subsequent months of Ca supplementation alone, the loss of TBCa resumed and amounted to 11 percent. The second patient increased TBCa by 9 percent after a total of 33 months of sCT and Ca supplementation. The third patient also showed a rapid decrease in TBCa of 8 percent during one year of sCT and Ca, but she was also receiving systemic corticosteroids for asthma. Her TBCa recovered to 8 percent above baseline eight months after stopping sCT, continuation of the Ca and a drastic decrease in the dose of corticosteroids. The action of sCT in this patient might have been impaired by the concomitant administration of corticosteroids. Urinary hydroxyproline decreased from initial normal values in two patients suggesting continued inhibition of bone resorption. The results confirm previous work using calcitonin in children with O.I. and suggest that sCT may also be of benefit in adults with O.I. (auth)

  15. Calcitonin gene-related peptide (CGRP) levels during glyceryl trinitrate (GTN)-induced headache in healthy volunteers

    DEFF Research Database (Denmark)

    Kruuse, C; Iversen, Helle Klingenberg; Jansen-Olesen, I

    2010-01-01

    calcitonin gene-related peptide (CGRP). CGRP, vasoactive intestinal peptide (VIP), neuropeptide Y (NPY) and somatostatin plasma levels were measured before and after placebo/sumatriptan injection and during GTN-induced headache. Following a double-blind randomized cross-over design, 10 healthy volunteers...

  16. A novel oral form of salmon calcitonin improves glucose homeostasis and reduces body weight in diet-induced obese rats

    DEFF Research Database (Denmark)

    Feigh, M; Henriksen, K; Andreassen, K V

    2011-01-01

    To investigate the effects of acute and chronic administration of a novel oral formulation of salmon calcitonin (sCT) on glycaemic control, glucose homeostasis and body weight regulation in diet-induced obese (DIO) rats-an animal model of obesity-related insulin resistance and type 2 diabetes....

  17. Parathyroid hormone, calcitonin, and vitamin D 1974: Present status of physiological studies and analysis of calcium homeostasis

    Science.gov (United States)

    Potts, J. T., Jr.; Swenson, K. G.

    1975-01-01

    The role of parathyroid hormone, calcitonin, and vitamin D in the control of calcium and bone metabolism was studied. Particular emphasis was placed on the physiological adaptation to weightlessness and, as a potential model for this purpose, on the immobilization characteristic of space flight or prolonged bed rest. The biosynthesis, control of secretion, and metabolism of these hormonal agents is considered.

  18. Acylation of salmon calcitonin modulates in vitro intestinal peptide flux through membrane permeability enhancement

    DEFF Research Database (Denmark)

    Trier, Sofie; Linderoth, Lars; Bjerregaard, Simon

    2015-01-01

    Acylation of peptide drugs with fatty acid chains has proven beneficial for prolonging systemic circulation, as well as increasing enzymatic stability and interactions with lipid cell membranes. Thus, acylation offers several potential benefits for oral delivery of therapeutic peptides, and we...... hypothesize that tailoring the acylation may be used to optimize intestinal translocation. This work aims to characterize acylated analogues of the therapeutic peptide salmon calcitonin (sCT), which lowers blood calcium, by systematically increasing acyl chain length at two positions, in order to elucidate...... is due to a solubilization of the cell membrane, similar to transcellular oral permeation enhancers. The effect is dependent on pH, with larger effect at lower pH, and is impacted by acylation chain length and position. Compared to the unacylated peptide backbone, N-terminal acylation with a short chain...

  19. Comparison between Brain Natriuretic Peptide and Calcitonin Gene Related Peptide in Children with Dilated Cardiomyopathy

    Directory of Open Access Journals (Sweden)

    Noor Mohammad Noori

    2017-09-01

    Full Text Available Background: Dilated cardiomyopathy (DCM is revealed with the left ventricular dilatation and systolic dysfunction. This study was performed to determine the level of Calcitonin Gene Related Peptide (CGRP and Brain Natriuretic Peptide (BNP in children with dilated cardiomyopathy and controls and comparison of these two biomarkers in patients. Materials and Methods: This case-control study was performed from April 2014 to March 2015 on patients with DCM. The levels of BNP and CGRP were measured by ELISA and final amounts of biomarkers were compared with echocardiographic finding.37 DCM patients compared with 30 healthy children selected randomly from those who referred to the hospital for routine checkup. Results: In this study the mean age was 10.567± 5.50 and 12.135 ± 4.626 years for controls and cases, respectively (P=0.321. The majority of echocardiography indices in the left and right heart had different means in case and controls (P

  20. Calcitonin gene-related peptide and its receptor components in the human sphenopalatine ganglion -- interaction with the sensory system

    DEFF Research Database (Denmark)

    Csati, Anett; Tajti, Janos; Tuka, Bernadett

    2012-01-01

    , but not in neurons. RAMP1 immunoreactivity was localized in many neurons and SGCs. Thus, the two CGRP receptor components together were found in the SGCs. In addition, Western blot revealed the presence of RAMP1 and CLR in rat SPG. Our results suggest a possible sensory influence in the parasympathetic cranial......Clinical studies have suggested a link between the sensory trigeminal system and the parasympathetic ganglia. Calcitonin gene-related peptide (CGRP) is a sensory neuropeptide which plays an important role in vasodilatation and pain transmission in craniocervical structures. The present study...... was designed to examine if CGRP and CGRP receptor components are present in the human sphenopalatine ganglion (SPG) in order to reveal an interaction between the sensory and parasympathetic systems. Indirect immunofluorescence technique was used for immunohistochemical demonstration of CGRP, the calcitonin...

  1. The Effect of Alendronate and Calcitonin Treatments on Bone Mineral Density and Quality of Life in Women With Postmenopausal Osteoporosis

    Directory of Open Access Journals (Sweden)

    F. Taşçıoğlu

    2002-06-01

    Full Text Available The aim of this study was to compare the effect of alendronate and calcitonin treatments on bone mineral density (BMD and quality of life of women with postmenopausal osteoporosis. One hundred ninety-three patients were randomly assigned to two groups: 93 patients received daily doses of 10 mg alendronate and calcium 1000 mg, and 98 patients used intranasal salmon calcitonin (sCt at a dosage of 200 IU/day and they also received daily doses of 1000 mg calcium supplements. DXA was used for the measurement of BMD of the lumbar spine and proximal femur before and after the study period. SF-36 was used as a measure of health-related quality of life. At the end of the treatment, ALN produced significant increases in BMD at the lumbar spine (p< 0.001, femur neck (p<0.05, trochanteric region (p<0.001 and at the Ward triangle (p<0.05. In contrast, intranasal sCt treatment resulted in a significant bone loss in the femur neck (p<0.01 and Ward triangle (p<0.05, and only a significant increase in BMD of the lumbar spine was observed with calcitonin treatment(p< 0.05. Quality of life as assessed by SF-36 improved significantly in both groups(p<0.05. In conclusion, alendronate seemed to be more effective than calcitonin, increasing both spinal and femoral BMD, for the treatment of postmenopausal osteoporosis. Both treatments were found to be effective for the improvement of quality of life.

  2. Immunohistochemical expression of alpha-smooth muscle actin and glucocorticoid and calcitonin receptors in central giant-cell lesions.

    Science.gov (United States)

    Maiz, Nancy Noya; de la Rosa-García, Estela; Camacho, María Esther Irigoyen

    2016-04-01

    Central giant-cell lesions (CGCLs) are reactive lesions that consist histologically of spindle-shaped stromal cells, (fibroblasts and myofibroblasts) loosely arranged in a fibrous stroma, multinucleated giant cells and mononuclear cells with haemorrhagic areas. This study identified the immunoexpression of alpha-smooth muscle actin in spindle-shaped stromal cells, and glucocorticoid and calcitonin receptors in multinucleated giant cells and mononuclear cells. Their association with the clinical and radiographic characteristics of these lesions was identified. Thirty-five cases of CGCLs were studied. Expression of alpha-smooth muscle actin, glucocorticoid and calcitonin was evaluated by immunohistochemistry. The labelling index was 100 times the quotient of the number of positive cells divided by the total number of cells of each type. Logistic regression analysis was applied. Alpha-smooth muscle actin was positive (54%) for spindle stromal cells (myofibroblasts). A significant association was observed with root resorption (P = 0.004) and cortical bone destruction (P = 0.024). Glucocorticoid immunoexpression was positive for 99% of the giant cells and 86.7% of the mononuclear cells. Glucocorticoid immunoexpression in the mononuclear cells was associated with root resorption (P = 0.031). A longer evolution time was associated with lower immunoexpression of glucocorticoid (OR 12.4: P = 0.047). Calcitonin immunoexpression was positive in 86% of the giant cells. Immunoexpression of calcitonin was associated with age (P = 0.040). Myofibroblasts are important components of CGCLs, stromal cells and alpha-smooth muscle. Actin immunoexpression was associated with root and cortical bone resorption. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  3. Bio-Oss® modified by calcitonin gene-related peptide promotes osteogenesis in vitro.

    Science.gov (United States)

    Li, Yuanjing; Yang, Lan; Zheng, Zhichao; Li, Zhengmao; Deng, Tian; Ren, Wen; Wu, Caijuan; Guo, Lvhua

    2017-11-01

    Bio-Oss® and α-calcitonin gene-related peptide (CGRP) are involved in osteogenesis. However, it has remained to be assessed how α-CGRP affects the effect of Bio-Oss. In the present study, primary osteoblasts were incubated with α-CGRP, Bio-Oss, α-GGRP-Bio-Oss or mimic-α-CGRP. The proliferation rate, mineralization nodules, alkaline phosphatase (ALP) activity and the expression of osteogenic genes were measured by a Cell Counting Kit-8 assay, Alizarin Red-S staining, ALP activity detection and reverse-transcription quantitative PCR as well as western blot analysis, respectively. The proliferation rate, ALP activity and the number of mineralization nodules were significantly increased in the α-CGRP-modified Bio-Oss group compared to that in the Bio-Oss group. The mRNA and protein levels of osteocalcin, Runt-related transcription factor-2 and ALP were significantly upregulated in the α-CGRP-Bio-Oss group compared with those in the Bio-Oss group. Furthermore, the effect of mimic-α-CGRP on osteogenesis was reduced as it carried a mutation. In conclusion, the present study was the first to demonstrate that Bio-Oss modified with CGRP contributed to osteogenesis and may provide a novel formulation applied in the clinic for restoration of large bone defects.

  4. Acupuncture as Treatment of Hot Flashes and the Possible Role of Calcitonin Gene-Related Peptide

    Directory of Open Access Journals (Sweden)

    Anna-Clara E. Spetz Holm

    2012-01-01

    Full Text Available The mechanisms behind hot flashes in menopausal women are not fully understood. The flashes in women are probably preceded by and actually initiated by a sudden downward shift in the set point for the core body temperature in the thermoregulatory center that is affected by sex steroids, β-endorphins, and other central neurotransmitters. Treatments that influence these factors may be expected to reduce hot flashes. Since therapy with sex steroids for hot flashes has appeared to cause a number of side effects and risks and women with hot flashes and breast cancer as well as men with prostate cancer and hot flashes are prevented from sex steroid therapy there is a great need for alternative therapies. Acupuncture affecting the opioid system has been suggested as an alternative treatment option for hot flashes in menopausal women and castrated men. The heat loss during hot flashes may be mediated by the potent vasodilator and sweat gland activator calcitonin gene-related peptide (CGRP the concentration of which increases in plasma during flashes in menopausal women and, according to one study, in castrated men with flushes. There is also evidence for connections between the opioid system and the release of CGRP. In this paper we discuss acupuncture as a treatment alternative for hot flashes and the role of CGRP in this context.

  5. Calcitonin gene–related peptide inhibits Langerhans cell–mediated HIV-1 transmission

    Science.gov (United States)

    Ganor, Yonatan; Drillet-Dangeard, Anne-Sophie; Lopalco, Lucia; Tudor, Daniela; Tambussi, Giuseppe; Delongchamps, Nicolas Barry; Zerbib, Marc

    2013-01-01

    Upon its mucosal entry, human immunodeficiency virus type 1 (HIV-1) is internalized by Langerhans cells (LCs) in stratified epithelia and transferred locally to T cells. In such epithelia, LCs are in direct contact with peripheral neurons secreting calcitonin gene–related peptide (CGRP). Although CGRP has immunomodulatory effects on LC functions, its potential influence on the interactions between LCs and HIV-1 is unknown. We show that CGRP acts via its receptor expressed by LCs and interferes with multiple steps of LC-mediated HIV-1 transmission. CGRP increases langerin expression, decreases selected integrins, and activates NF-κB, resulting in decreased HIV-1 intracellular content, limited formation of LC–T cell conjugates, and elevated secretion of the CCR5-binding chemokine CCL3/MIP-1α. These mechanisms cooperate to efficiently inhibit HIV-1 transfer from LCs to T cells and T cell infection. In vivo, HIV-1 infection decreases CGRP plasma levels in both vaginally SHIV-challenged macaques and HIV-1–infected individuals. CGRP plasma levels return to baseline after highly active antiretroviral therapy. Our results reveal a novel path by which a peripheral neuropeptide acts at the molecular and cellular levels to limit mucosal HIV-1 transmission and suggest that CGRP receptor agonists might be used therapeutically against HIV-1. PMID:24081951

  6. Repression of calcitonin gene-related peptide expression in trigeminal neurons by a Theobroma cacao extract.

    Science.gov (United States)

    Abbey, Marcie J; Patil, Vinit V; Vause, Carrie V; Durham, Paul L

    2008-01-17

    Cocoa bean preparations were first used by the ancient Maya and Aztec civilizations of South America to treat a variety of medical ailments involving the cardiovascular, gastrointestinal, and nervous systems. Diets rich in foods containing abundant polyphenols, as found in cocoa, underlie the protective effects reported in chronic inflammatory diseases. Release of calcitonin gene-related peptide (CGRP) from trigeminal nerves promotes inflammation in peripheral tissues and nociception. To determine whether a methanol extract of Theobroma cacao L. (Sterculiaceae) beans enriched for polyphenols could inhibit CGRP expression, both an in vitro and an in vivo approach was taken. Treatment of rat trigeminal ganglia cultures with depolarizing stimuli caused a significant increase in CGRP release that was repressed by pretreatment with Theobroma cacao extract. Pretreatment with Theobroma cacao was also shown to block the KCl- and capsaicin-stimulated increases in intracellular calcium. Next, the effects of Theobroma cacao on CGRP levels were determined using an in vivo model of temporomandibular joint (TMJ) inflammation. Capsaicin injection into the TMJ capsule caused an ipsilateral decrease in CGRP levels. Theobroma cacao extract injected into the TMJ capsule 24h prior to capsaicin treatment repressed the stimulatory effects of capsaicin. Our results demonstrate that Theobroma cacao extract can repress stimulated CGRP release by a mechanism that likely involves blockage of calcium channel activity. Furthermore, our findings suggest that the beneficial effects of diets rich in cocoa may include suppression of sensory trigeminal nerve activation.

  7. Repression of calcitonin gene-related peptide expression in trigeminal neurons by a Theobroma cacao extract☆

    Science.gov (United States)

    Abbey, Marcie J.; Patil, Vinit V.; Vause, Carrie V.; Durham, Paul L.

    2008-01-01

    Ethnopharmacological relevance Cocoa bean preparations were first used by the ancient Maya and Aztec civilizations of South America to treat a variety of medical ailments involving the cardiovascular, gastrointestinal, and nervous systems. Diets rich in foods containing abundant polyphenols, as found in cocoa, underlie the protective effects reported in chronic inflammatory diseases. Release of calcitonin gene-related peptide (CGRP) from trigeminal nerves promotes inflammation in peripheral tissues and nociception. Aim of the study To determine whether a methanol extract of Theobroma cacao L. (Sterculiaceae) beans enriched for polyphenols could inhibit CGRP expression, both an in vitro and an in vivo approach was taken. Results Treatment of rat trigeminal ganglia cultures with depolarizing stimuli caused a significant increase in CGRP release that was repressed by pretreatment with Theobroma cacao extract. Pretreatment with Theobroma cacao was also shown to block the KCl- and capsaicin-stimulated increases in intracellular calcium. Next, the effects of Theobroma cacao on CGRP levels were determined using an in vivo model of temporomandibular joint (TMJ) inflammation. Capsaicin injection into the TMJ capsule caused an ipsilateral decrease in CGRP levels. Theobroma cacao extract injected into the TMJ capsule 24 h prior to capsaicin treatment repressed the stimulatory effects of capsaicin. Conclusions Our results demonstrate that Theobroma cacao extract can repress stimulated CGRP release by a mechanism that likely involves blockage of calcium channel activity. Furthermore, our findings suggest that the beneficial effects of diets rich in cocoa may include suppression of sensory trigeminal nerve activation. PMID:17997062

  8. Calcitonin gene-related peptide regulates type IV hypersensitivity through dendritic cell functions.

    Directory of Open Access Journals (Sweden)

    Norihisa Mikami

    Full Text Available Dendritic cells (DCs play essential roles in both innate and adaptive immune responses. In addition, mutual regulation of the nervous system and immune system is well studied. One of neuropeptides, calcitonin gene-related peptide (CGRP, is a potent regulator in immune responses; in particular, it has anti-inflammatory effects in innate immunity. For instance, a deficiency of the CGRP receptor component RAMP 1 (receptor activity-modifying protein 1 results in higher cytokine production in response to LPS (lipopolysaccharide. On the other hand, how CGRP affects DCs in adaptive immunity is largely unknown. In this study, we show that CGRP suppressed Th1 cell differentiation via inhibition of IL-12 production in DCs using an in vitro co-culture system and an in vivo ovalbumin-induced delayed-type hypersensitivity (DTH model. CGRP also down-regulated the expressions of chemokine receptor CCR2 and its ligands CCL2 and CCL12 in DCs. Intriguingly, the frequency of migrating CCR2(+ DCs in draining lymph nodes of RAMP1-deficient mice was higher after DTH immunization. Moreover, these CCR2(+ DCs highly expressed IL-12 and CD80, resulting in more effective induction of Th1 differentiation compared with CCR2(- DCs. These results indicate that CGRP regulates Th1 type reactions by regulating expression of cytokines, chemokines, and chemokine receptors in DCs.

  9. Effects of calcitonin on plasma calcium and phosphate in the mudskipper, Periophthalmodon schlosseri (Teleostei), in water and during exposure to air.

    Science.gov (United States)

    Fenwick, J C; Lam, T J

    1988-05-01

    After 7 days in air on wet filter paper mudskippers had normal body weight and normal levels of plasma sodium, potassium, and phosphate. They were, however, significantly hypercalcemic. The hypercalcemia could be reduced by the daily intraperitoneal injection of synthetic eel calcitonin (1.67 microgram kg-1 day-1) and this effect was dose dependent with a maximal response at a dose of 3.33 micrograms kg-1 day-1. Calcitonin had no effect on plasma calcium levels of fish held in water but did induce significant hyperphosphatemia whether the fish were held in water or in air on wet filter paper with this effect being greater under the latter conditions. The hypocalcemic action of calcitonin was restricted to conditions under which the fish displayed patent hypercalcemia. Under no conditions did calcitonin produce significant hypocalcemia so it appears that the action of synthetic eel calcitonin in the mudskipper, Periophthalmodon schlosseri, is dependent upon the presence of excess plasma calcium and is thus more accurately described as being anti-hypercalcemic rather than hypocalcemic.

  10. Tapentadol inhibits calcitonin gene-related peptide release from rat brainstem in vitro.

    Science.gov (United States)

    Greco, Maria Cristina; Lisi, Lucia; Currò, Diego; Navarra, Pierluigi; Tringali, Giuseppe

    2014-06-01

    We have previously developed an in vitro model of rat brainstem explants. The latter release sizable amounts of calcitonin gene-related peptide (CGRP); basal release can be stimulated by such secretagogues as high KCl concentrations, veratridine or capsaicine. In this paradigm we investigated the activity of the analgesic agent tapentadol; the effects of tapentadol were compared to those of a classical opioid receptor agonist, morphine, and the selective noradrenaline reuptake inhibitor reboxetine. Morphine inhibited basal CGRP release, with statistical significance from 1 nM onward and maximal (-44%) inhibition at 100 μM. Morphine also inhibited K(+)-stimulated peptide release, with a significant effect from 1 μM and maximal (-39%) decrease at 100 μM, but failed to inhibit release stimulated by 10 μM capsaicin. At variance, reboxetine had no effect on baseline CGRP outflow, but was able to inhibit both K(+)-stimulated [significant inhibition from 1 μM onward and maximal (-37%) decrease at 100 μM], and capsaicin-stimulated release [significant effect from 1 μM and maximal (-31%) decrease at 100 μM]. Likewise, tapentadol had no effect on baseline CGRP release up to 100 μM, but decreased secretion stimulated by 56 mM KCl or capsaicin, with significant effects from 0.1 and 1 μM respectively; maximal inhibition over 56 mM KCl and capsaicin stimuli was -29% and -31%, respectively. Naloxone antagonized the effect of morphine, but not those of reboxetine and tapentadol, on K(+)-stimulated CGRP secretion. In conclusion the present study provides consistent pharmacological evidence that tapentadol acts as a noradrenaline reuptake inhibitor agent in this experimental model. Copyright © 2014 Elsevier Inc. All rights reserved.

  11. Oral salmon calcitonin improves fasting and postprandial glycemic control in lean healthy rats.

    Science.gov (United States)

    Feigh, M; Nielsen, R H; Hansen, C; Henriksen, K; Christiansen, C; Karsdal, M A

    2012-02-01

    A novel oral form of salmon calcitonin (sCT) was recently demonstrated to improve both fasting and postprandial glycemic control and induce weight loss in diet-induced obese and insulin-resistant rats. To further explore the glucoregulatory efficacy of oral sCT, irrespective of obesity and metabolic dysfunction, the present study investigated the effect of chronic oral sCT treatment on fasting and postprandial glycemic control in male lean healthy rats. 20 male rats were divided equally into a control group receiving oral vehicle or an oral sCT (2 mg/kg) group. All rats were treated twice daily for 5 weeks. Body weight and food intake were monitored during the study period and fasting blood glucose, plasma insulin and insulin sensitivity were determined and an oral glucose tolerance test (OGTT) performed at study end. Compared with the vehicle group, rats receiving oral sCT had improved fasting glucose homeostasis and insulin resistance, as measured by homeostatic model assessment of insulin resistance index (HOMA-IR), with no change in body weight or fasting plasma insulin. In addition, the rats receiving oral sCT had markedly reduced glycemia and insulinemia during OGTT. This is the first report showing that chronic oral sCT treatment exerts a glucoregulatory action in lean healthy rats, irrespective of influencing body weight. Importantly, oral sCT seems to exert a dual treatment effect by improving fasting and postprandial glycemic control and insulin sensitivity. This and previous studies suggest oral sCT is a promising agent for the treatment of obesity-related insulin resistance and type 2 diabetes. © Georg Thieme Verlag KG Stuttgart · New York.

  12. Calcitonin gene-related peptide neurons mediate sleep-specific circadian output in Drosophila.

    Science.gov (United States)

    Kunst, Michael; Hughes, Michael E; Raccuglia, Davide; Felix, Mario; Li, Michael; Barnett, Gregory; Duah, Janelle; Nitabach, Michael N

    2014-11-17

    Imbalances in amount and timing of sleep are harmful to physical and mental health. Therefore, the study of the underlying mechanisms is of great biological importance. Proper timing and amount of sleep are regulated by both the circadian clock and homeostatic sleep drive. However, very little is known about the cellular and molecular mechanisms by which the circadian clock regulates sleep. In this study, we describe a novel role for diuretic hormone 31 (DH31), the fly homolog of the vertebrate neuropeptide calcitonin gene-related peptide, as a circadian wake-promoting signal that awakens the fly in anticipation of dawn. Analysis of loss-of-function and gain-of-function Drosophila mutants demonstrates that DH31 suppresses sleep late at night. DH31 is expressed by a subset of dorsal circadian clock neurons that also express the receptor for the circadian neuropeptide pigment-dispersing factor (PDF). PDF secreted by the ventral pacemaker subset of circadian clock neurons acts on PDF receptors in the DH31-expressing dorsal clock neurons to increase DH31 secretion before dawn. Activation of PDF receptors in DH31-positive DN1 specifically affects sleep and has no effect on circadian rhythms, thus constituting a dedicated locus for circadian regulation of sleep. We identified a novel signaling molecule (DH31) as part of a neuropeptide relay mechanism for circadian control of sleep. Our results indicate that outputs of the clock controlling sleep and locomotor rhythms are mediated via distinct neuronal pathways. Copyright © 2014 Elsevier Ltd. All rights reserved.

  13. Calcitonin gene-related peptide down-regulates bleomycin-induced pulmonary fibrosis.

    Science.gov (United States)

    Li, Xian-Wei; Li, Xiao-Hui; Du, Jie; Li, Dai; Li, Yuan-Jian; Hu, Chang-Ping

    2016-12-01

    We have found that eIF3a plays an important role in bleomycin-induced pulmonary fibrosis, and up-regulation of eIF3a induced by TGF-β1 is mediated via the ERK1/2 pathway. Whether ERK1/2 - eIF3a signal pathway is involved in calcitonin gene-related peptide (CGRP)-mediated pathogenesis of bleomycin-induced pulmonary fibrosis remains unknown. Pulmonary fibrosis was induced by intratracheal instillation of bleomycin (5 mg/kg) in rats. Primary pulmonary fibroblasts were cultured to investigate the proliferation by BrdU incorporation method and flow cytometry. Sensory CGRP depletion by capsaicin exacerbated bleomycin-induced pulmonary fibrosis in rats, as shown by a significant disturbed alveolar structure, marked thickening of the interalveolar septa and dense interstitial infiltration by inflammatory cells and fibroblasts, accompanied with increased expression of TGF-β1, eIF3a, phosphorylated ERK1/2, α-SMA, collagen I, and collagen III. Exogenous application of CGRP significantly inhibited TGF-β1-induced proliferation and differentiation of pulmonary fibroblasts concomitantly with decreased expression of eIF3a, phosphorylated ERK1/2, α-SMA, collagen I, and collagen III. These effects of CGRP were abolished in the presence of CGRP 8-37 . These results suggest that endogenous CGRP is related to the development of pulmonary fibrosis induced by bleomycin, and the inhibitory effect of CGRP on proliferation of lung fibroblasts involves the ERK1/2 - eIF3a signaling pathway.

  14. Benefit of measuring basal serum calcitonin to detect medullary thyroid carcinoma in a Danish population with a high prevalence of thyroid nodules

    DEFF Research Database (Denmark)

    Hasselgren, Martin; Hegedüs, Laszlo; Godballe, Christian

    2009-01-01

    ; thyroidectomy was performed in 307 of these patients. RESULTS: Thirty-nine patients had elevated serum calcitonin; 6 of these patients had MTC detected by the initial diagnostic setup. No additional patient in the cohort was registered in the Danish Thyroid Cancer Database, reflecting that all patients with MTC......BACKGROUND: Routine measurement of serum calcitonin to detect medullary thyroid carcinoma (MTC) continues to be fiercely debated, although less attention has been paid to the positive predictive value (PPV) of this method. METHODS: We collected data from 959 patients with nontoxic nodular goiter....... The low PPV might lead to unnecessary thyroid surgery. Thus, the result of serum calcitonin measurement should always be interpreted in the context of other clinical variables. (c) 2009 Wiley Periodicals, Inc. Head Neck, 2009....

  15. Phosphodiesterases 3 and 5 express activity in the trigeminal ganglion and co-localize with calcitonin gene-related peptide

    DEFF Research Database (Denmark)

    Nordgaard, Julie C; Kruse, Lars S; Møller, Morten

    2014-01-01

    Understanding of the neuropathology leading to migraine pain has centered on either a vascular or neuronal origin. Sildenafil, a specific inhibitor of phosphodiesterase 5 (PDE5), induces migraine-like headache in a human headache model without concomitant artery dilation. The presence and activity...... of PDE3 and PDE5 is known in cerebral arteries. However, the presence in the neuronal part of the trigeminovascular pathway, i.e. the trigeminal ganglion and the possible co-localization with calcitonin gene-related peptide (CGRP), is not known....

  16. Involvement of calcitonin gene-related peptide in migraine: regional cerebral blood flow and blood flow velocity in migraine patients

    DEFF Research Database (Denmark)

    Lassen, L.H.; Jacobsen, V.B.; Haderslev, P.A.

    2008-01-01

    Calcitonin gene-related peptide (CGRP)-containing nerves are closely associated with cranial blood vessels. CGRP is the most potent vasodilator known in isolated cerebral blood vessels. CGRP can induce migraine attacks, and two selective CGRP receptor antagonists are effective in the treatment...... g/min) or placebo for 20 min was studied in 12 patients with migraine without aura outside attacks. Xenon-133 inhalation SPECT-determined regional cerebral blood flow (rCBF) and transcranial Doppler (TCD)-determined blood velocity (V-mean) in the middle cerebral artery (MCA), as well as the heart...

  17. Cytologic diagnosis of a medullary carcinoma of the thyroid by Sevier-Munger silver staining and calcitonin immunocytochemistry.

    Science.gov (United States)

    Rastad, J; Wilander, E; Lindgren, P G; Ljunghall, S; Stenkvist, B G; Akerström, G

    1987-01-01

    A medullary carcinoma of the thyroid was preoperatively diagnosed on ultrasonically guided fine needle aspiration biopsies. After cytocentrifugation, the tumor cells displayed a dense cytoplasmic silver granulation with the Sevier-Munger technique when applied to air-dried or acetone-ethanol-fixed samples and an obvious calcitonin immunoreactivity after fixation in Bouin's fluid. These methods may prove useful in the identification of nonpalpable metastases and recurrences of medullary carcinomas of the thyroid, especially since the cytologic typing of medullary thyroid carcinoma cells may be difficult with routine stainings.

  18. No Evidence of Increase in Calcitonin Concentrations or Development of C-Cell Malignancy in Response to Liraglutide for Up to 5 Years in the LEADER Trial

    DEFF Research Database (Denmark)

    Hegedüs, Laszlo; Sherman, Steven I; Tuttle, R Michael

    2018-01-01

    OBJECTIVE: To describe the changes in serum levels of calcitonin in liraglutide- and placebo-treated patients in the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial over a 3.5-5-year period. RESEARCH DESIGN AND METHODS: Patients (n = 9......,340) with type 2 diabetes and high risk for cardiovascular events were randomized 1:1 to liraglutide or placebo. We analyzed calcitonin levels throughout the trial, and thyroid and C-cell adverse events and neoplasms. RESULTS: At 36 months, patients randomized to liraglutide versus placebo showed no evidence...

  19. Gallium-68 Dotatate PET/CT is superior to other imaging modalities in the detection of medullary carcinoma of the thyroid in the presence of high serum calcitonin.

    Science.gov (United States)

    Tran, Kathryn; Khan, Sairah; Taghizadehasl, Mina; Palazzo, Fausto; Frilling, Andrea; Todd, Jeannie F; Al-Nahhas, Adil

    2015-01-01

    Medullary carcinoma of the thyroid (MTC) is a rare neuroendocrine tumour (NET) that expresses somatostatin receptors on the cell membrane and secretes calcitonin. Surgery is the primary curative modality but is achieved only when the diagnosis is timely so there is a high rate of persistent and recurrent disease indicated by a rise in the serum calcitonin levels. Successful management of recurrent disease requires accurate localisation with cross sectional and functional imaging. The introduction of gallium-68-Dotatate ((68)Ga-Dotatate) peptides positron emission tomography/computerized tomography (PET/CT) has significantly improved the detection of NET and has been reported as a valuable adjunct in MTC localisation. We retrospectively reviewed our cases of MTC to correlate the detectability of (68)Ga-Dotatate in relation to calcitonin levels and assess suitability of inoperable patients for peptide receptor radionuclide therapy (PRRT). Seven patients (age range 31-66 years, M:F 3:4) with raised calcitonin (mean=7,143pg/mL) were referred for (68)Ga-Dotatate PET/CT scan for localisation of persisting recurrent MTC. Six patients were known to have MTC treated with thyroidectomy and one patient was presenting for the first time. All patients had multiple imaging including ultrasound (US), CT, magnetic resonance imaging (MRI), fluorine-18-fluorodeoxyglucose ((18)F-FDG) PET/CT and iodine-123-metaiodobenzylguanidine ((123)I-MIBG). Positive findings were defined as areas of increased uptake other than the organs of normal distribution and were correlated with results of biopsies, other imaging, long term monitoring of calcitonin and clinical follow up. In 6/7 patients with very high serum calcitonin (range= 672-37,180, mean=8,320pg/mL) (68)Ga-Dotatate PET/CT confirmed the presence of active disease seen on other modalities or detected hitherto unsuspected lesions. In at least 3 cases, (68)Ga-Dotatate PET/CT showed many more lesions compared to other imaging combined. In 1

  20. Expression and localization of prohormone convertase PC1 in the calcitonin-producing cells of the bullfrog ultimobranchial gland.

    Science.gov (United States)

    Yaoi, Yuichi; Suzuki, Masakazu; Tomura, Hideaki; Kurabuchi, Shingo; Sasayama, Yuichi; Tanaka, Shigeyasu

    2003-11-01

    We examined the expression and localization of the prohormone convertases, PC1 and PC2, in the ultimobranchial gland of the adult bullfrog using immunohistochemical (IHC) and in situ hybridization (ISH) techniques. In the ultimobranchial gland, PC1-immunoreactive cells were columnar, and were present in the follicular epithelium. When serial sections were immunostained with anti-calcitonin, anti-CGRP, anti-PC1, and anti-PC2 sera, PC1 was found only in the calcitonin/CGRP-producing cells. No PC2-immunopositive cells were detected. In the ISH, PC1 mRNA-positive cells were detected in the follicle cells in the ultimobranchial gland. No PC2 mRNA-positive cells were detected. RT-PCR revealed expression of the mRNAs of PC1 and the PC2 in the ultimobranchial gland. However, very little of the PC2 mRNA is probably translated because no PC2 protein was detected either by IHC staining or by Western blotting analysis. We conclude that the main prohormone convertase that is involved in the proteolytic cleavage of procalcitonin in the bullfrog is PC1.

  1. Role for voltage gated calcium channels in calcitonin gene-related peptide release in the rat trigeminovascular system

    DEFF Research Database (Denmark)

    Amrutkar, D V; Ploug, K B; Olesen, J

    2011-01-01

    Clinical and genetic studies have suggested a role for voltage gated calcium channels (VGCCs) in the pathogenesis of migraine. Release of calcitonin gene-related peptide (CGRP) from trigeminal neurons has also been implicated in migraine. The VGCCs are located presynaptically on neurons and are i......Clinical and genetic studies have suggested a role for voltage gated calcium channels (VGCCs) in the pathogenesis of migraine. Release of calcitonin gene-related peptide (CGRP) from trigeminal neurons has also been implicated in migraine. The VGCCs are located presynaptically on neurons...... and are involved in the release of these peptides to different stimuli. We have examined the presence and importance of VGCCs in controlling the CGRP release from rat dura mater, freshly isolated trigeminal ganglion (TG) and trigeminal nucleus caudalis (TNC). Each of the four VGCCs, P/Q-, N-, and L- and T...... the potassium induced CGRP release. In the absence of calcium ions (Ca2+) and in the presence of a cocktail of blockers, the stimulated CGRP release from dura mater was reduced almost to the same level as basal CGRP release. In the TG ¿-conotoxin GVIA inhibited the potassium induced CGRP release significantly...

  2. Role for voltage gated calcium channels in calcitonin gene-related peptide release in the rat trigeminovascular system

    DEFF Research Database (Denmark)

    Amrutkar, D V; Ploug, K B; Olesen, J

    2011-01-01

    Clinical and genetic studies have suggested a role for voltage gated calcium channels (VGCCs) in the pathogenesis of migraine. Release of calcitonin gene-related peptide (CGRP) from trigeminal neurons has also been implicated in migraine. The VGCCs are located presynaptically on neurons and are i......Clinical and genetic studies have suggested a role for voltage gated calcium channels (VGCCs) in the pathogenesis of migraine. Release of calcitonin gene-related peptide (CGRP) from trigeminal neurons has also been implicated in migraine. The VGCCs are located presynaptically on neurons...... and are involved in the release of these peptides to different stimuli. We have examined the presence and importance of VGCCs in controlling the CGRP release from rat dura mater, freshly isolated trigeminal ganglion (TG) and trigeminal nucleus caudalis (TNC). Each of the four VGCCs, P/Q-, N-, and L- and T...... the potassium induced CGRP release. In the absence of calcium ions (Ca2+) and in the presence of a cocktail of blockers, the stimulated CGRP release from dura mater was reduced almost to the same level as basal CGRP release. In the TG ω-conotoxin GVIA inhibited the potassium induced CGRP release significantly...

  3. Permeation of Insulin, Calcitonin and Exenatide across Caco-2 Monolayers: Measurement Using a Rapid, 3-Day System

    Science.gov (United States)

    Gupta, Vivek; Doshi, Nishit; Mitragotri, Samir

    2013-01-01

    Objectives Caco-2 monolayers are one of the most widely used in vitro models for prediction of intestinal permeability of therapeutic molecules. However, the conventional Caco-2 monolayer model has several drawbacks including labor-intensive culture process, unphysiological growth conditions, lack of reproducibility and limited throughput. Here, we report on the use of 3-day Caco-2 monolayers for assessing permeability of polypeptide drugs. Methods The 3-day monolayers were grown in a commercially available transwell set-up, which facilitates rapid development of the Caco-2 monolayers in an intestinal epithelial differentiation mimicking environment. This set-up included use of serum-free medium of defined composition with supplements such as butyric acid, hormones, growth factors, and other metabolites, reported to regulate the differentiation of intestinal epithelial cells in vivo. We measured permeability of 3 different therapeutic polypeptides; insulin, calcitonin, and exenatide across the monolayer. Results Preliminary validation of the monolayer was carried out by confirming dose-dependent permeation of FITC-insulin and sulforhodamine-B. Transport of insulin, calcitonin, and exenatide measured at different loading concentrations suggests that the permeability values obtained with 3-day cultures resemble more closely the values obtained with ex vivo models compared to permeability values obtained with conventional 21-day cultures. Conclusions Short-term 3-day Caco-2 monolayers provide new opportunities for developing reproducible and high-throughput models for screening of therapeutic macromolecules for oral absorption. PMID:23483881

  4. De novo sequencing of two novel peptides homologous to calcitonin-like peptides, from skin secretion of the Chinese Frog, Odorrana schmackeri

    Directory of Open Access Journals (Sweden)

    Geisa P.C. Evaristo

    2015-09-01

    Full Text Available An MS/MS based analytical strategy was followed to solve the complete sequence of two new peptides from frog (Odorrana schmackeri skin secretion. This involved reduction and alkylation with two different alkylating agents followed by high resolution tandem mass spectrometry. De novo sequencing was achieved by complementary CID and ETD fragmentations of full-length peptides and of selected tryptic fragments. Heavy and light isotope dimethyl labeling assisted with annotation of sequence ion series. The identified primary structures are GCD[I/L]STCATHN[I/L]VNE[I/L]NKFDKSKPSSGGVGPESP-NH2 and SCNLSTCATHNLVNELNKFDKSKPSSGGVGPESF-NH2, i.e. two carboxyamidated 34 residue peptides with an aminoterminal intramolecular ring structure formed by a disulfide bridge between Cys2 and Cys7. Edman degradation analysis of the second peptide positively confirmed the exact sequence, resolving I/L discriminations. Both peptide sequences are novel and share homology with calcitonin, calcitonin gene related peptide (CGRP and adrenomedullin from other vertebrates. Detailed sequence analysis as well as the 34 residue length of both O. schmackeri peptides, suggest they do not fully qualify as either calcitonins (32 residues or CGRPs (37 amino acids and may justify their classification in a novel peptide family within the calcitonin gene related peptide superfamily. Smooth muscle contractility assays with synthetic replicas of the S–S linked peptides on rat tail artery, uterus, bladder and ileum did not reveal myotropic activity.

  5. Early detection of response in small cell bronchogenic carcinoma by changes in serum concentrations of creatine kinase, neuron specific enolase, calcitonin, ACTH, serotonin and gastrin releasing peptide

    DEFF Research Database (Denmark)

    Bork, E; Hansen, M; Urdal, P

    1988-01-01

    Creatine kinase (CK-BB), neuron specific enolase (NSE), ACTH, calcitonin, serotonin and gastrin releasing peptide (GRP) were measured in serum or plasma before and immediately after initiation of treatment in patients with small cell lung cancer (SCC). Pretherapeutic elevated concentrations of CK...

  6. No Evidence of Increase in Calcitonin Concentrations or Development of C-Cell Malignancy in Response to Liraglutide for Up to 5 Years in the LEADER Trial.

    Science.gov (United States)

    Hegedüs, Laszlo; Sherman, Steven I; Tuttle, R Michael; von Scholten, Bernt J; Rasmussen, Søren; Karsbøl, Julie D; Daniels, Gilbert H

    2017-12-26

    To describe the changes in serum levels of calcitonin in liraglutide- and placebo-treated patients in the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial over a 3.5-5-year period. Patients (n = 9,340) with type 2 diabetes and high risk for cardiovascular events were randomized 1:1 to liraglutide or placebo. We analyzed calcitonin levels throughout the trial, and thyroid and C-cell adverse events and neoplasms. At 36 months, patients randomized to liraglutide versus placebo showed no evidence of increase in calcitonin concentrations in male (estimated treatment ratio [ETR] 1.03 [95% CI 1.00, 1.06]; P = 0.068) and female (ETR 1.00 [95% CI 0.97, 1.02]; P = 0.671) subgroups. There were no episodes of C-cell hyperplasia or medullary thyroid carcinoma in liraglutide-treated patients. There was no evidence of a difference in calcitonin concentrations between the liraglutide and placebo groups, and no C-cell malignancies occurred in the liraglutide group. © 2018 by the American Diabetes Association.

  7. Contribution of kv7.4/kv7.5 heteromers to intrinsic and calcitonin gene-related Peptide-induced cerebral reactivity

    DEFF Research Database (Denmark)

    Chadha, Preet S; Jepps, Thomas A; Carr, Georgina

    2014-01-01

    Middle cerebral artery (MCA) diameter is regulated by inherent myogenic activity and the effect of potent vasodilators such as calcitonin gene-related peptide (CGRP). Previous studies showed that MCAs express KCNQ1, 4, and 5 potassium channel genes, and the expression products (Kv7 channels...

  8. Mild to moderate increase of serum calcitonin levels only in presence of large medullary thyroid cancer deposits.

    Science.gov (United States)

    Pelizzo, M R; Torresan, F; Da Roit, A; Merante Boschin, I; Chondrogiannis, S; Rampin, L; Colletti, P M; Vinjamury, S; Perkins, A J; Rubello, D

    2015-01-01

    Many open questions remain to be elucidated about the diagnosis, treatment and prognosis of medullary thyroid cancer (MTC). The most intriguing concerns the outcome of MTC patients after surgery. Great importance is usually given to serum calcitonin (Ct) and carcinoembryonic (CEA) levels. It is commonly believed that the higher are the levels of these tumor markers and their kinetics (double time and velocity of markers levels) the worst is the prognosis. However, this is not the rule, as there are huge MTC metastatic deposits characterized by low serum Ct and CEA levels, and this condition is not closely related to the outcome of the disease during post-surgical follow-up. A series is reported here of patients who have these characteristics, as well as a description of their prognosis and clinical outcome. Copyright © 2015 Elsevier España, S.L.U. and SEMNIM. All rights reserved.

  9. Sumatriptan does not change calcitonin gene-related peptide in the cephalic and extracephalic circulation in healthy volunteers

    DEFF Research Database (Denmark)

    Hansen, Jakob Møller; Petersen, Jesper; Wienecke, Troels

    2009-01-01

    sumatriptan modulate the baseline CGRP levels in vivo, under conditions without trigeminovascular system activation. We sampled blood from the internal and external jugular, the cubital veins, and the radial artery before and after administration of subcutaneous sumatriptan in 16 healthy volunteers. Repeated-measure...... not differ between the four vascular compartments (P=0.49). It was found that Sumatriptan did not change the levels of circulating CGRP in the intra or extracerebral circulation in healthy volunteers. This speaks against a direct CGRP-reducing effect of sumatriptan in vivo in humans when the trigemino......Triptans are effective and well tolerated in acute migraine management but their exact mechanism of action is still debated. Triptans might exert their antimigraine effect by reducing the levels of circulating calcitonin gene-related peptide (CGRP). To examine this question, we examined whether...

  10. Fmoc Solid-Phase Synthesis of Human a-Calcitonin Gene- Related Peptide and Two Carboxyfluorescein-labeled Analogs

    DEFF Research Database (Denmark)

    Ahmed, L. Sabbah; Abdolalizadeh, Bahareh; Sheykhzade, Majid

    Human-alpha-Calcitonin Gene-Related Peptide (h-alpha-CGRP) is a naturally occurring 37 amino acid vasodilatory neuropeptide amide, ACDTATCVTHRLAGLLSRSGGVVKNNFVPTNVGSKAF, with a disulfide bond between residues 2 and 7. The peptide is found in primary afferent sensory nerves and is widely distributed...... for biological activity and onset of signal transduction. Fluorescent h-alpha-CGRP analogs are useful for investigating the mechanism of action behind (re)uptake of h-alpha-CGRP into the sensory nerve terminals and monitoring trafficking of CGRP receptors. As part of an ongoing study on the mechanism of action......–17. Following purification by preparative HPLC, concentration-response curves were made with fluorescent CGRP analogues on isolated human subcutaneous arteries. CGRP (fluolysine35) and CGRP (wildtype) showed similar potency (pIC50 = 9.40) while CGRP (fluolysine24) showed approximately 5-fold less potency (pIC50...

  11. Direct interactions between calcitonin-like receptor (CLR) and CGRP-receptor component protein (RCP) regulate CGRP receptor signaling.

    Science.gov (United States)

    Egea, Sophie C; Dickerson, Ian M

    2012-04-01

    Calcitonin gene-related peptide (CGRP) is a neuropeptide with multiple neuroendocrine roles, including vasodilation, migraine, and pain. The receptor for CGRP is a G protein-coupled receptor (GPCR) that requires three proteins for function. CGRP binds to a heterodimer composed of the GPCR calcitonin-like receptor (CLR) and receptor activity-modifying protein (RAMP1), a single transmembrane protein required for pharmacological specificity and trafficking of the CLR/RAMP1 complex to the cell surface. In addition, the CLR/RAMP1 complex requires a third protein named CGRP-receptor component protein (RCP) for signaling. Previous studies have demonstrated that depletion of RCP from cells inhibits CLR signaling, and in vivo studies have demonstrated that expression of RCP correlates with CLR signaling and CGRP efficacy. It is not known whether RCP interacts directly with CLR to exert its effect. The current studies identified a direct interaction between RCP and an intracellular domain of CLR using yeast two-hybrid analysis and coimmunoprecipitation. When this interacting domain of CLR was expressed as a soluble fusion protein, it coimmunoprecipitated with RCP and inhibited signaling from endogenous CLR. Expression of this dominant-negative domain of CLR did not significantly inhibit trafficking of CLR to the cell surface, and thus RCP may not have a chaperone function for CLR. Instead, RCP may regulate CLR signaling in the cell membrane, and direct interaction between RCP and CLR is required for CLR activation. To date, RCP has been found to interact only with CLR and represents a novel neuroendocrine regulatory step in GPCR signaling.

  12. Effect of a calcitonin gene-related peptide-binding L-RNA aptamer on neuronal activity in the rat spinal trigeminal nucleus

    OpenAIRE

    Fischer, Michael J. M.; Schmidt, Jakob; Koulchitsky, Stanislav; Klussmann, Sven; Vater, Axel; Messlinger, Karl

    2018-01-01

    Background Calcitonin gene-related peptide (CGRP) plays a major role in the pathogenesis of migraine and other primary headaches. Spinal trigeminal neurons integrate nociceptive afferent input from trigeminal tissues including intracranial afferents, and their activity is thought to reflect facial pain and headache in man. CGRP receptor inhibitors and anti-CGRP antibodies have been demonstrated to be therapeutically effective in migraine. In parallel, CGRP receptor inhibition has been shown t...

  13. Molecular cloning of otoconin-22 complementary deoxyribonucleic acid in the bullfrog endolymphatic sac: effect of calcitonin on otoconin-22 messenger ribonucleic acid levels.

    Science.gov (United States)

    Yaoi, Yuichi; Suzuki, Masakazu; Tomura, Hideaki; Sasayama, Yuichi; Kikuyama, Sakae; Tanaka, Shigeyasu

    2003-08-01

    Anuran amphibians have a special organ called the endolymphatic sac (ELS), containing many calcium carbonate crystals, which is believed to have a calcium storage function. The major protein of aragonitic otoconia, otoconin-22, which is considered to be involved in the formation of calcium carbonate crystals, has been purified from the saccule of the Xenopus inner ear. In this study, we cloned a cDNA encoding otoconin-22 from the cDNA library constructed for the paravertebral lime sac (PVLS) of the bullfrog, Rana catesbeiana, and sequenced it. The bullfrog otoconin-22 encoded a protein consisting of 147 amino acids, including a signal peptide of 20 amino acids. The protein had cysteine residues identical in a number and position to those conserved among the secretory phospholipase A(2) family. The mRNA of bullfrog otoconin-22 was expressed in the ELS, including the PVLS and inner ear. This study also revealed the presence of calcitonin receptor-like protein in the ELS, with the putative seven-transmembrane domains of the G protein-coupled receptors. The ultimobranchialectomy induced a prominent decrease in the otoconin-22 mRNA levels of the bullfrog PVLS. Supplementation of the ultimobranchialectomized bullfrogs with synthetic salmon calcitonin elicited a significant increase in the mRNA levels of the sac. These findings suggest that calcitonin secreted from the ultimobranchial gland, regulates expression of bullfrog otoconin-22 mRNA via calcitonin receptor-like protein on the ELS, thereby stimulating the formation of calcium carbonate crystals in the lumen of the ELS.

  14. Differential utilization of calcitonin gene regulatory DNA sequences in cultured lines of medullary thyroid carcinoma and small-cell lung carcinoma.

    OpenAIRE

    De Bustros, A; Lee, R Y; Compton, D; Tsong, T.Y.; Baylin, S B; Nelkin, B D

    1990-01-01

    Regulation of expression of the human calcitonin gene was found to differ between two tumor lines of different tissue origin, medullary thyroid carcinoma (TT line) and small-cell lung carcinoma (DMS53 line). Distal 5' DNA elements between -750 and -2000 exhibited a stronger basal activity in DMS53 than in TT cells, whereas proximal DNA sequences between -132 and -252 mediated a dramatic cyclic AMP response in TT but not DMS53 cells.

  15. Calcitonin gene-related peptide in blood: is it increased in the external jugular vein during migraine and cluster headache? A review

    DEFF Research Database (Denmark)

    Tfelt-Hansen, Peer; Le, Han

    2009-01-01

    The involvement of calcitonin gene-related peptide (CGRP) in migraine pathophysiological mechanisms is shown by the facts that CGRP can induce migraine and that two CGRP antagonists, olcegepant and telcagepant, are effective in the treatment of migraine attacks. Increase of the neuropeptide CGRP ...... likely a 'nervous vasodilatory drive' in the extracranial vascular bed. It remains an enigma how the observed increase of CGRP in the EJV fits into the mechanisms of migraine and cluster headache....

  16. Preparation and in vivo absorption evaluation of spray dried powders containing salmon calcitonin loaded chitosan nanoparticles for pulmonary delivery

    Directory of Open Access Journals (Sweden)

    Sinsuebpol C

    2013-08-01

    Full Text Available Chutima Sinsuebpol, Jittima Chatchawalsaisin, Poj Kulvanich Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand Purpose: The aim of the present study was to prepare inhalable co-spray dried powders of salmon calcitonin loaded chitosan nanoparticles (sCT-CS-NPs with mannitol and investigate pulmonary absorption in rats. Methods: The sCT-CS-NPs were prepared by the ionic gelation method using sodium tripolyphosphate (TPP as a cross-linking polyion. Inhalable dry powders were obtained by co-spray drying aqueous dispersion of sCT-CS-NPs and mannitol. sCT-CS-NPs co-spray dried powders were characterized with respect to morphology, particle size, powder density, aerodynamic diameter, protein integrity, in vitro release of sCT, and aerosolization. The plasmatic sCT levels following intratracheal administration of sCT-CS-NPs spray dried powders to the rats was also determined. Results: sCT-CS-NPs were able to be incorporated into mannitol forming inhalable microparticles by the spray drying process. The sCT-CS-NPs/mannitol ratios and spray drying process affected the properties of the microparticles obtained. The conformation of the secondary structures of sCTs was affected by both mannitol content and spray dry inlet temperature. The sCT-CS-NPs were recovered after reconstitution of spray dried powders in an aqueous medium. The sCT release profile from spray dried powders was similar to that from sCT-CS-NPs. In vitro inhalation parameters measured by the Andersen cascade impactor indicated sCT-CS-NPs spray dried powders having promising aerodynamic properties for deposition in the deep lung. Determination of the plasmatic sCT levels following intratracheal administration to rats revealed that the inhalable sCT-CS NPs spray dried powders provided higher protein absorption compared to native sCT powders. Conclusion: The sCT-CS-NPs with mannitol based spray dried powders were

  17. Effects of NSAIDs on the Release of Calcitonin Gene-Related Peptide and Prostaglandin E2 from Rat Trigeminal Ganglia

    Directory of Open Access Journals (Sweden)

    Vittorio Vellani

    2017-01-01

    Full Text Available Nonsteroidal anti-inflammatory drugs (NSAIDs are frequently used to treat migraine, but the mechanisms of their effects in this pathology are not fully elucidated. The trigeminal ganglia and calcitonin gene-related peptide (CGRP have been implicated in the pathophysiology of migraine. The release of CGRP and prostaglandin E2 (PGE2 from freshly isolated rat trigeminal ganglia was evaluated after oral administration of nimesulide, etoricoxib, and ketoprofen, NSAIDs with different pharmacological features. Thirty minutes after oral administration, nimesulide, 10 mg/Kg, decreased the GCRP release induced by an inflammatory soup, while the other NSAIDs were ineffective at this point in time. Two hours after oral nimesulide (5 and 10 mg/Kg and ketoprofen (10 mg/Kg, but not of etoricoxib, a significant decrease in the CGRP release was observed. All drugs reduced PGE2, although with some differences in timing and doses, and the action on CGRP does not seem to be related to PGE2 inhibition. The reduction of CGRP release from rat trigeminal ganglia after nimesulide and ketoprofen may help to explain the mechanism of action of NSAIDs in migraine. Since at 30 minutes only nimesulide was effective in reducing CGRP release, these results suggest that this NSAID may exert a particularly rapid effect in patients with migraine.

  18. Role of extracellular calcitonin gene-related peptide in spinal cord mechanisms of cancer-induced bone pain.

    Science.gov (United States)

    Hansen, Rikke R; Vacca, Valentina; Pitcher, Thomas; Clark, Anna K; Malcangio, Marzia

    2016-03-01

    Severe pain is a common and debilitating complication of metastatic bone cancer. Current analgesics provide insufficient pain relief and often lead to significant adverse effects. In models of cancer-induced bone pain, pathological sprouting of sensory fibers at the tumor-bone interface occurs concomitantly with reactive astrocytosis in the dorsal horn of the spinal cord. We observed that calcitonin gene-related peptide (CGRP)-fiber sprouting in the bone was associated with an increase in CGRP content in sensory neuron cell bodies in the dorsal root ganglia (DRG) and increased basal and activity-evoked release of CGRP from their central terminals in the dorsal horn. Intrathecal administration of a peptide antagonist (α-CGRP8-37) attenuated referred allodynia in the hind paw ipsilateral to bone cancer. CGRP receptor components (CLR and RAMP1) were up-regulated in dorsal horn neurons and expressed by reactive astrocytes. In primary cultures of astrocytes, CGRP incubation led to a concentration-dependent increase of forskolin-induced cAMP production, which was attenuated by pretreatment with CGRP8-37. Furthermore, CGRP induced ATP release in astrocytes, which was inhibited by CGRP8-37. We suggest that the peripheral increase in CGRP content observed in cancer-induced bone pain is mirrored by a central increase in the extracellular levels of CGRP. This increase in CGRP not only may facilitate glutamate-driven neuronal nociceptive signaling but also act on astrocytic CGRP receptors and lead to release of ATP.

  19. Oral salmon calcitonin enhances insulin action and glucose metabolism in diet-induced obese streptozotocin-diabetic rats

    DEFF Research Database (Denmark)

    Feigh, Michael; Hjuler, Sara T; Andreassen, Kim V

    2014-01-01

    We previously reported that oral delivery of salmon calcitonin (sCT) improved energy and glucose homeostasis and attenuated diabetic progression in animal models of diet-induced obesity (DIO) and type 2 diabetes, although the glucoregulatory mode of action was not fully elucidated. In the present...... was enhanced in conjunction with protection of pancreatic insulin content. The results of the present study indicate that oral sCT exerts a novel insulin-sensitizing effect to improve glucose metabolism in obesity and type 2 diabetes....... study we hypothesized that oral sCT as pharmacological intervention 1) exerted anti-hyperglycemic efficacy, and 2) enhanced insulin action in DIO-streptozotocin (DIO-STZ) diabetic rats. Diabetic hyperglycemia was induced in male selectively bred DIO rats by a single low dose (30mg/kg) injection of STZ....... Oral sCT by gavage was delivered as once-daily administration with lead-in (2mg/kg) and maintenance (0.5mg/kg) dose of oral sCT for a total of 21 days. Food intake, body weight, blood glucose, HbA1c, glucose and insulin tolerance test, and parameters of insulin sensitivity were investigated. Plasma...

  20. Skin-bacteria communication: Involvement of the neurohormone Calcitonin Gene Related Peptide (CGRP) in the regulation of Staphylococcus epidermidis virulence

    Science.gov (United States)

    N’Diaye, Awa R.; Leclerc, Camille; Kentache, Takfarinas; Hardouin, Julie; Poc, Cecile Duclairoir; Konto-Ghiorghi, Yoan; Chevalier, Sylvie; Lesouhaitier, Olivier; Feuilloley, Marc G. J.

    2016-01-01

    Staphylococci can sense Substance P (SP) in skin, but this molecule is generally released by nerve terminals along with another neuropeptide, Calcitonin Gene Related Peptide (CGRP). In this study, we investigated the effects of αCGRP on Staphylococci. CGRP induced a strong stimulation of Staphylococcus epidermidis virulence with a low threshold (Staphylococcus aureus was insensitive to CGRP. We observed that CGRP-treated S. epidermidis induced interleukin 8 release by keratinocytes. This effect was associated with an increase in cathelicidin LL37 secretion. S. epidermidis displayed no change in virulence factors secretion but showed marked differences in surface properties. After exposure to CGRP, the adherence of S. epidermidis to keratinocytes increased, whereas its internalization and biofilm formation activity were reduced. These effects were correlated with an increase in surface hydrophobicity. The DnaK chaperone was identified as the S. epidermidis CGRP-binding protein. We further showed that the effects of CGRP were blocked by gadolinium chloride (GdCl3), an inhibitor of MscL mechanosensitive channels. In addition, GdCl3 inhibited the membrane translocation of EfTu, the Substance P sensor. This work reveals that through interaction with specific sensors S. epidermidis integrates different skin signals and consequently adapts its virulence. PMID:27739485

  1. Regulation of calcitonin gene-related peptide receptors in the rat uterus during pregnancy and labor and by progesterone.

    Science.gov (United States)

    Yallampalli, C; Gangula, P R; Kondapaka, S; Fang, L; Wimalawansa, S

    1999-10-01

    Calcitonin gene-related peptide (CGRP) is a potent smooth muscle relaxant in a variety of tissues. We recently demonstrated that CGRP relaxes uterine tissue during pregnancy but not during labor. In the present study we examined whether uterine (125)I-CGRP binding and immunoreactive CGRP receptors are regulated by pregnancy and labor and by sex steroid hormones. We found that (125)I-CGRP binding to membrane preparations from uteri was elevated during pregnancy and decreased during labor and postpartum. Changes in immunoreactive CGRP receptors were similar to the changes in (125)I-CGRP binding in these tissues, suggesting pregnancy-dependent regulation of CGRP receptor protein. CGRP receptors were elevated by Day 7 of gestation, and a precipitous decrease in these receptors occurred on Day 22 of gestation prior to the onset of labor. Both (125)I-CGRP-binding and immunofluorescence studies indicated that CGRP receptors were localized to myometrial cells. Hormonal control of uterine CGRP receptors was assessed by the use of antiprogesterone RU-486, progesterone, and estradiol-17beta. RU-486 induced a decrease in uterine CGRP receptors during pregnancy (Day 19). On the other hand, progesterone prevented the fall in uterine CGRP receptors at term (Day 22). In addition, progesterone also increased uterine CGRP receptors in nonpregnant, ovariectomized rats, while estradiol had no effects. These hormone-induced changes in uterine CGRP receptors were demonstrated by (125)I-CGRP-binding, Western immunoblotting, and immunolocalization methods. These results indicate that CGRP receptors and CGRP binding in the rat uterus are increased with pregnancy and decreased at term. These receptors are localized to the myometrial cells, and progesterone is required for maintaining CGRP receptors in the rat uterus. Thus, the inhibitory effects of CGRP on uterine contractility are mediated through the changes in CGRP receptors and may play a role in uterine quiescence during pregnancy.

  2. Non-excitatory electrical stimulation attenuates myocardial infarction via homeostasis of calcitonin gene-related peptide in myocardium.

    Science.gov (United States)

    Guo, Zhi-Jia; Guo, Zheng

    2015-03-01

    Electrical stimulation has been shown protection of brain, retina, optic nerves and pancreatic β-cells but the effect on cardio-protection is still unknown. Calcitonin gene-related peptide (CGRP) participates in the pathology of injury and protection of myocardium but whether or not electrical stimulation modulates endogenous CGRP is not clear. Male Sprague-Dawley rats were divided into 4 groups: (1) control group, without any treatment. (2) I/R group, animals were subjected to 30 min of myocardial ischemia followed by 60 min reperfusion. (3) NES+I/R group, non-excitatory electrical stimulation (NES) was commenced from 15 min before coronary artery occlusion till the end of reperfusion. (4) I/R+CGRP8-37 group, animals were given with CGRP8-37 (an antagonist of CGRP receptor, 10(-7) mol/L, 0.3 ml, i.v.) at 5 min before reperfusion without any electrical stimulation. The hemodynamics and electrocardiogram were monitored and recorded. Infarct size and troponin I were examined and CGRP expression in the myocardium and serum was analyzed. It was found that the infarct size and TnI were significantly reduced in NES+I/R group, by 45% and 58% respectively, accompanied by an obvious fall back of CGRP in myocardium, compared to I/R group (all pTreatment with CGRP8-37 resulted in the same protection on myocardium as NES did. No significant difference in hemodynamics or ventricular tachycardia was detected among the groups (all p>0.05). It can be concluded that NES reduced the infarction size after acute myocardial ischemia and reperfusion, for which the underlying mechanism may be associated with modulation of endogenous CGRP in myocardium. Copyright © 2015 Elsevier Inc. All rights reserved.

  3. Elevated levels of calcitonin gene-related peptide in upper spinal cord promotes sensitization of primary trigeminal nociceptive neurons.

    Science.gov (United States)

    Cornelison, Lauren E; Hawkins, Jordan L; Durham, Paul L

    2016-12-17

    Orofacial pain conditions including temporomandibular disorder (TMD) and migraine are characterized by peripheral and central sensitization of trigeminal nociceptive neurons. The goal of this study was to investigate the role of calcitonin gene-related peptide (CGRP) in promoting bidirectional signaling within the trigeminal system to mediate sensitization of primary nociceptive neurons. Adult male Sprague-Dawley rats were injected intercisternally with CGRP or co-injected with the receptor antagonist CGRP8-37 or KT 5720, a protein kinase A (PKA) inhibitor. Nocifensive head withdrawal response to mechanical stimulation was investigated using von Frey filaments. Expression of PKA, glial fibrillary acidic protein (GFAP), and ionized calcium-binding adapter molecule 1 (Iba1) in the spinal cord and phosphorylated extracellular signal-regulated kinase (P-ERK) in the ganglion was studied using immunohistochemistry. Some animals were co-injected with CGRP and Fast Blue dye and the ganglion was imaged using fluorescent microscopy. CGRP increased nocifensive responses to mechanical stimulation when compared to control. Co-injection of CGRP8-37 or KT 5720 with CGRP inhibited the nocifensive response. CGRP stimulated PKA and GFAP expression in the spinal cord, and P-ERK in ganglion neurons. Seven days post injection, Fast Blue was observed in ganglion neurons and satellite glial cells. Our results demonstrate that elevated levels of CGRP in the upper spinal cord promote sensitization of primary nociceptive neurons via a mechanism that involves activation of PKA centrally and P-ERK in ganglion neurons. Our findings provide evidence of bidirectional signaling within the trigeminal system that facilitate increased neuron-glia communication within the ganglion associated with trigeminal sensitization. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  4. Calcitonin gene-related peptide exerts anti-inflammatory property through regulating murine macrophages polarization in vitro.

    Science.gov (United States)

    Duan, Jia-Xi; Zhou, Yong; Zhou, Ai-Yuan; Guan, Xin-Xin; Liu, Tian; Yang, Hui-Hui; Xie, Hui; Chen, Ping

    2017-11-01

    Acute lung injury (ALI) is a condition resulting from direct or indirect lung injury associated with high mortality and morbidity. The phenotype of macrophages in lung contributes to the pathological progress of ALI. Calcitonin gene-related peptide (CGRP) is one of the most abundant neuropeptides in lung, and attenuates lipopolysaccharide (LPS)-induced ALI in rats. However, the exact effect of CGRP on the activation of macrophages remains unknown. Here we investigate the effect of CGRP on the macrophages activation and inflammation in murine macrophages in vitro. We found that LPS increased the expression of CGRP in a LPS-induced ALI murine model and LPS-stimulated murine macrophages. Although CGRP didn't alter the expression of tumor necrosis factor-α (a marker of pro-inflammatory phenotype of macrophages, M1 macrophages) or Arginase 1 (Arg1, a marker of M2 macrophages) in non-differentiated macrophages, CGRP significantly reduced the NLRP3 and pro-IL-1β mRNA expression induced by LPS, as well as NLRP3 protein and IL-1β secretion induced by LPS+ATP in macrophages in vitro. On the other hand, CGRP dramatically enhanced the Arg1 expression and activity induced by IL-4 in the time- and dose-dependent manners. CGRP also promoted the expression of markers of M2 macrophages (IL-10, Fizz1 and Mrc1) induced by IL-4 in murine macrophages. These effects of CGRP were also observed in primary murine peritoneal macrophages. In addition, we found that CGRP regulated macrophages polarization partially through calmodulin, PKC and PKA pathways. Specifically, CGRP could inhibit the degradation of I-κB induced by LPS, and enhance the phosphorylation of STAT6 induced by IL-4 in macrophages. In conclusion, our results indicate that CGRP regulates macrophage polarization and inhibits inflammation in murine macrophages. Copyright © 2017 Elsevier Ltd. All rights reserved.

  5. A Role for the Calcitonin Receptor to Limit Bone Loss During Lactation in Female Mice by Inhibiting Osteocytic Osteolysis.

    Science.gov (United States)

    Clarke, Michele V; Russell, Patricia K; Findlay, David M; Sastra, Stephen; Anderson, Paul H; Skinner, Jarrod P; Atkins, Gerald J; Zajac, Jeffrey D; Davey, Rachel A

    2015-09-01

    During lactation, the large transfer of calcium from the mother to the milk is primarily sourced from the maternal skeleton. To determine whether the calcitonin receptor (CTR) plays a physiological role to protect the skeleton from excessive resorption during lactation, we assessed the maternal skeleton of global CTR knockout (CTRKO) and littermate control mice at the end of lactation (postnatal day 21). Micro-computed tomography analyses showed no effect on trabecular or cortical bone in the distal femur and L1 vertebra of maternal global CTR deletion at the end of lactation in global CTRKO mice compared with that in control mice. Bone resorption, as assessed by osteoclast number and activity at the end of lactation, was unaffected by maternal CTR deletion. Cathepsin K, carbonic anhydrase 2, matrix metalloproteinase 13, and receptor activator of nuclear factor-κB ligand mRNA levels, however, were markedly elevated by 3- to 6.5-fold in whole bone of lactating global CTRKO females. Because these genes have been shown to be up-regulated in osteocytes during lactation when osteocytes resorb their surrounding bone matrix, together with their reported expression of the CTR, we determined the osteocyte lacunar area in cortical bone. After lactation, the top 20% of osteocyte lacunar area in global CTRKO mice was 10% larger than the top 20% in control mice. These data are consistent with an increased osteocytic osteolysis in global CTRKO mice during lactation, which is further supported by the increased serum calcium observed in global CTRKO mice after lactation. These results provide evidence for a physiological role for the CTR to protect the maternal skeleton during lactation by a direct action on osteocytes to inhibit osteolysis.

  6. Basal and stimulated calcitonin levels in patients with type 2 diabetes did not change during 1 year of Liraglutide treatment.

    Science.gov (United States)

    Lunati, Maria Elena; Grancini, Valeria; Colombo, Carla; Palmieri, Eva; Resi, Veronica; Perrino, Michela; Orsi, Emanuela; Fugazzola, Laura

    2016-01-01

    The administration of Liraglutide, a long-acting GLP-1 receptor (GLP-1R) agonist, is associated with C-cell adenomas and carcinomas in rats. In humans, GLP-1R is highly expressed in C-cells hyperplasia (CCH) and in medullary thyroid cancer (MTC), though no changes in basal serum calcitonin (bCT) levels were recorded in type 2 diabetic (T2DM) patients treated with Liraglutide. To diagnose the possible development of CCH during Liraglutide treatment, we evaluated CT levels stimulated by calcium test (sCT). bCT and sCT and metabolic and anthropometric parameters were evaluated in 26 T2DM patients at baseline and at 1, 3, 6 and 12 months of treatment. In all patients, bCT remained within the normal range during the entire study period. In females and males, the higher sCT values were reached after 3 months and 1 month, respectively, with a progressive reduction at 6-12 months. The greater decrease of HbA1c values was reached at 3 months, while body weight and waist circumference decreased over the first 4 weeks of therapy. Lipase levels significantly increased, with a peak value at 1 month. The chronic administration of Liraglutide did not lead to statistically significant variations in both bCT and sCT. Stimulated CT levels increased, though always below the normal range, during the first 1-3 months of treatment, and progressively decreased to baseline levels. This finding is consistent with the effects recorded at the glycometabolic level, and suggests the possible induction of a drug tolerance involving also the C cells and thus preventing CCH. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. High arterial compliance in cirrhosis is related to low adrenaline and elevated circulating calcitonin gene related peptide but not to activated vasoconstrictor systems

    DEFF Research Database (Denmark)

    Henriksen, Jens Henrik; Møller, Søren; Schifter, S

    2001-01-01

    catecholamines, renin activity, endothelin-1, and calcitonin gene related peptide (CGRP) at baseline and during oxygen inhalation. RESULTS: COMP(art) was significantly increased in cirrhotic patients compared with controls (1.32 v 1.06 ml/mm Hg; p....53; prenin activity, or endothelin-1. COMP(art) was positively related to plasma volume (r=0.50; p... to COMP(art) disappeared. The relation of COMP(art) to CGRP and circulatory variables remained unchanged. CONCLUSION: Elevated arterial compliance in cirrhosis is related to low adrenaline, high CGRP, and systemic hyperdynamics but not to indicators of the activated vasoconstrictor systems (noradrenaline...

  8. Localization of large conductance calcium-activated potassium channels and their effect on calcitonin gene-related peptide release in the rat trigemino-neuronal pathway

    DEFF Research Database (Denmark)

    Wulf-Johansson, H.; Amrutkar, D.V.; Hay-Schmidt, Anders

    2010-01-01

    Large conductance calcium-activated potassium (BK(Ca)) channels are membrane proteins contributing to electrical propagation through neurons. Calcitonin gene-related peptide (CGRP) is a neuropeptide found in the trigeminovascular system (TGVS). Both BK(Ca) channels and CGRP are involved in migraine...... pathophysiology. Here we study the expression and localization of BK(Ca) channels and CGRP in the rat trigeminal ganglion (TG) and the trigeminal nucleus caudalis (TNC) as these structures are involved in migraine pain. Also the effect of the BK(Ca) channel blocker iberiotoxin and the BK(Ca) channel opener NS...

  9. Presence and function of the calcitonin gene-related peptide receptor on rat pial arteries investigated in vitro and in vivo

    DEFF Research Database (Denmark)

    Petersen, K A; Nilsson, E; Olesen, J

    2005-01-01

    Calcitonin gene-related peptide (CGRP) and related peptides may be involved in migraine pathogenesis. To understand their vasomotor role in the cerebral circulation, we performed two studies, a pressurized arteriography study of the middle cerebral artery (MCA) and a genuine closed cranial window......, this was probably secondary to a decrease in blood pressure of 44.8 +/- 3.3 mmHg and 49.2 +/- 3.3 mmHg. Our results suggest that CGRP receptors are probably functional on the smooth muscle cells and not on the endothelium of rat cerebral arteries....

  10. The Dual Amylin- and Calcitonin-Receptor Agonist KBP-042 Increases Insulin Sensitivity and Induces Weight Loss in Rats with Obesity

    DEFF Research Database (Denmark)

    Hjuler, Sara Toftegaard; Gydesen, Sofie; Andreassen, Kim Vietz

    2016-01-01

    Objective: In this study, KBP-042, a dual amylin- and calcitonin-receptor agonist, was investigated as a treatment of obesity and insulin resistance in five different doses (0.625 μg/kg-10 μg/kg) compared with saline-treated and pair-fed controls. Methods: Rats with obesity received daily s.c. ad...... combines two highly relevant features, namely weight loss and insulin sensitivity, and is thus an excellent candidate for chronic treatment of obesity and insulin resistance....... a sustained weight loss of up to 20% without any significant weight reduction in the pair-fed groups. Decreases in adipose tissues and lipid deposition in the liver were observed, while plasma adiponectin was increased and plasma leptin levels were decreased. Acute administration of KBP-042 led to impaired......Objective: In this study, KBP-042, a dual amylin- and calcitonin-receptor agonist, was investigated as a treatment of obesity and insulin resistance in five different doses (0.625 μg/kg-10 μg/kg) compared with saline-treated and pair-fed controls. Methods: Rats with obesity received daily s...

  11. Coated minispheres of salmon calcitonin target rat intestinal regions to achieve systemic bioavailability: Comparison between intestinal instillation and oral gavage.

    Science.gov (United States)

    Aguirre, Tanira A S; Aversa, Vincenzo; Rosa, Mónica; Guterres, Sílvia S; Pohlmann, Adriana R; Coulter, Ivan; Brayden, David J

    2016-09-28

    Achieving oral peptide delivery is an elusive challenge. Emulsion-based minispheres of salmon calcitonin (sCT) were synthesized using single multiple pill (SmPill®) technology incorporating the permeation enhancers (PEs): sodium taurodeoxycholate (NaTDC), sodium caprate (C10), or coco-glucoside (CG), or the pH acidifier, citric acid (CA). Minispheres were coated with an outer layer of Eudragit® L30 D-55 (designed for jejunal release) or Surelease®/Pectin (designed for colonic release). The process was mild and in vitro biological activity of sCT was retained upon release from minispheres stored up to 4months. In vitro release profiles suggested that sCT was released from minispheres by diffusion through coatings due to swelling of gelatin and the polymeric matrix upon contact with PBS at pH6.8. X-ray analysis confirmed that coated minispheres dissolved at the intended intestinal region of rats following oral gavage. Uncoated minispheres at a dose of ~2000I.U.sCT/kg were administered to rats by intra-jejunal (i.j.) or intra-colonic (i.c.) instillation and caused hypocalcaemia. Notable sCT absolute bioavailability (F) values were: 5.5% from minispheres containing NaTDC (i.j), 17.3% with CG (i.c.) and 18.2% with C10 (i.c.). Coated minispheres administered by oral gavage at threefold higher doses also induced hypocalcaemia. A highly competitive F value of 2.7% was obtained for orally-administered sCT-minispheres containing CG (45μmol/kg) and coated with Eudragit®. In conclusion, the SmPill® technology is a potential dosage form for several peptides when formulated with PEs and coated for regional delivery. PK data from instillations over-estimates oral bioavailability and poorly predicts rank ordering of formulations. Copyright © 2016 Elsevier B.V. All rights reserved.

  12. Preparation and in vivo absorption evaluation of spray dried powders containing salmon calcitonin loaded chitosan nanoparticles for pulmonary delivery.

    Science.gov (United States)

    Sinsuebpol, Chutima; Chatchawalsaisin, Jittima; Kulvanich, Poj

    2013-01-01

    The aim of the present study was to prepare inhalable co-spray dried powders of salmon calcitonin loaded chitosan nanoparticles (sCT-CS-NPs) with mannitol and investigate pulmonary absorption in rats. The sCT-CS-NPs were prepared by the ionic gelation method using sodium tripolyphosphate (TPP) as a cross-linking polyion. Inhalable dry powders were obtained by co-spray drying aqueous dispersion of sCT-CS-NPs and mannitol. sCT-CS-NPs co-spray dried powders were characterized with respect to morphology, particle size, powder density, aerodynamic diameter, protein integrity, in vitro release of sCT, and aerosolization. The plasmatic sCT levels following intratracheal administration of sCT-CS-NPs spray dried powders to the rats was also determined. sCT-CS-NPs were able to be incorporated into mannitol forming inhalable microparticles by the spray drying process. The sCT-CS-NPs/mannitol ratios and spray drying process affected the properties of the microparticles obtained. The conformation of the secondary structures of sCTs was affected by both mannitol content and spray dry inlet temperature. The sCT-CS-NPs were recovered after reconstitution of spray dried powders in an aqueous medium. The sCT release profile from spray dried powders was similar to that from sCT-CS-NPs. In vitro inhalation parameters measured by the Andersen cascade impactor indicated sCT-CS-NPs spray dried powders having promising aerodynamic properties for deposition in the deep lung. Determination of the plasmatic sCT levels following intratracheal administration to rats revealed that the inhalable sCT-CS NPs spray dried powders provided higher protein absorption compared to native sCT powders. The sCT-CS-NPs with mannitol based spray dried powders were prepared to have appropriate aerodynamic properties for pulmonary delivery. The developed system was able to deliver sCT via a pulmonary route into the systemic circulation.

  13. Role of KATP channels in cephalic vasodilatation induced by calcitonin gene-related peptide, nitric oxide, and transcranial electrical stimulation in the rat

    DEFF Research Database (Denmark)

    Gozalov, Aydin; Jansen-Olesen, Inger; Klærke, Dan Arne

    2008-01-01

    arteries causes a throbbing, migraine-like pain. Both CGRP and NO are potent vasodilators that can induce migraine. Their antagonists are effective in the treatment of migraine attacks. K(ATP) channel openers cause headache in the majority of healthy subjects suggesting a role for K(ATP) channels......OBJECTIVE: The objective of this study was to explore the role of K(ATP) channels in vasodilatation induced by calcitonin gene-related peptide (CGRP), nitric oxide (NO), and transcranial electrical stimulation (TES) in intracranial arteries of rat. BACKGROUND: Dilatation of cerebral and dural...... in migraine pathogenesis. We hypothesized that vasodilatation induced by CGRP and the NO donor glyceryltrinitrate (GTN) is mediated via K(ATP) channels. METHODS: We examined the effects of the K(ATP) channel inhibitor glibenclamide on dural and pial vasodilatation induced by CGRP, NO, and endogenously...

  14. The Dual Amylin- and Calcitonin-Receptor Agonist KBP-042 Increases Insulin Sensitivity and Induces Weight Loss in Rats with Obesity

    DEFF Research Database (Denmark)

    Hjuler, Sara Toftegaard; Gydesen, Sofie; Andreassen, Kim Vietz

    2016-01-01

    Objective: In this study, KBP-042, a dual amylin- and calcitonin-receptor agonist, was investigated as a treatment of obesity and insulin resistance in five different doses (0.625 μg/kg-10 μg/kg) compared with saline-treated and pair-fed controls. Methods: Rats with obesity received daily s...... combines two highly relevant features, namely weight loss and insulin sensitivity, and is thus an excellent candidate for chronic treatment of obesity and insulin resistance........c. administrations for 56 days, and glucose tolerance was assessed after one acute injection, 3 weeks of treatment, and again after 7 weeks of treatment. To assess the effect on insulin sensitivity, rats received 5 μg/kg KBP-042 for 21 days before hyperinsulinemic-euglycemic clamp. Results: KBP-042 induced...

  15. Optimization of tolerability and efficacy of the novel dual amylin and calcitonin receptor agonist KBP-089 through dose escalation and combination with a GLP-1 analog

    DEFF Research Database (Denmark)

    Gydesen, Sofie; Andreassen, Kim Vietz; Hjuler, Sara Toftegaard

    2017-01-01

    Amylin and GLP-1 agonism induce a well-known anorexic effect at dose initiation, which is managed by dose escalation. In this study we investigated how to optimize tolerability while maintaining efficacy of a novel, highly potent dual amylin and calcitonin receptor agonist (DACRA), KBP-089......, and the following treatment with 2.5, 10, and 40 µg/kg resulted in an ~15% vehicle-corrected weight loss, a corresponding reduction in adipose tissue (AT), and, in all treatment groups, improved oral glucose tolerance (P ...-089 was well tolerated and induced and sustained a significant weight loss and a reduction in AT in lean and HFD rats, underscoring the potential of KBP-089 as an anti-obesity agent....

  16. Nitric oxide synthase, calcitonin gene-related peptide and NK-1 receptor mechanisms are involved in GTN-induced neuronal activation

    DEFF Research Database (Denmark)

    Ramachandran, Roshni; Bhatt, Deepak Kumar; Ploug, Kenneth Beri

    2014-01-01

    BACKGROUND AND AIM: Infusion of glyceryltrinitrate (GTN), a nitric oxide (NO) donor, in awake, freely moving rats closely mimics a universally accepted human model of migraine and responds to sumatriptan treatment. Here we analyse the effect of nitric oxide synthase (NOS) and calcitonin gene......-related peptide (CGRP) systems on the GTN-induced neuronal activation in this model. MATERIALS AND METHODS: The femoral vein was catheterised in rats and GTN was infused (4 µg/kg/min, for 20 minutes, intravenously). Immunohistochemistry was performed to analyse Fos, nNOS and CGRP and Western blot for measuring n......NOS protein expression. The effect of olcegepant, L-nitro-arginine methyl ester (L-NAME) and neurokinin (NK)-1 receptor antagonist L-733060 were analysed on Fos activation. RESULTS: GTN-treated rats showed a significant increase of nNOS and CGRP in dura mater and CGRP in the trigeminal nucleus caudalis (TNC...

  17. The calcitonin receptor gene is a candidate for regulation of susceptibility to herpes simplex type 1 neuronal infection leading to encephalitis in rat.

    Directory of Open Access Journals (Sweden)

    Nada Abdelmagid

    Full Text Available Herpes simplex encephalitis (HSE is a fatal infection of the central nervous system (CNS predominantly caused by Herpes simplex virus type 1. Factors regulating the susceptibility to HSE are still largely unknown. To identify host gene(s regulating HSE susceptibility we performed a genome-wide linkage scan in an intercross between the susceptible DA and the resistant PVG rat. We found one major quantitative trait locus (QTL, Hse1, on rat chromosome 4 (confidence interval 24.3-31 Mb; LOD score 29.5 governing disease susceptibility. Fine mapping of Hse1 using recombinants, haplotype mapping and sequencing, as well as expression analysis of all genes in the interval identified the calcitonin receptor gene (Calcr as the main candidate, which also is supported by functional studies. Thus, using unbiased genetic approach variability in Calcr was identified as potentially critical for infection and viral spread to the CNS and subsequent HSE development.

  18. Muscle injury in rats induces upregulation of inflammatory cytokines in injured muscle and calcitonin gene-related peptide in dorsal root ganglia innervating the injured muscle.

    Science.gov (United States)

    Sakuma, Yoshihiro; Miyagi, Masayuki; Inoue, Gen; Ishikawa, Tetsuhiro; Kamoda, Hiroto; Yamauchi, Kazuyo; Orita, Sumihisa; Suzuki, Miyako; Oikawa, Yasuhiro; Inage, Kazuhide; Kubota, Go; Sainoh, Takeshi; Sato, Jun; Takahashi, Kazuhisa; Ohtori, Seiji

    2016-10-01

    In this study we evaluated the relationships among the behavioral changes after muscle injury, histological changes, changes in inflammatory cytokines in the injured muscle, and changes in the sensory nervous system innervating the muscle in rats. We established a model of muscle injury in rats using a dropped weight. Behavior was assessed using the CatWalk system. Subsequently, bilateral gastrocnemius muscles and dorsal root ganglia (DRGs) were resected. Muscles were stained with hematoxylin and eosin, and inflammatory cytokines in injured muscles were assayed. DRGs were immunostained for calcitonin gene-related peptide (CGRP). Changes of behavior and upregulation of inflammatory cytokines in injured muscles subsided within 2 days of injury. Repaired tissue was observed 3 weeks after injury. However, upregulation of CGRP in DRG neurons continued for 2 weeks after injury. These findings may explain in part the pathological mechanism of persistent muscle pain. Muscle Nerve 54: 776-782, 2016. © 2016 The Authors Muscle & Nerve Published by Wiley Periodicals, Inc.

  19. Receptor activity-modifying protein dependent and independent activation mechanisms in the coupling of calcitonin gene-related peptide and adrenomedullin receptors to Gs.

    Science.gov (United States)

    Woolley, Michael J; Reynolds, Christopher A; Simms, John; Walker, Christopher S; Mobarec, Juan Carlos; Garelja, Michael L; Conner, Alex C; Poyner, David R; Hay, Debbie L

    2017-10-15

    Calcitonin gene-related peptide (CGRP) or adrenomedullin (AM) receptors are heteromers of the calcitonin receptor-like receptor (CLR), a class B G protein-coupled receptor, and one of three receptor activity-modifying proteins (RAMPs). How CGRP and AM activate CLR and how this process is modulated by RAMPs is unclear. We have defined how CGRP and AM induce Gs-coupling in CLR-RAMP heteromers by measuring the effect of targeted mutagenesis in the CLR transmembrane domain on cAMP production, modeling the active state conformations of CGRP and AM receptors in complex with the Gs C-terminus and conducting molecular dynamics simulations in an explicitly hydrated lipidic bilayer. The largest effects on receptor signaling were seen with H295A5.40b, I298A5.43b, L302A5.47b, N305A5.50b, L345A6.49b and E348A6.52b, F349A6.53b and H374A7.47b (class B numbering in superscript). Many of these residues are likely to form part of a group in close proximity to the peptide binding site and link to a network of hydrophilic and hydrophobic residues, which undergo rearrangements to facilitate Gs binding. Residues closer to the extracellular loops displayed more pronounced RAMP or ligand-dependent effects. Mutation of H3747.47b to alanine increased AM potency 100-fold in the CGRP receptor. The molecular dynamics simulation showed that TM5 and TM6 pivoted around TM3. The data suggest that hydrophobic interactions are more important for CLR activation than other class B GPCRs, providing new insights into the mechanisms of activation of this class of receptor. Furthermore the data may aid in the understanding of how RAMPs modulate the signaling of other class B GPCRs. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  20. Conjugation of salmon calcitonin to a combed-shaped end functionalized poly(poly(ethylene glycol) methyl ether methacrylate) yields a bioactive stable conjugate.

    Science.gov (United States)

    Ryan, Sinéad M; Wang, Xuexuan; Mantovani, Guiseppe; Sayers, Claire T; Haddleton, David M; Brayden, David J

    2009-04-02

    Salmon calcitonin (sCT) was conjugated via its N-terminal cysteine to a comb-shaped end-functionalized poly(poly(ethylene glycol) methyl ether methacrylate) (PolyPEG, 6.5 kDa), and to linear PEG (5 kDa). Conjugate molecular weight and purity was assessed by SEC-HPLC and MALDI-TOF MS. Bioactivity of conjugates was measured by cyclic AMP assay in T47D cells. Calcium and calcitonin levels were measured in rats following intravenous injections. Stability of conjugates was tested against serine proteases, intestinal and liver homogenates and serum. Cytotoxicity of conjugates was assessed by lactate dehydrogenase (LDH) assay and by haemolytic assay of rat red blood cells. Results showed that the two conjugates were of high purity with molecular weights similar to predictions. Both conjugates retained more than 85% bioactivity in vitro and had nanomolar EC(50) values similar to sCT. While both sCT-PolyPEG(6.5 K) and sCT-PEG(5 K) were resistant to metabolism by serine proteases, homogenates and serum, PolyPEG (6.5 K) was more so. Although both conjugates reduced serum calcium to levels similar to those achieved with sCT, PolyPEG(6.5 K) extended the T(1/2) and AUC of serum sCT over values achieved with sCT-PEG and sCT itself. None of PolyPEG, PEG or methacrylic acid displayed significant cytotoxicity. PolyPEG may therefore have potential to improve pharmacokinetic profiles of injected peptides.

  1. Calcitonin gene-related peptide erases the fear memory and facilitates long-term potentiation in the central nucleus of the amygdala in rats.

    Science.gov (United States)

    Wu, Xin; Zhang, Jie-Ting; Liu, Jue; Yang, Si; Chen, Tao; Chen, Jian-Guo; Wang, Fang

    2015-11-01

    Calcitonin gene-related peptide (CGRP) is a 37 amino acid neuropeptide, which plays a critical role in the central nervous system. CGRP binds to G protein-coupled receptors, including CGRP1, which couples positively to adenylyl cyclase (AC) and protein kinase A (PKA) activation. CGRP and CGRP1 receptors are enriched in central nucleus of the amygdala (CeA), the main part of the amygdala, which regulates conditioned fear memories. Here, we reported the importance of CGRP and CGRP1 receptor for synaptic plasticity in the CeA and the extinction of fear memory in rats. Our electrophysiological and behavioral in vitro and in vivo results showed exogenous application of CGRP induced an immediate and lasting long-term potentiation in the basolateral nucleus of amygdala-CeA pathway, but not in the lateral nucleus of amygdala-CeA pathway, while bilateral intra-CeA infusion CGRP (0, 5, 13 and 21 μM/side) dose dependently enhanced fear memory extinction. The effects were blocked by CGRP1 receptor antagonist (CGRP8-37 ), N-methyl-d-aspartate receptors antagonist MK801 and PKA inhibitor H89. These results demonstrate that CGRP can lead to long-term potentiation of basolateral nucleus of amygdala-CeA pathway through a PKA-dependent postsynaptic mechanism that involved N-methyl-d-aspartate receptors and enhance the extinction of fear memory in rats. Together, the results strongly support a pivotal role of CGRP in the synaptic plasticity of CeA and extinction of fear memory. Calcitonin gene-related peptide (CGRP) plays an essential role in synaptic plasticity in the amygdala and fear memory. We found that CGRP-induced chemical long-term potentiation (LTP) in a dose-dependent way in the BLA-CeA (basolateral and central nucleus of amygdala, respectively) pathway and enhanced fear memory extinction in rats through a protein kinase A (PKA)-dependent postsynaptic mechanism that involved NMDA receptors. These results support a pivotal role of CGRP in amygdala. © 2015 International

  2. Calcitonin gene-related peptide protects the myocardium from ischemia induced by endothelin-1: intravital microscopic observation and (31)P-MR spectroscopic studies.

    Science.gov (United States)

    Homma, Satoshi; Kimura, Taizo; Sakai, Satoshi; Yanagi, Ken-ichi; Miyauchi, Yumi; Aonuma, Kazutaka; Miyauchi, Takashi

    2014-11-24

    Calcitonin gene-related peptide (CGRP) is a potent vasodilator neuropeptide. We investigated the ameliorating effect of CGRP in myocardial ischemia induced by endothelin-1 (ET-1), with special emphasis on myocardial microvascular hemodynamics and levels of energy-related metabolites. The Langendorff preparations of rat isolated heart were perfused at a constant flow rate. Microvascular blood flow was also visualized in the anterior epicardium of the left ventricle by means of an intravital fluorescence microscope system. Energy-related metabolite contents in the myocardium were measured by means of (31)P-magnetic resonance spectroscopy ((31)P-MRS). Intracoronary bolus injections of CGRP caused dose-dependent decreases in coronary perfusion pressure (CPP) in the hearts exposed to ET-1 (30 pmol). The vasodilator potency of CGRP was about 10,000-fold greater than that of nitroglycerin and 1,000-fold greater than that of isobutylmethylxanthine. Vasodilation of the small-sized arterioles (10-40 μm in diameter) in response to CGRP (100 pmol) was confirmed by direct microscopic observation. After ET-1 (30 pmol) plus vehicle administration, high energy phosphates (phosphocreatine (PCr), ATP) were markedly reduced (pchanges in the myocardium (decrease in PCr) and macrohemodynamic alterations (increase in CPP, decrease in dP/dt etc.) induced by ET-1. We conclude that CGRP effectively confers hemodynamic and metabolic protections to isolated beating hearts against ET-1-induced myocardial ischemia. Copyright © 2014. Published by Elsevier Inc.

  3. A research design for the quantification of the neuropeptides substance p and calcitonin gene-related Peptide in rat skin using Western blot analysis.

    Science.gov (United States)

    Lapin, Guilherme Abbud Franco; Hochman, Bernardo; Nishioka, Michele Akemi; Maximino, Jessica Ruivo; Chadi, Gerson; Ferreira, Lydia Masako

    2015-06-01

    To describe and standardize a protocol that overcomes the technical limitations of Western blot (WB) analysis in the quantification of the neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) following nociceptive stimuli in rat skin. Male Wistar rats (Rattus norvegicus albinus) weighing 250 to 350 g were used in this study. Elements of WB analysis were adapted by using specific manipulation of samples, repeated cycles of freezing and thawing, more thorough maceration, and a more potent homogenizer; increasing lytic reagents; promoting greater inhibition of protease activity; and using polyvinylidene fluoride membranes as transfer means for skin-specific protein. Other changes were also made to adapt the WB analysis to a rat model. University research center. Western blot analysis adapted to a rat model. This research design has proven effective in collecting and preparing skin samples to quantify SP and CGRP using WB analysis in rat skin. This study described a research design that uses WB analysis as a reproducible, technically accessible, and cost-effective method for the quantification of SP and CGRP in rat skin that overcomes technical biases.

  4. Dynamics of calcitonin gene-related peptide-like cells changes in the lungs of two-kidney, one-clip rats

    Directory of Open Access Journals (Sweden)

    I. Kasacka

    2012-03-01

    Full Text Available Taking into consideration renal hypertension-induced homeostatic disorders and the key role of calcitonin gene-related peptide (CGRP in many, systemic functions regulating systems, a question arises as to what an extent arterial hypertension affects the morphology and dynamics of pulmonary CGRP-immunopositive cell changes. The aim of the present study was to examine the distribution, morphology and dynamics of changes of CGRP-containing cells in the lungs of rats in the two-kidney, one-clip (2K1C renovascular hypertension model. The studies were carried out on the lungs of rats after 3, 14, 28, 42, and 91 days long period from the renal artery clipping procedure. In order to identify neuroendocrine cells, immunohistochemical reaction was performed with the use of a specific antibody against CGRP. It was revealed that renovascular hypertension caused changes in the neuroendocrine, CGRP-containing cells in the lungs of rats. The changes, observed in the neuroendocrine cells, depended on time periods from experimentally induced hypertension. The highest intensity of changes in the neuroendocrine cells was observed in the lungs of rats after 14 days from the surgery.

  5. Impact of Food Components on in vitro Calcitonin Gene-Related Peptide Secretion—A Potential Mechanism for Dietary Influence on Migraine

    Science.gov (United States)

    Slavin, Margaret; Bourguignon, Julia; Jackson, Kyle; Orciga, Michael-Angelo

    2016-01-01

    Calcitonin gene-related peptide (CGRP) is a pivotal messenger in the inflammatory process in migraine. Limited evidence indicates that diet impacts circulating levels of CGRP, suggesting that certain elements in the diet may influence migraine outcomes. Interruption of calcium signaling, a mechanism which can trigger CGRP release, has been suggested as one potential route by which exogenous food substances may impact CGRP secretion. The objective of this study was to investigate the effects of foods and a dietary supplement on two migraine-related mechanisms in vitro: CGRP secretion from neuroendocrine CA77 cells, and calcium uptake by differentiated PC12 cells. Ginger and grape pomace extracts were selected for their anecdotal connections to reducing or promoting migraine. S-petasin was selected as a suspected active constituent of butterbur extract, the migraine prophylactic dietary supplement. Results showed a statistically significant decrease in stimulated CGRP secretion from CA77 cells following treatment with ginger (0.2 mg dry ginger equivalent/mL) and two doses of grape pomace (0.25 and 1.0 mg dry pomace equivalent/mL) extracts. Relative to vehicle control, CGRP secretion decreased by 22%, 43%, and 87%, respectively. S-petasin at 1.0 μM also decreased CGRP secretion by 24%. Meanwhile, S-petasin and ginger extract showed inhibition of calcium influx, whereas grape pomace had no effect on calcium. These results suggest that grape pomace and ginger extracts, and S-petasin may have anti-inflammatory propensity by preventing CGRP release in migraine, although potentially by different mechanisms, which future studies may elucidate further. PMID:27376323

  6. A novel dual amylin and calcitonin receptor agonist, KBP-089, induces weight loss through a reduction in fat, but not lean mass, while improving food preference.

    Science.gov (United States)

    Gydesen, Sofie; Hjuler, Sara Toftegaard; Freving, Zenia; Andreassen, Kim Vietz; Sonne, Nina; Hellgren, Lars I; Karsdal, Morten Asser; Henriksen, Kim

    2017-04-01

    Obesity and associated co-morbidities, such as type 2 diabetes and non-alcoholic fatty liver disease, are major health challenges. Hence, there is an important need to develop weight loss therapies with the ability to reduce the co-morbidities. The effect of the dual amylin and calcitonin receptor agonist (DACRA), KBP-089, on body weight, glucose homeostasis and fatty acid accumulation in liver and muscle tissue and on food preference was investigated. Furthermore, we elucidated weight-independent effects of KBP-089 using a weight-matched group. Rats fed a high-fat diet were treated, s.c., with KBP-089 0.625, 1.25, 2.5 μg·kg-1 or vehicle. KB-089 induced in a dose-dependent and sustained weight loss (~17% by 2.5 μg·kg-1 ). Moreover, KBP-089 reduced fat depot size and reduced lipid accumulation in muscle and liver. In Zucker Diabetic Fatty rats, KBP-089 improved glucose homeostasis through improved insulin action. To obtain a weight-matched group, significantly less food was offered (9% less than in the KBP-089 group). Weight matching led to improved glucose homeostasis by reducing plasma insulin; however, these effect were inferior compared to those of KBP-089. In the food preference test, rats fed a normal diet obtained 74% of their calories from chocolate. KBP-089 reduced total caloric intake and induced a relative increase in chow consumption while drastically reducing chocolate consumption compared with vehicle. The novel DACRA, KBP-089, induces a sustained weight loss, leading to improved metabolic parameters including food preference, and these are beyond those observed simply by diet-induced weight loss. © 2017 The British Pharmacological Society.

  7. Function of the cytoplasmic tail of human calcitonin receptor-like receptor in complex with receptor activity-modifying protein 2

    Energy Technology Data Exchange (ETDEWEB)

    Kuwasako, Kenji, E-mail: kuwasako@fc.miyazaki-u.ac.jp [Frontier Science Research Center, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692 (Japan); Kitamura, Kazuo; Nagata, Sayaka; Hikosaka, Tomomi [Division of Circulation and Body Fluid Regulation, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692 (Japan); Kato, Johji [Frontier Science Research Center, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692 (Japan)

    2010-02-12

    Receptor activity-modifying protein 2 (RAMP2) enables calcitonin receptor-like receptor (CRLR) to form an adrenomedullin (AM)-specific receptor. Here we investigated the function of the cytoplasmic C-terminal tail (C-tail) of human (h)CRLR by co-transfecting its C-terminal mutants into HEK-293 cells stably expressing hRAMP2. Deleting the C-tail from CRLR disrupted AM-evoked cAMP production or receptor internalization, but did not affect [{sup 125}I]AM binding. We found that CRLR residues 428-439 are required for AM-evoked cAMP production, though deleting this region had little effect on receptor internalization. Moreover, pretreatment with pertussis toxin (100 ng/mL) led to significant increases in AM-induced cAMP production via wild-type CRLR/RAMP2 complexes. This effect was canceled by deleting CRLR residues 454-457, suggesting Gi couples to this region. Flow cytometric analysis revealed that CRLR truncation mutants lacking residues in the Ser/Thr-rich region extending from Ser{sup 449} to Ser{sup 467} were unable to undergo AM-induced receptor internalization and, in contrast to the effect on wild-type CRLR, overexpression of GPCR kinases-2, -3 and -4 failed to promote internalization of CRLR mutants lacking residues 449-467. Thus, the hCRLR C-tail is crucial for AM-evoked cAMP production and internalization of the CRLR/RAMP2, while the receptor internalization is dependent on the aforementioned GPCR kinases, but not Gs coupling.

  8. Role of peptidergic nerve terminals in the skin: reversal of thermal sensation by calcitonin gene-related peptide in TRPV1-depleted neuropathy.

    Directory of Open Access Journals (Sweden)

    Yu-Lin Hsieh

    Full Text Available To investigate the contribution of peptidergic intraepidermal nerve fibers (IENFs to nociceptive responses after depletion of the thermal-sensitive receptor, transient receptor potential vanilloid subtype 1 (TRPV1, we took advantage of a resiniferatoxin (RTX-induced neuropathy which specifically affected small-diameter dorsal root ganglion (DRG neurons and their corresponding nerve terminals in the skin. Thermal hypoalgesia (p<0.001 developed from RTX-treatment day 7 (RTXd7 and became normalized from RTXd56 to RTXd84. Substance P (SP(+ and TRPV1(+ neurons were completely depleted (p = 0.0001 and p<0.0001, respectively, but RTX had a relatively minor effect on calcitonin gene-related peptide (CGRP(+ neurons (p = 0.029. Accordingly, SP(+ (p<0.0001 and TRPV1(+ (p = 0.0008 IENFs were permanently depleted, but CGRP(+ IENFs (p = 0.012 were only transiently reduced and had recovered by RTXd84 (p = 0.83. The different effects of RTX on peptidergic neurons were attributed to the higher co-localization ratio of TRPV1/SP than of TRPV1/CGRP (p = 0.029. Thermal hypoalgesia (p = 0.0018 reappeared with an intraplantar injection of botulinum toxin type A (botox, and the temporal course of withdrawal latencies in the hot-plate test paralleled the innervation of CGRP(+ IENFs (p = 0.0003 and CGRP contents in skin (p = 0.01. In summary, this study demonstrated the preferential effects of RTX on depletion of SP(+ IENFs which caused thermal hypoalgesia. In contrast, the skin was reinnervated by CGRP(+ IENFs, which resulted in a normalization of nociceptive functions.

  9. Oral salmon calcitonin protects against impaired fasting glycemia, glucose intolerance, and obesity induced by high-fat diet and ovariectomy in rats.

    Science.gov (United States)

    Feigh, Michael; Andreassen, Kim V; Hjuler, Sara T; Nielsen, Rasmus H; Christiansen, Claus; Henriksen, Kim; Karsdal, Morten A

    2013-07-01

    Oral salmon calcitonin (sCT) has demonstrated clinical efficacy in treating osteoporosis in postmenopausal women. The postmenopausal state is also associated with obesity-related insulin resistance (IR) and type 2 diabetes. The aim of this study was to investigate the preventive effects of oral sCT on energy and glucose homeostasis in high-fat diet (HFD)- and ovariectomy (OVX)-induced obese rats. Furthermore, the weight-regulatory and gluco-regulatory effects of short-term oral sCT intervention on HFD-induced obese rats were explored. For prevention, female rats exposed to HFD with or without OVX were treated with oral sCT for 5 weeks. As intervention, HFD-induced obese male rats were treated with oral sCT for 4 days. Body weight, food intake, and plasma glucose, insulin, and leptin levels were measured, and the clinical homeostasis model assessment for insulin resistance (HOMA-IR) index was calculated. In addition, oral glucose tolerance was evaluated in the systemic and portal circulations. For prevention, oral sCT reduced body weight by ∼16% to 19% (P fasting glycemia (P obesity. Furthermore, oral sCT significantly reduced the incremental area under the curve for plasma glucose and insulin by ∼40% and ∼70%, respectively, during glucose tolerance testing. As intervention in HFD-induced obese rats, oral sCT reduced body weight, fasting glycemia, and insulinemia in conjunction with HOMA-IR (P obese rats, indicating the clinical usefulness of oral sCT in postmenopausal obesity-related IR and type 2 diabetes.

  10. Somatostatin, substance P and calcitonin gene-related peptide-positive intramural nerve structures of the human large intestine affected by carcinoma.

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    Jerzy Kaleczyc

    2010-11-01

    Full Text Available The aim of this study was to investigate the arrangement and chemical coding of enteric nerve structures in the human large intestine affected by cancer. Tissue samples comprising all layers of the intestinal wall were collected during surgery form both morphologically unchanged and pathologically altered segments of the intestine (n=15, and fixed by immersion in buffered paraformaldehyde solution. The cryostat sections were processed for double-labelling immunofluorescence to study the distribution of the intramural nerve structures (visualized with antibodies against protein gene-product 9.5 and their chemical coding using antibodies against somatostatin (SOM, substance P (SP and calcitonin gene-related peptide (CGRP. The microscopic observations revealed distinct morphological differences in the enteric nerve system structure between the region adjacent to the cancer invaded area and the intact part of the intestine. In general, infiltration of the cancer tissue resulted in the gradual (depending on the grade of invasion first decomposition and reduction to final partial or complete destruction and absence of the neuronal elements. A comparative analysis of immunohistochemically labeled sections (from the unchanged and pathologically altered areas revealed a statistically significant decrease in the number of CGRP-positive neurons and nerve fibres in both submucous and myenteric plexuses in the transitional zone between morphologically unchanged and cancer-invaded areas. In this zone, a decrease was also observed in the density of SP-positive nerve fibres in all intramural plexuses. Conversely, the investigations demonstrated statistically insignificant differences in number of SP- and SOM-positive neurons and a similar density of SOM-positive nerve fibres in the plexuses of the intact and pathologically changed areas. The differentiation between the potential adaptive changes in ENS or destruction of its elements by cancer invasion should be

  11. The central anorexigenic mechanism of amylin in Japanese quail (Coturnix japonica) involves pro-opiomelanocortin, calcitonin receptor, and the arcuate nucleus of the hypothalamus.

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    Yuan, Jingwei; Gilbert, Elizabeth R; Cline, Mark A

    2017-08-01

    Amylin is a 37-amino acid peptide hormone that exerts anorexigenic effects in humans and animals. We demonstrated that central injection of amylin into chicks affected feeding and related behaviors via the hypothalamus and brainstem, although the molecular mechanisms remained elusive. Thus, the objective of this study was to investigate the molecular mechanisms underlying anorexigenic effects of amylin in 7 day-old Japanese quail. Food but not water intake was reduced after intracerebroventricular amylin injection, and the behavior analysis indicated that this was associated with decreased food pecks and preening. Whole hypothalamus and hypothalamic nuclei including the arcuate nucleus (ARC), paraventricular nucleus (PVN), ventromedial hypothalamus (VMH), dorsomedial nucleus (DMN) and lateral hypothalamic area (LH) were extracted from quail at 1h post-injection for total RNA isolation. Real time PCR was performed to quantify mRNA abundance of amylin receptors, appetite-associated neuropeptides and monoamine-synthesis-related enzymes. Central amylin injection increased the mRNA abundance of calcitonin receptor (CALCR), receptor activity modifying protein 1 (RAMP1), pro-opiomelanocortin (POMC), and aromatic l-amino acid decarboxylase (AADC) in the hypothalamus and individual hypothalamic nuclei. Relative quantities of CALCR and POMC mRNA were greater in the ARC of the amylin- than vehicle-treated group. Thus, amylin-mediated effects on food intake may involve POMC, monoamine synthesis, and amylin receptor 1 (a complex of CALCR and RAMP1) in the ARC. Together, these data provide novel insights on the hypothalamic-specific molecular mechanisms of amylin-induced food intake. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Cervical lymph node metastases from thyroid cancer: does thyroglobulin and calcitonin measurement in fine needle aspirates improve the diagnostic value of cytology?

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    Baldini Enke

    2013-02-01

    Full Text Available Abstract Background Measurement of thyroglobulin (Tg protein in the washout of the needle used for fine needle aspiration biopsy cytology (FNAB-C has been shown to increase the sensitivity of FNAB-C in identifying cervical lymph node (CLN metastasis from well-differentiated thyroid cancer (TC. In this study, we evaluated whether routine measurement of Tg protein (FNAB-Tgp, Tg mRNA (FNAB-Tgm and calcitonin (CT mRNA (FNAB-CTm in the FNAB washout of CLN increases the accuracy of FNAB-C in the diagnosis of suspicious metastatic CLN. Methods In this prospective study 35 CLN from 28 patients were examined. Histology showed metastatic papillary TC (PTC in 26 CLN, metastatic medullary TC (MTC in 3 CLN, metastatic anaplastic TC (ATC in 3 CLN and 3 metastatic CLN from extra-thyroidal cancers. Results The overall accuracy of FNAB-C was 84.4%, reaching 95.7% when the analysis was restricted to PTC. Both FNAB-Tgp and FNAB-Tgm compared favorably with FNAB-C and shown diagnostic performances not statistically different from that of FNAB-C. However, FNAB-Tgp and FNAB-Tgm/FNAB-CTm were found useful in cases in which cytology results were inadequate or provided diagnosis inconsistent with patient's clinical parameters. Conclusions We demonstrated that FNAB-C, Tg/CT mRNA and Tg protein determination in the fine-needle washout showed similar accuracy in the diagnosis of metastatic CLN from TC. The results of this study suggest that samples for Tg protein and Tg/CT mRNA measurements from CLN suspicious for metastatic TC should be collected, but their measurements should be restricted to cases in which FNAB-C provides uninformative or inconsistent diagnosis with respect to patient's clinical parameters.

  13. Crocin improved locomotor function and mechanical behavior in the rat model of contused spinal cord injury through decreasing calcitonin gene related peptide (CGRP).

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    Karami, Masoume; Bathaie, S Zahra; Tiraihi, Taqi; Habibi-Rezaei, Mehran; Arabkheradmand, Jalil; Faghihzadeh, Soghrat

    2013-12-15

    Various approaches have been offered to alleviate chronic pain resulting from spinal cord injuries (SCIs). Application of herbs and natural products, with potentially lower adverse effects, to cure diseases has been recommended in both traditional and modern medicines. Here, the effect of crocin on chronic pain induced by spinal cord contusion was investigated in an animal model. Female Wistar rats were randomly divided into five groups (5 rats in each); three groups were contused at the L1 level. One group was treated with crocin (150mg/kg) two weeks after spinal cord injury; the second group, control, was treated with vehicle only; and the third group was treated with ketoprofen. Two normal groups were also considered with or without crocin treatment. The mechanical behavioral test, the locomotor recovery test and the thermal behavioral test were applied weekly to evaluate the injury and recovery of rats. Significant improvements (p<0.05) in mechanical behavioral and locomotor recovery tests were seen in the rats treated with crocin. Thermal behavioral test did not show any significant changes due to crocin treatment. Plasma concentration of calcitonin-gene related peptide (CGRP) changed from 780.2±2.3 to 1140.3±4.5pg/ml due to SCI and reached 789.1±2.7pg/ml after crocin treatment. These changes were significant at the level of p<0.05. The present study shows the beneficial effects of crocin treatment on chronic pain induced by SCI, through decreasing CGRP as an important mediator of inflammation and pain. Copyright © 2013 Elsevier GmbH. All rights reserved.

  14. Amygdalin improves microcirculatory disturbance and attenuates pancreatic fibrosis by regulating the expression of endothelin-1 and calcitonin gene-related peptide in rats.

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    Zhang, Xiangqun; Hu, Jiangong; Zhuo, Yuzhen; Cui, Lihua; Li, Caixia; Cui, Naiqiang; Zhang, Shukun

    2017-11-09

    The pathogenesis of chronic pancreatitis (CP) is a complex process of interaction between tissue injury and repair, which involves microcirculatory disturbance. Amygdalin, an effective component extracted from Semen Persicae (a kind of Chinese herbal medicine), can decrease blood viscosity and improve microcirculation. In this study, we investigated the therapeutic effects of amygdalin on pancreatic fibrosis in rats with CP. The rat CP model was induced by injecting dibutyltin dichloride (DBTC) into the right caudal vein. Amygdalin was administrated via the penile vein at a dose of 10 mg/(kg d) from the next day, after the induction of CP, once a day for the previous 3 days, and then once every 2 days, until the end of the experiment. Body weight was observed every 7 days. Pancreatic blood flow and histopathological changes were assessed at 28 days. The activation of pancreatic stellate cells (PSCs) was estimated by the expression of α-smooth muscle actin (α-SMA). At the same time, the expression of platelet-derived growth factor-BB (PDGF-BB), transforming growth factor β-1 (TGFβ-1), endothelin-1 (ET-1), and calcitonin gene-related peptide (CGRP) of pancreatic tissues were detected. Treatment of CP rats with amygdalin improved body weight and pancreatic blood flow, as well as alleviated pancreatic fibrosis and acinar destruction, accompanied by the down-regulation of the expressions of α-SMA, PDGF-BB, TGFβ-1, and ET-1, and the up-regulation of the CGRP's expression. Amygdalin could reduce the production of pro-fibrotic cytokines, inhibit the activation of PSCs, and attenuate pancreatic fibrosis in a rat with CP. The mechanism probably includes improving microcirculatory disturbance by regulating the production of ET-1 and CGRP. Copyright © 2017. Published by Elsevier Taiwan LLC.

  15. Design of salmon calcitonin particles for nasal delivery using spray-drying and novel supercritical fluid-assisted spray-drying processes.

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    Cho, Wonkyung; Kim, Min-Soo; Jung, Min-Sook; Park, Junsung; Cha, Kwang-Ho; Kim, Jeong-Soo; Park, Hee Jun; Alhalaweh, Amjad; Velaga, Sitaram P; Hwang, Sung-Joo

    2015-01-15

    The overall aim of this study was to prepare a nasal powder formulation of salmon calcitonin (sCT) using an absorption enhancer to improve its bioavailability. In this work, powder formulations for nasal delivery of sCT were studied using various absorption enhancers and stabilizers. Powders were prepared by two different methods: conventional spray-drying (SD) and novel supercritical fluid-assisted spray-drying (SASD) to investigate the role of CO2 in the particle formation process. The prepared sCT powder formulations were characterized by several analyses; powder X-ray diffractometry (PXRD), scanning electron microscopy (SEM), and the Fourier transform infrared (FT-IR) spectroscopy method. The particle size distribution was also evaluated. In vivo absorption tests were carried out in Sprague-Dawley rat using the prepared powder formulations, and the results were compared to those of raw sCT. Quantitative analysis by high-performance liquid chromatography (HPLC) indicated that sCT was chemically stable after both the SD and SASD processes. Results of PXRD, SEM, and FT-IR did not indicate a strong interaction or defragmentation of sCT. The in vivo absorption test showed that SD- and SASD-processed sCT powders increased the bioavailability of the drug when compared to the nasal administration of raw sCT. In addition, SASD-processed sCT exhibited higher nasal absorption when compared with SD-processed sCT in all formulations due to a reduction of particle size. The results from this study illustrate that the preparation of nasal powders using the SASD process could be a promising approach to improve nasal absorption of sCT. Copyright © 2014 Elsevier B.V. All rights reserved.

  16. [The expression of calcitonin gene-related peptide in the sensory and motor neurons associated with "Hegu" (LI 4) in the rat].

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    Ha, Li-Juan; Cui, Jing-Jing; Wang, Fu-Chun; Jing, Xiang-Hong; Bai, Wan-Zhu

    2014-04-01

    To investigate the chemical expression of the primary sensory and motor neurons associated with "Hegu" (LI 4) area by using neural tracing and fluorescent immunohistochemical techniques. A total of 4 SD rats were used in the present study. After anesthesia, the rats received microinjection of 5 microL of Alexa Fluor 594 conjugated cholera toxin subunit B (AF 594-CTB) into the right "Hegu" (LI 4) area for observing the distribution of the related primary sensory neurons in dorsal root ganglia (DRGs) and motor neurons in the spinal cord (C 1 - C 5). Three days after the microinjection, the rats were anesthetized and transcardiacally perfused with 4% paraformaldehyde, followed by routine section of the DRGs and spinal cord tissues. The labeled neurons were observed by light microscope and their chemical characteristics determined by calcitonin gene-related peptide (CGRP) fluorescent immunohistochemical method. All the AF 594-CTB labeled neurons in DRGs and spinal cord were located on the side of the tracer injection. The labeled sensory neurons distributed in DRGs of cervical (C) 5 to thoracic (T) 1 segments with a high concentration in C 7 DRG in which 73.5% sensory neurons were shown to be CGRP-positive. The labeled motor neurons were found to be in the dorsolateral region of the spinal anterior horns from C 6 to T 1 segments, with a high concentration at C 8 in which 100% motor neurons were shown to be CGRP-positive. Acupoint LI 4 is innervated by sensory neurons from DRGs of C 5 - T 1 and motor neurons from anterior horns of the same segmental spinal cord in rats. Among them, 73.5% of the sensory neurons and 100% of the motor neurons are CGRP-positive, suggesting an involvement of CGRP in acupuncture stimulation-LI 4 induced therapeutic effects.

  17. Impact of Food Components on in vitro Calcitonin Gene-Related Peptide Secretion—A Potential Mechanism for Dietary Influence on Migraine

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    Margaret Slavin

    2016-07-01

    Full Text Available Calcitonin gene-related peptide (CGRP is a pivotal messenger in the inflammatory process in migraine. Limited evidence indicates that diet impacts circulating levels of CGRP, suggesting that certain elements in the diet may influence migraine outcomes. Interruption of calcium signaling, a mechanism which can trigger CGRP release, has been suggested as one potential route by which exogenous food substances may impact CGRP secretion. The objective of this study was to investigate the effects of foods and a dietary supplement on two migraine-related mechanisms in vitro: CGRP secretion from neuroendocrine CA77 cells, and calcium uptake by differentiated PC12 cells. Ginger and grape pomace extracts were selected for their anecdotal connections to reducing or promoting migraine. S-petasin was selected as a suspected active constituent of butterbur extract, the migraine prophylactic dietary supplement. Results showed a statistically significant decrease in stimulated CGRP secretion from CA77 cells following treatment with ginger (0.2 mg dry ginger equivalent/mL and two doses of grape pomace (0.25 and 1.0 mg dry pomace equivalent/mL extracts. Relative to vehicle control, CGRP secretion decreased by 22%, 43%, and 87%, respectively. S-petasin at 1.0 μM also decreased CGRP secretion by 24%. Meanwhile, S-petasin and ginger extract showed inhibition of calcium influx, whereas grape pomace had no effect on calcium. These results suggest that grape pomace and ginger extracts, and S-petasin may have anti-inflammatory propensity by preventing CGRP release in migraine, although potentially by different mechanisms, which future studies may elucidate further.

  18. A potent and selective calcitonin gene-related peptide (CGRP) receptor antagonist, MK-8825, inhibits responses to nociceptive trigeminal activation: Role of CGRP in orofacial pain.

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    Romero-Reyes, Marcela; Pardi, Vanessa; Akerman, Simon

    2015-09-01

    Temporomandibular disorders (TMDs) are orofacial pains within the trigeminal distribution, which involve the masticatory musculature, the temporomandibular joint or both. Their pathophysiology remains unclear, as inflammatory mediators are thought to be involved, and clinically TMD presents pain and sometimes limitation of function, but often appears without gross indications of local inflammation, such as visible edema, redness and increase in temperature. Calcitonin gene-related peptide (CGRP) has been implicated in other pain disorders with trigeminal distribution, such as migraine, of which TMD shares a significant co-morbidity. CGRP causes activation and sensitization of trigeminal primary afferent neurons, independent of any inflammatory mechanisms, and thus may also be involved in TMD. Here we used a small molecule, selective CGRP receptor antagonist, MK-8825, to dissect the role of CGRP in inducing spontaneous nociceptive facial grooming behaviors, neuronal activation in the trigeminal nucleus, and systemic release of pro-inflammatory cytokines, in a mouse model of acute orofacial masseteric muscle pain that we have developed, as a surrogate of acute TMD. We show that CFA masseteric injection causes significant spontaneous orofacial pain behaviors, neuronal activation in the trigeminal nucleus, and release of interleukin-6 (IL-6). In mice pre-treated with MK-8825 there is a significant reduction in these spontaneous orofacial pain behaviors. Also, at 2 and 24h after CFA injection the level of Fos immunoreactivity in the trigeminal nucleus, used as a marker of neuronal activation, was much lower on both ipsilateral and contralateral sides after pre-treatment with MK-8825. There was no effect of MK-8825 on the release of IL-6. These data suggest that CGRP may be involved in TMD pathophysiology, but not via inflammatory mechanisms, at least in the acute stage. Furthermore, CGRP receptor antagonists may have therapeutic efficacy in the treatment of TMD, as they

  19. Nocistatin inhibits pregnant rat uterine contractions in vitro: roles of calcitonin gene-related peptide and calcium-dependent potassium channel.

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    Deák, Beáta H; Klukovits, Anna; Tekes, Kornélia; Ducza, Eszter; Falkay, George; Gáspár, Róbert

    2013-08-15

    The endogenous neuropeptide nociceptin/orphanin FQ, translated from the prepronociceptin gene, exerts a contraction-inhibitory effect on the rat uterus. As nocistatin has been reported to cause functional antagonism of the pro-nociceptive effects of nociceptin, we set out to investigate its effects on the pregnant rat uterus and to elucidate its signalling pathway. The expression of prepronociceptin mRNA in the uterus and nocistatin levels in the uterus and the plasma were confirmed by RT-PCR and radioimmunoassay. The uterine levels of prepronociceptin mRNA and nocistatin were significantly increased by the last day of pregnancy, while the plasma nocistatin levels remained unchanged. In the isolated organ bath studies nocistatin inhibited the prostaglandin- and the KCl-evoked contractions in the uterus dose-dependently. This latter effect was decreased by preincubation with capsaicin. Incubation with calcitonin gene-related peptide after capsaicin treatment caused an elevation in the contraction-inhibitory effect of nocistatin. The effect of nocistatin was also decreased by the Ca(2+)-dependent K(+) channel inhibitor paxilline, against spontaneous uterine contractions. Nociceptin potentiated the action of nocistatin. Naloxone decreased the effect of nocistatin administered either alone or in combination with nociceptin. In Ca(2+)-poor environment, this effect of naloxone was suspended. Enzyme immunoassay for the uterine intracellular cAMP levels partially confirmed the results of in vitro contractility studies. We conclude that nocistatin, generated locally in the uterus, exerts an inhibitory effect, the mechanism being mediated in part by Ca(2+)-dependent K(+) channels, the elevation of cAMP levels and sensory neuropeptides. Copyright © 2013 Elsevier B.V. All rights reserved.

  20. Diffusion of calcitonin through the wall of the root canal Avaliação da difusão da calcitonina através da dentina radicular

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    Selma Cristina Cury Camargo

    2004-03-01

    Full Text Available The aim of this study was to evaluate the in vitro diffusion of synthetic salmon calcitonin (CT, used as an intracanal medication, to the external root surface, with or without the presence of intact root cementum. Fifty-four human central incisors were used in the experiment, and were divided into two groups of 21 (test groups and two groups of 6 teeth (control groups. After root canal preparation, 10 ml of calcitonin was inserted within the root canal chamber. The root was sealed and made externally impermeable. Specimens were then placed in tubes with saline solution buffered with phosphates and stored at 37°C. The diffusion of calcitonin was measured after 1, 4 and 7 days. To count calcitonin present at the external media (PBS, ELISA test (an antigen-antibody reaction was used. Results showed that there was calcitonin diffusion through dentin in all of the test samples. The absence of cementum increased the diffusion of calcitonin (p=0.05. The highest counts of CT were obtained on day 7 for groups with or without cementum - showing a direct relation between time and diffusion of the medication.O presente estudo determinou in vitro a difusão da calcitonina sintética de salmão, como medicação intracanal, até a superfície externa radicular, com e sem a presença de cemento radicular. Foram utilizados cinqüenta e quatro incisivos centrais humanos, divididos em dois grupos com 21 dentes cada e dois grupos com 6 dentes cada (controle negativo. Após o preparo endodôntico, os dentes receberam 10 ml de calcitonina como medicação intracanal. Feitos o selamento e a impermeabilização externa da raiz, os espécimes foram acondicionados em tubos com solução salina tamponada com fosfatos e incubados em estufa a 37°C. Foram colhidas amostras da solução salina nos períodos de 1, 4 e 7 dias. Para a análise das soluções teste, utilizou-se teste ELISA. Os resultados mostram que existe a difusão da medicação testada até a superf

  1. A Study of the Early Changes of the Level of Calcitonin Gene-Related Peptide and Histopathology of Penises of Rats with Experimentally Induced Type I Diabetes Mellitus by Streptozocin

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    El-Kamshoushi, Abdel Aal M; Abdallah, Wafaa I; Helal, Suzan F; El Azhary, Nesrine M; Hassan, Eman M

    2013-01-01

    Introduction Diabetes mellitus (DM) is a multiorgan disease that leads to neurovascular complications that disturb the normal erectile function. Aim The aim of the current work was to study the early changes occurring in the level of calcitonin gene-related peptide (CGRP) and histopathological changes in penile tissues of uncontrolled diabetic rats. Materials and Methods This study was carried on 50 adult male Sprague-Dawley rats divided into two main groups: group I (control, n = 10) and group II (diabetic, n = 40). Type I DM was induced by a single intraperitoneal injection of streptozotocin (60 mg/kg). The tissue level of CGRP and histopathological examination of rat penises were assessed at 2, 4, 6, and 8 weeks after induction of DM. Results CGRP was higher in the diabetic group at 4, 6, and 8 weeks than in the control group. However, endothelial changes and decreased smooth muscles mass started only 2 weeks after induction of DM. Conclusion Deterioration of histopathological features of the uncontrolled diabetic rats corporeal tissues is time dependent. Furthermore, vascular changes seem to precede the neurological changes. El-Kamshoushi AAM, Abdallah WI, Helal SF, El Azhary NM, and Hassan EM. A study of the early changes of the level of calcitonin gene-related peptide and histopathology of penises of rats with experimentally induced type I diabetes mellitus by streptozocin. Sex Med 2013;1:21–29. PMID:25356283

  2. Calcitonin gene-related peptide receptor as a novel target for the management of people with episodic migraine: current evidence and safety profile of erenumab

    Directory of Open Access Journals (Sweden)

    Giamberardino MA

    2017-12-01

    Full Text Available Maria Adele Giamberardino,1,* Giannapia Affaitati,1,* Raffaele Costantini,2 Francesco Cipollone,3,* Paolo Martelletti4,* 1Department of Medicine and Science of Aging, Headache Center, Geriatrics Clinic and Ce.S.I.-Met, “G. D’Annunzio” University of Chieti, Chieti, Italy; 2Department of Medical, Oral and Biotechnological Sciences, Institute of Surgical Pathology, “G. D’Annunzio” University of Chieti, Chieti, Italy; 3Department of Medicine and Science of Aging, Medical Clinic and Ce.S.I.-Met, “G. D’Annunzio” University of Chieti, Chieti, Italy; 4Department of Clinical and Molecular Medicine, Regional Referral Headache Center, Sant’Andrea Hospital, Sapienza University of Rome, Rome, Italy *These authors contributed equally to this work Abstract: Migraine is a highly disabling neurological condition, and preventative treatment still remains problematic, due to aspecificity of the majority of the currently available prophylactic drugs. Calcitonin-gene-related peptide (CGRP plays a crucial role in migraine pathophysiology; agents aimed at blocking its activity have, therefore, been developed in recent years, among which are monoclonal antibodies (mAbs against CGRP, to prevent migraine. Erenumab is the only mAb that targets the CGRP receptor instead of the ligand, with high specificity and affinity of binding. This review will report on the most recent data on erenumab characteristics and on the results of clinical trials on its employment in the prevention of episodic migraine (4–14 monthly migraine days: one Phase II and two Phase III trials (completed and one Phase III trial (ongoing. Monthly subcutaneous administration (70 mg or 140 mg of erenumab vs placebo for 3–6 months showed significantly higher efficacy in reducing the mean monthly number of migraine days and the use of migraine-specific medication, and in decreasing physical impairment and impact of migraine on everyday activities (P<0.001. A favorable safety profile

  3. A calcitonin receptor (CALCR) single nucleotide polymorphism is associated with growth performance and bone integrity in response to dietary phosphorus deficiency.

    Science.gov (United States)

    Alexander, L S; Qu, A; Cutler, S A; Mahajan, A; Rothschild, M F; Cai, W; Dekkers, J C; Stahl, C H

    2010-03-01

    Although concerns over the environmental impact of excess P in the excreta from pig production and governmental regulations have driven research toward reducing dietary supplementation of P to swine diets for over a decade, recent dramatic increases in feed costs have further motivated researchers to identify means to further reduce dietary P supplementation. We have demonstrated that genetic background impacts P utilization in young pigs and have identified genetic polymorphisms in several target genes related to mineral utilization. In this study, we examined the impact of a SNP in the calcitonin receptor gene (CALCR) on P utilization in growing pigs. In Exp. 1, 36 gilts representing the 3 genotypes identified by this CALCR SNP (11, 12, and 22) were fed a P-adequate (PA) or a marginally P-deficient (approximately 20% less available P; PD) diet for 14 wk. As expected, P deficiency reduced plasma P concentration, bone strength, and mineral content (P < 0.05). However, the dietary P deficiency was mild enough to not affect the growth performance of these pigs. A genotype x dietary P interaction (P < 0.05) was observed in measures of bone integrity and mineral content, with the greatest reduction in bone strength and mineral content due to dietary P deficiency being associated with the allele 1. In Exp. 2, 168 pigs from a control line and low residual feed intake (RFI) line were genotyped for the CALCR SNP and fed a PA diet. As expected, pigs from the low RFI line consumed less feed but also gained less BW when compared with the control line (P < 0.05). Although ADFI did not differ between genotypes, pigs having the 11 genotype gained less BW (P < 0.05) than pigs having the 12 or 22 genotypes. Pigs of the 11 and 12 genotypes had bones that tolerated greater load when compared with animals having the 22 genotype (P < 0.05). A similar trend was observed in bone modulus and ash % (P < 0.10). These data are supportive of the association of this CALCR SNP with bone

  4. A Novel α-Calcitonin Gene-Related Peptide Analogue Protects Against End-Organ Damage in Experimental Hypertension, Cardiac Hypertrophy, and Heart Failure.

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    Aubdool, Aisah A; Thakore, Pratish; Argunhan, Fulye; Smillie, Sarah-Jane; Schnelle, Moritz; Srivastava, Salil; Alawi, Khadija M; Wilde, Elena; Mitchell, Jennifer; Farrell-Dillon, Keith; Richards, Daniel A; Maltese, Giuseppe; Siow, Richard C; Nandi, Manasi; Clark, James E; Shah, Ajay M; Sams, Anette; Brain, Susan D

    2017-07-25

    Research into the therapeutic potential of α-calcitonin gene-related peptide (α-CGRP) has been limited because of its peptide nature and short half-life. Here, we evaluate whether a novel potent and long-lasting ( t ½ ≥7 hours) acylated α-CGRP analogue (αAnalogue) could alleviate and reverse cardiovascular disease in 2 distinct murine models of hypertension and heart failure in vivo. The ability of the αAnalogue to act selectively via the CGRP pathway was shown in skin by using a CGRP receptor antagonist. The effect of the αAnalogue on angiotensin II-induced hypertension was investigated over 14 days. Blood pressure was measured by radiotelemetry. The ability of the αAnalogue to modulate heart failure was studied in an abdominal aortic constriction model of murine cardiac hypertrophy and heart failure over 5 weeks. Extensive ex vivo analysis was performed via RNA analysis, Western blot, and histology. The angiotensin II-induced hypertension was attenuated by cotreatment with the αAnalogue (50 nmol·kg -1 ·d -1 , SC, at a dose selected for lack of long-term hypotensive effects at baseline). The αAnalogue protected against vascular, renal, and cardiac dysfunction, characterized by reduced hypertrophy and biomarkers of fibrosis, remodeling, inflammation, and oxidative stress. In a separate study, the αAnalogue reversed angiotensin II-induced hypertension and associated vascular and cardiac damage. The αAnalogue was effective over 5 weeks in a murine model of cardiac hypertrophy and heart failure. It preserved heart function, assessed by echocardiography, while protecting against adverse cardiac remodeling and apoptosis. Moreover, treatment with the αAnalogue was well tolerated with neither signs of desensitization nor behavioral changes. These findings, in 2 distinct models, provide the first evidence for the therapeutic potential of a stabilized αAnalogue, by mediating (1) antihypertensive effects, (2) attenuating cardiac remodeling, and (3

  5. Calcitonin Gene-Related Peptide Effects on Phenotype and IL-12 Production of Monocyte-Derived Dendritic Cells in Rheumatoid Arthritis Patients

    Directory of Open Access Journals (Sweden)

    Azam Brook

    2010-09-01

    Full Text Available Objective(sRecent studies on human indicate that the introduction of therapeutic use of tolerogenic dendritic cell (DC for chronic inflammatory conditions is imminent. For the purpose of defining CGRP potency in tolerogenic DC production, we investigated the phenotype and IL-12 production of DCs generated from the monocytes of rheumatoid arthritis (RA patients in the presence of the calcitonin gene-related peptide (CGRP, as a multifunctional neuropeptide.Materials and MethodsDCs were generated from isolated monocytes from four resistant and two early female RA patients using IL-4, GM-CSF, and CGRP at concentrations of 0, 1, and 100 nM. Then, the phenotype of neuropeptide-treated or untreated DCs was determined using flow cytometry and the IL-12 production was measured by ELISA.ResultsOur study showed that, on the last day of the culture, at a concentration of 1 nM CGRP, the mean fluorescence intensity (MFI for CD80 increased (14.13% and the MFIs for CD83, CD86, and HLA-DR decreased (14.57%, 5.28%, and 6.88% respectively. Moreover, at 100 nM CGRP concentration, the MFI for CD80 increased (11.10% and the MFIs for CD83, CD86, and HLA-DR decreased (4.27%, 18.60%, and 19.75% respectively. In addition, our results indicated that the mean concentrations of IL-12 produced at 0, 1, and 100 nm CGRP concentrations measured 13.72±2.41, 11.01±1.61, and 7±1.34 pg/ml respectively. ConclusionDecreased CD83, CD86, and HLA-DR expression and reduced IL-12 production by CGRP were found in the RA patients' monocyte-derived DCs. CD83 is a well-defined DC activation marker. HLA-DR and CD86 are appropriate molecules for inducing an immune response. IL-12 promotes cell-mediated immunity. Therefore we suggest that CGRP may be used as an inducer in the production of tolerogenic DCs.

  6. Prognostic factors for survival and for biochemical cure in medullary thyroid carcinoma: results in 899 patients. The GETC Study Group. Groupe d'étude des tumeurs à calcitonine.

    Science.gov (United States)

    Modigliani, E; Cohen, R; Campos, J M; Conte-Devolx, B; Maes, B; Boneu, A; Schlumberger, M; Bigorgne, J C; Dumontier, P; Leclerc, L; Corcuff, B; Guilhem, I

    1998-03-01

    Prognostic factors of sporadic or inherited medullary thyroid carcinoma (MTC) are still controversial and have been assessed in old and small series. A better knowledge of these factors would improve patient management. To evaluate factors involved in the prognosis of MTC in a large series of cases, using uni- and multivariate analysis. Clinical, biological, surgical and epidemiological data on 899 MTC patients, diagnosed between 1952 and 1996, were collected by the French Calcitonin Tumors Study Group (GETC) with a standardized questionnaire, and processed in a national database. Survival and biochemical cure (i.e. normal basal post-operative serum calcitonin levels) were analysed with Kaplan and Meier and log-rank test statistical procedures. Data are presented as adjusted rather than observed survival, to consider only patients who died of MTC. Cox's forward-stepping proportional hazard model was used to analyse factors with a significant influence on survival by univariate analysis. Apart from the large proportion of familial forms (43%), the general characteristics of our population were similar to those in other studies: mean age at surgery = 43.4 years; sex ratio = 1 male/1.35 female; stage I = 20.8%; stage II = 21.2%; stage III = 46.5% and stage IV = 11.5%. 863 (96%) patients underwent surgery; 43% of operated patients were biochemically cured. Adjusted survival was 85.7 +/- 1.5% at 5 years and 78.4 +/- 2.1% at 10 years. Multivariate analysis showed that age and stage were independent predictive factors of survival. Gender, type of surgery, type of familial form were predictive only in univariate analysis. Biochemical cure predicts a survival rate of 97.7% at 10 years. Authentic recurrence, that is subsequent elevation of calcitonin (CT) after post-operative normalization, was found in 4.9%. In non-cured patients (57%), survival was still good: 80.2% (+/- 2.2%) and 70.3% (+/- 2.9%) at 5 and 10 years, respectively. Similarly, prediction of biochemical cure

  7. The effect and safety of monoclonal antibodies to calcitonin gene-related peptide and its receptor on migraine: a systematic review and meta-analysis.

    Science.gov (United States)

    Hou, Min; Xing, Haiyan; Cai, Yongqing; Li, Bin; Wang, Xianfeng; Li, Pan; Hu, Xiaolin; Chen, Jianhong

    2017-12-01

    Migraine has been recognized as one of the leading causes of disability in the 2013 Global Burden of Disease Study and seriously affects the quality of patients' life, current treatment options are not ideal. Monoclonal antibodies to calcitonin gene-related peptide and its receptor (CGRP-mAbs) appear more promising for migraine because of considerably better effect and safety profiles. The objective of this study is to systematically assess the clinical efficacy and safety of CGRP-mAbs for migraine therapy. A systematic literature search in PubMed, Cochrane Library and Baidu Scholar was performed to identify randomized controlled trials (RCTs), which compared the effect and safety of CGRP-mAbs with placebo on migraine. Regarding the efficacy, the reduction of monthly migraine days from baseline to weeks 1-4, 5-8, and 9-12; responder rates were extracted as the outcome measures of the effects of CGRP-mAbs. Regarding the safety, total adverse events, the main adverse events, and other adverse events were evaluated. We found significant reduction of monthly migraine days in CGRP-mAbs vs. placebo (weeks 1-4: SMD -0.49, 95% CI -0.61 to -0.36; weeks 5-8: SMD -0.43, 95% CI -0.56 to -0.30; weeks 9-12: SMD -0.37, 95% CI -0.49 to -0.24). 50% and 75% responder rates (OR 2.59, 95% CI 1.99 to 3.37; and OR 2.91, 95% CI 2.06 to 4.10) were significantly increased compared with placebo. There was no significant difference in total adverse events (OR 1.17, 95% CI 0.91 to 1.51), and the main adverse events including upper respiratory tract infection (OR 1.44, 95% CI 0.82 to 2.55), nasopharyngitis (OR 0.59, 95% CI 0.30 to 1.16), nausea (OR 0.61, 95% CI 0.29 to 1.32), injection-site pain (OR 1.73, 95% CI 0.95 to 3.16) and back pain (OR 0.97, 95% CI 0.49 to 1.90) were not obviously changed compared with placebo control, but the results showed significant increase of dizziness in CGRP-mAbs vs. placebo (OR 3.22, 95% CI 1.09 to 9.45). This meta-analysis suggests that CGRP-mAbs are

  8. mRNA expression of 5-hydroxytryptamine 1B, 1D, and 1F receptors and their role in controlling the release of calcitonin gene-related peptide in the rat trigeminovascular system

    DEFF Research Database (Denmark)

    Amrutkar, Dipak V; Ploug, Kenneth B; Hay-Schmidt, Anders

    2012-01-01

    Triptans, a family of 5-hydroxytryptamine (5-HT) 1B, 1D, and 1F receptor agonists, are used in the acute treatment of migraine attacks. The site of action and subtypes of the 5-HT(1) receptor that mediate the antimigraine effect have still to be identified. This study investigated the m......RNA expression of these receptors and the role of 5-HT(1) receptor subtypes in controlling the release of calcitonin gene-related peptide (CGRP) in rat dura mater, trigeminal ganglion (TG), and trigeminal nucleus caudalis (TNC). The mRNA for each receptor subtype was quantified by quantitative real......-time polymerase chain reaction. A high potassium concentration was used to release CGRP from dura mater, isolated TG, and TNC in vitro. The immunoreactive CGRP (iCGRP) release was measured by enzyme-linked immunoassay. The mRNA transcripts of the 3 5-HT(1) receptor subtypes were detected in the trigeminovascular...

  9. Influence of fluor salts, hormone replacement therapy and calcitonin on the concentration of insulin-like growth factor (IGF)-I, IGF-II and transforming growth factor-beta 1 in human iliac crest bone matrix from patients with primary osteoporosis.

    Science.gov (United States)

    Pepene, C E; Seck, T; Diel, I; Minne, H W; Ziegler, R; Pfeilschifter, J

    2004-01-01

    Data from cell culture experiments suggest that local growth factors (GFs) may mediate the effects of estrogens, calcitonin or fluor ions on the skeleton. To assess the in vivo relevance of the in vitro reports, the effect of fluor salts, hormone replacement therapy (HRT) and calcitonin on the concentrations of IGF-I, IGF-II and transforming growth factor (TGF)-beta 1 in bone matrix extracts from osteoporotic patients was evaluated. Iliac crest bone biopsies were obtained from 170 patients (76 men and 94 women) with primary osteoporosis aged 55.5+/-0.8 Years. Bone matrix extraction was performed based on a guanidine-HCl/ethylendiamine-tetra-acetic acid method. In comparison with age- and body mass index (BMI)-matched controls, no influence of long-term therapy with fluor ions (n=41) or calcitonin (n=16) on the bone matrix concentration of GFs was noticed. Postmenopausal women with osteoporosis on HRT (n=39) had lower skeletal IGF-I but not IGF-II levels as compared with age- and BMI-matched non-users. However, the lower rate of bone turnover in women with HRT may account for this difference, since the significance was lost after adjustment for alkaline phosphatase. Likewise, a tendency for lower TGF-beta 1 levels was observed in HRT users as compared with non-users but was lost after adjustment for bone turnover. None of the therapies influenced the serum levels of GFs when patients receiving continuous therapy for at least 1 Year before bone biopsy were considered. Our data suggest no direct effect of fluor therapy on skeletal GFs levels. At the concentrations used, neither HRT nor calcitonin appeared to exert any significant influence on serum or bone matrix GF levels.

  10. A randomized, double-blind, multicenter, placebo-controlled study to evaluate the efficacy and safety of oral salmon calcitonin in the treatment of osteoporosis in postmenopausal women taking calcium and vitamin D.

    Science.gov (United States)

    Henriksen, Kim; Byrjalsen, Inger; Andersen, Jeppe R; Bihlet, Asger R; Russo, Luis A; Alexandersen, Peter; Valter, Ivo; Qvist, Per; Lau, Edith; Riis, Bente J; Christiansen, Claus; Karsdal, Morten A

    2016-10-01

    This randomized, double-blind, placebo-controlled phase III study was conducted to assess the efficacy and safety of oral calcitonin (SMC021) for the treatment of postmenopausal osteoporosis. A total of 4665 postmenopausal women with osteoporosis were randomized 1:1 to receive calcium and vitamin D plus either SMC021 tablets (0.8mg/d) or placebo for 36months. The primary endpoint was the proportion of patients with a new vertebral fracture. The two groups were well balanced at baseline with regards to demographic and clinical data. No effect of SMC021 on preventing new vertebral fractures was observed, nor was any effect seen on new hip or non-vertebral fractures. Women receiving SMC021 had a mean 1.02% (±0.12%) increase in lumbar spine bone mineral density (BMD) compared with a mean 0.18% (±0.12%) increase in the placebo group by the end of the study (p<0.0001). Similarly, small increases in BMD were observed at the femoral neck and hip in both groups. Levels of the biomarkers of bone turnover, urinary CTX-I and CTX-II, were 15% lower in the SMC021 group than in the placebo arm at 12 and 24months, but not at 36months. No change in quality of life between groups, assessed by the Qualeffo-14 questionnaire, was observed in either group between baseline and month 36. Pharmacokinetics analysis confirmed exposure to SMC021, but the drug levels were markedly lower than expected. Approximately 92% of subjects in each treatment group experienced an adverse event (AE), the majority of which were mild or moderate in intensity. AEs associated with SMC021 were primarily of gastrointestinal origin and included nausea, vomiting and abdominal pain, as well as hot flushes which were the reason for the slightly higher drop-out rate in the active treatment arm compared to placebo. The number of severe AEs was low in both groups. Thirty-five deaths were reported but none were considered treatment-related. Due to the lack of efficacy in preventing fractures, the development of the

  11. The Influence of Low Doses of Zearalenone and T-2 Toxin on Calcitonin Gene Related Peptide-Like Immunoreactive (CGRP-LI Neurons in the ENS of the Porcine Descending Colon

    Directory of Open Access Journals (Sweden)

    Krystyna Makowska

    2017-03-01

    Full Text Available The enteric nervous system (ENS can undergo adaptive and reparative changes in response to physiological and pathological stimuli. These manifest primarily as alterations in the levels of active substances expressed by the enteric neuron. While it is known that mycotoxins can affect the function of the central and peripheral nervous systems, knowledge about their influence on the ENS is limited. Therefore, the aim of the present study was to investigate the influence of low doses of zearalenone (ZEN and T-2 toxin on calcitonin gene related peptide-like immunoreactive (CGRP-LI neurons in the ENS of the porcine descending colon using a double immunofluorescence technique. Both mycotoxins led to an increase in the percentage of CGRP-LI neurons in all types of enteric plexuses and changed the degree of co-localization of CGRP with other neuronal active substances, such as substance P, galanin, nitric oxide synthase, and cocaine- and amphetamine-regulated transcript peptide. The obtained results demonstrate that even low doses of ZEN and T-2 can affect living organisms and cause changes in the neurochemical profile of enteric neurons.

  12. Acid activation of Trpv1 leads to an up-regulation of calcitonin gene-related peptide expression in dorsal root ganglion neurons via the CaMK-CREB cascade: a potential mechanism of inflammatory pain.

    Science.gov (United States)

    Nakanishi, Masako; Hata, Kenji; Nagayama, Tomotaka; Sakurai, Teruhisa; Nishisho, Toshihiko; Wakabayashi, Hiroki; Hiraga, Toru; Ebisu, Shigeyuki; Yoneda, Toshiyuki

    2010-08-01

    Increased production of calcitonin gene-related peptide (CGRP) in sensory neurons is implicated in inflammatory pain. The inflammatory site is acidic due to proton release from infiltrating inflammatory cells. Acid activation of peripheral nociceptors relays pain signals to the CNS. Here, we examined whether acid activated the transient receptor potential vanilloid subtype 1 (Trpv1), a widely recognized acid-sensing nociceptor and subsequently increased CGRP expression. Chemically induced inflammation was associated with thermal hyperalgesia and increased CGRP expression in dorsal root ganglion (DRG) in rats. In organ cultures of DRG, acid (pH 5.5) elevated CGRP expression and the selective Trpv1 antagonist 5'-Iodoresiniferatoxin decreased it. Trpv1-deficient DRG showed reduced CGRP increase by acid. Of note, many of CGRP/Trpv1-positive DRG neurons exhibited the phosphorylation of cAMP response element-binding protein (CREB), a nociceptive transcription factor. Knockdown of CREB by small interfering RNA or a dominant-negative form of CREB diminished acid-elevated CGRP expression. Acid elevated the transcriptional activity of CREB, which in turn stimulated CGRP gene promoter activity. These effects were inhibited by a Ca(2+)/calmodulin-dependent protein kinase (CaMK) inhibitor KN-93. In conclusion, our results suggest that inflammatory acidic environments activate Trpv1, leading to an up-regulation of CGRP expression via CaMK-CREB cascade, a series of events that may be associated with inflammatory pain.

  13. Steroid Treatment Reduces Allergic Airway Inflammation and Does Not Alter the Increased Numbers of Dendritic Cells and Calcitonin Gene-Related Peptide-Expressing Neurons in Airway Sensory Ganglia.

    Science.gov (United States)

    Le, Duc Dung; Funck, Ulrike; Wronski, Sabine; Heck, Sebastian; Tschernig, Thomas; Bischoff, Markus; Sester, Martina; Herr, Christian; Bals, Robert; Welte, Tobias; Braun, Armin; Dinh, Quoc Thai

    2016-01-01

    Our previous data demonstrated that allergic airway inflammation induces migration of dendritic cells (DC) into airway sensory jugular and nodose ganglia (jugular-nodose ganglion complex; JNC). Here we investigated the effects of steroid treatment regarding the expression and migration of DC and calcitonin gene-related peptide (CGRP)-immunoreactive neurons of vagal sensory ganglia during allergic airway inflammation. A house dust mite (HDM) model for allergic airway inflammation was used. The mice received 0.3 mg fluticasone propionate per kilogram of body weight in the last 9 days. JNC slices were analyzed on MHC II, the neuronal marker PGP9.5, and the neuropeptide CGRP. Allergic airway inflammation increased the numbers of DC and CGRP-expressing neurons in the JNC significantly in comparison to the controls (DC/neurons: HDM 44.58 ± 1.6% vs. saline 33.29 ± 1.6%, p neurons/total neurons: HDM 30.65 ± 1.9% vs. saline 19.49 ± 2.3%, p neurons in the JNC compared to HDM-treated mice. The present findings indicate an important role of DC and CGRP-containing neurons in the pathogenesis of allergic airway inflammation. However, steroid treatment did not have an effect on the population of DC and neurons displaying CGRP in the JNC, whereas steroid treatment was found to suppress allergic airway inflammation. © 2015 S. Karger AG, Basel.

  14. Role of low-affinity nerve growth factor receptor inhibitory antibody in reducing pain behavior and calcitonin gene-related Peptide expression in a rat model of wrist joint inflammatory pain.

    Science.gov (United States)

    Iwakura, Nahoko; Ohtori, Seiji; Orita, Sumihisa; Yamashita, Masaomi; Takahashi, Kazuhisa; Kuniyoshi, Kazuki

    2010-02-01

    Nerve growth factor (NGF), via the high-affinity receptor, tyrosine kinase A, has been widely reported as a mediator of pain caused by inflammation. A clinical trial has suggested that anti-NGF antibody is effective for pain caused by osteoarthritis of the knee. However, adverse events such as headache (8.9%), upper respiratory tract infection (7.3%), and paresthesia (6.8%) were reported. We hypothesized that inhibition of the low-affinity NGF receptor, p75 neurotrophin receptor (p75NTR), is also effective for joint pain and may reduce side effects. This study examined suppression of pain behavior and expression of pain-inducing neuropeptides such as calcitonin gene-related peptide (CGRP) and p75NTR in dorsal root ganglia neurons by a p75NTR inhibitory antibody in a rat model of wrist joint inflammatory pain. We injected complete Freund's adjuvant (CFA) into the wrist joint of rats and used this as a model of inflammatory pain. We applied 10 microL of saline (CFA + saline group; n = 20) or 1, 10, or 50 microL of a p75NTR inhibitory antibody (CFA + p75NTR inhibitory antibody group; n = 40) directly to the inflamed joint in the rats. Mechanical hyperalgesia was measured for 2 weeks using von Frey filaments. We assessed CGRP and p75NTR expression in C8 dorsal root ganglia immunochemically. Adverse events such as loss of weight and/or appetite, constipation, and infection were examined. p75NTR inhibitory antibody reduced mechanical hyperalgesia caused by CFA (pwrist inflammation (p<.01). p75NTR inhibition may be a therapeutic target for inflamed joint pain treatment with reduced adverse events. Copyright 2010. Published by Elsevier Inc.

  15. Diagnostic utility of PET/CT with (18)F-DOPA and (18)F-FDG in persistent or recurrent medullary thyroid carcinoma: the importance of calcitonin and carcinoembryonic antigen cutoff.

    Science.gov (United States)

    Romero-Lluch, Ana Reyes; Cuenca-Cuenca, Juan Ignacio; Guerrero-Vázquez, Raquel; Martínez-Ortega, Antonio Jesús; Tirado-Hospital, Juan Luis; Borrego-Dorado, Isabel; Navarro-González, Elena

    2017-11-01

    This study sought to evaluate and compare the utility of 18-F-fluorodihydroxyphenylalanine ((18)F-DOPA) and 18-F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography/computed tomography (PET/CT) for identification of lesions in patients with recurrent medullary thyroid carcinoma (MTC). In addition, we analyzed the correlation between the calcitonin (Ct), carcinoembryonic antigen (CEA) levels, each doubling time (DT), and PET positivity. We evaluated the reliability of the 150 pg/mL Ct cutoff set by the American Thyroid Association guidelines for further imaging (including (18)F-DOPA PET/CT). We prospectively recruited 18 patients with recurrent MTC, identified by elevation of Ct or CEA. Each patient underwent a (18)F-FDG PET/CT and a (18)F-DOPA PET/CT. Abnormal uptakes were detected with (18)F-DOPA (n=12) and (18)F-FDG (n=9), (sensitivity of 66.7% vs. 50%; pPET/CT (sensitivity 72.7% vs. 14.3%; p=0.025). Using a CEA cutoff of ≥5 ng/mL, detection rates of (18)F-DOPA and (18)F-FDG PET/CT were 81.1% and 72.7%, respectively. No correlation between Ct-DT or CEA-DT and PET positivity was found. Histological confirmation was obtained in eight patients. (18)F-DOPA PET/CT appears to be superior to (18)F-FDG PET/CT in detecting and locating lesions in patients with recurrent MTC. This technique tends to be especially useful in patients with negative results in other imaging modalities and Ct≥150 pg/mL or CEA≥5 ng/mL.

  16. Stereological analysis of Ca(2+)/calmodulin-dependent protein kinase II alpha -containing dorsal root ganglion neurons in the rat: colocalization with isolectin Griffonia simplicifolia, calcitonin gene-related peptide, or vanilloid receptor 1.

    Science.gov (United States)

    Carlton, Susan M; Hargett, Gregory L

    2002-06-17

    The enzyme Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is widely distributed in the nervous system. A previous report describes immunostaining for CaMKII alpha in dorsal root ganglion (DRG) neurons. In this study, CaMKII alpha is colocalized in the rat with three putative markers of nociceptive DRG neurons, isolectin Griffonia simplicifolia (I-B4), identifying small-diameter, "peptide-poor" neurons; calcitonin gene-related peptide (CGRP), identifying " peptide-rich" neurons; or the vanilloid receptor 1 (VR1), identifying neurons activated by heat, acid, and capsaicin. Lumbar 4 and 5 DRG sections were labeled using immunofluorescence or lectin binding histochemistry, and percentages of single and double-labeled CaMKIIalpha neurons were determined. Stereological estimates of total neuron number in the L4 DRG were 13,815 +/- 2,798 and in the L5 DRG were 14,111 +/- 4,043. Percentages of single-labeled L4 DRG neurons were 41% +/- 2% CaMKII alpha, 38% +/- 3% I-B4, 44% +/- 3% CGRP, and 32% +/- 6% VR1. Percentages of single-labeled L5 DRG neurons were 44% +/- 5% CaMKII alpha, 48% +/- 2% I-B4, 41% +/- 7% CGRP, and 39% +/- 14% VR1. For L4 and L5, respectively, estimates of double-labeled CaMKII alpha neurons showed 34% +/- 2% and 38% +/- 17% labeled for I-B4, 25% +/- 14% and 19% +/- 10% labeled for CGRP, and 37% +/- 7% and 38% +/- 5% labeled for VR1. Conversely, for L4 and L5, respectively, 39% +/- 14% and 38% +/- 7% I-B4 binding neurons, 24% +/- 12% and 23% +/- 10% CGRP neurons, and 42% +/- 7% and 35% +/- 7% VR1 neurons labeled for CaMKIIalpha. The mean diameter of CaMKII alpha - labeled neurons was approximately 27 microm, confirming that this enzyme was preferentially localized in small DRG neurons. The results indicate that subpopulations of DRG neurons containing CaMKII alpha are likely to be involved in the processing of nociceptive information. Thus, this enzyme may play a critical role in the modulation of nociceptor activity and plasticity of primary

  17. Morning or evening administration of nasal calcitonin?

    DEFF Research Database (Denmark)

    Schlemmer, A; Ravn, Pernille; Hassager, C

    1997-01-01

    the second study. After a washing-out period of 2 weeks the participants were given 200 IE of sCT at the reverse time of the day 5 days prior to and during the third study. At all timepoints, urinary CrossLaps/Cr exhibited a significant (p rhythm with its zenith in early morning and nadir...

  18. Aneurysmal bone cyst at C2: imaging evaluation after intralesional injection of calcitonin and methylprednisolone Cisto ósseo aneurismático em C2: avaliação por imagem após injeção intralesional de calcitonina e metilprednisolona

    Directory of Open Access Journals (Sweden)

    Elise T. Tonomura

    2008-01-01

    Full Text Available Objective: To demonstrate imaging findings during the follow-up of patients with aneurysmal bone cyst (ABC of C2 treated with intralesional injection of calcitonin and methylprednisolone. METHOD: Three patients with ABC of C2 were treated percutaneously with intralesional injection of calcitonin and methylprednisolone. All the patients were females, with ages varying from 6 to 13 years. All of them presented with cervical masses, but without neurological symptoms. RESULTS: Imaging follow-up with CT and plain films showed progressive ossification and reduction of the blood-filled cavities with volume reduction of all lesions. No recurrence was noted during the follow-up.  Conclusion: Intralesional injection of calcitonin and methylprednisolone is a safe treatment option for cervical ABC. The CT scan is especially valuable as a guide of injection site and for the follow-up of ossification of the treated ABCs.OBJETIVO: Demonstrar os aspectos de imagem no acompanhamento de pacientes submetidos ao tratamento de cisto ósseo aneurismático com injeção intralesional de calcitonina e metilprednisolona. MÉTODO: Três pacientes com cisto ósseo aneurismático em C2 foram tratados com injeção intralesional percutânea de calcitonina e metilprednisolona. Os três pacientes eram do sexo feminino com idades variando de 6 a 13 anos. Os três pacientes apresentavam massa cervical sem sintomas neurológicos. RESULTADOS: O acompanhamento por imagem com tomografia computadorizada e radiografia simples demonstrou ossificação progressiva e redução das cavidades preenchidas por sangue, com redução do volume das lesões. Não foi percebida recidiva durante o acompanhamento. CONCLUSÃO: A injeção intralesional de calcitonina e metilprednisolona é uma opção de tratamento segura para o cisto ósseo aneurismático cervical. A tomografia computadorizada é especialmente útil para orientar o sítio da punção e para o acompanhamento da ossifica

  19. Effect of combined treatment with calcitonin on bone densitometry of patients with treated hypothyroidism Influência da terapêutica associada com calcitonina sobre a densitometria óssea de pacientes com hipotiroidismo tratado

    Directory of Open Access Journals (Sweden)

    F. J. da C. Stamato

    2000-06-01

    Full Text Available INTRODUCTION: Thyroid hormones (TH may affect bone metabolism and turnover, inducing a loss of bone mass among hyperthyroid and in hypothyroid patients under hormone replacement treatment. Thyroid dysfunction leads to changes in the dynamics of parathyroid hormone (PTH and calcitonin (CT secretion. OBJECTIVE: The objective of the study was to determine the usefulness of CT as adjuvant therapy in the prevention of bone loss during the treatment of hypothyroidism. MATERIAL AND METHODS: We studied 16 female patients with recently diagnosed primary hypothyroidism, divided into two groups: group G1 (n=8 submitted to treatment with thyroxine (L-T4, and Group 2 (n=8 that, in addition to being treated with L-T4, received a nasal CT spray. All patients were submitted to determination of TSH, free T4, bone mineral densitometry (BMD and total bone calcium (TBC at the time of diagnosis, after 6 to 9 months of treatment, and after 12 months of treatment. RESULTS: No statistical significant differences were detected in either group between the total BMD values obtained for the femur and lumbar spine before and after treatment. However, group G1 presented a statistical significant TBC loss after 12 months of treatment compared to initial values. In contrast, no TBC loss was observed in the group treated with LT-4 in combination with CT, a fact that may suggest that CT was responsible for the lower bone reabsorption during treatment of hypothyroidism.INTRODUÇÃO: Os hormônios tiroidianos (HT podem influenciar o metabolismo e o "turnover" ósseo, induzindo perda de massa óssea em hipertiróideos e em hipótiroideos na vigência de reposição hormonal. As disfunções tiroidianas levam a alterações na dinâmica de secreção de paratormônio (PTH e de calcitonina (CT. OBJETIVO: Esclarecer a utilidade da CT como terapêutica coadjuvante na prevenção de perda óssea durante o tratamento do hipotiroidismo. MATERIAL E MÉTODOS: Dezeseis pacientes do sexo

  20. Biochemical markers identify influences on bone and cartilage degradation in osteoarthritis - the effect of sex, Kellgren-Lawrence (KL score, Body Mass Index (BMI, oral salmon calcitonin (sCT treatment and diurnal variation

    Directory of Open Access Journals (Sweden)

    Henriksen K

    2010-06-01

    Full Text Available Abstract Background Osteoarthritis (OA involves changes in both bone and cartilage. These processes might be associated under some circumstances. This study investigated correlations between bone and cartilage degradation in patients with OA as a function of sex, Kellgren-Lawrence (KL score, Body Mass Index (BMI, oral salmon calcitonin (sCT treatment and diurnal variation. Methods This study was a 2-week, double-blind, double-dummy, randomized study including 37 postmenopausal women and 36 men, aged 57-75 years, with painful knee OA, and a KL-score of I - III. Subjects were allocated to one of three treatment arms: 0.6 mg or 0.8 mg oral sCT, or placebo given twice-daily for 14 days. Correlations between gender, KL score, or BMI and the bone resorption marker, serum C-terminal telopeptide of collagen type I (CTX-I, or the cartilage degradation marker, urine C-terminal telopeptide of collagen type II (CTX-II were investigated. Results At baseline, biomarkers indicated women with OA experienced higher bone and cartilage degradation than men. CTX-I levels were significantly higher, and CTX-II levels only marginally higher, in women than in men (p = 0.04 and p = 0.06, respectively. Increasing KL score was not correlated with bone resorption, but was significantly associated with the cartilage degradation CTX-II marker in both men and women (p = 0.007. BMI was significantly and negatively correlated to the bone resorption marker CTX-I, r = -0.40 (p = 0.002, but showed only a borderline positive correlation to CTX-II, r = 0.25 (p = 0.12. Before morning treatments on days 1 and 14, no correlation was seen between CTX-I and CTX-II in either the sCT or placebo group. However, oral sCT and food intake induced a clear correlation between these bone and cartilage degradation markers. Four hours after the first sCT dose on treatment days 1 and 14, a significant correlation (r = 0.71, p p = 0.02, but not on day 14. Conclusion Bone resorption was higher in

  1. Avaliação histométrica da ação local da calcitonina de salmão no processo de reparo ósseo: estudo em ratos Histometrical evaluation of the local effects of salmon calcitonin on the bone healing process: a study in rats

    Directory of Open Access Journals (Sweden)

    Emerson CANAVERO

    2000-06-01

    Full Text Available Neste estudo avaliou-se histometricamente a ação local da calcitonina de salmão em defeitos ósseos provocados cirurgicamente em fêmur de ratos. As avaliações foram feitas aos 7, 14 e 21 dias após o ato cirúrgico. Não se observou diferenças estatísticas aos 7 dias, entretanto no período de 14 dias houve diferenças com maior formação óssea no grupo tratado. No período de 21 dias, em ambos os grupos, não foi possível diferenciar o tecido ósseo neoformado e o adjacente. Os resultados demonstraram, que o efeito da calcitonina foi observado somente no início do processo de reparo dos defeitos ósseos criados cirurgicamente.The purpose of the present study was to histometrically evaluate the effects of salmon calcitonin on the bone healing of surgically created bone defects in rats. The animals were sacrificed 7, 14 and 21 days after the surgical procedure. After the 7- and 21-day periods, differences between the experimental and control groups were not observed (P > 0.01. After the 14-day period, a larger amount of new bone was observed in the experimental group (P < 0.01. Thus, within the limits of the present study, it can be concluded that although salmon calcitonin positively participated in the initial phase of bone healing, it did not result in a larger amount of new bone at the end of the experimental period.

  2. Pro-calcitonin and inflammation in chronic hemodialysis

    Directory of Open Access Journals (Sweden)

    Hernán Trimarchi

    2013-10-01

    Full Text Available Procalcitonin (PCT has emerged as a marker of infection, a frequent complication in hemodialysis (HD. We analyzed PCT levels in chronic non-acutely infected HD subjects, assessed its correlation with inflammatory and nutritional markers and propose a PCT reference value for non-infected HD patients.In an observational cross-sectional study, 48 chronic HD patients and 36 controls were analyzed. Variables: age, gender, time on HD; diabetes; vascular access, PCT, C-reactive protein (CRP, albumin, malnutrition inflammatory score (MIS, hematocrit, leukocyte count, and body mass index (BMI. Subsequently, control (G1, n = 36, 43% vs. non-infected patients (G2, n = 48, 57% groups were compared. In control subjects (G1, age: 54.3 ± 13.7 years, range (r: 30-81; males: 19 (53%; median PCT 0.034 ng/ml (r: 0.02-0.08; median CRP 0.80 mg/dl (r: 0.36-3.9; p95 PCT level: 0.063 ng/ml. In G2, age: 60.2 ± 15.2 years; males 32 (67%, time on HD: 27.0 ± 24.4; diabetics: 19 (32%; median PCT: 0.26 ng/ml (r: 0.09-0.82; CRP: 1.1 mg/dl (r: 0.5-6.2; p95 PCT level: 0.8 ng/ml. In control subjects, PCT and CRP were significantly lower than in G2: PCT: 0.034 vs. 0.26 ng/ml, p = 0.0001; CRP: 0.8 vs. 1.1 mg/dl, p = 0.0004. PCT-CRP correlation in G2: ρ = 0.287, p = 0.048. PCT and CRP concentrations are elevated in chronic non-acutely infected HD subjects, independently of infection, diabetes and vascular access. A p95 PCT level of 0.8 ng/ml may be considered as the upper normal reference value in non-acutely infected HD subjects. The PCT cut-off level in HD is yet to be determined in HD.

  3. Mapping the calcitonin receptor in human brain stem

    DEFF Research Database (Denmark)

    Bower, Rebekah L; Eftekhari, Sajedeh; Waldvogel, Henry J

    2016-01-01

    understanding of these hormone systems by mapping CTR expression in the human brain stem, specifically the medulla oblongata. Widespread CTR-like immunoreactivity was observed throughout the medulla. Dense CTR staining was noted in several discrete nuclei, including the nucleus of the solitary tract...... receptors (AMY) are a heterodimer formed by the coexpression of CTR with receptor activity-modifying proteins (RAMPs). CTR with RAMP1 responds potently to both amylin and CGRP. The brain stem is a major site of action for circulating amylin and is a rich site of CGRP binding. This study aimed to enhance our...

  4. Calcitonin-negative primary neuroendocrine tumor of the thyroid ...

    African Journals Online (AJOL)

    nonmedullary" in humans is a rare tumor that arises primarily in the thyroid gland and may be mistaken for medullary thyroid carcinoma; it is characterized by the immunohistochemical (IHC) expression of neuroendocrine markers and the absence of ...

  5. Calcitonin Gene-Related Peptide Regulates Type IV Hypersensitivity through Dendritic Cell Functions: e86367

    National Research Council Canada - National Science Library

    Norihisa Mikami; Kaori Sueda; Yusuke Ogitani; Ippei Otani; Miku Takatsuji; Yasuko Wada; Keiko Watanabe; Rintaro Yoshikawa; Satoshi Nishioka; Nagisa Hashimoto; Yayoi Miyagi; So-ichiro Fukada; Hiroshi Yamamoto; Kazutake Tsujikawa

    2014-01-01

    .... In this study, we show that CGRP suppressed Th1 cell differentiation via inhibition of IL-12 production in DCs using an in vitro co-culture system and an in vivo ovalbumin-induced delayed-type hypersensitivity (DTH) model...

  6. Acute effects of nasal salmon calcitonin on calcium and bone metabolism

    DEFF Research Database (Denmark)

    Thamsborg, G; Skousgaard, S G; Daugaard, H

    1993-01-01

    and urine samples were collected for 26 hours. There was a significant decrease in serum ionized calcium with a nadir 4 hours after administration of nasal SCT accompanied by a significant increase in serum parathyroid hormone (P = 0.01) and serum calcitriol (P = 0.04). Nasal SCT did not reduce urinary...

  7. Calcitonin gene-related peptide does not cause the familial hemiplegic migraine phenotype

    DEFF Research Database (Denmark)

    Hansen, J.M.; Thomsen, L.L.; Olesen, J.

    2008-01-01

    with aura associated with several gene mutations. FHM shares many phenotypical similarities with common types of migraine, indicating common neurobiological pathways. We tested the hypothesis that the FHM genotype confers a CGRP hypersensitive phenotype. Methods: We included 9 FHM patients with known...

  8. Use of Calcitonin in Recalcitrant Phantom Limb Pain Complicated by Heterotopic Ossification

    Directory of Open Access Journals (Sweden)

    Ricardo Viana

    2015-01-01

    Full Text Available A common complication following amputation is phantom sensation, which may include experiencing pain in the phantom limb. This study details the management of phantom limb pain in a 72-year-old man, in whom comorbid heterotopic ossification was present. In addition, the authors provide a review of the literature regarding phantom limb pain management, and summarize the current understanding of heterotopic ossification and its possible link to peripheral nerve injury.

  9. Medullary thyroid carcinoma and duodenal calcitonin-secreting neuroendocrine tumour: more than coincidence?

    OpenAIRE

    Huguet, I; Lamas, C; Vera, R; Lomas, A; Quilez, R P; Grossman, A.; Botella, F.

    2013-01-01

    Summary Neuroendocrine tumours (NETs) are a heterogeneous group of neoplasms whose management can be problematic. In many cases, multiple tumours may occur in the same patient or his or her family, and some of these have now been defined genetically, although in other cases the underlying gene or genes involved remain unclear. We describe a patient, a 63-year-old female, who was diagnosed with a medullary thyroid carcinoma (MTC), which was confirmed pathologically after thyroidectomy, but who...

  10. Kidney Involvement in Systemic Calcitonin Amyloidosis Associated With Medullary Thyroid Carcinoma

    NARCIS (Netherlands)

    Koopman, Timco; Niedlich-den Herder, Cindy; Stegeman, Coen A.; Links, Thera P.; Bijzet, Johan; Hazenberg, Bouke P. C.; Diepstra, Arjan

    A 52-year-old woman with widely disseminated medullary thyroid carcinoma developed nephrotic syndrome and slowly decreasing kidney function. A kidney biopsy was performed to differentiate between malignancy-associated membranous glomerulopathy and tyrosine kinase inhibitor-induced focal segmental

  11. Dual Amylin and Calcitonin Receptor Agonists: A Novel Treatment for Obesity and Related Co-Morbidities

    DEFF Research Database (Denmark)

    Gydesen, Sofie

    accumulation was eliminated by KBP treatment, and interestingly, KBPs alleviated hyperinsulinemia and improved glucose tolerance even with significantly lower insulin levels. KBP treatment increased the glucose infusion rate during a hyperinsulinemic euglycemic clamp indicating enhanced insulin action....... Importantly, KBPs also improved glucose homeostasis and enhanced insulin action in Zucker Diabetic Fatty rats. To investigate beneficial effects beyond weight loss, a weight-matched group was implemented. Of interest, weight matching led to improved glucose homeostasis through lowered plasma insulin; however...... the combination resulted in a 12% body weight reduction. Moreover, the combination improved glucose tolerance. In a rat model resembling the phenotype of human NASH, KBP treatment led to a reduction of the high fat, high cholesterol and cholate diet induced increase in liver weight and circulating aspartate...

  12. Treatment of central giant cell granuloma of the jaw with calcitonin

    NARCIS (Netherlands)

    de Lange, J.; Rosenberg, A. J.; van den Akker, H. P.; Koole, R.; Wirds, J. J.; van den Berg, H.

    1999-01-01

    Giant cell granuloma of the jaw is a benign lesion that may cause local destruction of bone and displacement of teeth. The common therapy is curettage or resection, which may be associated with loss of teeth and, in younger patients, loss of dental germs. An alternative treatment has recently been

  13. CALCITONIN-LIKE IMMUNOREACTIVITY IN SERUM AND TISSUES OF THE BONNETHEAD SHARK, SPHYRNA TIBURO. (R826128)

    Science.gov (United States)

    The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

  14. [Readaptation processes in the calcitonin-producing system of the rat's thyroid following 30-day suspension].

    Science.gov (United States)

    Loginov, V I

    2007-01-01

    Immunocytochemical and cytomorphological studies of ca/citonin-producing cells (C-cells) in the thyroid of rats were conducted on days 0, 2, 8, 14, 30 and 60 of readaptation from 30-d tail-suspension. It was shown that suspension reduced the C-cell pool by 35% and size of C-cell nuclei and cytoplasm by 15% and 12%, respectively. On the contrary, the amount of inactive cells within the total pool increased by 33% at the expense of actively secreting cells (17% loss) and secret depot cells (13% loss). The data suggest a dramatic inhibition of the C-cell functional activity due to insufficient loading of the musculoskeletal system. In 48 hrs. after suspension, biosynthesis in the C-cell population was obviously stimulated as indicated by the increase of nuclei size by 11%. The total C-cell population as well as the proportion of C-cell functional varieties regained normal values by day 8 of readaptation; however, nuclear size remained abnormal which could be consequence of elevated biosynthetic activity in that period. Investigations of morphometric indices of the C-cell functional activity fulfilled on days 14 and 30 of readaptation failed to detect any differences between the suspended rats and their controls. Investigations performed on days 30 and 60 of readaptation showed increases in C-cell population resulting from daily and total body mass gain.

  15. GLP-1 and Calcitonin Concentration in Humans: Lack of Evidence of Calcitonin Release from Sequential Screening in over 5000 Subjects with Type 2 Diabetes or Nondiabetic Obese Subjects Treated with the Human GLP-1 Analog, Liraglutide

    DEFF Research Database (Denmark)

    Hegedüs, Laszlo; Moses, Alan C; Zdravkovic, Milan

    2011-01-01

    . There are no longitudinal studies measuring CT in humans without medullary thyroid carcinoma or a family history of medullary thyroid carcinoma and no published studies on the effect of GLP-1 receptor agonists on human serum CT concentrations. Aim: The aim of the study was to determine serum CT response over time....... Results: Basal mean CT concentrations were at the low end of normal range in all treatment groups and remained low throughout the trials. At 2 yr, estimated geometric mean values were no greater than 1.0 ng/liter, well below upper normal ranges for males and females. Proportions of subjects whose CT...... levels increased above a clinically relevant cutoff of 20 ng/liter were very low in all groups. There was no consistent dose or time-dependent relationship and no consistent difference between treatment groups. Conclusions: These data do not support an effect of GLP-1 receptor activation on serum CT...

  16. Isolation and molecular characterization of porcine calcitonin gene-related peptide (CGRP) and its endocrine effects in the porcine pancreas

    DEFF Research Database (Denmark)

    Rasmussen, T N; Bersani, M; Schmidt, P

    1998-01-01

    was found in the two tissues. The adrenal peptide was sequenced and found to differ from human alpha-CGRP at six positions and from human beta-CGRP at three positions. By immunohistochemistry, CGRP was found in nerve fibers in the pancreatic ganglia. A synthetic replica of the porcine peptide was infused...... significantly by 10(-8) M CGRP. In immunoneutralization studies (n = 6) using a high-affinity somatostatin antibody, the inhibitory effect of CGRP at 10(-8) M was reversed to a significant stimulation of insulin and glucagon secretion. Insulin secretion in response to square-wave increases in glucose...

  17. Localisation and neural control of the release of calcitonin gene-related peptide (CGRP) from the isolated perfused porcine ileum

    DEFF Research Database (Denmark)

    Rasmussen, T N; Schmidt, P; Poulsen, S S

    2001-01-01

    By immunohistochemistry, CGRP-like immunoreactive (CGRP-LI) nerve fibres were found in the lamina propria along small vessels and in the lamina muscularis mucosae in the porcine ileum. Immunoreactive nerve cell bodies were found in the submucous and myenteric plexus. Upon HPLC-analysis of ileal...

  18. Calcitonin gene-related peptide modulates heat nociception in the human brain - An fMRI study in healthy volunteers

    DEFF Research Database (Denmark)

    Asghar, Mohammad Sohail; Becerra, Lino; Larsson, Henrik B.W.

    2016-01-01

    blood-oxygenation-level-dependent (BOLD) signals in the brain by functional MRI after infusion of CGRP in a double-blind placebo-controlled crossover study of 27 healthy volunteers. BOLD-signals were recorded in response to noxious heat stimuli in the V1-area of the trigeminal nerve. In addition, we...... measured BOLD-signals after injection of sumatriptan (5-HT1B/1D antagonist). Results: Brain activation to noxious heat stimuli following CGRP infusion compared to baseline resulted in increased BOLD-signal in insula and brainstem, and decreased BOLD-signal in the caudate nuclei, thalamus and cingulate...

  19. Limited regression of central giant cell granuloma by interferon alpha after failed calcitonin therapy: a report of 2 cases

    NARCIS (Netherlands)

    de Lange, J.; van den Akker, H.P.; van den Berg, H.; Richel, D.J.; Gortzak, R.A.T.

    2006-01-01

    Central giant cell granuloma (CGCG) is a benign lesion of the jaws with a sometimes locally aggressive behaviour. The most common therapy is surgical curettage which has a high recurrence rate, especially in lesions with aggressive signs and symptoms (i.e. pain, paresthesia, root-resorption and

  20. The analgesic agent tapentadol inhibits calcitonin gene-related peptide release from isolated rat brainstem via a serotonergic mechanism.

    Science.gov (United States)

    Greco, Maria Cristina; Navarra, Pierluigi; Tringali, Giuseppe

    2016-01-15

    In this study we tested the hypothesis that tapentadol inhibits GGRP release from the rat brainstem through a mechanism mediated by the inhibition of NA reuptake; as a second alternative hypothesis, we investigated whether tapentadol inhibits GGRP release via the inhibition of 5-HT reuptake. Rat brainstems were explanted and incubated in short-term experiments. CGRP released in the incubation medium was taken as a marker of CGRP release from the central terminals of trigeminal neurons within the brainstem. CGRP levels were measured by radioimmunoassay under basal conditions or in the presence of tapentadol; NA, 5-HT, clonidine, yohimbine and ondansetron were used as pharmacological tools to investigate the action mechanism of tapentadol. The α2-antagonist yohimbine failed to counteract the effects of tapentadol. Moreover, neither NA nor the α2-agonist clonidine per se inhibited K(+)-stimulated CGRP release, thereby indicating that the effects of tapentadol are nor mediated through the block of NA reuptake. Further experiments showed that 5-HT and tramadol, which inhibits both NA and 5-HT reuptake, significantly reduced K(+)-stimulated CGRP release. Moreover, the 5-HT3 antagonist ondansetron was able to counteract the effects of tapentadol in this system. This study provided pharmacological evidence that tapentadol inhibits stimulated CGRP release from the rat brainstem in vitro through a mechanism involving an increase in 5-HT levels in the system and the subsequent activation of 5-HT3 receptors. Copyright © 2015 Elsevier Inc. All rights reserved.

  1. Transcerebral exchange kinetics of nitrite and calcitonin gene-related peptide in acute mountain sickness: evidence against trigeminovascular activation?

    DEFF Research Database (Denmark)

    Bailey, Damian M; Taudorf, Sarah; Berg, Ronan M G

    2009-01-01

    BACKGROUND AND PURPOSE: High-altitude headache is the primary symptom associated with acute mountain sickness, which may be caused by nitric oxide-mediated activation of the trigeminovascular system. Therefore, the present study examined the effects of inspiratory hypoxia on the transcerebral...... from the radial artery and jugular venous bulb. Plasma CGRP and NO(2)(*) were analyzed via radioimmunoassay and ozone-based chemiluminescence. Net cerebral exchange was calculated by the Fick principle and acute mountain sickness/headache scores assessed via clinically validated questionnaires. RESULTS......: Hypoxia increased cerebral blood flow with a corresponding increase in acute mountain sickness and headache scores (P

  2. Calcium, Magnesium, and Phosphorus Metabolism, and Parathyroid- Calcitonin Function during Prolonged Exposure to Elevated CO2 Concentrations on Submarines

    Science.gov (United States)

    1975-12-01

    de sous-marins. Undersea Biomed. Res. Sub. Suppl.: S57-S70.—On a etudie le metabolisme du calcium et du phosphore et I’equilibre acido -basique chez...du calcium soit regie par la consomma- tion et l’elimination osseuses de COj. L’equtlibre acido -basique serait regie par les phases de tamponnage

  3. A novel oral dual amylin and calcitonin receptor agonist (KBP-042) exerts antiobesity and antidiabetic effects in rats

    DEFF Research Database (Denmark)

    Andreassen, Kim V; Feigh, Michael; Hjuler, Sara T

    2014-01-01

    a superior and pronounced reduction in food intake in conjunction with a sustained pair-fed corrected weight loss in DIO rats. Concomitantly, KBP-042 improved glucose homeostasis and reduced hyperinsulinemia and hyperleptinemia in conjunction with enhanced insulin sensitivity. In ZDF rats, KBP-042 induced...

  4. [Effect of secretory human calcitonin gene-related peptide recombinant AAV on penile erection in streptozotocin-induced diabetic rat].

    Science.gov (United States)

    Xing, Jun-ping; Cui, Xian-feng; Sun, Jian-hua; Qiu, Shu-dong

    2005-10-01

    To determine whether recombinant adeno-associated virus-mediated overexpression of hCGRP in the corpus cavernosum can affect the continuous production of hCGRP in the penile tissue and enhance erectile responses in STZ-induced diabetic rats. Diabetes mellitus was induced by a single intraperitoneal injection of 60 mg/kg streptozotocin in male SD rats. VssHGCMV-hCGRP, VssCMV-GFP and rAAV solution were injected into the corporal cavernosum of STZ-induced diabetic rats, respectively. The corporal tissue was obtained from groups of 8 rats on day 5 post-injection, and the expressions of CGRP and GFP in cavernosal tissue were detected using immunohistochemistry and laser scanning confocal microscopy, respectively. Cavemosal tissue cAMP and cGMP levels were measured using radioimmunoassay. On day 5 post-injection, intracavernous pressure induced by electrostimulation of penile dorsal nerves was measured and recorded with a biological signal processing system in each group rat. rAAV transduction efficiency of GFP reporter gene was measured by laser scanning confocal microscopy and was observed in the penile tissue, especially in the corporal cavernosum and the vessel 5 days after transfection with VssCMV-GFP. Immunohistochemistry showed that the CGRP increased in the corporal cavernosum. In addition, both cAMP and cGMP levels in the corpora cavernosa transfected with VssHGCMV-hCGRP were significantly increased, compared with controls [(48.4 +/- 6.5) nmol/L and (21.2 +/- 13.6) nmol/L vs (16.7 +/- 2.5) nmol/L and (0.42 +/- 0.12) nmol/L, respectively]. More importantly, 5 days after administration of VssHGCMV-hCGRP,a significant increase was observed in the erectile response to penile dorsal nerve stimulation in the diabetic rat [(60.5 +/- 4.5) mm Hg vs (22. 3 +/- 1.3) mm Hg]. This results demonstrate that rAAV-mediated transfer of the CGRP gene can increase production of endogenous CGRP, cAMP and cGMP in corpora cavernosa of STZ-induced diabetic rats. Moreover, overexpression of CGRP enhances ICP and the erectile response to penile dorsal nerve stimulation in the diabetic rat.

  5. Unaltered mRNA expression of calcitonin-like receptor and receptor activity modifying proteins in human arteries in stroke and myocardial infarction

    DEFF Research Database (Denmark)

    Eskesen, Karen; János, Tajti; Tibor, Hortobágyi

    2007-01-01

    (CA), pulmonary (PA) and middle cerebral arteries (MCA), and 2. to examine the level of mRNA expression in cerebra- and cardiovascular diseases. The method was validated with respect to the use of postmortem tissue and we compared beta-actin and GAPDH as housekeeping genes. There was no time......-dependent change in total RNA and level of mRNA for p-actin or GAPDH could be detected in vessels removed from 1 and 5 days post mortem. The expression of beta-actin appears lower in coronary artery than in pulmonary artery and middle cerebral artery with no significant difference for GAPDH; both worked well...

  6. Long-lasting physiological antagonism of calcitonin gene-related peptide towards endothelin-1 in rat mesenteric arteries and human coronary arteries

    DEFF Research Database (Denmark)

    Labruijere, Sieneke; Compeer, Matthijs G; van den Bogaerdt, Antoon J

    2013-01-01

    Endothelin-1 causes long-lasting contraction via endothelin type A receptor (ETAR) in isolated rat mesenteric arteries (RMA) that cannot be readily terminated by removing the agonist, or by adding the ETAR antagonist BQ123 or the NO donor sodium nitroprusside. It could be terminated by adding......-lasting non-selective arterial smooth muscle relaxation that may add to the neuropeptide being a physiological antagonist of arterial effects of ET-1. Long-lasting, washout-resistant ET-1/ETAR interaction does not occur in HCMAs....

  7. 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

    2001-01-01

    We studied the effect of porcine CGRP (pCGRP) in concentrations from 10(-10) to 10(-8) mol L(-1) on the motility and on the release of substance P, neurokinin A, somatostatin and gastrin in the antrum using the isolated perfused porcine antrum as experimental model. In addition, we studied...... 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....... in addition, pCGRP increases the release of somatostatin but has no effect on gastrin release in the isolated perfused porcine antrum....

  8. Effects of glyceryl trinitrate and calcitonin-gene-related peptide on BOLD signal and arterial diameter –methodological studies by fMRI and MRA

    DEFF Research Database (Denmark)

    Asghar, Mohammed Sohail; Ashina, Messoud

    2013-01-01

    Over the last decades MRI has proved to be very useful in the field of drug development and discovery. Pharmacological MRI (phMRI) explores the interaction between brain physiology, neuronal activity and drugs[1]. The BOLD-signal is an indirect method to investigate brain activity by way of measu......Over the last decades MRI has proved to be very useful in the field of drug development and discovery. Pharmacological MRI (phMRI) explores the interaction between brain physiology, neuronal activity and drugs[1]. The BOLD-signal is an indirect method to investigate brain activity by way...... of measuring task-related hemodynamic changes. Pharmacological substances that induce hemodynamic changes can therefore potentially alter the BOLD-signal that in turn falsely can be interpreted as changes in neuronal activity. It is therefore important to characterize possible effects of a pharmacological...

  9. High arterial compliance in cirrhosis is related to low adrenaline and elevated circulating calcitonin gene related peptide but not to activated vasoconstrictor systems

    DEFF Research Database (Denmark)

    Henriksen, Jens Henrik Sahl; Møller, S; Schifter, S

    2001-01-01

    to COMP(art) disappeared. The relation of COMP(art) to CGRP and circulatory variables remained unchanged. CONCLUSION: Elevated arterial compliance in cirrhosis is related to low adrenaline, high CGRP, and systemic hyperdynamics but not to indicators of the activated vasoconstrictor systems (noradrenaline......BACKGROUND AND AIMS: Static and dynamic functions of the wall of large arteries are largely unknown in cirrhosis in vivo. The present study was undertaken to determine arterial compliance (COMP(art)) in relation to vasodilator and vasoconstrictor systems in patients with cirrhosis. In addition......, vasoactivity was manipulated by inhalation of oxygen. STUDY POPULATION AND METHODS: In 20 patients with alcoholic cirrhosis and 12 controls we determined COMP(art) (stroke volume relative to pulse pressure), cardiac output, plasma volume, systemic vascular resistance, central circulation time, plasma...

  10. Safety and efficacy of ALD403, an antibody to calcitonin gene-related peptide, for the prevention of frequent episodic migraine

    DEFF Research Database (Denmark)

    Dodick, David W; Goadsby, Peter J; Silberstein, Stephen D

    2014-01-01

    group compared with -4·6 (3·6) for the placebo group (difference -1·0, 95% CI -2·0 to 0·1; one-sided p=0·0306). INTERPRETATION: No safety concerns were noted with an intravenous dose of ALD403 1000 mg. This study also provides preliminary evidence for the efficacy of ALD403 in the preventive treatment......-controlled, exploratory, proof-of-concept phase 2 trial, patients aged 18-55 years with five to 14 migraine days per 28-day period were randomly assigned (1:1) via an interactive web response system to receive an intravenous dose of ALD403 1000 mg or placebo. Site investigators, patients, and the sponsor were masked...

  11. A Novel α-Calcitonin Gene-Related Peptide Analogue Protects Against End-Organ Damage in Experimental Hypertension, Cardiac Hypertrophy and Heart Failure

    DEFF Research Database (Denmark)

    Aubdool, Aisah A; Thakore, Pratish; Argunhan, Fulye

    2017-01-01

    was investigated over 14 days. Blood pressure was measured by radio-telemetry. The ability of the αAnalogue to modulate heart failure was studied in an abdominal aortic constriction (AAC) model of murine cardiac hypertrophy and heart failure over 5 weeks. Extensive ex vivo analysis was performed via RNA analysis...... by reduced hypertrophy and biomarkers of fibrosis, remodelling, inflammation and oxidative stress. In a separate study, the αAnalogue reversed AngII-induced hypertension and associated vascular and cardiac damage. The αAnalogue was effective over 5 weeks in a murine model of cardiac hypertrophy and heart......, Western blot and histology. Results -The AngII-induced hypertension was attenuated by co-treatment with the αAnalogue (50nmol/kg/day, s.c., at a dose selected for lack of long term hypotensive effects at baseline). The αAnalogue protected against vascular, renal and cardiac dysfunction, characterised...

  12. A novel Dual Amylin and Calcitonin Receptor Agonist (DACRA), KBP-089, induces weight loss through a reduction in fat, but not lean mass, while improving food preference

    DEFF Research Database (Denmark)

    Gydesen, Sofie; Hjuler, Sara Toftegaard; Freving, Zenia

    2017-01-01

    . In the food preference test, normal diet rats obtained 74% of their calories from chocolate. KBP-089 administration reduced total caloric intake, and induced a relative increase in chow consumption while drastically lowering the chocolate compared to vehicle. Conclusion The novel DACRA, KBP-089 induces...

  13. An Ongoing Role of α-Calcitonin Gene–Related Peptide as Part of a Protective Network Against Hypertension, Vascular Hypertrophy, and Oxidative Stress

    DEFF Research Database (Denmark)

    Smillie, Sarah-Jane; King, Ross; Kodji, Xenia

    2014-01-01

    at the vascular level. Wild-type and αCGRP knockout mice that have similar baseline blood pressure were investigated in the angiotensin II hypertension model for 14 and 28 days. αCGRP knockout mice exhibited enhanced hypertension and aortic hypertrophy. αCGRP gene expression was increased in dorsal root ganglia...... and at the conduit and resistance vessel level of wild-type mice at both time points. βCGRP gene expression was also observed and shown to be linked to plasma levels of CGRP. Mesenteric artery contractile and relaxant responses in vitro and endothelial NO synthase expression were similar in all groups. The aorta...

  14. A novel Dual Amylin and Calcitonin Receptor Agonist (DACRA), KBP-089, induces weight loss through a reduction in fat, but not lean mass, while improving food preference

    DEFF Research Database (Denmark)

    Gydesen, Sofie; Hjuler, Sara Toftegaard; Freving, Zenia

    2017-01-01

    Background and Purpose Obesity and associated co-morbidities, such as type 2 diabetes and non-alcoholic fatty liver disease, are major health challenges – hence, development of weight loss therapies with the ability to reduce the co-morbidities is key. Experimental Approach The effect of the dual...... rats were treated with KBP-089 s.c., at 0.625, 1.25, 2.5 µg∙kg-1 and vehicle resulting in a dose-dependent and sustained ~17% weight loss by the 2.5 µg∙kg-1 (p ... a sustained weight loss, leading to improved metabolic parameters including food preference, and these are beyond those observed simply by diet-induced weight loss....

  15. The Bacterial Gene IfpA Influences the Potent Induction of Calcitonin Receptor and Osteoclast-Related Genes in Burkholderia Pseudomallei-Induced TRAP-Positive Multinucleated Giant Cells

    Science.gov (United States)

    2006-06-13

    Nair et al., 1996). Multinucle- ation and TRAP production by spleen cells has been reported following treatment with Porphyromonas gingiva- lis, a...Wilson, M., Meghji, S., Barber, P., and Henderson, B. (1993) Biological activities of surface-associated material from Porphyromonas gingivalis. FEMS

  16. Distribution of CGRP and CGRP receptor components in the rat brain

    DEFF Research Database (Denmark)

    Warfvinge, Karin; Edvinsson, Lars

    2017-01-01

    Background Calcitonin gene-related peptide and its receptor, consisting of receptor activity-modifying protein 1 and calcitonin receptor-like receptor, are of considerable interest because of the role they play in migraine and recently developed migraine therapies. Methods To better understand th...... a possible role in migraine. However, currently, the presence of calcitonin gene-related peptide and the nature of its receptors throughout the brain is an enigma yet to be solved....

  17. (CGRP) on gastric mucosal barrier in stress induced rats

    African Journals Online (AJOL)

    STORAGESEVER

    2009-04-20

    Apr 20, 2009 ... The aim of this investigation was to examine and compare the effects of calcitonin gene related peptide. (CGRP) and salmon calcitonin (sCT) on gastric lesions and mucosal barrier components such as mucus and phospholipids in rats exposed to cold + restraint stress (CRS). Twenty-eight Wistar albino.

  18. Effects of ionotropic glutamate receptor antagonists on rat dural artery diameter in an intravital microscopy model

    DEFF Research Database (Denmark)

    Chan, K Y; Gupta, S; de Vries, R

    2010-01-01

    During migraine, trigeminal nerves may release calcitonin gene-related peptide (CGRP), inducing cranial vasodilatation and central nociception; hence, trigeminal inhibition or blockade of craniovascular CGRP receptors may prevent this vasodilatation and abort migraine headache. Several preclinical...

  19. Insulin-like growth factors I and II in healthy women with and without established osteoporosis

    DEFF Research Database (Denmark)

    Ravn, Pernille; Spencer, E M; Christiansen, C

    1995-01-01

    -controlled treatment with continuous estrogen/progestogen, anabolic steroids, salmon calcitonin or placebo and the IGFs were measured every 6 months. Women less than 35 years of age had 29% higher levels of IGF-I (p

  20. GPCR Interaction: 208 [GRIPDB[Archive

    Lifescience Database Archive (English)

    Full Text Available growth hormone releasing hormone (GHRH), and interfaces of SecR C Secretin ... SecR C Growth hormone releasing...releasing hormone ... GHRH Experiment SecR does not interact with CTR (calcitonin receptor). 18401761 BRET,

  1. The disease modifying osteoarthritis drug (DMOAD): Is it in the horizon?

    DEFF Research Database (Denmark)

    Qvist, Per; Bay-Jensen, Anne-Christine; Christiansen, Claus

    2008-01-01

    trials, including compounds inhibiting matrix-metalloproteinases (MMPs), bisphosphonates, cytokine blockers, calcitonin, inhibitors of inducible nitric oxide synthase (iNOS), doxycycline, glucosamine, and diacereine. We discuss the challenges associated with the drug development process in general...

  2. Multiple endocrine neoplasia similar to human subtype 2A in a dog ...

    African Journals Online (AJOL)

    Primary hyperparathyroidism was diagnosed by biochemical testing. Histopathology report was consistent with diagnosis of bilateral pheochromocytoma and parathyroid adenoma. Immunohistochemical staining was positive for calcitonin and synaptophysin, and negative for thyroglobulin, which confirmed medullary thyroid ...

  3. Long-term tolerability of telcagepant for acute treatment of migraine in a randomized trial

    DEFF Research Database (Denmark)

    Connor, Kathryn M; Aurora, Sheena K; Loeys, Tom

    2011-01-01

    To evaluate the long-term tolerability of telcagepant for acute treatment of intermittent migraine attacks. Background.- Telcagepant is a calcitonin gene-related peptide (CGRP) receptor antagonist being investigated for the acute treatment of migraine....

  4. Clinical relevance of18F-FDG PET and18F-DOPA PET in recurrent medullary thyroid carcinoma

    NARCIS (Netherlands)

    H.H.G. Verbeek (Hans H.); J.T. Plukker (John); K.P. Koopmans (Klaas Pieter); J. de Groot (Jan); R.M.W. Hofstra (Robert); A.C. Muller Kobold (Anneke); A.N.A. van der Horst-Schrivers (Anouk); A.H. Brouwers (A.); T.P. Links (Thera)

    2012-01-01

    textabstractThe transition from stable to progressive disease is unpredictable in patients with biochemical evidence of medullary thyroid carcinoma (MTC). Calcitonin and carcinoembryonic antigen (CEA) doubling times are currently the most reliable markers for progression, but for accurate

  5. Clinical Relevance of F-18-FDG PET and F-18-DOPA PET in Recurrent Medullary Thyroid Carcinoma

    NARCIS (Netherlands)

    Verbeek, Hans H. G.; Plukker, John T. M.; Koopmans, Klaas Pieter; de Groot, Jan Willem B.; Hofstra, Robert M. W.; Kobold, Anneke C. Muller; van der Horst-Schrivers, Anouk N. A.; Brouwers, Adrienne H.; Links, Thera P.

    2012-01-01

    The transition from stable to progressive disease is unpredictable in patients with biochemical evidence of medullary thyroid carcinoma (MTC). Calcitonin and carcinoembryonic antigen (CEA) doubling times are currently the most reliable markers for progression, but for accurate determination, serial

  6. Evidence for CGRP re‐uptake in rat dura mater encephali

    National Research Council Canada - National Science Library

    Gupta, Saurabh; Amrutkar, Dipak Vasantrao; Mataji, Aydin; Salmasi, Hassan; Hay‐Schmidt, Anders; Sheykhzade, Majid; Messlinger, Karl; Olesen, Jes; Jansen‐Olesen, Inger

    2010-01-01

    BACKGROUND AND PURPOSE Calcitonin gene‐related peptide (CGRP) is widely distributed in the trigeminovascular system and released from sensory fibres of the cranial dura mater upon noxious stimulation...

  7. Long-term tolerability of telcagepant for acute treatment of migraine in a randomized trial

    DEFF Research Database (Denmark)

    Connor, Kathryn M; Aurora, Sheena K; Loeys, Tom

    2011-01-01

    To evaluate the long-term tolerability of telcagepant for acute treatment of intermittent migraine attacks. Background.- Telcagepant is a calcitonin gene-related peptide (CGRP) receptor antagonist being investigated for the acute treatment of migraine.......To evaluate the long-term tolerability of telcagepant for acute treatment of intermittent migraine attacks. Background.- Telcagepant is a calcitonin gene-related peptide (CGRP) receptor antagonist being investigated for the acute treatment of migraine....

  8. Staining of rat thyroid parafollicular (C-) cells with the Sevier-Munger silver technique.

    Science.gov (United States)

    Wilander, E; Juntti-Berggren, L; Lundqvist, M; Grimelius, L

    1980-09-01

    The argyrophil silver stain of Grimelius and of Sevier-Munger was studied in rat thyroid parafollicular (C-) cells after formation and Bouin fixation. The strongest and most easily reproducible staining reaction was obtained in tissue fixed with Bouin's fluid and stained by the Sevier-Munger technique. The identify of the argyrophil cell as the calcitonin-containing C-cells was established by re-staining the same sections with calcitonin antibodies according to the method of Sternberger.

  9. Le cancer medullaire de la thyroide ou, comment des marqueurs tumoraux et les outils de la genetique autorisent le deploiement de mesures preventives.

    OpenAIRE

    Meurisse, Nicolas; Defechereux, Thierry; Hamoir, Etienne; Maweja, Sylvie; Meurisse, Michel; Beckers, Albert

    2003-01-01

    Medullary thyroid cancer (MTC) arises from parafollicular C cells secreting calcitonin. MTC occurs both as sporadic tumors and as part of specific inherited autosomal dominant syndromes in which point mutations within a discrete set of RET codons were described. Total thyroidectomy and aggressive neck dissection represents the only chance for cure in the affected patients. Therefore, all patients with thyroid nodular disease should undergo measurement of calcitonin plasma levels to allow prec...

  10. [Experimental study on Yougui recipe in preventing osteolysis surrounding artificial prosthesis].

    Science.gov (United States)

    Cai, Yun-Huo; Zhao, Peng; Mao, Qiang; Bao, Hang-Xing; Wang, Jin-Fa; Hu, Miao-Feng; Xiao, Lu-Wei; Tong, Pei-Jian

    2012-12-01

    To explore effects of Yougui recipe (see text) and salmon calcitonin acetate in preventing osteolysis surrounding artificial prosthesis. Thirty-two SD male rats with weighted (250 +/- 20) g, aged 8 weeks, were randomly divided into four groups: blank group, model group, salmon calcitonin acetate group and Yougui recipe (see text) group, and 8 rats in each group. Blank group did not undergo any process, other 24 rats underwent anesthesia by chloral hydrate, their knee joints were exposed through medial patellar side,drilling from fermoral condyle nest to marrow cavity,high density of polythlene particles were injected into hole, titanium nail were put into, bone wax closed the window, then suturing step by step. After the molding, saline were used to gavaged in blank group and model group, Yougui recipe (see text) for Yougui recipe (see text) group, salmon calcitonin maximus injection for calcitonin group. After 10 weeks' mediation, rats were executed, and arterial blood and bilateral femoral organization were collected to biochemical, imaging morphology, tissue pathology and molecular biology detection. The key gene expression of activiting osteoclast were inhibited in Yougui recipe (see text) group and calcitonin group. The level of OPG, Ca, ALP in Yougui recipe group were higher than calcitonin group (Partificial joint prosthesis, and Yougui recipe (see text) has better effect in promoting bone formation. The effect of Yougui recipe (see text) in promoting bone formation, inhibiting osteoclasts to provide a new method to treating surrounding osteolysis of artificial joint prosthesis.

  11. LEADER 2

    DEFF Research Database (Denmark)

    Daniels, G H; Hegedüs, L; Marso, S P

    2015-01-01

    AIMS: To report preliminary data on baseline serum calcitonin concentrations and associated clinical characteristics in a global population with type 2 diabetes before liraglutide or placebo randomization. METHODS: The ongoing LEADER trial has enrolled 9340 people with type 2 diabetes and at high...... committee of thyroid experts will oversee calcitonin monitoring throughout the trial and will review all calcitonin concentrations ≥20 ng/l. RESULTS: The mean age of participants was 64.3 ± 7.2 years, 64.3% were men, and mean the body mass index was 32.5 ± 6.3 kg/m(2) . The median (interquartile range...... with higher serum calcitonin concentrations that were statistically significant. A 20 ml/min/1.73 m(2) decrease in estimated GFR (eGFR) was associated with a 14% increase in serum calcitonin in women and an 11% increase in men. CONCLUSIONS: In the LEADER population, the prevalence of elevated serum calcitonin...

  12. Noninvasive delivery systems for peptides and proteins in osteoporosis therapy: a retroperspective.

    Science.gov (United States)

    Hoyer, Herbert; Perera, Glen; Bernkop-Schnürch, Andreas

    2010-01-01

    The aim of this review is to provide the reader general and inspiring prospects in various attempts to make noninvasive delivery systems of calcitonin and teriparatide feasible and as convenient as possible. Calcitonin and teriparatide play an important role in both calcium homeostasis and bone remodelling. Currently calcitonin is available as a subcutaneous injection and as a nasal spray whereas teriparatide is administered subcutaneously. In the past few years, an increasing number of articles about drug delivery systems for calcitonin and teriparatide have been published. These delivery systems have been developed to overcome the inherent barriers for the uptake across the diverse membranes on the various routes for protein and peptide delivery. Co-administration of permeation enhancers, mucoadhesive agents, viscosity modifying agents, multifunctional polymers, protease inhibitors as well as encapsulation and chemical modification are utilized in order to improve calcitonin and teriparatide absorption after oral, nasal, pulmonal, or buccal administration. The majority of research groups have been working on the development of formulations based on the encapsulation of molecules in biodegradable and biocompatible polymeric nanoparticles. However these observations are based on data obtained under different experimental conditions. Hence, it is difficult to compare the obtained results in order to draw general conclusions about the most promising characteristics required for oral and nasal formulations for these peptides.

  13. Osteoclasts Are Required for Hematopoietic Stem and Progenitor Cell Mobilization but Not for Stress Erythropoiesis in Plasmodium chabaudi adami Murine Malaria

    Directory of Open Access Journals (Sweden)

    Hugo Roméro

    2016-01-01

    Full Text Available The anemia and inflammation concurrent with blood stage malaria trigger stress haematopoiesis and erythropoiesis. The activity of osteoclasts seems required for the mobilization of hematopoietic stem and progenitor cells (HSPC from the bone marrow to the periphery. Knowing that BALB/c mice with acute Plasmodium chabaudi adami malaria have profound alterations in bone remodelling cells, we evaluated the extent to which osteoclasts influence their hematopoietic response to infection. For this, mice were treated with osteoclast inhibiting hormone calcitonin prior to parasite inoculation, and infection as well as hematological parameters was studied. In agreement with osteoclast-dependent HSPC mobilization, administration of calcitonin led to milder splenomegaly, reduced numbers of HSPC in the spleen, and their retention in the bone marrow. Although C-terminal telopeptide (CTX levels, indicative of bone resorption, were lower in calcitonin-treated infected mice, they remained comparable in naive and control infected mice. Calcitonin-treated infected mice conveniently responded to anemia but generated less numbers of splenic macrophages and suffered from exacerbated infection; interestingly, calcitonin also decreased the number of macrophages generated in vitro. Globally, our results indicate that although osteoclast-dependent HSC mobilization from bone marrow to spleen is triggered in murine blood stage malaria, this activity is not essential for stress erythropoiesis.

  14. The immunohistochemical demonstration of parafollicular cells and evaluation of calcium-phosphate balance in patients with thyroid hemiagenesis

    Directory of Open Access Journals (Sweden)

    Jerzy Sowinski

    2011-07-01

    Full Text Available Thyroid hemiagenesis (TH is characterized by the congenital absence of one thyroid lobe. The aim of this study was to evaluate the calcium-phosphate balance in TH. Twenty patients with TH and 20 controls with a bilobed thyroid were studied. Serum concentrations of total calcium, parathormon and calcitonin were measured. Additionally, the immunohistochemical expression of calcitonin, chromogranin A (chA, neuron-specific enolase (NSE and calcitonin gene-related peptide (CGRP was evaluated in surgical specimens from patients with TH and controls. There were no significant differences in biochemical parameters between TH and controls. Positive staining for calcitonin was demonstrated in 3/8 thyroid sections from three patients with TH, but only in 2/33 sections from four controls (p < 0.005. All sections from patients with TH positive for calcitonin also expressed chA, NSE and CGRP. Two sections from controls positive for calcitonin presented an additionally positive reaction for chA, and one of them also for NSE. None presented positive staining for CGRP. Of three TH sections, in one, hyperplasia of C cells of medium grade, and in another hyperplasia of C cells of high grade, could be detected. In the controls, hyperplasia of C cells of low and medium grade was observed. TH was associated with slightly enhanced C cells hyperplasia compared to controls, which might indicate compensatory proliferation. However, the calcium-phosphate balance does not seem to be significantly affected. (Folia Histochemica et Cytobiologica 2011; Vol. 49, No. 2, pp. 299–305

  15. The calcium endocrine system of adolescent rhesus monkeys and controls before and after spaceflight

    Science.gov (United States)

    Arnaud, Sara B.; Navidi, Meena; Deftos, Leonard; Thierry-Palmer, Myrtle; Dotsenko, Rita; Bigbee, Allison; Grindeland, Richard E.

    2002-01-01

    The calcium endocrine system of nonhuman primates can be influenced by chairing for safety and the weightless environment of spaceflight. The serum of two rhesus monkeys flown on the Bion 11 mission was assayed pre- and postflight for vitamin D metabolites, parathyroid hormone, calcitonin, parameters of calcium homeostasis, cortisol, and indexes of renal function. Results were compared with the same measures from five monkeys before and after chairing for a flight simulation study. Concentrations of 1,25-dihydroxyvitamin D were 72% lower after the flight than before, and more than after chairing on the ground (57%, P parathyroid hormone did not reach significance. Calcitonin showed modest decreases postflight (P animals.

  16. Magnesium-based implants: Beyond fixators

    Directory of Open Access Journals (Sweden)

    Xiaodan Chen

    2017-07-01

    The translational potential of this article: For the first time, magnesium is shown to be beneficial for fracture healing at the weight-bearing site. In addition, calcitonin gene-related peptide-delivery system will also be another translational direction, as the promotive role of calcitonin gene-related peptide in fracture healing is supportive. These cost-effective and innovative treatment approaches will definitely bring a reduction not only in the suffering of patients, but also in the economic burden for their families and our society.

  17. Differential inhibitory response to telcagepant on αCGRP induced vasorelaxation and intracellular Ca(2+) levels in the perfused and non-perfused isolated rat middle cerebral artery

    DEFF Research Database (Denmark)

    Erdling, André; Sheykhzade, Majid; Edvinsson, Lars

    2017-01-01

    BACKGROUND: Calcitonin gene-related peptide (CGRP) is one of the most potent endogenous vasodilators identified to date. The present study elucidates the differential interaction of CGRP, its receptor and the effect of the CGRP-receptor antagonist telcagepant on intracellular Ca(2+) -levels and t...

  18. Genomics, transcriptomics, and peptidomics of Daphnia pulex neuropeptides and protein hormones

    DEFF Research Database (Denmark)

    Dircksen, Heinrich; Neupert, Susanne; Predel, Reinhard

    2011-01-01

    hormone, allatostatin-A, allatostatin-B, allatotropin, Ala(7)-CCAP, CCHamide, Arg(7)-corazonin, DENamides, CRF-like (DH52) and calcitonin-like (DH31) diuretic hormones, two ecdysis-triggering hormones, two FIRFamides, one insulin, two alternative splice forms of ion transport peptide (ITP), myosuppressin...

  19. Domain Modeling: NP_001732.1 [SAHG[Archive

    Lifescience Database Archive (English)

    Full Text Available NP_001732.1 chr11 Solution Conformation of A Non-Amyloidogenic Analogue of Human Ca...lcitonin in Sodium Dodecyl Sulfate Micelles p2jxza_ chr11/NP_001732.1/NP_001732.1_holo_85-117.pdb blast 108Q,115A,116P,117G NH2 0 ...

  20. Cholecystokinin-From Local Gut Hormone to Ubiquitous Messenger

    DEFF Research Database (Denmark)

    Rehfeld, Jens F

    2017-01-01

    pancreatic enzyme secretion and growth, gallbladder contraction, and gut motility, satiety and inhibit acid secretion from the stomach. Moreover, they are major neurotransmitters in the brain and the periphery. CCK peptides also stimulate calcitonin, insulin, and glucagon secretion, and they may act...

  1. Topical non-peptide antagonists of sensory neurotransmitters substance P and CGRP do not modify patch test and prick test reactions

    DEFF Research Database (Denmark)

    Wallengren, Joanna; Edvinsson, Lars

    2014-01-01

    Immunologic responses in the skin can be modulated by such neurotransmitters of sensory nerve fibers as substance P (SP) and calcitonin gene-related peptide (CGRP). The first-generation receptor antagonists were peptides with large molecules and had to be injected intracutaneously. The aim of thi...

  2. Pharmacological characterisation of capsaicin-induced relaxations in human and porcine isolated arteries

    NARCIS (Netherlands)

    S. Gupta (Sanjay); J. Lozano-Cuenca (Jair); C.M. Villalón (Carlos); R. de Vries (René); I.M. Garrelds (Ingrid); C.J.J. Avezaat (Cees); J.P. van Kats (Sjors); P.R. Saxena (Pramod Ranjan); A. Maassen van den Brink (Antoinette)

    2007-01-01

    textabstractCapsaicin, a pungent constituent from red chilli peppers, activates sensory nerve fibres via transient receptor potential vanilloid receptors type 1 (TRPV1) to release neuropeptides like calcitonin gene-related peptide (CGRP) and substance P. Capsaicin-sensitive nerves are widely

  3. ll REPLACEMENT VALUE OF MILLET WASTE FOR MAlZE ON THE ...

    African Journals Online (AJOL)

    However. further study is needed to test the efficacy of higher levels of ... supplementary feeds for ruminants most monogastrics (Lang. l981). during the .... (Chapin and Smith. 1967: Cheeke. 1976) unlike in other species. Homeostasis of blood Ca by calcitonin and Parathormone does not take place (Lang. 1981). Probably ...

  4. Anti-osteoporotic effect of Gengnian Jianshen decoction in rats

    African Journals Online (AJOL)

    humans and animals. Therefore, estrogen deficiency in post-menopausal women has been ... parathyroid hormone), or inhibit bone resorption. (e.g., bisphosphonates and calcitonin) may prevent progression of bone ... was approved by Animal Care and Use. Committee of Second Affiliated Hospital of. Nanjing University of ...

  5. Effects of Adding Chymosin to Milk on Calcium Homeostasis

    DEFF Research Database (Denmark)

    Møller, Ulla Kristine; Jensen, Lars Thorbjørn; Mosekilde, Leif

    2014-01-01

    either chymosin or similar placebo was added. Compared with placebo, chymosin did not affect 24-h urinary calcium, calcium/creatinine ratio, plasma parathyroid hormone, calcitonin or ionized calcium levels. However, during the first 4 h after intake of milk with chymosin, urinary calcium-creatinine ratio...

  6. JMBR - SEPTEMBER 2013.cdr

    African Journals Online (AJOL)

    FinePrint

    KEYWORD: Calcium, vitamin D, parathyroid hormone, calcitonin. Irerih, L.A., Inneh, C. A. and Ugwu, A. C.. Department of Physiology, College of Medical Sciences,. University of ..... haemorheologic functions of plasma viscosity measurements. REFERENCES. 1. Chien S. Blood rheology in hypertension and cardiovascular ...

  7. Endocrine System (For Parents)

    Science.gov (United States)

    ... to the thyroid are four tiny glands that function together called the parathyroids. They release parathyroid hormone, which regulates the level of calcium in the blood with the help of calcitonin, which is produced in the ... a different function. The outer part, the adrenal cortex, produces hormones ...

  8. Prediction of bleeding and thrombosis by standard biochemical coagulation variables in haematological intensive care patients

    DEFF Research Database (Denmark)

    Russell, L.; Madsen, M. B.; Dahl, M.

    2018-01-01

    -dimer and fibrinogen, and markers of infection (C-reactive protein, pro-calcitonin), kidney function (creatinine) and tissue damage (lactate dehydrogenase (LDH)). Results: We included 116 patients; 66 (57%) had at least one bleeding episode and 11 (9%) patients had at least one thrombotic event. The differences...

  9. DRAFT: Russian Association of Endocrinologists Clinic Guidelines for Thyroid Nodules Diagnostic and Treatment

    Directory of Open Access Journals (Sweden)

    Vladimir Eduardovich Vanushko

    2015-05-01

    Full Text Available Russian guidelines for diagnostic of thyroid nodules gained some actual questions: necessity of ultrasound (US-screening of the thyroid cancer, indications for fine needle aspiration and exam of calcitonin, necessity of unification of US and cytopathology classification for signs of thyroid nodules. 

  10. Disseminated medullary thyroid carcinoma despite early thyroid surgery in the multiple endocrine neoplasia-2A syndrome

    NARCIS (Netherlands)

    van Santen, H. M.; Aronson, D. C.; van Trotsenburg, A. S. P.; ten Kate, F. J. W.; van de Wetering, M. D.; Wiersinga, W. M.; de Vijlder, J. J. M.; Vulsma, T.

    2005-01-01

    A 5 1/2-year-old boy, with a family history of multiple endocrine neoplasia (MEN)-2A syndrome, was evaluated for presence of MEN-2A and medullary thyroid carcinoma (MTC). DNA diagnostics confirmed MEN-2A. Basal (360 ng/L) and pentagastrin stimulated (430 ng/L) calcitonin (CT) levels were slightly

  11. Diagnosis of medullary thyroid cancer and prognostic factors of disease aggressiveness

    Directory of Open Access Journals (Sweden)

    D O Gazizova

    2013-12-01

    Full Text Available In the study were enrolled 137 patients with medullary thyroid cancer (MTC. Low 35%-sensitivity of FNAC and high accuracy of basal calcitonin in MTC diagnostics were found. Mutation analysis of the RET pro- tooncogene in familial and sporadic MTC, RAS -gene in sporadic MTC were done. The correlation between type of the mutation and disease aggressiveness was found.

  12. Regression of central giant cell granuloma by a combination of imatinib and interferon: a case report

    NARCIS (Netherlands)

    de Lange, J.; van Rijn, R.R.; van den Berg, H.; van den Akker, H.P.

    2009-01-01

    Central giant cell granuloma is a benign lesion of the jaws which is sometimes aggressive locally. The most common treatment is curettage which has a high recurrence rate. particularly, in more aggressive lesions. Other treatments Such as interferon (IFN) and calcitonin have been described. We

  13. CGRP infusion in unanesthetized rats increases expression of c-Fos in the nucleus tractus solitarius and caudal ventrolateral medulla, but not in the trigeminal nucleus caudalis

    DEFF Research Database (Denmark)

    Bhatt, Deepak K; Ramachandran, Roshni; Christensen, Sarah Louise Tangsgaard

    2015-01-01

    BACKGROUND AND AIMS: Calcitonin gene-related peptide (CGRP) and glyceryl trinitrate (GTN) infusion in migraineurs provokes headache resembling spontaneous migraine, and CGRP receptor antagonists are effective in the treatment of acute migraine. We hypothesized that CGRP infusion would increase mo...

  14. CGRP may play a causative role in migraine

    DEFF Research Database (Denmark)

    Lassen, L H; Haderslev, P A; Jacobsen, V B

    2002-01-01

    Calcitonin gene-related peptide (CGRP) has been detected in increased amounts in external jugular venous blood during migraine attacks. However, it is unknown whether this is secondary to migraine or whether CGRP may cause headache. In a double-blind crossover study, the effect of human alphaCGRP...... attacks may play a causative role....

  15. Excellent tolerability but relatively low initial clinical efficacy of telcagepant in migraine

    DEFF Research Database (Denmark)

    Tfelt-Hansen, Peer

    2011-01-01

    In 3 randomized clinical trials (n = 1585) the calcitonin gene-related peptide antagonist telcagepant 300 mg orally had an incidence of adverse events similar to placebo when used in the acute treatment of migraine. Telcagepant, thus, has excellent tolerability in migraine. Only a quarter (26%) (...

  16. Is thyroidectomy necessary in RET mutations carriers of the familial medullary thyroid carcinoma syndrome?

    DEFF Research Database (Denmark)

    Hansen, H S; Torring, H; Godballe, C

    2000-01-01

    BACKGROUND: The results and consequences of genetic testing in a family with familial medullary thyroid carcinoma (FMTC) are described. METHODS: In the screening of relatives, serum calcitonin is replaced by RET mutation analysis that was performed in families suspected of hereditary medullary th...

  17. Circulating levels of vasoactive peptides in patients with acute bacterial meningitis

    DEFF Research Database (Denmark)

    Berg, Ronan M G; Strauss, Gitte Irene; Tofteng, Flemming

    2009-01-01

    PURPOSE: The underlying mechanisms for cerebral blood flow (CBF) abnormalities in acute bacterial meningitis (ABM) are largely unknown. Putative mediators include vasoactive peptides, e.g. calcitonin-gene related peptide (CGRP), vasoactive intestinal peptide (VIP), and endothelin-1 (ET-1), all...

  18. Safety and efficacy of erenumab for preventive treatment of chronic migraine

    DEFF Research Database (Denmark)

    Tepper, Stewart; Ashina, Messoud; Reuter, Uwe

    2017-01-01

    BACKGROUND: The calcitonin gene-related peptide (CGRP) pathway is important in migraine pathophysiology. We assessed the efficacy and safety of erenumab, a fully human monoclonal antibody against the CGRP receptor, in patients with chronic migraine. METHODS: This was a phase 2, randomised, double...

  19. Biological and technological effects of some mulberry varieties and ...

    African Journals Online (AJOL)

    egyptian hak

    Ecotoxicology & Environmental Safety 60: 193-. 197. Peignoux-Deville J, Lopez E, Lallier F, Bagot EM & Milet C (1975) Responses of ultimobranchial body in eels. (Anguilla anguilla L.) maintained in seawater and experimentally matured to injections of synthetic salmon calcitonin. Cell & Tissue Research 164: 73-83.

  20. Drug: D09392 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available 09392.gif Treatment of migraine calcitonin receptor-like (CALCRL) antagonist [HSA:10203] [KO:K04577] hsa0408...D09392 Drug Telcagepant potassium (USAN) C26H26F5N6O3. C2H6O. K 650.2042 650.6818 D

  1. Cloning and biosynthetic studies of rat somatostatin.

    Science.gov (United States)

    Dixon, J E; Andrews, P C; Collier, K; Deschenes, R; Funckes, C; Lorenz, L; Magazin, M; Minth, C D; Nichols, R; Tavianini, M

    1983-01-01

    The predicted amino acid sequence of rat preprosomatostatin has been obtained by cloning and subsequent DNA sequence analysis of a cDNA obtained from mRNA prepared from a rat medullary thyroid carcinoma (MTC). The predicted preprosomatostatin is 116 amino acid residues in length. Somatostatin-14 is located at the C-terminus of the preprohormone and the amino terminus contains a 'signal' peptide of 24 amino acids. A somatostatin amino terminal protein of 78 residues is found between the signal peptide and somatostatin-14. Both somatostatin-14 and somatostatin-28 are observed in the thyroid tumour C-cells. A comparison of the rat and human preprosomatostatin amino acid sequences shows only 4 substitutions observed in 116 amino acids. Patients with localized MTC often exhibit high serum calcitonin levels while patients showing cellular heterogeneity in the MTC appear to have lower calcitonin levels and a virulent neoplasia with a grave prognosis. Numerous rat MTCs have been examined by two dimensional gel electrophoresis. It is possible to distinguish characteristic differences in protein profiles of tumours producing high levels of calcitonin from those showing low calcitonin and high somatostatin levels. This analysis can be done with less than 1 mg of tissue and may represent a valuable prognostic tool in evaluating the clinical variability of MTC.

  2. Improvement of the closed cranial window model in rats by intracarotid infusion of signalling molecules implicated in migraine

    DEFF Research Database (Denmark)

    Gupta, S; Bhatt, D K; Boni, L J

    2010-01-01

    Intravital microscopy on a closed cranial window allows one to measure change in the diameter of cranial blood vessels after intravenous (i.v.) administration of pharmacodynamic substances. Putative targets being pursued in migraine are large vasodilating peptide molecules such as calcitonin gene...

  3. Zerumbone improved immunoreactivity of neuropeptides in ...

    African Journals Online (AJOL)

    The main objective of this investigation was to explore the improvement effect of oral administration of zerumbone on the density of protein gene product; calcitonin gene related peptide and neuropeptide Y immunoreactive nerve fibers against monosodium iodoacetate induced osteoarthritis changes in rat's knee synovial ...

  4. High-Sensitivity LC-MS/MS Quantification of Peptides and Proteins in Complex Biological Samples : The Impact of Enzymatic Digestion and Internal Standard Selection on Method Performance

    NARCIS (Netherlands)

    Bronsema, Kees J.; Bischoff, Rainer; van de Merbel, Nico C.

    2013-01-01

    Two important aspects of peptide and protein quantification by LC-MS/MS, the enzymatic digestion step and the internal standardization approach, were systematically investigated with a small protein, salmon calcitonin, which could be analyzed both without and with digestion. Quantification of

  5. Author Details

    African Journals Online (AJOL)

    Caneda Aristarain, M.E.. Vol 6, No 3 (2016) - Articles Multiple endocrine neoplasia similar to human subtype 2A in a dog: Medullary thyroid carcinoma, bilateral pheochromocytoma and parathyroid adenoma. Abstract PDF · Vol 6, No 3 (2016) - Articles Calcitonin-negative primary neuroendocrine tumor of the thyroid ...

  6. Disease: H01593 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available h age. It has been estimated that approximately 50% of all women will have osteop... calcitonin receptor gene are associated with bone mineral density in postmenopausal Italian women. ... JOURNA...rming growth factor-beta-1 gene polymorphism in Chinese men and women. ... JOURNAL ... J Bone Miner Metab 22:148

  7. Purification of recombinant C-terminus polyhistidine tagged human ...

    African Journals Online (AJOL)

    Human calcitonin (hCT) is a 32 amino acid peptide that participates in the regulation of calcium and phosphorus metabolism in human. It is used in clinics for the treatment of diseases related to bone decalcification, such as Paget disease, osteoporosis imperfecta and parathyroid gland carcinoma. In this research ...

  8. The effects of duodenal peptides on glucagon-like peptide-1 secretion from the ileum. A duodeno--ileal loop?

    DEFF Research Database (Denmark)

    Hansen, Lene; Holst, Jens Juul

    2002-01-01

    is regulated by local somatostatin secretion. In search for an endocrine pathway, we studied the effect of a range of concentrations of cholecystokinin octapeptide (26-33) (CCK 8), gastric inhibitory peptide 1-42 (GIP), secretin, motilin, calcitonin gene-related peptide (CGRP), and the modified amino acid, 5...... agents from the duodenum regulate GLP-1 secretion in pigs....

  9. Hypocalcitonemia in Handigodu Disease: a spondylo epi (meta) physeal dysplasia.

    Science.gov (United States)

    Badadani, Mallikarjun; Shetty, K Taranath; Agarwal, Ss

    2010-04-25

    Handigodu Disease (HD) is a disorder of the osteoarticular system which is highly prevalent in several villages of two districts viz, Shimoga and Chikmaglur of the state of Karnataka, southern India. The scientific name of the disease is Spondylo-epi-(meta) physeal Dysplasia, Autosomal Dominant variety, Handigodu syndrome. The same has been listed in the International Classification of Skeletal Dysplasias. The calcium homeostasis study was lack in HD. The serum calcium, phosphorus, parathyroid hormone and calcitonin levels after overnight fast state, and 24 hour urinary excretion of calcium and phosphorus were quantified. The decreased level of calcitonin associated with decreased serum total calcium and urinary calcium in HD were observed. The levels of parathyroid hormone, serum phosphorus and urinary phosphorus remain unchanged among HD affected. The Vitamin D3 levels also noticed unchanged in HD affected. Since calcitonin has antiresorption effect on bone, the observed low calcitonin in HD may imply reosrption of bone leading to deformity and causes hypocalcaemia and hypocalciuria. The hypocalcitonemia without change in iPTH associated with hypocalcaemia may be a mutation in Vit D receptor (VDR) or may be an epiphenomenon.

  10. The vasorelaxant effect of adrenomedullin, proadrenomedullin N-terminal 20 peptide and amylin in human skin

    DEFF Research Database (Denmark)

    Hasbak, Philip; Eskesen, Karen; Lind, Peter Henrik

    2006-01-01

    In this study we aimed to assess in vivo, the vasodilator effects of adrenomedullin, proadrenomedullin N-terminal 20 peptide (PAMP) and amylin in human skin vasculature and compare the responses to the effects mediated by the endogenous neuropeptides calcitonin gene-related peptide (CGRP......) and substance P and to examine the mRNA expression of calcitonin receptor-like receptor (CL-R) and receptor-activity modifying proteins, RAMP1, RAMP 2 and RAMP3 in human subcutaneous arteries. Changes in skin blood flow of the forearm were measured using a Laser Doppler Imager after intradermal injection...... to the transient response induced by substance P. PAMP (10(-6)-10(-5) M) caused distinct itch sensation and local erythema. This effect could be abolished when combining the histamine H1-receptor antagonist mepyramin and PAMP. Real-time PCR data showed a higher level of mRNA for RAMP2 than CL-R, RAMP1 and RAMP3...

  11. Induction of increased cAMP levels in articular chondrocytes blocks matrix metalloproteinase-mediated cartilage degradation, but not aggrecanase-mediated cartilage degradation

    DEFF Research Database (Denmark)

    Karsdal, Morten Asser; Sumer, Eren Ufuk; Wulf, Helle

    2007-01-01

    -dependently inhibited by forskolin and IBMX. The highest concentration of IBMX lowered cytokine-induced release of sGAG by 72%. CONCLUSION: Levels of cAMP in chondrocytes play a key role in controlling catabolic activity. Increased cAMP levels in chondrocytes inhibited MMP expression and activity and consequently......OBJECTIVE: Calcitonin has been suggested to have chondroprotective effects. One signaling pathway of calcitonin is via the second messenger cAMP. We undertook this study to investigate whether increased cAMP levels in chondrocytes would be chondroprotective. METHODS: Cartilage degradation...... was induced in bovine articular cartilage explants by 10 ng/ml oncostatin M (OSM) and 20 ng/ml tumor necrosis factor (TNF). In these cultures, cAMP levels were augmented by treatment with either forskolin (4, 16, or 64 microM) or 3-isobutyl-1-methyl xanthine (IBMX; 4, 16, or 64 microM). Cartilage degradation...

  12. Smoldering medullary thyroid carcinoma liver metastasis 37 years after resection of an organ-confined tumor.

    Science.gov (United States)

    Waters, Kevin M; Ali, Syed Z; Erozan, Yener S; Olson, Matthew T

    2015-01-01

    Medullary thyroid carcinoma (MTC) is an uncommon thyroid tumor that usually behaves aggressively. After resection, serological surveillance for calcitonin and carcinoembryonic antigen (CEA) is used to prompt a radiographic search for metastatic disease. We report a case of a 65-year-old woman who presented with a large liver metastasis 37 years after she underwent thyroidectomy for organ-confined MTC. Her clinical course over that time showed a smoldering pattern in which she was symptom free until presentation even though her serum calcitonin and CEA concentrations were elevated for 17 years, and a small equivocal radiographic lesion in the liver was detected 10 years prior to presentation. Cytopathology from an ultrasound guided fine needle aspiration of the hepatic lesion was diagnostic for metastatic MTC. This case highlights the ability for smoldering residual MTC to suddenly transform to aggressive biological behavior after a long period of clinical remission. © 2014 Wiley Periodicals, Inc.

  13. Depicting Medullary Thyroid Cancer Recurrence: The Past and the Future of Nuclear Medicine Imaging

    OpenAIRE

    Skoura, Evangelia

    2013-01-01

    Context: Inherited and sporadic medullary thyroid cancer (MTC) is an uncommon and medically challenging malignancy. Even if the extent of initial surgery is deemed adequate, the recurrence rate remains high, up to 50% in most series. Measurement of serum calcitonin is important in the follow-up of patients with MTC, and reliably reflects the existence of the disease. Evidence Acquisition: There is no single sensitive diagnostic imaging method to reveal all MTC recurrences or metastases. Conve...

  14. Neuropeptides and polypeptide hormones in echinoderms: new insights from analysis of the transcriptome of the sea cucumber Apostichopus japonicus.

    Science.gov (United States)

    Rowe, Matthew L; Achhala, Sufyan; Elphick, Maurice R

    2014-02-01

    Echinoderms are of special interest for studies in comparative endocrinology because of their phylogenetic position in the animal kingdom as deuterostomian invertebrates. Furthermore, their pentaradial symmetry as adult animals provides a unique context for analysis of the physiological and behavioral roles of peptide signaling systems. Here we report the first extensive survey of neuropeptide and peptide hormone precursors in a species belonging to the class Holothuroidea. Transcriptome sequence data obtained from the sea cucumber Apostichopus japonicus were analyzed to identify homologs of precursor proteins that have recently been identified in the sea urchin Strongylocentrotus purpuratus (class Echinoidea). A total of 17 precursor proteins have been identified in A. japonicus, including precursors of peptides related to thyrotropin-releasing hormone, pedal peptide/orcokinin-type peptides, AN peptides/tachykinins, luqins, corticotropin-releasing hormone (CRH), GPA2-type glycoprotein hormone subunits and bursicon. In addition, an unusual finding was an A. japonicus calcitonin-type precursor protein (AjCTLPP), the first to be discovered that comprises two calcitonin-like peptides; this contrasts with the products of the alternatively-spliced calcitonin/CGRP gene in vertebrates, which comprise either calcitonin or CGRP. Collectively, the data obtained provide new insights on the evolution and diversity of neuropeptides and polypeptide hormones. Furthermore, because A. japonicus is one of several sea cucumber species that are used for human consumption, our findings may have practical and economic impact by providing a basis for neuroendocrine-based strategies to improve methods of aquaculture. Copyright © 2013 Elsevier Inc. All rights reserved.

  15. Anterograde transneuronal viral tract tracing reveals central sensory circuits from brown fat and sensory denervation alters its thermogenic responses

    OpenAIRE

    Vaughan, Cheryl H.; Bartness, Timothy J.

    2012-01-01

    Brown adipose tissue (BAT) thermogenic activity and growth are controlled by its sympathetic nervous system (SNS) innervation, but nerve fibers containing sensory-associated neuropeptides [substance P, calcitonin gene-related peptide (CGRP)] also suggest sensory innervation. The central nervous system (CNS) projections of BAT afferents are unknown. Therefore, we used the H129 strain of the herpes simplex virus-1 (HSV-1), an anterograde transneuronal viral tract tracer used to delineate sensor...

  16. The contribution of the genomes of a termite and a locust to our understanding of insect neuropeptides and neurohormones

    Directory of Open Access Journals (Sweden)

    Jan Adrianus Veenstra

    2014-11-01

    Full Text Available The genomes of the migratory locust Locusta migratoria and the termite Zootermopsis nevadensis were mined for genes encoding neuropeptides, neurohormones and their G-protein coupled receptors (GPCRs. Both species have retained a larger number of neuropeptide and neuropeptide GPCRs than the better known holometabolous insect species, while other genes that in holometabolous species appear to have a single transcript produce two different precursors in the locust, the termite or both. Thus the recently discovered CNMa neuropeptide gene has two transcripts predicted to produce two structurally different CNMa peptides in the termite, while the locust produces two different myosuppressin peptides in the same fashion. Both these species also have a calcitonin gene, which is different from the gene encoding the calcitonin-like insect diuretic hormone. This gene produces two types of calcitonins, calcitonins A and B. It is also present in Lepidoptera and Coleoptera and some Diptera, but absent from mosquitoes and Drosophila. However, in holometabolous insect species, only the B transcript is produced. Their putative receptors were also identified. In contrast, Locusta has a highly unusual gene that codes for a salivation stimulatory peptide. The Locusta genes for neuroparsin and vasopressin are particularly interesting. The neuroparsin gene produces five different transcripts, of which only one codes for the neurohormone identified from the corpora cardiaca. The other four transcripts code for neuroparsin-like proteins, which lack four amino acid residues, and that for that reason we called neoneuroparsins. The number of transcripts for the neoneuroparsins is about two hundred times larger than the number of neuroparsin transcripts. The first exon and the putative promoter of the vasopressin genes, of which there are about seven copies in the genome, is very well conserved, but the remainder of these genes is not. The relevance of these findings is

  17. Study of the cell biology and biochemistry of cherubism.

    Science.gov (United States)

    Southgate, J; Sarma, U; Townend, J V; Barron, J; Flanagan, A M

    1998-01-01

    AIMS: To establish whether the multinucleate cells in lesions of patients with cherubism are also osteoclasts and if this is the case whether they were responsive to calcitonin; to carry out cytogenetic studies on two members of the same family affected by cherubism in an attempt to identify any major chromosomal defects; and to perform an in-depth modern biochemical study of four children in the same family. SUBJECTS AND METHODS: Four related children with cherubism were studied. Tissue taken from one of the children at elective decompression of an optic nerve was submitted to in vitro bone resorption studies. Cytogenetic studies were done on two of the children and biochemical studies on all four. RESULTS: The multinucleate cells in the cherubic lesions were shown to be osteoclasts since they synthesised tartrate resistant acid phosphatase, expressed the vitronectin receptor, and resorbed bone. Bone resorption by the cultured multinucleate cells was significantly inhibited by calcitonin. High resolution cytogenetic studies failed to detect any chromosomal abnormalities in two children with cherubism. The biochemistry profile of all four children with cherubism showed that serum calcium, parathyroid hormone, parathyroid related hormone, calcitonin, and alkaline phosphatase were within normal levels. Urine analysis of pyridinium and deoxypyridinium cross links, hydroxyproline, and calcium in relation to urine creatinine were measured to assess bone resorption in these children, and the values were at the upper end of the normal range in all four. CONCLUSIONS: Further studies are required to determine whether calcitonin treatment will control this grossly deforming disease until the time when the physiological changes that occur at puberty rectify the pathology. It is not recommended that biochemical markers of bone resorption are used in isolation to monitor the activity of cherubism in individuals because the results are based on a small number of children and

  18. Histopathological and immunohistochemical findings of primary and metastatic medullary thyroid carcinoma in a young dog.

    Science.gov (United States)

    Piñeyro, Pablo; Vieson, Miranda D; Ramos-Vara, José A; Moon-Larson, Martha; Saunders, Geoffrey

    2014-01-01

    This report describes the gross, histological, and immunohistochemical features of medullary thyroid carcinoma (MTC) with pulmonary metastases in a young dog. Sheets of pleomorphic cells supported by fibrous stroma characterized the primary mass, while metastatic nodules had a neuroendocrine pattern. Despite differing histologic features, all masses showed marked immunoreactivity against calcitonin and multiple neuroendocrine markers consistent with MTC. Although MTC is a well-recognized entity, it may be difficult to distinguish this mass from other thyroid neoplasms, necessitating immunohistochemical characterization.

  19. Histopathological and immunohistochemical findings of primary and metastatic medullary thyroid carcinoma in a young dog

    OpenAIRE

    Piñeyro, Pablo; Vieson, Miranda D.; Ramos-Vara, José A.; Moon-Larson, Martha; Saunders, Geoffrey

    2014-01-01

    This report describes the gross, histological, and immunohistochemical features of medullary thyroid carcinoma (MTC) with pulmonary metastases in a young dog. Sheets of pleomorphic cells supported by fibrous stroma characterized the primary mass, while metastatic nodules had a neuroendocrine pattern. Despite differing histologic features, all masses showed marked immunoreactivity against calcitonin and multiple neuroendocrine markers consistent with MTC. Although MTC is a well-recognized enti...

  20. The Relationship of Blood Pressure with Intra- Or extracellular and Bone Calcium Merabolisms in the Elderly

    OpenAIRE

    Sugihara, Nobuyuki; Matsuzaki, Masunori

    1994-01-01

    We investigated the correlations of blood pressure with intra- or extracellular and bone calcium matabolisms in the elderly. We measured serum calcium (Ca), inorganic phosphorus (Pi), C-terminal parathyroid hormone fragment (PTH-C), and calcitonin. Intracellular free calcium ([Ca2+]I) in platelet and erythrocyte was measured by fura- 2/AM from dual excitation wavelength using a fluorescence spectrophotometer. We calculated bone mineral content (BMC) of lumbar vertebral body using a calibratio...

  1. Pharmacokinetic-Pharmacodynamic Relationship of Erenumab (AMG 334) and Capsaicin-Induced Dermal Blood Flow in Healthy and Migraine Subjects

    OpenAIRE

    Vu, Thuy; Ma, Peiming; Chen, Jiyun Sunny; de Hoon, Jan; Van Hecken, Anne; Yan, Lucy; Wu, Liviawati Sutjandra; Hamilton, Lisa; Vargas, Gabriel

    2017-01-01

    Purpose Capsaicin-induced dermal blood flow (CIDBF) is a validated biomarker used to evaluate the target engagement of potential calcitonin gene-related peptide-blocking therapeutics for migraine. To characterize the pharmacokinetics (PK) and quantify the inhibitory effects of erenumab (AMG 334) on CIDBF, CIDBF data were pooled from a single- and a multiple-dose study in healthy and migraine subjects. Methods Repeated capsaicin challenges and DBF measurements were performed and serum erenumab...

  2. Substance P receptor binding sites are expressed by glia in vivo after neuronal injury.

    OpenAIRE

    Mantyh, P W; Johnson, D J; Boehmer, C G; Catton, M D; Vinters, H V; Maggio, J E; Too, H P; Vigna, S R

    1989-01-01

    In vitro studies have demonstrated that glia can express functional receptors for a variety of neurotransmitters. To determine whether similar neurotransmitter receptors are also expressed by glia in vivo, we examined the glial scar in the transected optic nerve of the albino rabbit by quantitative receptor autoradiography. Receptor binding sites for radiolabeled calcitonin gene-related peptide, cholecystokinin, galanin, glutamate, somatostatin, substance P, and vasoactive intestinal peptide ...

  3. Randomized, controlled trial of telcagepant over four migraine attacks

    DEFF Research Database (Denmark)

    Ho, Andrew P; Dahlöf, Carl Gh; Silberstein, Stephen D

    2010-01-01

    This study evaluated the calcitonin gene-related peptide (CGRP) receptor antagonist telcagepant (tablet formulation) for treatment of a migraine attack and across four attacks. Adults with migraine were randomized, double-blind, to telcagepant 140 mg, telcagepant 280 mg, or control treatment sequ...... was defined as ≥ 3 successes, and lack of consistent efficacy was defined as ≥ 2 failures, in treatment response. A total of 1677 patients treated ≥ 1 attack and 1263 treated all four attacks....

  4. The contribution of the genomes of a termite and a locust to our understanding of insect neuropeptides and neurohormones

    Science.gov (United States)

    Veenstra, Jan A.

    2014-01-01

    The genomes of the migratory locust Locusta migratoria and the termite Zootermopsis nevadensis were mined for the presence of genes encoding neuropeptides, neurohormones, and their G-protein coupled receptors (GPCRs). Both species have retained a larger number of neuropeptide and neuropeptide GPCRs than the better known holometabolous insect species, while other genes that in holometabolous species appear to have a single transcript produce two different precursors in the locust, the termite or both. Thus, the recently discovered CNMa neuropeptide gene has two transcripts predicted to produce two structurally different CNMa peptides in the termite, while the locust produces two different myosuppressin peptides in the same fashion. Both these species also have a calcitonin gene, which is different from the gene encoding the calcitonin-like insect diuretic hormone. This gene produces two types of calcitonins, calcitonins A and B. It is also present in Lepidoptera and Coleoptera and some Diptera, but absent from mosquitoes and Drosophila. However, in holometabolous insect species, only the B transcript is produced. Their putative receptors were also identified. In contrast, Locusta has a highly unusual gene that codes for a salivation stimulatory peptide. The Locusta genes for neuroparsin and vasopressin are particularly interesting. The neuroparsin gene produces five different transcripts, of which only one codes for the neurohormone identified from the corpora cardiaca. The other four transcripts code for neuroparsin-like proteins, which lack four amino acid residues, and that for that reason we called neoneuroparsins. The number of transcripts for the neoneuroparsins is about 200 times larger than the number of neuroparsin transcripts. The first exon and the putative promoter of the vasopressin genes, of which there are about seven copies in the genome, is very well-conserved, but the remainder of these genes is not. The relevance of these findings is discussed

  5. Degeneration of capsaicin sensitive sensory nerves enhances myocardial injury in acute myocardial infarction in rats.

    Science.gov (United States)

    Zhang, Rui-Lin; Guo, Zheng; Wang, Li-Li; Wu, Jie

    2012-09-20

    Evidence indicated an involvement of afferent nerves in the pathology of acute myocardial infarction. This study was undertaken to clarify the role and mechanisms by which the sensory afferent degeneration exacerbates the myocardial injury in acute myocardial infarction in rats. The myocardial injury was assessed by analysis of 1) the differences in the infarct size, myocyte apoptosis, the caspase activity in the myocardium and cardiac troponin I in serum between the denervated and non-denervated rats; 2) the differences in the size of infarctiom with and without antagonisms of endogenous neurokinin 1 receptor or calcitonin gene related peptide receptor in acute myocardial infarction. Degeneration of the afferent nerves resulted in marked increase in the pain threshold and decrease in substance P and calcitonin gene related peptide in dorsal root ganglia, spinal dorsal horn and myocardium. Increases of the infarction size (39% ± 4% vs. 26% ± 4%,), troponin-I (28.4 ± 8.89 ng/ml, vs. 14.6 ± 9.75 ng/ml), apoptosis of myocytes (by 1.8 ± 0.2 folds) and caspase-3 activity (1.6 ± 0.3 vs. 1.05 ± 0.18) were observed in the denervated animals at 6h of myocardial infarction, compared with the non-denervated rats. Antagonisms of the endogenous neurokinin 1 receptor or calcitonin gene related peptide receptor caused increase of the size of infarction in the animals. Degeneration of capsaicin sensitive afferent nerves enhances the myocardial injury of acute myocardial infarction, possibly due to reduction of endogenous calcitonin gene related peptide and substance P. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  6. Alternate Splicing of CD44 Messenger RNA in Prostate Cancer Growth

    Science.gov (United States)

    2009-10-01

    University of Colorado Health Science Center); to the physical necessities of the move; and to the need to recruit by advertising ; and to administrative...Chien J, Wong E, Nikes E, Noble MJ, Pantazis CG, Shah GV. Constitutive activation of stimulatory guanine nucleotide binding protein (Gsα-QL)-medicated...for cyclic AMP- dependent protein kinase A in calcitonin action. Int J Cancer 2005, 117:551-560. 17. Chien J, Wong E, Nikes E, Noble MJ, Pantazis CG

  7. Surgical approach to medullary thyroid cancer.

    Science.gov (United States)

    Lundgren, Catharina Ihre; Delbridg, Leigh; Learoyd, Diana; Robinson, Bruce

    2007-07-01

    Medullary thyroid cancer (MTC) compromises 3-5% of all thyroid cancers and arises from parafollicular or calcitonin-producing C cells. It may be sporadic (75% of cases), or may occur as a manifestation of either the hereditary syndrome Multiple Endocrine Neoplasia type 2 (MEN 2A or MEN 2B) (25% of cases), or rarely as an isolated familial syndrome (FMTC). Complete surgical resection comprising in most cases total thyroidectomy with central lymph node dissection at an early stage of the disease is the only potential cure for MTC. The familial form of the disease, MEN-2A occupies a unique place in surgical history, having been the first disease where surgical removal of an affected organ was undertaken before the development of malignancy, solely on the basis of genetic testing. Total thyroidectomy prior to the development of invasive cancer completely avoids an otherwise lethal malignancy. Timing of prophylactic surgery is based on models that utilise genotype-phenotype correlations, which have now been stratified into three risk groups based on the specific codon involved. MTC should be followed with postoperative serial serum calcitonin levels to survey for persistent or recurrent disease as indicated by detectable levels. The challenge however, if calcitonin levels are increased, is to find the source of its production. The first localisation technique recommended would be ultrasound of the neck, since there is a high frequency of local recurrence and cervical node metastasis, followed by a total body CT scan and bone scintigraphy.

  8. Alteration of parafollicular (C cells activity in the experimental model of hypothyroidism in rats.

    Directory of Open Access Journals (Sweden)

    Zbigniew Puchalski

    2007-06-01

    Full Text Available Our previous study has shown the alteration of C cells activity in rats with experimental model of hyperthyroidism. The aim of the present study was the evaluation of parafollicular cells activity in rats with hypothyroidism evoked by propylthiouracil (PTU given in drinking water over 21 days. Histological, ultrastructural and immunocytochemical studies using specific antibodies against calcitonin and CGRP were performed on thyroid glands taken from experimental and control groups of rats. Moreover, in all animals the calcitonin plasma levels were evaluated by radioimmunoassay. After chronic administration of PTU, thyroid image showed predominant microfollicular hyperplasia and attenuated density of parafollicular cells. The intensity of immunocytochemical reactions for CT and CGRP were weaker in the majority of C cells in comparison to the control rats, in which strong immunocytochemical reaction was observed. Examination in the electron microscope reveals the features of hypoactivity both in follicular and parafollicular cells, in which the quantity and electron density of secretory granules were smaller in comparison to the control group. These microscopic changes were accompanied by a significant decrease of calcitonin plasma concentration. Alteration of C cells activity in the experimental model of hypothyroidism, accompanied by microfollicular hypertrophy, may point to the mutual cooperation between parafollicular and follicular cells.

  9. Use of the gamma probe and of 99mTc-DMSA (V) in the identification of the neck recurrence of medullary carcinoma thyroid; Uso do gama probe e do 99mTc-DMSA (V) na identificacao de recorrencias cervicais de carcinoma medular de tireoide

    Energy Technology Data Exchange (ETDEWEB)

    Melo, Rosana Leite de; Kowalski, Luiz P.; Ubrich, Fabio F. [Hospital do Cancer A.C. Camargo, Sao Paulo, SP (Brazil). Centro de Tratamento e Pesquisa. Dept. de Cirurgia de Cabeca e Pescoco e Otorrinolaringologia; Lima, Eduardo N. Pereira; Torres, Ivone C.G. [Hospital do Cancer A.C. Camargo, Sao Paulo, SP (Brazil). Centro de Tratamento e Pesquisa. Dept. de Medicina Nuclear

    2003-03-01

    Medullary carcinoma of the thyroid, a malignant neoplasm of para follicular C cells, represent about 5-10% of thyroid tumors. The symptoms are related to local invasion and hormonal secretion. The clinical course is variable, from indolent cases to extremely aggressive. Many radionuclide imaging have been described to locate metastasis of medullary cancer. Tl-201 and Tc-99m (V)DMS A showed to be useful in the evaluation o persistent elevated serum calcitonin levels. On the other hand, the use of the 131 I-Mibg, that is the isotope more used, has not been demonstrating efficiency in identifying metastasis. Our objective is to report a case of a patient with medullary thyroid carcinoma in which the follow-up use DMS A(V) demonstrated a recurrence no identified for other methods. A 34-year-old man had a diagnosis of medullary thyroid carcinoma and has submitted a total thyroidectomy and neck lymph node dissection. He presented elevated serum calcitonin levels and DMS A(V) scintigraphy demonstrated focal area of pathologic uptake at the medline of the neck, but the surgical exploration was negative. He persisted with high calcitonin levels and it was used a new DMS A(V). On this occasion he was submitted to the radio-guided surgery that located the recurrence and it was confirmed with anatomo-pathologic exam. This case allowed to demonstrate that the use of radionuclide associated to the gamma-probe is promising, allowing a precise surgical approach. (author)

  10. Role of [(18)F]FDG-PET/CT in the detection of occult recurrent medullary thyroid cancer.

    Science.gov (United States)

    Skoura, Evangelia; Rondogianni, Phivi; Alevizaki, Maria; Tzanela, Marinella; Tsagarakis, Stylianos; Piaditis, George; Tolis, George; Datseris, Ioannis E

    2010-06-01

    Many patients with medullary thyroid carcinoma (MTC) have persistently elevated calcitonin levels after initial treatment, indicating disease recurrence. Conventional imaging is often negative or shows equivocal findings. In this study we report our experience with 2-deoxy-2-[(18)F]fluoro-D-glucose positron emission tomography/computed tomography ([(18)F]FDG-PET/CT) in the evaluation of this specific group. Between February 2007 and May 2009, 38 [(18)F]FDG-PET/CT scans were performed on 32 patients with MTC and elevated calcitonin levels for localization of recurrent disease. Six of these patients had a second [(18)F]FDG-PET/CT scan. Among the 38 [(18)F]FDG-PET/CT scans there were 18 positive and 20 negative scans. Out of the 18 positive scans, 17 were true positive and one false positive. These findings suggest that [(18)F]FDG-PET/CT provides additional information in almost half of all cases (overall per patient sensitivity of 47.4%) but using a serum calcitonin cut-off of 1000 pg/ml this rate is increased to 80%. An interesting finding of the study was that none of the six patients with multiple endocrine neoplasia type IIA syndrome had a positive [(18)F]FDG-PET/CT scan for MTC. When these patients were excluded, the overall per patient sensitivity rose to 60% and in patients with calcitonin levels >1000 pg/ml this rate increased to 100%. The mean SUV(max) of all lesions showing [(18)F]FDG uptake was 3.96 + or - 1.61 (range, 2-7). [(18)F]FDG-PET/CT seems to be valuable for the detection of recurrence in patients with highly elevated calcitonin levels and negative conventional imaging findings. In addition, it seems that the sensitivity of [(18)F]FDG-PET/CT may be higher in patients with sporadic or familial MTC than in patients with MTC as part of multiple endocrine neoplasia type IIA syndrome.

  11. A study of FoxA1 expression in thyroid tumors.

    Science.gov (United States)

    Nonaka, Daisuke

    2017-07-01

    FoxA1 regulates a variety of tissues during embryogenesis and early life. In thyroid, FoxA1 expression has recently been shown in C cells and medullary thyroid carcinomas but not in follicular cells. FoxA1 has also been proposed as a potential oncogene in anaplastic thyroid carcinomas. However, FoxA1 expression has not been extensively investigated in a spectrum of thyroid nonneoplastic lesions and tumors. A variety of thyroid tumors and lesions and their morphologic mimics were stained with monoclonal anti-FoxA1 antibody. For the medullary carcinomas, its expression pattern was compared with those of other conventional markers. All 67 medullary thyroid carcinomas (100%), including 1 calcitonin-negative medullary carcinoma, showed diffuse and strong FoxA1 nuclear expression. The expression pattern was homogeneous throughout the tumor. Expressions of other markers in medullary thyroid carcinomas were as follows: calcitonin, 94.7%; CEA, 91.2%; and chromogranin, 100%, generally in variable intensity. FoxA1 was completely negative in follicular neoplasms, papillary thyroid carcinomas, and poorly differentiated carcinomas, whereas it was expressed in 55% of anaplastic thyroid carcinomas (33/60) in variable intensity. FoxA1 was also strongly expressed in C-cell hyperplasia as well as solid cell nests. No FoxA1 expression was seen in thyroid gland affected by nodular hyperplasia, Hashimoto thyroiditis, and Graves disease, or in paragangliomas or parathyroid lesions. FoxA1 discriminates between medullary thyroid carcinoma and tumors of follicular derivation with sensitivity and specificity greater than calcitonin and CEA; therefore, it may serve as a reliable ancillary marker for the diagnosis of medullary thyroid carcinoma because of its reliably uniform quality of staining. Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.

  12. Differentiated treatment of patients with acne and concomitant candida infection

    Directory of Open Access Journals (Sweden)

    Yaakubi Randa

    2016-12-01

    Full Text Available There are a lot of works, which are devoted to the study of acne, but these data are often contradictory on the issue of interrelationship and interdependence of clinical manifestations, course and some factors in the pathogenesis of acne and candida infection. Aim of the research was to study the effect of the recommended differentiated therapy on the pathogenetic disorders in patients with acne and concomitant Candida infection. Methods and results. 120 patients with acne were examined. In 100 of them concomitant skin malasseziosis was set in the form of pityriasis rosea, kerosis, comedones, folliculitis, seborrhea, multicolored zoster, with some features, as well as candidiasis. Methods of the research – bacterioscopic, bacteriological, study of skin oiliness and moisture, skin pH, the level of Ca ++, parathyroid hormone and calcitonin. In patients with acne significant shifts in the composition of water-lipid mantle, increased oiliness and decreased moisture of skin, pH changes with a shift to the alkaline side were revealed, the most pronounced – in acne patients with Candida infection. The content of Ca ++ in the organism, as well as parathyroid hormone and calcitonin was increased and also the most indicative it was in patients with acne and concomitant Candida infection. After the comparative analysis on the basis of different levels of clinical and laboratory violations two clinical-therapeutic groups were distinguished, in accordance with that the differentiated therapy offered by us was conducted. Increased oiliness and Рh of skin, decline of moisture before the treatment, especially in patients with III and IV stages of acne, complicated by Candida infection, were normalized after treatment, unlike in patients treated traditionally. Conclusion. After treatment intensity of microbal colonization and also microbal associations of skin was diminished, the level of Ca++, parathyroid hormone and calcitonin went down.

  13. The 14th quality control survey for radioisotope in vitro tests in Japan, 1992

    Energy Technology Data Exchange (ETDEWEB)

    1993-11-01

    This report presents the results of the 14th quality control nationwide survey. Of 490 facilities performing RI in vitro tests as of December 1992, 261 (53.3%) participated in the present 1992 survey. Free testosterone and renin were added to the following conventional 37 test items: adrenocorticotropic hormone (ACTH), growth hormone (GH), somatomedin C, follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin, thyroid stimulating hormone (TSH), triiodothyronine (T[sub 3]), free T[sub 3], thyroxine (T[sub 4]), free T[sub 4], T[sub 3] uptake, thyroglobulin, T[sub 3] binding globulin (TBG), parathyroid hormone (PTH), calcitonin, insulin, C-peptide, glucagon, gastrin, testosterone, estradiol, progesterone, 17[alpha]-hydroxyprogesterone, aldosterone, cortisol, immunoglobulin E (IgE), digoxin, [alpha]-fetoprotein, carcinoembryonic antigen (CEA), tissue polypeptide antigen (TPA), CA125, CA19-9, CA15-3, prostatic acid phosphatase (PAP), [beta][sub 2]-microglobulin, and ferritin. Measurement data for each kit were analyzed by a mean value of measurements, standard deviation, and coefficient of variation (CV). Both 'within kit variation' between facilities and 'between kit variation' showed a CV of 20% or less for GH, somatomedin C, TSH, T[sub 3], T[sub 4], T[sub 3] uptake, TBG, cortisol, IgE, CA125, PAP, and [beta][sub 2]-microglobulin, revealing satisfactory results. There was a great 'within kit variation' between facilities in ACTH, free T[sub 4], and calcitonin; and there was a great 'between kit variation' in ACTH, LH, free T[sub 4], thyroglobulin, PTH, calcitonin, and [alpha]-fetoprotein. (N.K.).

  14. Additive effect of elcatonin to risedronate for chronic back pain and quality of life in postmenopausal women with osteoporosis: a randomized controlled trial.

    Science.gov (United States)

    Hongo, Michio; Miyakoshi, Naohisa; Kasukawa, Yuji; Ishikawa, Yoshinori; Shimada, Yoichi

    2015-07-01

    Calcitonin has been reported to reduce acute and chronic back pain in osteoporotic patients. The additive effect of calcitonin with a bisphosphonate on chronic back pain remains unclear. The purpose of this study was to evaluate the effect of combining elcatonin (eel calcitonin) with risedronate for patients with chronic back pain. Forty-five postmenopausal women diagnosed as having osteoporosis with chronic back pain persisting for more than 3 months, after excluding women with fresh vertebral fractures within the last 6 months, were randomly allocated to a risedronate group (risedronate alone, n = 22) and a combined group (risedronate and elcatonin, n = 23). The study period was 6 months. Pain was evaluated with a visual analogue scale (VAS) and the Roland-Morris questionnaire (RDQ). Back extensor strength, bone mineral density, and quality of life on the SF-36 and the Japanese osteoporosis quality of life score were also evaluated. Significant improvements were found in the combined group for VAS at final follow-up compared with baseline and 3 months, mental health status on the SF-36, and JOQOL domains for back pain and general health. The JOQOL domain for back pain improved significantly, but no change was found in the VAS or other domains in the risedronate group. Bone mineral density increased significantly in the two groups, but no significant difference was found between the groups. Back extensor strength did not change in both groups. In conclusion, the use of elcatonin in addition to risedronate for more than 3 months reduced chronic back pain. The additional therapy of risedronate with elcatonin may be a useful and practical choice for the treatment of osteoporosis with chronic back pain persisting more than 3 months.

  15. Effect of exendin (exenatide)--GLP 1 receptor agonist on the thyroid and parathyroid gland in a rat model.

    Science.gov (United States)

    Bulchandani, Deepti; Nachnani, Jagdish S; Herndon, Betty; Molteni, Agostino; Pathan, Muhammad H; Quinn, Tim; Hamdan, Hana A; Alba, Laura M; Graves, Leland

    2012-09-15

    Exenatide or Exendin-4 is a 39-amino acid agonist of the glucagon like peptide (GLP-1) receptor approved for the adjunctive treatment for type 2 diabetes. Recent reports suggest that GLP-1 agonists may also have distant effects including C-cell thyroid hyperplasia. The aim of this study was to evaluate the effect of exendin-4 on the thyroid and parathyroid cells in a rat model. Rat thyroids were stained for calcitonin, H&E and for carcinoembryonic antigen (CEA). Thyroid C-cell hyperplasia was graded on H&E stained slides using cell size and secretory granule numbers, morphological features of the parathyroid glands and the serum calcium concentrations of the rats were also evaluated. Counts of stained cells/high power field and intensity of staining were recorded by two pathologists. Data were analyzed by ANOVA/post-tests. C cell hypertrophy was elevated in exenatide-treated vs. untreated animals (22.5 ± 8.7 vs. 10.5 ± 2.7 cells/HPF). CEA staining failed to show effects by exendin. Calcitonin staining was significantly elevated in exenatide treated controls (PParathyroid glands were histologically normal in both groups, and serum calcium levels were within normal range in all animals. In summary, exenatide was associated with C cell hyperplasia and increased calcitonin staining of thyroids, but was unrelated to CEA levels. These data raise important concerns about the effects of exenatide which, given its wide clinical use, should be clarified with urgency. Copyright © 2012 Elsevier B.V. All rights reserved.

  16. Vandetanib induces a marked anti-tumor effect and amelioration of ectopic Cushing’s syndrome in a medullary thyroid carcinoma patient

    Directory of Open Access Journals (Sweden)

    Hashem Bseiso

    2016-10-01

    Full Text Available A 55-year-old woman diagnosed with sporadic MTC underwent total thyroidectomy 20 years ago. After the first surgery, elevated calcitonin levels in parallel with local disease persistence were noted and therefore she underwent repeated neck dissections. During follow-up, multiple foci of metastatic disease were noted in the neck and mediastinal lymph nodes, lungs and bones; however, the disease had an indolent course for a number of years, in parallel with a calcitonin doubling time of more than two years and without significant symptoms. During a routine follow-up visit 2 years ago, findings suggestive of Cushing’s syndrome were observed on physical examination. The biochemical evaluation demonstrated markedly elevated serum calcitonin level, in parallel with lack of cortisol suppression after an overnight 1 mg dexamethasone suppression test, lack of cortisol and ACTH suppression after high-dose IV dexamethasone 8 mg, elevated plasma ACTH up to 79 pg/mL (normal <46 pg/mL and elevated 24-h urinary free cortisol up to 501 μg/24 h (normal 9–90 μg/24 h. After a negative pituitary MRI, she underwent IPSS, which was compatible with EAS. Whole-body CT demonstrated progressive disease at most of the tumor sites. Treatment with vandetanib at a dosage of 200 mg/day was commenced. The patient showed a significant, rapid and consistent clinical improvement already after two months of treatment, in parallel with biochemical improvement, whereas a decrease in tumor size was demonstrated on follow-up CT.

  17. {sup 18}F-DOPA PET/CT in the diagnosis and localization of persistent medullary thyroid carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Archier, Aurelien; Mundler, Olivier [Aix-Marseille University, Department of Nuclear Medicine, La Timone University Hospital, Marseille (France); Aix-Marseille University, European Center for Research in Medical Imaging, Marseille (France); Heimburger, Celine [University Hospitals of Strasbourg, Department of Biophysics and Nuclear Medicine, Strasbourg (France); Guerin, Carole; Palazzo, Fausto F.; Henry, Jean-Francois; Sebag, Frederic [Aix-Marseille University, Department of Endocrine Surgery, Conception Hospital, Marseille (France); Morange, Isabelle [Aix-Marseille University, Department of Endocrinology, Conception Hospital, Marseille (France); Schneegans, Olivier [Paul Strauss Cancer Center, Department of Nuclear Medicine, Strasbourg (France); Abdullah, Ahmad Esmaeel [Aix-Marseille University, Department of Nuclear Medicine, La Timone University Hospital, Marseille (France); Imperiale, Alessio [University Hospitals of Strasbourg, Department of Biophysics and Nuclear Medicine, Strasbourg (France); ICube, UMR 7357 University of Strasbourg/CNRS and FMTS, Faculty of Medicine, Strasbourg (France); Taieb, David [Aix-Marseille University, Department of Nuclear Medicine, La Timone University Hospital, Marseille (France); Aix-Marseille University, European Center for Research in Medical Imaging, Marseille (France); Institut Paoli-Calmettes, Inserm UMR1068 Marseille Cancerology Research Center, Marseille (France)

    2016-06-15

    To evaluate the performance of {sup 18}F-l-dihydroxyphenylalanine ({sup 18}F-DOPA) PET/CT in the detection of locoregional and distant medullary thyroid carcinoma (MTC) metastases and to compare imaging findings with histological data. We retrospectively evaluated 86 MTC patients with persistently high serum calcitonin levels after initial surgery who had undergone {sup 18}F-DOPA PET/CT between January 2007 and December 2014 in two referral centres. They were followed up for at least 6 months after the PET/CT assessment. The results were compared with histological data or with the findings obtained during follow-up using a complementary imaging modality. {sup 18}F-DOPA PET/CT was positive in 65 of the 86 patients, corresponding to a patient-based sensitivity of 75.6 %. Distant metastatic disease (M1) was seen in 29 patients including 11 with previously unknown metastases revealed only by PET/CT. Among the 36 patients without distant metastatic spread, 25 had nodal involvement limited to the neck, and 10 of these 25 patients underwent reoperation. The lymph node compartment-based sensitivity of {sup 18}F-DOPA PET/CT was 100 % in the two institutions but lesion-based sensitivity was only 24 %. Preoperative and postoperative median calcitonin levels were 405 pg/mL (range 128 - 1,960 pg/mL) and 259 pg/mL (range 33 - 1,516 pg/mL), respectively. None of the patients achieved normalization of serum calcitonin after reoperation. {sup 18}F-DOPA PET/CT enables early diagnosis of a significant number of patients with distant metastasis. It has a limited sensitivity in the detection of residual disease but provides high performance for regional analysis. A surgical compartment-oriented approach could be the approach of choice whatever the number of nodes revealed by {sup 18}F-DOPA PET/CT. (orig.)

  18. Double labelling immunohistochemistry on the sympathetic trunk ganglia neurons projecting to the extrinsic penile smooth musculature of the pig: an experimental study on the retractor penis muscle.

    Science.gov (United States)

    Botti, Maddalena; Gazza, Ferdinando; Ragionieri, Luisa; Minelli, Luisa Bo; Panu, Rino

    2013-01-01

    Retrograde neuronal tracing and double labelling immunofluorescence methods were used to define the neurochemical content of sympathetic trunk ganglia neurons projecting to the pig retractor penis muscle, which was taken as an experimental model of the male genital smooth musculature. After the injection of Fast Blue into the bulbo-penile portion of the retractor penis muscle, the eventual co-existence of the catecholaminergic marker tyrosine hydroxylase with calcitonine gene related peptide, leu-enkephalin, neuropeptide Y, neuronal nitric oxide synthase, substance P, vasoactive intestinal polypeptide or vesicular acetylcholine transporter was studied in the ipsilateral S1 sympathetic trunk ganglia, which resulted to contain the greatest number of autonomic retractor penis muscle projecting cells. The observation of Fast Blue positive neurons under the fluorescent microscope allowed the identification of different subpopulations of catecholaminergic and non-catecholaminergic retractor penis muscle-projecting neurons. The majority of catecholaminergic cells contained tyrosine hydroxylase alone, while the remaining part showed co-localization of tyrosine hydroxylase with all the other tested markers. These last neurons were immunoreactive, in decreasing percentages, for neuropeptide Y, leu-enkephalin, neuronal nitric oxide synthase, substance P, calcitonine gene related peptide, vasoactive intestinal polypeptide and vesicular acetylcholine transporter. The majority of non-catecholaminergic neurons were immunonegative for all the tested markers. The remaining non-catecholaminergic cells contained, in decreasing percentages, neuropeptide Y, neuronal nitric oxide synthase, leu-enkephalin, vasoactive intestinal polypeptide, vesicular acetylcholine transporter, substance P and calcitonine gene related peptide. Our findings documented the complexity of the neurochemical interactions that regulate both the motor functions of RPM and the blood flow through the muscle.

  19. Changes of serum calcium level following thyroid surgery--reasons and clinical implications.

    Science.gov (United States)

    Kovács, L; Góth, M I; Vörös, A; Hubina, E; Szilágyi, G; Szabolcs, I

    2000-01-01

    The reasons of transient hypocalcemia, frequently occurring after thyroid surgery, were investigated. Serum total calcium (seCa) and phosphorus (seP) levels were determined in 185 patients with benign nodular goiter before and after thyroid surgery. Beside these, in 27 additional patients, serum magnesium (seMg), total protein, albumin, calcitonin, parathormone (PTH) and 25-OH-D3 vitamin (25-OH-D3) levels were determined; corrected calcium (cCa) values, reflecting ionized calcium concentrations, were calculated. The daily changes of seCa and protein levels were measured in 20 patients. Another twenty patients, undergoing non-endocrinological surgery served as controls. Transient, mild but significant decrease of seCa was observed after surgery, while seP values were increased. Mild hypocalcemia (seCalevels was more pronounced in elderly, female patients. SeMg, total protein and albumin decreased, while cCa, PTH, calcitonin and 25-OH-D3 values did not change. Positive correlation was demonstrated between the change of seCa and albumin levels. Similar results were obtained in the general surgery group. In the thyroid operated group, in case of severe hypocalcemia, PTH levels decreased significantly into the pathological range. It may be concluded that transient, mild postoperative hypocalcemia is not a thyroid surgery-dependent phenomenon; it can also be observed after other operations accompanied by similar blood loss; in its development hypoalbuminemia plays a role. The causal role of PTH, calcitonin and 25-OH-D3 could not be proved in this study. Hypoparathyroidism can be responsible for the development of severe, prolonged hypocalcemia occurring at rare occasions.

  20. Genetic and Epigenetic of Medullary Thyroid Cancer

    Science.gov (United States)

    Khatami, Fatemeh; Tavangar, Seyed Mohammad

    2017-11-11

    Medullary thyroid carcinoma (MTC) is an infrequent, calcitonin producing neuroendocrine tumor and initiates from the parafollicular C cells of the thyroid gland. Several genetic and epigenetic alterations are collaterally responsible for medullary thyroid carcinogenesis. In this review article, we shed light on all the genetic and epigenetic hallmarks of MTC. From the genetic perspective, RET, HRAS, and KRAS are the most important genes that are characterized in MTC. From the epigenetic perspective, Ras-association domain family member 1A, telomerase reverse transcriptase promoter methylations, overexpression of histone methyltransferases, EZH2 and SMYD3, and wide ranging increase and decrease in non-coding RNAs can be responsible for medullary thyroid carcinogenesis.

  1. The calcium endocrine system of adolescent rhesus monkeys and controls before and after spaceflight

    Science.gov (United States)

    Arnaud, Sara B.; Navidi, Meena; Deftos, Leonard; Thierry-Palmer, Myrtle; Dotsenko, Rita; Bigbee, Allison; Grindeland, Richard E.

    2002-01-01

    The calcium endocrine system of nonhuman primates can be influenced by chairing for safety and the weightless environment of spaceflight. The serum of two rhesus monkeys flown on the Bion 11 mission was assayed pre- and postflight for vitamin D metabolites, parathyroid hormone, calcitonin, parameters of calcium homeostasis, cortisol, and indexes of renal function. Results were compared with the same measures from five monkeys before and after chairing for a flight simulation study. Concentrations of 1,25-dihydroxyvitamin D were 72% lower after the flight than before, and more than after chairing on the ground (57%, P animals.

  2. KATP channel openers in the trigeminovascular system

    DEFF Research Database (Denmark)

    Ploug, K.B.; Amrutkar, D.V.; Baun, M.

    2012-01-01

    The ATP-sensitive K(+) (K(ATP)) channel openers levcromakalim and pinacidil are vasodilators that induce headache in healthy people. The neuropeptide calcitonin gene-related peptide (CGRP) induces headache in healthy people and migraine in migraineurs, potentially through a mechanism that involves...... opening of vascular or neuronal K(ATP) channels and mast cell degranulation. Using rat as a model, we studied the molecular presence of K(ATP) channels in the trigeminovascular system. Furthermore, we examined whether K(ATP) channel openers stimulate the in vitro release of CGRP and whether...

  3. Emerging migraine treatments and drug targets

    DEFF Research Database (Denmark)

    Olesen, Jes; Ashina, Messoud

    2011-01-01

    Migraine has a 1-year prevalence of 10% and high socioeconomic costs. Despite recent drug developments, there is a huge unmet need for better pharmacotherapy. In this review we discuss promising anti-migraine strategies such as calcitonin gene-related peptide (CGRP) receptor antagonists and 5....... Tonabersat, a cortical spreading depression inhibitor, has shown efficacy in the prophylaxis of migraine with aura. Several new drug targets such as nitric oxide synthase, the 5-HT(1D) receptor, the prostanoid receptors EP(2) and EP(4), and the pituitary adenylate cyclase receptor PAC1 await development...

  4. Codon Y791F mutations in a large kindred: is prophylactic thyroidectomy always indicated?

    DEFF Research Database (Denmark)

    Vestergaard, Peter; Vestergaard, Else Marie; Brockstedt, Helle

    2007-01-01

    . Mutation analysis was done by direct bidirectional sequencing of PCR products on an ABI 3100 Genetic Analyzer (Applied Biosystems, Foster City, CA, USA). RESULTS: The index person was screened genetically due to goitre at a young age. A total of 27 members of the family underwent genetic testing. Twelve......: Eight members of a Danish family with the Y791F mutation participated. All gene carriers underwent pentagastrin testing, and measurements of serum calcitonin. In the index person, exons 10, 11, and 13-16 of the RET proto-oncogene were screened. In the rest of the individuals only exon 13 was analysed...

  5. Dendritic outgrowth of myenteric plexus neurons in primary culture.

    Science.gov (United States)

    Mulholland, M W; Romanchuk, G; Flowe, K

    1992-04-01

    Myenteric plexus neurons derived from neonatal guinea pigs, when exposed to serum, demonstrated a characteristic pattern of growth, including a proliferating outgrowth zone of glial cells, peripheral extension of dendritic processes, and progressive dendritic growth. Serum effects upon dendritic growth, measured morphometrically, was strongly dose- and temporally dependent. Dendritic density was increased 10-fold (120 hr) by the addition of 6% serum, while mean dendritic length was increased 3-fold. Development of cholinergic function was reflected by release of [3H]ACh in response to cholecystokinin octapeptide, vasoactive intestinal peptide, substance P, and calcitonin gene-related peptide (10(-10) and 10(-8) M).

  6. Influence of meal composition on postprandial peripheral plasma concentrations of vasoactive peptides in man

    DEFF Research Database (Denmark)

    Pedersen-Bjergaard, U; Høst, U; Kelbaek, H

    1996-01-01

    In a randomized cross-over study healthy non-obese male human subjects received standardized isocaloric, isovolumetric meals consisting of either carbohydrate, protein or fat and a non-caloric control meal consisting of an equal volume of water. Peripheral venous plasma concentrations of calcitonin...... that the postprandial peripheral plasma concentrations of CGRP, VIP and PYY are dependent on the caloric meal composition. The VIP, but not the CGRP and PYY concentrations seem to be influenced by gastric distension. The physiological significance of the postprandial alterations in peripheral concentrations...

  7. Positive inotropy mediated via CGRP receptors in isolated human myocardial trabeculae

    DEFF Research Database (Denmark)

    Saetrum Opgaard, O; Hasbak, P; de Vries, R

    2000-01-01

    Isometric contractile force were studied on isolated human myocardial trabeculae that were paced at 1.0 Hz in tissue baths. Alpha calcitonin gene-related peptide (alpha-CGRP) had a potent positive inotropic effect in most trabeculae from both the right atrium and left ventricle, and this effect...... was partially antagonized by the CGRP(1) receptor antagonist alpha-CGRP-(8-37) (10(-6) M). Amylin and the CGRP(2) receptor agonist [Cys(acetylmethoxy)(2, 7)]CGRP had a positive inotropic effect in some trabeculae, whereas adrenomedullin had no inotropic effect. Using reverse transcriptase-polymerase chain...

  8. Modern aspects of thyroid nodules diagnostic: radial diagnostic view

    Directory of Open Access Journals (Sweden)

    A V Borsukov

    2015-06-01

    Full Text Available In a discussion paper a number of Russian proposals in the draft Recommendations for the diagnosis of nodular goiter is proposed by the position of radiological diagnostics specialist. The ultrasound diagnostic section introduces the concept of an integrated ultrasound, which assesses not only the gray-scale features, but also color Doppler mapping and vascular elastography of the focus and organ. Fine-needle aspiration biopsy is proposed to carry out only under ultrasound navigation and multifocally. The problem of calcitonin should be considered from the perspective of false-positive and false-negative data and its optimal results after fine-needle aspiration biopsy.

  9. Conjugation-induced fluorescent labeling of proteins and polymers using dithiomaleimides.

    Science.gov (United States)

    Robin, Mathew P; Wilson, Paul; Mabire, Anne B; Kiviaho, Jenny K; Raymond, Jeffery E; Haddleton, David M; O'Reilly, Rachel K

    2013-02-27

    Dithiomaleimides (DTMs) with alkyl substituents are shown to be a novel class of highly emissive fluorophores. Variable solubility and further functionalization can easily be tailored through the choice of N and S substituents. Inclusion of a DTM unit into a ROP/RAFT initiator or insertion into the disulfide bond of salmon calcitonin (sCT) demonstrates the utility for fluorescent labeling of polymers and proteins. Simultaneous PEGylation and fluorescent labeling of sCT is also demonstrated, using the DTM unit as both a linker and a fluorophore. It is anticipated that DTMs will offer an attractive alternative to commonly used bulky, planar fluorophores.

  10. Lumbar canal stenosis.

    Science.gov (United States)

    Mazanec, D J; Drucker, Y; Segal, A M

    1997-04-01

    Lumbar canal stenosis is an increasingly recognized condition in patients more than 65 years of age. The clinical syndrome is dominated by neurogenic claudication. The natural history of the Condition is not yet well described. Long-term results of surgical therapy are frequently disappointing, and reoperation is required in more than 10% of patients. Nonoperative treatment options include physical therapy exercise programs, calcitonin, analgesics, and epidural steroid injections. A clinical pathway for management of symptomatic stenosis, emphasizing an initial nonoperative approach, is suggested.

  11. Mechanisms of calcium transport in small intestine. Progress report, March 1, 1976--September 30, 1977. [Chickens, rats, lead

    Energy Technology Data Exchange (ETDEWEB)

    DeLuca, H.F.

    1977-01-01

    Progress is reported on the following research projects: subcellular location of 1,25-dihydroxyvitamin D/sub 3/(1,25-(OH)/sub 2/D/sub 3/) in intestine of chickens; studies on receptor proteins in intestine for 1,25-(OH)/sub 2/D3; studies on intestinal cytosol receptors in chickens and rats; control of intestinal calcium transport; effect of calcitonin on 25-OH-D/sub 3/-1-hydroxylase; isolation and identification of the active principle of Solonum glaucophyllum, the South American plant that causes metastatic calcification and death to grazing animals; and studies on lead transport in vitro and in vivo. (HLW)

  12. Putative mechanisms of the relationship between obesity and migraine progression.

    Science.gov (United States)

    Bigal, Marcelo E; Lipton, Richard B

    2008-06-01

    Studies suggest that obesity is associated with migraine progression from an episodic into a chronic form. We discuss putative mechanisms to justify this relationship. Several of the inflammatory mediators that are increased in obese individuals are important in migraine pathophysiology, including interleukins and calcitonin gene-related peptide. Both migraine and obesity are prothrombotic states. Substances that are important in metabolic control are nociceptive at certain levels. Hypothalamic dysfunction in the orexin pathways seems to be a risk factor for both conditions. In addition, we discuss the importance of metabolic syndrome and autonomic dysfunction in modulating the obesity/migraine progression relationship.

  13. Carbopol-lectin conjugate coated liposomes for oral peptide delivery.

    Science.gov (United States)

    Werle, Martin; Makhlof, Abdallah; Takeuchi, Hirofumi

    2010-03-01

    Within the current study, a delivery system based on a novel polymer-lectin conjugate (carbopol-lectin) was evaluated for the oral delivery of therapeutic peptides and proteins. It was demonstrated that covalent attachment of lectin to carbopol does neither decrease nor abolish the specific binding properties of lectin. Bioadhesion studies revealed that liposomes coated with carbopol lectin are more bioadhesive than liposomes coated with unmodified carbopol. Finally, the in vivo data suggest that carbopol-lectin conjugate coated liposomes are effective oral peptide delivery systems which are capable of increasing the pharmacological effect of orally administered calcitonin.

  14. Sexual influence on bone metabolism in uremic patients on regular dialytic treatment.

    Science.gov (United States)

    Luisetto, G; Bertoli, M

    1994-01-01

    In order to evaluate the influence of sex on bone metabolism in patients on regular dialytic treatment, 82 patients (51 males and 31 females) were studied. All the women were amenorrheic and none of them took estrogens. Women showed radiological features of hyperparathyroidism more frequently than men and, in addition, higher bone GLA protein and lower calcitonin serum levels. In both sexes a significant positive correlation was observed between PTH and BGP, but the slope was higher in females, even though not significant. These results suggest that the uremic females show an increased skeletal sensitivity to PTH, probably due to the lack of protective effect of estrogens.

  15. Parosteal aneurysmal bone cyst☆

    Science.gov (United States)

    Meohas, Walter; de Sá Lopes, Ana Cristina; da Silveira Möller, João Victor; Barbosa, Luma Duarte; Oliveira, Marcelo Bragança dos Reis

    2015-01-01

    The incidence of aneurysmal bone cysts is 0.14 cases per 100,000 individuals. Parosteal aneurysmal bone cysts are the least prevalent subtype and represent 7% of all aneurysmal bone cysts. We present the case of a 38-year-old male patient with pain and bulging in his right arm for eight months. He had previously been diagnosed as presenting giant-cell tumor, but his slides were reviewed and his condition was then diagnosed as parosteal aneurysmal bone cyst. The patient was treated with corticosteroid and calcitonin infiltration into the lesion and evolved with clinical and radiological improvement within the first five weeks after the operation. PMID:26535209

  16. Innervation of the human middle meningeal artery

    DEFF Research Database (Denmark)

    Edvinsson, L; Gulbenkian, S; Barroso, C P

    1998-01-01

    The majority of nerve fibers in the middle meningeal artery and branching arterioles are sympathetic, storing norepinephrine and neuropeptide Y (NPY). A sparse supply of fibers contain acetylcholinesterase activity and immunoreactivity toward vasoactive intestinal peptide (VIP), peptidine histidine...... methionine (PHM), and calcitonin gene-related peptide (CGRP). Only few substance P and neuropeptide K immunoreactive fibers are noted. Electronmicroscopy shows axons and terminals at the adventitial medial border of the human middle meningeal artery, with a fairly large distance to the smooth muscle cells...

  17. Finding new drug targets for the treatment of migraine attacks

    DEFF Research Database (Denmark)

    Olesen, J; Tfelt-Hansen, P; Ashina, M

    2009-01-01

    No new preventive drugs specific to migraine have appeared for the last 20 years and existing acute therapies need improvement. Unfortunately, no animal models can predict the efficacy of new therapies for migraine. Because migraine attacks are fully reversible and can be aborted by therapy......, the headache- or migraine-provoking property of naturally occurring signalling molecules can be tested in a human model. This model has predicted efficacy of nitric oxide synthase inhibition and calcitonin gene-related peptide receptor blockade. The pharmaceutical industry should pay more attention to human...

  18. Q-T interval (QT(C)) in patients with cirrhosis: relation to vasoactive peptides and heart rate

    DEFF Research Database (Denmark)

    Henriksen, Jens Henrik Sahl; Gülberg, V; Fuglsang, S

    2007-01-01

    OBJECTIVE: Prolonged Q-T interval (QT) has been reported in patients with cirrhosis who also exhibit profound abnormalities in vasoactive peptides and often present with elevated heart rate (HR). The aim of this study was to relate QT to the circulating level of endothelins (ET-1 and ET-3......) and calcitonin gene-related peptide (CGRP) in patients with cirrhosis. In addition, we studied problems with HR correction of QT. MATERIAL AND METHODS: Forty-eight patients with cirrhosis and portal hypertension were studied during a haemodynamic investigation. Circulating levels of ETs and CGRP were determined...

  19. Investigation of Bone Health Subsequent to Vitamin D Supplementation in Children Following Burn Injury.

    Science.gov (United States)

    Mayes, Theresa; Gottschlich, Michele M; Khoury, Jane; Kagan, Richard J

    2015-12-01

    The effect of supplemental vitamin D on fracture occurrence following burn injuries is unclear. The objective of this study was to evaluate postintervention incidence of fractures in children during the rehabilitative phase postburn (PB) following participation in a randomized clinical trial of vitamin D supplementation. Follow-up for fracture evaluation was obtained in 39 of 50 patients randomized to daily enteral vitamin D2, D3, or placebo throughout the acute burn course. Serum 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, D2, D3, calcitonin, and bone alkaline phosphatase (BAP) measurements were obtained PB day 7, midpoint, discharge, and 1-year PB. Urinary calcium was obtained PB day 7 and midpoint. Dual-energy x-ray absorptiometry (DXA) was performed at discharge and 1-year PB. Fractures were reported in 6 of 39 respondents. Four fractures occurred in the placebo group, 2 in the D2 group, and none in the D3 group. Serum vitamin D, calcitonin, BAP, and urinary calcium were similar between fracture groups. The group with fracture morbidity had larger burn size (83.8% ± 4.9% vs 53.0% ± 2.9%, P vitamin D3 in reducing postdischarge fracture risk. Results reaffirm the importance of monitoring bone health in pediatric patients postburn. © 2015 American Society for Parenteral and Enteral Nutrition.

  20. Inhibition of neurogenic inflammation by the Amazonian herbal medicine sangre de grado.

    Science.gov (United States)

    Miller, M J; Vergnolle, N; McKnight, W; Musah, R A; Davison, C A; Trentacosti, A M; Thompson, J H; Sandoval, M; Wallace, J L

    2001-09-01

    This study was designed to determine if the Amazonian medicinal sangre de grado, confers benefit by suppressing the activation of sensory afferent nerves. (i) vasorelaxation of rat mesenteric arteries in response to calcitonin gene-related peptide; (ii) rat paw edema in response to protease- activating peptide receptor 2-activating peptide; (iii) rat paw hyperalgesia in response to low-dose protease-activating peptide receptor 2-activating peptide or prostaglandin E2; (iv) gastric hyperemia in response luminal capsaicin; (v) a clinical trial of a sangre de grado balm in pest control workers. The parent botanical was fractionated for evaluation of potential active components. In preconstricted rat mesenteric arteries, highly diluted sangre de grado (1:10,000) caused a shift to the right of the calcitonin gene-related peptide dose-response curve (p sangre de grado balm (1% concentration, p sangre de grado balm. A fraction possessing analgesic and capsaicin antagonistic properties was isolated and high-performance liquid chromatography and gas chromatography-mass spectrometry analysis indicated that it was a proanthocyandin oligomer. In pest control workers, sangre de grado balm (Zangrado) was preferred over placebo, for the relief of itching, pain, discomfort, edema, and redness in response to wasps, fire ants, mosquitoes, bees, cuts, abrasions, and plant reactions. Subjects reported relief within minutes. We conclude that sangre de grado is a potent inhibitor of sensory afferent nerve mechanisms and supports its ethnomedical use for disorders characterized by neurogenic inflammation.

  1. Structural Basis for Receptor Activity-Modifying Protein-Dependent Selective Peptide Recognition by a G Protein-Coupled Receptor.

    Science.gov (United States)

    Booe, Jason M; Walker, Christopher S; Barwell, James; Kuteyi, Gabriel; Simms, John; Jamaluddin, Muhammad A; Warner, Margaret L; Bill, Roslyn M; Harris, Paul W; Brimble, Margaret A; Poyner, David R; Hay, Debbie L; Pioszak, Augen A

    2015-06-18

    Association of receptor activity-modifying proteins (RAMP1-3) with the G protein-coupled receptor (GPCR) calcitonin receptor-like receptor (CLR) enables selective recognition of the peptides calcitonin gene-related peptide (CGRP) and adrenomedullin (AM) that have diverse functions in the cardiovascular and lymphatic systems. How peptides selectively bind GPCR:RAMP complexes is unknown. We report crystal structures of CGRP analog-bound CLR:RAMP1 and AM-bound CLR:RAMP2 extracellular domain heterodimers at 2.5 and 1.8 Å resolutions, respectively. The peptides similarly occupy a shared binding site on CLR with conformations characterized by a β-turn structure near their C termini rather than the α-helical structure common to peptides that bind related GPCRs. The RAMPs augment the binding site with distinct contacts to the variable C-terminal peptide residues and elicit subtly different CLR conformations. The structures and accompanying pharmacology data reveal how a class of accessory membrane proteins modulate ligand binding of a GPCR and may inform drug development targeting CLR:RAMP complexes. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  2. Spontaneous proliferative and neoplastic lesions in thyroid and parathyroid glands of nondomestic felids.

    Science.gov (United States)

    Pope, Jenny P; Steeil, James; Ramsay, Edward C; Reel, Danielle; Newman, Shelley J

    2017-01-01

    Based on microscopic and immunohistochemical characterization, we documented spontaneous proliferative and neoplastic lesions in the thyroid and parathyroid glands of nondomestic felids. Ten animals (4 leopards, 3 tigers, and 3 cougars), all with a previous diagnosis of thyroid neoplasia were identified from the University of Tennessee College of Veterinary Medicine database. The mean age of affected animals was 15.9 y. Twelve neoplasms were identified; 2 animals had 2 concurrent neoplasms. After immunohistochemical characterization using a panel of chromogranin A, thyroglobulin, and calcitonin, 7 of the former thyroid neoplasms were diagnosed as thyroid adenomas, 1 was diagnosed as a thyroid carcinoma, and 4 were diagnosed as parathyroid adenomas. No thyroid medullary neoplasms (C-cell tumors) were diagnosed in the current study. Most of the diagnosed neoplasms were benign (11 of 12), and metastasis was not documented in the single carcinoma. Only 2 animals were suspected to have functional neoplasms (1 thyroid adenoma and 1 parathyroid adenoma), based on associated tissue lesions or serum biochemistry. Other documented lesions in the thyroid and parathyroid glands included thyroid nodular hyperplasia ( n = 7), parathyroid hyperplasia associated with chronic renal disease ( n = 2), a thyroid abscess, and a branchial cyst. Parathyroid adenomas were more commonly diagnosed than expected in comparison with domestic cats. We demonstrated that an immunohistochemistry panel for thyroglobulin, calcitonin, and chromogranin A can be used to differentiate neoplasms of thyroid from parathyroid origin in nondomestic felids.

  3. Periosteum Metabolism and Nerve Fiber Positioning Depend on Interactions between Osteoblasts and Peripheral Innervation in Rat Mandible

    Science.gov (United States)

    Mauprivez, Cédric; Bataille, Caroline; Baroukh, Brigitte; Llorens, Annie; Lesieur, Julie; Marie, Pierre J.; Saffar, Jean-Louis; Biosse Duplan, Martin; Cherruau, Marc

    2015-01-01

    The sympathetic nervous system controls bone remodeling by regulating bone formation and resorption. How nerves and bone cells influence each other remains elusive. Here we modulated the content or activity of the neuropeptide Vasoactive Intestinal Peptide to investigate nerve-bone cell interplays in the mandible periosteum by assessing factors involved in nerve and bone behaviors. Young adult rats were chemically sympathectomized or treated with Vasoactive Intestinal Peptide or Vasoactive Intestinal Peptide10-28, a receptor antagonist. Sympathectomy depleted the osteogenic layer of the periosteum in neurotrophic proNerve Growth Factor and neurorepulsive semaphorin3a; sensory Calcitonin-Gene Related Peptide-positive fibers invaded this layer physiologically devoid of sensory fibers. In the periosteum non-osteogenic layer, sympathectomy activated mast cells to release mature Nerve Growth Factor while Calcitonin-Gene Related Peptide-positive fibers increased. Vasoactive Intestinal Peptide treatment reversed sympathectomy effects. Treating intact animals with Vasoactive Intestinal Peptide increased proNerve Growth Factor expression and stabilized mast cells. Vasoactive Intestinal Peptide10-28 treatment mimicked sympathectomy effects. Our data suggest that sympathetic Vasoactive Intestinal Peptide modulate the interactions between nervous fibers and bone cells by tuning expressions by osteogenic cells of factors responsible for mandible periosteum maintenance while osteogenic cells keep nervous fibers at a distance from the bone surface. PMID:26509533

  4. Association of bone mineral density, parameters of bone turnover, and body composition in patients with chronic obstructive pulmonary disease.

    Science.gov (United States)

    Fountoulis, Georgios A; Minas, Markos; Georgoulias, Panagiotis; Fezoulidis, Ioannis V; Gourgoulianis, Konstantinos I; Vlychou, Marianna

    2012-01-01

    Patients with chronic obstructive pulmonary disease (COPD) often develop osteoporosis. Many hormones regulate bone metabolism and body composition, and some of them are affected in COPD patients vs controls. In 46 COPD patients, we measured hip neck, total hip, lumbar spine, and whole-body T-score with dual-energy X-ray absorptiometry, parameters of body composition (body mass index [BMI], fat mass index [FMI], and fat-free mass index [FFMI]), and adiponectin, leptin, parathormone, osteocalcin, calcitonin, and insulin-like growth factor I (IGF-I) serum levels and correlated them with COPD stage. Our results suggest that total hip bone mineral density (BMD) is affected by FFMI and COPD stage; lumbar spine BMD is affected by FMI and COPD stage; and whole-body BMD is affected by BMI, COPD stage, and leptin. Adiponectin, parathormone, osteocalcin, calcitonin, and IGF-I levels were not significantly correlated to BMD at any of the measured sites. Our findings are in agreement with the current literature in that a decline in lung function is correlated to a decline in BMD. Copyright © 2012 The International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved.

  5. Lack of adrenomedullin in the central nervous system results in apparently paradoxical alterations on pain sensitivity.

    Science.gov (United States)

    Fernández, Ana P; Serrano, Julia; Martínez-Murillo, Ricardo; Martínez, Alfredo

    2010-10-01

    Adrenomedullin (AM) is a regulatory peptide, coded by the adm gene, which is involved in numerous physiological processes, including pain sensitivity. Previous studies have shown that intrathecal injection of AM induced hyperalgesia in the rat. Here, we explore pain sensitivity in a mouse conditional knockout for adm in neurons of the central nervous system, including the spinal cord and dorsal root ganglia. Double immunofluorescence in wild-type (WT) animals shows that AM immunoreactivity is found in calcitonin gene-related peptide-positive neurons of the dorsal root ganglia but not in neurons that bind isolectin B4. Mice lacking adm had modified expression of canonical sensorial neuropeptides, having significantly more calcitonin gene-related peptide and less substance P and enkephalin than their WT littermates. Furthermore, the spinal cord of adm knockout mice expressed higher levels of the AM receptor components, suggesting a compensation attempt to deal with the lack of afferent AM signaling. Behavioral nociceptive tests also found differences between genotypes. In the tail-flick test, which measures mostly spinal reflexes, the adm-null animals had a longer latency than their WT counterparts. On the other hand, in the hotplate test, which requires encephalic processing, mice lacking adm had shorter latencies than normal littermates. These results suggest that AM acts as a nociceptive modulator in spinal reflexes, whereas it may have an analgesic function at higher cognitive levels. This study confirms the important role of AM in pain sensitivity processing but unveils a more complex scenario than previously surmised.

  6. Adrenomedullin A Novel Peptide Requires Coordination Of Genetic Physiologic And Environmental Factors

    Directory of Open Access Journals (Sweden)

    K. R. Padma

    2015-08-01

    Full Text Available A healthy pregnancy requires strict coordination of genetic physiologic and environmental factors. The relatively common incidence of infertility and pregnancy complications has resulted in increased interest in understanding the mechanisms that underlie normal versus abnormal pregnancy. The peptide hormone adrenomedullin has recently been the focus of some exciting breakthroughs in the pregnancy field. Adrenomedullin ADM is a 52-amino acid peptide with structural homology to calcitonin gene-related peptide CGRP initially isolated from human pheochromocytoma. ADM is synthesized by many mammalian tissues including the adrenal medulla endothelial and vascular smooth muscle cells myocardium and central nervous system. ADM binds to plasma membrane receptors composed of calcitonin receptor-like receptor CRLR a member of serpentine receptor superfamily and receptor activity modifying protein RAMP type 2 or 3. ADM has also some affinity for CGRP receptor composed of CRLR and RAMP1. Supported by mechanistic studies in genetic animal models there continues to be a growing body of evidence demonstrating the importance of adrenomedullin protein levels in a variety of human pregnancy complications. With measurement of foetal resorption sites we can examine the importance of adrenomedullin a peptide hormone in pregnancy which alters due to genetic physiologic and environmental factors. A growing body of evidence illustrates AM as a pivotal component in normal physiology and disease with marked beneficial effects in the host defense mechanism.

  7. Analysis of nerve and neuropeptide patterns in vacuum-assisted closure-treated diabetic murine wounds.

    Science.gov (United States)

    Younan, George; Ogawa, Rei; Ramirez, Michelle; Helm, Douglas; Dastouri, Pouya; Orgill, Dennis P

    2010-07-01

    Reestablishment of the peripheral nervous system occurs in parallel with wound healing. With accelerated wound healing seen with the vacuum-assisted closure device, the authors studied its effects on nerve fiber regeneration, nerve sprouting, and the stimulation of neuropeptides and neurotrophins. A vacuum-assisted closure device was applied to a full-thickness diabetic mouse wound using continuous or cyclical modes and compared with foam dressing or occlusive dressing controls, using 10 mice per group. Nerve fibers, substance P, calcitonin gene-related peptide, and nerve growth factor were analyzed using two-dimensional immunohistochemistry and real-time reverse-transcriptase polymerase chain reaction. A significant increase in dermal and epidermal nerve fiber densities and in substance P, calcitonin gene-related peptide, and nerve growth factor expression was seen in vacuum-assisted closure-treated wounds. Cyclical treatment mode correlated with the largest increase in granulation tissue production, wound surface microdeformations, and a slightly faster wound closure rate. This study suggests that vacuum-assisted closure therapy can modulate nerve fiber and neuropeptide production in the wound. Optimized kinetics of vacuum-assisted closure application may provide an opportunity for clinicians to further improve wound healing in denervated wounds such as pressure sores and diabetic foot ulcerations.

  8. In vitro and in vivo evaluation of WGA-carbopol modified liposomes as carriers for oral peptide delivery.

    Science.gov (United States)

    Makhlof, Abdallah; Fujimoto, Shiho; Tozuka, Yuichi; Takeuchi, Hirofumi

    2011-02-01

    Surface modification of liposomal nanocarriers with a novel polymer-lectin conjugate was proposed for enhancing the systemic uptake of encapsulated peptide and protein therapeutics after oral administration. Wheat germ agglutinin (WGA) was covalently attached to carbopol (CP) using the carbodiimide method. The prepared WGA-CP conjugate retained the biological cell binding activity of WGA without any evidence of cytotoxicity to Caco-2 monolayers. Cationic liposomes in the size range of 100 nm were prepared by the lipid film hydration method followed by probe sonication and surface modification with negatively charged WGA-CP. The uptake of WGA-CP liposomes by Caco-2 cells was significantly higher than that of non-modified or CP liposomes. The uptake was dependent on the surface concentration of WGA, temperature, and incubation period and was significantly inhibited in the presence of chlorpromazine and 10-fold excess of free WGA. These results suggest the involvement of active transport mechanism for the cellular uptake of the modified liposomes, mediated mainly by binding of WGA to its specific cell membrane receptors. Dual channel confocal microscopy confirmed the simultaneous association and internalization of the polymer conjugate and the liposomal carrier by Caco-2 cells and intestinal membrane of rats. In addition, the pharmacological efficacy of calcitonin, a model peptide drug, was enhanced by more than 20- and 3-fold following peroral administration of calcitonin-loaded WGA-CP liposomes when compared to non-modified and CP liposomes, respectively. Copyright © 2010 Elsevier B.V. All rights reserved.

  9. Surface modification of liposomes using polymer-wheat germ agglutinin conjugates to improve the absorption of peptide drugs by pulmonary administration.

    Science.gov (United States)

    Murata, Mitsutaka; Yonamine, Takashi; Tanaka, Shota; Tahara, Kohei; Tozuka, Yuichi; Takeuchi, Hirofumi

    2013-04-01

    In this study, we investigated the feasibility of a system based on liposomal surface modification with a novel mucoadhesive polymer-lectin conjugate for the pulmonary delivery of therapeutic peptides and proteins. We covalently attached wheat germ agglutinin (WGA), a ligand that specifically interacts with alveolar epithelial cells, to carbopol (CP), a mucoadhesive polymer, using the carbodiimide method and then evaluated the efficacy and potential toxicity of CP-WGA surface-modified liposomes in vivo and in vitro. In association studies, CP-WGA modification enhanced the interaction with A549 lung epithelial cells compared with unmodified or CP-modified liposomes. This increased association was dependent on temperature and the surface concentration of free WGA. These results suggested synergy of WGA and CP, and retention of the biological cell binding activity of WGA, leading to improved liposome-cell interactions. Moreover, improvement of liposomal bioadhesion to lung epithelia significantly enhanced and prolonged the therapeutic efficacy of calcitonin, a model peptide drug, without any evidence of toxicity, following administration of calcitonin-loaded CP-WGA-modified liposomes. Hence, surface modification of liposomes with CP-WGA has potential for effective pulmonary administration of peptides. Copyright © 2013 Wiley Periodicals, Inc.

  10. Evaluation of symptomatic slow-acting drugs in osteoarthritis using the GRADE system

    Directory of Open Access Journals (Sweden)

    Rizzoli René

    2008-12-01

    Full Text Available Abstract Background Symptomatic slow-acting drugs (SYSADOA have been largely studied over the last decade. The objective of this study is to prepare a document providing recommendations for the use of SYSADOA in osteoarthritis (OA. Methods The following interventions were taken into consideration: avocado/soybean unsaponifiables, chondroitin sulfate, diacereine, glucosamine sulfate, hyaluronic acid, oral calcitonin, risedronate, strontium ranelate. Recommendations were based on the GRADE (Grading of Recommendations Assessment, Development and Evaluation system. The GRADE system is based on a sequential assessment of the quality of evidence, followed by assessment of the balance between benefits versus downsides and subsequent judgment about the strength of recommendations. Results Chondroitin sulfate, diacereine, glucosamine sulfate, avocado/soybean unsaponifiables and hyaluronic acid have demonstrated pain reduction and physical function improvement with very low toxicity, with moderate to high quality evidence. Even if pre-clinical data and some preliminary in vivo studies have suggested that oral calcitonin and strontium ranelate could be of potential interest in OA, additional well-designed studies are needed. Conclusion In the benefit/risk ratio, the use of chondroitin sulfate, diacereine, glucosamine sulfate, avocado/soybean unsaponifiables and hyaluronic acid could be of potential interest for the symptomatic management of OA.

  11. Clinical biochemistry of epilepsy. II. Observations on two types of epileptiform convulsions induced in rabbits with corticotropin.

    Science.gov (United States)

    Natelson, S; Miletich, D J; Seals, C F; Visintine, D J; Albrecht, R F

    1979-06-01

    We propose than an alarm mechanism is operative in animals, designed to regulate neuromuscular irritability by regulating [Ca2+]. Epinephrine or corticotropin (ACTH), injected intramuscularly into animals, causes a hypercitricemia, resulting in decreased [Ca2+]. This increases muscular excitability to facilitate escape. To avoid over reaction, [Cl-] is shifted into the plasma without a concomitant shift of Na+, thus generating an acidosis and an increase in ionization of Ca. Plasma pH, pCO2, total CO2, and [K+] decrease, and [Mg2+] increases. The acidosis, decrease in K+, and increase in [Mg2+] serve to counteract the effect of the decrease in [Ca2+], to protect against tetany. In the rabbit the hypercitricemia observed upon ACTH administration is accompained by a severe hypocalcemia and drop in blood pressure, resluting in tetanic convulsions. This seems to indicate calcitonin release, independent of the hypercitricemia. Thyroidectomized rabbits show only mild hypocalcemia when given ACTH, but develop a severe acidosis and typical grand mal epileptiform seizures. Administration of ACTH and then calcitonin to the goat, an animal resistant to the effects of ACTH alone, simulates the effect observed in the rabbit with respect to changes in blood components and blood pressure. Changes in the blood in the goat and rabbit resemble those in humans before an epileptic seizure. alpha-Melanotropin, containing a portion of the ACTH sequence, reacts in a manner similar to ACTH but more rapidly.

  12. The Anti-Osteoporotic Drug Preferences of Physiatrists: A Multicenter Descriptive Study

    Directory of Open Access Journals (Sweden)

    Yeşim Gökçe Kutsal

    2012-08-01

    Full Text Available Aim: The purpose of this multicenter descriptive study is to determine the preferences of physiatrists in our country for anti-osteoporotic drugs in patients with primary and secondary osteoporosis. Materials and Methods: This study was carried out in 10 provinces of Turkey. The diagnosis of osteoporosis was based on World Health Organization criteria using dual-energy x-ray absorptiometry. Patients with a spine and/or hip T-score ≤-2.5 were considered as osteoporotic. 714 patients over 18 years old with primary or secondary osteoporosis were included in the study. In addition to socio-demographic characteristics and chronic use of medications and/or additional systemic diseases that cause secondary osteoporosis were questioned and antiosteoporotic drugs that are recommended by their physicians were recorded.Results: The physicians’ preferred vitamin D and calcium as the prior treatment both in primary and secondary osteoporosis. The most commonly used anti-osteoporotic agent was alendronate from the biphosphonate group. It was followed by ibandronate, risedronate, strontium ranelate, calcitonin, zoledronate, raloxifene, parathyroid hormone (PTH and hormone replacement therapy (HRT in the primary osteoporosis and risedronate, ibandronate, calcitonin, strontium ranelate, zoledronate, PTH, HRT and raloxifene in the secondary osteoporosis, respectively. Conclusion: The physician should choose the most suitable treatment for the patient based on fracture risk, medical history, previous treatments for osteoporosis, concomitant diseases, treatment-induced risks and benefits, and the relation between financial cost and potential benefit. (Turkish Journal of Osteoporosis 2012;18: 42-6

  13. Perioperative Pain Management Strategies for Amputation: A Topical Review.

    Science.gov (United States)

    Kent, Michael L; Hsia, Hung-Lun John; Van de Ven, Thomas J; Buchheit, Thomas E

    2017-03-01

    To review acute pain management strategies in patients undergoing amputation with consideration of preoperative patient factors, pharmacologic/interventional modalities, and multidisciplinary care models to alleviate suffering in the immediate post-amputation setting. Regardless of surgical indication, patients undergoing amputation suffer from significant residual limb pain and phantom limb pain in the acute postoperative phase. Most studies have primarily focused on strategies to prevent persistent pain with inclusion of immediate postoperative outcomes as secondary measures. Pharmacologic agents, including gabapentin, ketamine, and calcitonin, and interventional modalities such as neuraxial and perineural catheters, have been examined in the perioperative period. Focused Literature Review. Pharmacologic agents (gabapentin, ketamine, calcitonin) have not shown consistent efficacy. Neuraxial analgesia has demonstrated both an opioid sparing and analgesic benefit while results have been mixed regarding perineural catheters in the immediate post-amputation setting. However, several early studies of perineural catheters employed sub-optimal techniques (distal surgical placement), and prolonged use of perineural catheters may provide a sustained benefit. Regardless of analgesic technique, a multidisciplinary approach is necessary for optimal care. Patient-tailored analgesic regimens utilizing catheter-based techniques are essential in the acute post-amputation phase and should be implemented in all patients undergoing amputation. Future research should focus on improved measurement of acute pain and comparisons of effective analgesic regimens instead of single techniques.

  14. Toll-like receptor 4 signaling contributes to Paclitaxel-induced peripheral neuropathy.

    Science.gov (United States)

    Li, Yan; Zhang, Haijun; Zhang, Hongmei; Kosturakis, Alyssa K; Jawad, Abdul Basit; Dougherty, Patrick M

    2014-07-01

    This paper tests the contribution of the toll-like receptors, TLR4 in particular, in the initiation and maintenance of paclitaxel-related chemotherapy-induced peripheral neuropathy. TLR4 and its immediate downstream signaling molecules-myeloid differentiation primary response gene 88 (MyD88) and toll/interleukin 1 receptor domain-containing adapter-inducing interferon-β (TRIF)-were found to be increased in the dorsal root ganglion (DRG) using Western blot by day 7 of paclitaxel treatment. The behavioral phenotype, the increase of both TLR4 and MyD88, was blocked by cotreatment with the TLR4 antagonist lipopolysaccharide-Rhodobacter sphaeroides during chemotherapy. A similar, but less robust, behavioral effect was observed using intrathecal treatment of MyD88 homodimerization inhibitory peptide. DRG levels of TLR4 and MyD88 reduced over the next 2 weeks, whereas these levels remained increased in spinal cord through day 21 following chemotherapy. Immunohistochemical analysis revealed TLR4 expression in both calcitonin gene-related peptide-positive and isolectin B4-positive small DRG neurons. MyD88 was only found in calcitonin gene-related peptide-positive neurons, and TRIF was found in both calcitonin gene-related peptide-positive and isolectin B4-positive small DRG neurons as well as in medium- and large-size DRG neurons. In the spinal cord, TLR4 was only found colocalized to astrocytes but not with either microglia or neurons. Intrathecal treatment with the TLR4 antagonist lipopolysaccharide-R. sphaeroides transiently reversed preestablished chemotherapy-induced peripheral neuropathy mechanical hypersensitivity. These results strongly implicate TLR4 signaling in the DRG and the spinal cord in the induction and maintenance of paclitaxel-related chemotherapy-induced peripheral neuropathy. The toll-like receptor TLR4 and MyD88 signaling pathway could be a new potential therapeutic target in paclitaxel-induced painful neuropathy. Copyright © 2014 American Pain

  15. [PREOPERATIVE DIAGNOSTICS OF THYROID MEDULLARY CARCINOMA WITH EMPHASIS ON CYTOMORPHOLOGICAL FEATURES AND DIFFERENTIAL DIAGNOSIS OF PRIMARY AND SECONDARY THYROID TUMORS].

    Science.gov (United States)

    Katović, Sandra Kojić; Vasilj, Ankica

    2014-12-01

    Medullary thyroid cancer is a rare neuroendocrine neoplasm that arises from the parafollicular C cells that produce calcitonin, a hormone essential for the regulation of calcium metabolism. It accounts for 4%-10% of all thyroid cancers. In most cases (75%-80%), it is sporadic, while in other cases it is part of the multiple endocrine neoplasia (MEN) syndrome. Most often, medullary thyroid carcinoma is presenting as a solitary nodule. At the time of diagnosis, about half of the patients have enlarged cervical lymph nodes, while a small number of patients have distant metastases in the liver, lungs, bones and brain. If the tumor is hormone active, the patient may have systemic symptoms such as diarrhea or flushing. Ultrasonically, medullary carcinoma usually appears as a hypoechogenic node with marked vascularity and uneven contours that can sometimes contain microcalcifications, and in most cases is located in the upper poles of the thyroid. The sample obtained by fine needle aspiration is usually cellular, tumor cells are disseminated or arranged in poorly cohesive groups. They are most often plasmacytoid, but sometimes can also be spindled. The nuclei are eccentric and chromatin shows features of neuroendocrine tumors. Cytoplasms of tumor cells are abundant, triangular or polygonal, amphophilic, finely granulated and unsharply limited. Background is clean and sometimes amyloid can be found. Depending on the cytologic picture, differential diagnostic problems can be well differentiated thyroid tumors, primarily follicular neoplasm, lymphomas, poorly differentiated insular carcinoma, metastatic small cell carcinoma, mesenchymal tumors or melanoma. In case of differential diagnostic difficulties, of great help is to determine calcitonin immunocytochemically or in aspirate or serum. Medullary carcinoma may show low progression and long-time survival, but can also be a rapidly progressive tumor where survival is measured in months. Good prognostic indicators are

  16. Evolution of the CT/CGRP family: comparative study with new data from models of teleosts, the eel, and cephalopod molluscs, the cuttlefish and the nautilus.

    Science.gov (United States)

    Lafont, Anne-Gaëlle; Dufour, Sylvie; Fouchereau-Peron, Martine

    2007-01-01

    In mammals, alternative splicing of the calcitonin gene generates two distinct peptides: calcitonin (CT), synthesised in the thyroid C cells and involved in the regulation of calcium metabolism, and calcitonin gene-related peptide (CGRP), brain neuromediator synthesised in the peripheral and central nerves. CGRP is well represented and molecularly conserved during evolution whereas CT has not been detected in any of the invertebrates analysed so far. In order to better understand the evolution of this CT/CGRP peptide family we reviewed the major data concerning its evolution from the literature and our recent data obtained in models of teleosts and cephalopod molluscs. The presence of both CGRP-like molecules and its specific bindings sites in the central nervous system of eel, cuttlefish and nautilus, suggests that the brain neurotransmitter role of CGRP could represent an ancient role in metazoa, already present in cephalopods and conserved among vertebrates, as still observed in mammals. In contrast, the presence of CGRP specific binding sites, and not the peptide itself, in the gills suggests an endocrine role for CGRP, in cephalopods and teleosts, that may have been lost during the evolution of the tetrapod lineage. These data, and the absence of CT-like molecules that we observed in cephalopods, support the hypothesis that CGRP represents the ancestral molecule of the CT/CGRP family, appeared in metazoa before the vertebrate emergence. The distinction between CT and CGRP receptors appears to be an event posterior to the emergence of ecdysozoan and lophotrochozoan protostomes, probably in relation to the CT appearance. The evolution of the CT/CGRP peptide family is probably similar to the evolution of the CT/CGRP receptor family. In fact, the genic duplication that induced the appearance of the two separate molecules, CT and CGRP, may constitute an event close to that, which induced the appearance of the two specific receptors. These events remain to be

  17. [Postoperative external beam radiotherapy for medullary thyroid carcinoma with high risk of locoregional relapse].

    Science.gov (United States)

    Compagnon, F; Zerdoud, S; Rives, M; Laprie, A; Sarini, J; Grunenwald, S; Chaltiel, L; Graff, P

    2016-07-01

    To assess the outcome of locally advanced medullary thyroid carcinoma treated with surgery and adjuvant external beam radiotherapy. Twenty-nine consecutive patients with non-metastatic medullary thyroid carcinoma treated in our institution between January 1995 and December 2012 were retrospectively evaluated. All underwent curative-intended optimal surgery, followed by external beam radiotherapy because of high risk of locoregional relapse. Twelve patients were stage III, 16 IVa and 1 IVb. Positive surgical margins were present in 11 cases (10 R1 and 1 R2). Median and average preradiotherapy serum calcitonin were 141pg/mL and 699pg/mL, respectively. Fourteen patients received 3D-conformal radiotherapy and 15 received intensity-modulated radiotherapy. Median prescribed dose was 63Gy to the high-risk volumes and 54Gy to the low-risk volumes. Treatment was delivered in 30 fractions. The median gap between surgery and radiotherapy was 1.9months. Median follow-up was 76.4months. Kaplan-Meier estimates of 5-year locoregional relapse-free survival and overall survival were 79 and 96 %, respectively. Among the five locoregional relapses, two were related to a macroscopic metastatic cervical lymph node that was unfortunately not removed during the lymphadenectomy. Eight of ten patients with microscopic positive margins (R1) were controlled regarding the thyroidectomy bed. Eight patients had normal serum calcitonin after external beam radiotherapy, of whom only one developed a locoregional relapse during follow-up. Regarding the 21 patients with persistent positive serum calcitonin after treatment, only ten developed a macroscopic locoregional or distant relapse. One grade III and no grade IV acute morbidity were reported. Fifteen patients reported grade II chronic morbidity and no grade III/IV. Maximal surgery followed by adjuvant external beam radiotherapy as a treatment for locally advanced medullary thyroid carcinoma provides a high rate of long

  18. The distribution of kisspeptin and its receptor GPR54 in rat dorsal root ganglion and up-regulation of its expression after CFA injection.

    Science.gov (United States)

    Mi, Wen-Li; Mao-Ying, Qi-Liang; Liu, Qiong; Wang, Xiao-Wei; Li, Xiu; Wang, Yan-Qing; Wu, Gen-Cheng

    2009-03-16

    Kisspeptin/GPR54 system plays a crucial role in the control of puberty onset and reproductive function. In the present study, we gave the first report that kisspeptin and GPR54 were expressed in the small- to large-sized neurons, and co-localized with Bandeiraea simplicifolia isolectin B4 (IB4), calcitonin-gene-related peptide (CGRP) and neurofilament 200 (NF200) in the L4/5 dorsal root ganglion (DRG) of naïve rats, detected by the double immunofluorescent staining. Interestingly, a marked elevation in the levels of KiSS-1 and GPR54 mRNA as well as protein was observed in the spinal dorsal horn and DRG 4 and 14 days following intra-articular injection of complete Freund's adjuvant (CFA), indicating a possible involvement of the kisspeptin/GPR54 system in chronic inflammatory pain.

  19. The role of anti-CGRP antibodies in the pathophysiology of primary headaches.

    Science.gov (United States)

    Barbanti, Piero; Aurilia, Cinzia; Fofi, Luisa; Egeo, Gabriella; Ferroni, Patrizia

    2017-05-01

    Calcitonin gene-related peptide (CGRP), a potent vasodilator and pain-signaling neuropeptide, is a validated therapeutic target for migraine and cluster headache. Four anti-CGRP monoclonal antibodies (mAbs) have been developed, representing the first specific, mechanism-based, migraine prophylactic treatment. CGRP mAbs demonstrated good efficacy coupled to excellent tolerability and safety in 5 phase II clinical trials. Notably, CGRP mAbs induced complete migraine remission in a patients' subset. To date, more than 20 phase III trials using CGRP mAbs for of episodic and chronic migraine and cluster headache prevention are ongoing. Future investigations will shed light on migraine endophenotypes predictive of good CGRP mAbs responsiveness and provide answers on their long-term cardiovascular safety.

  20. Arterial hypertension and chronic liver disease

    DEFF Research Database (Denmark)

    Henriksen, Jens Henrik Sahl; Møller, S

    2005-01-01

    , calcitonin gene-related peptide, nitric oxide, and other vasodilators, and is most pronounced in the splanchnic area. This provides an effective (although relative) counterbalance to raised arterial blood pressure. Subjects with arterial hypertension (essential, secondary) may become normotensive during...... the development of chronic liver disease, and arterial hypertension is rarely manifested in patients with cirrhosis, even in those with renovascular disease and high circulating renin activity. There is much dispute as to the understanding of homoeostatic regulation in cirrhotic patients with manifest arterial......This review looks at the alterations in the systemic haemodynamics of patients with chronic liver disease (cirrhosis) in relation to essential hypertension and arterial hypertension of renal origin. Characteristic findings in patients with cirrhosis are vasodilatation with low overall systemic...

  1. Dosing rationale for liraglutide in type 2 diabetes mellitus: a pharmacometric assessment.

    Science.gov (United States)

    Ingwersen, Steen H; Khurana, Manoj; Madabushi, Rajanikanth; Watson, Estelle; Jonker, Daniël M; Le Thi, Tu Duyen; Jacobsen, Lisbeth V; Tornøe, Christoffer W

    2012-12-01

    The glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide was approved in 2010 by the US Food and Drug Administration (FDA) as an adjunct treatment to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. This article provides insights into the use of pharmacometric analyses for regulatory review with a focus on the dosing recommendations. The assessment was based on the totality of exploratory and confirmatory analysis of dose-finding and pivotal clinical data and was structured around a set of key questions in accordance with current FDA review practice. For the pharmacometric review of liraglutide, the key questions focused on exposure-response relationships for effects on fasting plasma glucose, hemoglobin A(1c), and calcitonin and on variability in exposure across demographic subgroups of patients. The importance of conducting exploratory exposure-response analysis and population pharmacokinetic studies in clinical drug development to support dosing recommendations is highlighted.

  2. Profiles of blood biomarkers in alternating hemiplegia of childhood--increased MMP-9 and decreased substance P indicates its pathophysiology.

    Science.gov (United States)

    Inui, Takehiko; Saito, Yoshiaki; Sakuma, Hiroshi; Hatakeyama, Hideyuki; Goto, Yu-ichi; Arai, Hidee; Sasaki, Masayuki

    2012-03-01

    Alternating hemiplegia of childhood (AHC) is a rare disorder characterized by repeated plegic attacks, movement disorders, autonomic phenomena, and developmental delay. To obtain insights into the pathophysiology of AHC, we determined the concentrations of matrix metalloproteinase-9 (MMP-9), tissue inhibitor of MMP-1 (TIMP-1), calcitonin gene-related peptide (CGRP), and substance P (SP) in the serum/plasma of AHC patients (n=6) and control subjects (n=11) by performing enzyme-linked immunosorbent assay (ELISA). Decreased levels of serum SP (382±161 pg/ml), increased levels of plasma MMP-9 (111.0±99.3 ng/mL) and increased MMP-9/TIMP-1 ratio (0.65±0.44) were revealed, compared to those in control subjects (SP: 620±223 pg/mL, pChild Neurology. Published by Elsevier B.V. All rights reserved.

  3. Recent advances in the management of migraine [version 1; referees: 3 approved

    Directory of Open Access Journals (Sweden)

    Mark Obermann

    2016-11-01

    Full Text Available Migraine remains one of the most disabling disorders worldwide. The high prevalence in the general population and the often-delicate treatment of patients account for that. Therapeutic management of migraine relies mainly on non-specific medical treatment and is affected by low patient adherence to the treatment regimens applied. The introduction of specific anti-migraine treatment occurred over 20 years ago when the first triptan was approved by regulatory authorities (sumatriptan, 28 December 1992. Triptan use is limited by side effects, time- and frequency-restricted application, and the risk of developing medication overuse headache. Within the past few years, new and promising drugs such as more specific 5-HT 1F receptor agonists (that is, lasmiditan and monoclonal calcitonin gene-related peptide (CGRP receptor antibodies entered advanced development phases while non-invasive neuromodulatory approaches were suggested to be potentially effective as non-pharmaceutical interventions for migraine.

  4. Glukokortikoid-induzierte Osteoporose

    Directory of Open Access Journals (Sweden)

    Gasser RW

    2001-01-01

    Full Text Available Die Osteoporose ist eine gravierende Nebenwirkung einer langfristigen Glukokortikoid-Therapie. Steroide wirken sich negativ auf den Knochenstoffwechsel aus, vorwiegend durch Hemmung der Osteoblastenaktivität, durch Verminderung der enteralen Kalziumabsorption, durch Steigerung der renalen Kalziumausscheidung sowie durch einen steroidinduzierten Hypogonadismus. Eine langfristige Steroidtherapie führt zu einer Abnahme der Knochendichte und in der Folge zu einer erhöhten Frakturinzidenz. Die Glukokortikoid-induzierte Osteoporose ist potentiell reversibel, daher sind präventive und therapeutische Maßnahmen bei jeder langfristigen Glukokortikoid-Therapie (5 mg oder mehr Prednison-Äquivalent über 3 oder mehr Monate erforderlich. Bisphosphonate sind die derzeit wirksamsten Medikamente in Prävention und Therapie der Glukokortikoid-induzierten Osteoporose. Eine Basistherapie mit Kalzium und Vitamin D sollte grundsätzlich erfolgen. Effektiv ist eine Hormonersatztherapie bei postmenopausalen Frauen. Adjuvant stehen Vitamin D-Metabolite und Calcitonin zur Verfügung.

  5. The calcium endocrine system of adolescent rhesus monkeys and controls before and after spaceflight

    Science.gov (United States)

    Arnaud, Sara B.; Navidi, Meena; Deftos, Leonard; Thierry-Palmer, Myrtle; Dotsenko, Rita; Bigbee, Allison; Grindeland, Richard E.

    2002-01-01

    The calcium endocrine system of nonhuman primates can be influenced by chairing for safety and the weightless environment of spaceflight. The serum of two rhesus monkeys flown on the Bion 11 mission was assayed pre- and postflight for vitamin D metabolites, parathyroid hormone, calcitonin, parameters of calcium homeostasis, cortisol, and indexes of renal function. Results were compared with the same measures from five monkeys before and after chairing for a flight simulation study. Concentrations of 1,25-dihydroxyvitamin D were 72% lower after the flight than before, and more than after chairing on the ground (57%, P endocrine system were similar to the effects of chairing on the ground, but were more pronounced. Reduced intestinal calcium absorption, losses in body weight, increases in cortisol, and higher postflight blood urea nitrogen were the changes in flight monkeys that distinguished them from the flight simulation study animals.

  6. Preventing recurrence of reflex sympathetic dystrophy in patients requiring an operative intervention at the site of dystrophy after surgery.

    Science.gov (United States)

    Marx, C; Wiedersheim, P; Michel, B A; Stucki, G

    2001-01-01

    The development of reflex sympathetic dystrophy (RSD) is a common complication after surgery. Exacerbation or recurrence of RSD is a major concern after a second intervention at the site of previous surgery and consecutive RSD. It is unclear whether the risk of recurrent RSD can be reduced by using appropriate precautions. The objective of our study was to examine, in a case series of consecutive patients, whether recurrences in patients with a history of RSD after surgery, who were reoperated at the same location, can be avoided by using a standardised intervention protocol containing perioperative calcitonin prophylaxis. None of the patients experienced a recurrence of RSD. We concluded that the recurrence of RSD in patients requiring operative intervention at the site of former dystrophy after surgery appears to be unlikely with careful perioperative management.

  7. Sygdomsmekanismer og nye behandlingsmetoder ved migræne

    DEFF Research Database (Denmark)

    Hansen, Jakob Møller; Ashina, Messoud

    2016-01-01

    Migraine is the most prevalent disabling neurological disorder. The management of patients with migraine has been hampered by lack of effective and well-tolerated acute and preventive therapies. Based on improved insights into the basic mechanisms of migraine, new and targeted treatments are curr......Migraine is the most prevalent disabling neurological disorder. The management of patients with migraine has been hampered by lack of effective and well-tolerated acute and preventive therapies. Based on improved insights into the basic mechanisms of migraine, new and targeted treatments...... are currently undergoing large-scale testing. Among the most promising agents for migraine prevention are humanized antibodies against calcitonin gene-related peptide (CGRP) or the CGRP receptor. If proven effective, these new treatments may emerge to improve the lives of millions of individuals worldwide...

  8. Pituitary adenylate cyclase-activating peptide stimulates neurite growth in PC12 cells.

    Science.gov (United States)

    Hernandez, A; Kimball, B; Romanchuk, G; Mulholland, M W

    1995-01-01

    The ability of PACAP-38 to stimulate morphological development was studied using rat pheochromocytoma PC12 cells. PACAP-38 produced concentration-dependent increases in percentage of cells exhibiting neurite extension. Similar increases were produced by forskolin (28 +/- 2% at 96 h) and 8-bromo cAMP (30 +/- 2%). Vasoactive intestinal peptide and alpha-calcitonin gene-related peptide were without effect. PACAP-38 produced significant increases in PC12 cell cAMP content and inositol phosphate turnover. Intracellular [Ca2+] increased from 169 +/- 14 nM to 560 +/- 58 nM in response to 1 microM PACAP-38. PACAP-stimulated neurite outgrowth was abolished by RpcAMPS, an inhibitor of cAMP-dependent kinases but was unaffected by the protein kinase C antagonist H7.

  9. Migraine pathogenesis and state of pharmacological treatment options

    Directory of Open Access Journals (Sweden)

    Goadsby Peter J

    2009-11-01

    Full Text Available Abstract Migraine is a largely inherited disorder of the brain characterized by a complex, but stereotypical, dysfunction of sensory processing. Often the most obvious clinical symptom is head pain, but non-headache symptoms such as photophobia, phonophobia and nausea are clearly part of the typical presentation. This review discusses the current pathophysiological concepts of migraine and migraine aura, such as a possible brainstem dysfunction and cortical spreading depression. Acute and preventive migraine treatment approaches are briefly covered with a focus on shortcomings of the currently available treatment options. A number of different receptors, such as calcitonin gene-related peptide (CGRP, TRPV1 and glutamate receptors, are currently being targeted by potential novel migraine therapeutics. The prospects of this research are exciting and are likely to improve patient care.

  10. mRNA distribution of CGRP and its receptor components in the trigeminovascular system and other pain related structures in rat brain, and effect of intracerebroventricular administration of CGRP on Fos expression in the TNC

    DEFF Research Database (Denmark)

    Bhatt, Deepak Kumar; Gupta, Saurabh; Ploug, Kenneth B

    2014-01-01

    . The level of Fos protein expression in TNC was analysed by immunohistochemistry (IHC). mRNA expression of CGRP and its receptor components in trigeminovascular and other pain processing structures in the brain was also studied. CGRP i.c.v. infusion did not induce Fos activation in the TNC. mRNA expression...... profile showed that CGRP and its receptor components were widely distributed in trigeminovascular and other pain processing structures. The widespread presence of CGRP receptor mRNA in the various central pain pathways suggests that CGRP might play a role in migraine pathogenesis.......Calcitonin gene-related peptide (CGRP) infusion in humans provokes headache resembling spontaneous migraine, and CGRP receptor antagonists are effective against acute migraine. We hypothesized that CGRP infusion in the lateral ventricle (LV) will induce neuronal activation reflected by increase...

  11. Comprehensive management of an orthognathic surgery patient with aggressive central giant cell granuloma of the mandible.

    Science.gov (United States)

    Sharifi, Reza J; Closmann, James J; Pogrel, M Anthony

    2012-01-01

    This article presents a case involving a 16-year-old boy who came to the Tripler Army Medical Center Oral and Maxillofacial Surgery with a central giant cell granuloma (CGCG) on the anterior mandible. Initial management consisted of surgical curettage and intralesional injection of corticosteroids. Upon completion of steroid therapy, there was clinical and radiographic evidence of remission; however, radiographic evidence of lesion recurrence was seen at a six-month follow-up visit. The CGCG was retreated with curettage and five months of systemic injections of calcitonin, both of which failed. The lesion was most likely an aggressive form of CGCG that progressed despite conservative therapy, with destruction of hard and soft tissues, root resorption, tooth displacement, and paraesthesia in the anterior mandible. The authors present a treatment algorithm with comprehensive management involving surgical resection, reconstruction, orthodontics, and orthognathic surgery with prosthodontic considerations.

  12. Localisation of the neuropeptide PACAP and its receptors in the rat parathyroid and thyroid glands

    DEFF Research Database (Denmark)

    Fahrenkrug, Jan; Hannibal, Jens

    2011-01-01

    PACAP (pituitary adenylate cyclase activating polypeptide) is widely distributed neuropeptide acting via three subtypes of receptors, PAC(1), VPAC(1) and VPAC(2). Here we examined the localisation and nature of PACAP-immunoreactive nerves in the rat thyroid and parathyroid glands and defined...... the distribution of PAC(1), VPAC(1) and VPAC(2) receptor mRNA's. In the parathyroid gland a large number of nerve fibres displaying PACAP-immunoreactivity were distributed beneath the capsule, around blood vessels and close to glandular cells. Most of the PACAP-nerves were sensory, since they co-stored CGRP...... (calcitonin-gene-related peptide) and were sensitive to capsaicin-treatment. mRNA's for PAC(1) and VPAC(2) receptors occurred in the parathyroid gland, mainly located in the glandular cells. In the thyroid gland PACAP-immunoreactive nerve fibres were associated with blood vessels, thyroid follicles...

  13. [Recent advances on the "active" vitamin D: 1alpha,25-dihydroxicholecalciferol (author's transl)].

    Science.gov (United States)

    Montanari, L

    1976-01-01

    The researches on the mode of action of vitamin D have shown that vitamin D3 in animals is not utilized as such but after Hydrosylation of carbon 25 in the liver and of carbon 1 in the kidney. 1alpha,25-dihdroxycholecalciferol (1alpha,25-(OH)2D3) is the active on two target organis the intestin and bones, acting as a steroid hormone. In the intestin it controls the syntesis of a specific calcium binding protein (CaPB) responsable for calcium absorption. At the bone level it act on the deposition of calcium salts, and whenever necessary on its mobilization. Therefore 1alpha,25(OH)2D3 is active part of the calcium homeostatic system in the organism together with specific hormones such as parathyroid hormone and calcitonin.

  14. Metabolic cleavage of cell-penetrating peptides in contact with epithelial models

    DEFF Research Database (Denmark)

    Tréhin, Rachel; Nielsen, Hanne Mørck; Jahnke, Heinz-Georg

    2004-01-01

    We assessed the metabolic degradation kinetics and cleavage patterns of some selected CPP (cell-penetrating peptides) after incubation with confluent epithelial models. Synthesis of N-terminal CF [5(6)-carboxyfluorescein]-labelled CPP, namely hCT (human calcitonin)-derived sequences, Tat(47...... models and the CPP. The Calu-3 model exhibited the highest proteolytic activity. The patterns of metabolic cleavage of hCT(9-32) were similar in all three models. Initial cleavage of this peptide occurred at the N-terminal domain, possibly by endopeptidase activity yielding both the N- and the C......-57) and penetratin(43-58), was through Fmoc (fluoren-9-ylmethoxycarbonyl) chemistry. Metabolic degradation kinetics of the tested CPP in contact with three cell-cultured epithelial models, MDCK (Madin-Darby canine kidney), Calu-3 and TR146, was evaluated by reversed-phase HPLC. Identification of the resulting...

  15. Plasma levels of cAMP, cGMP and CGRP in sildenafil-induced headache

    DEFF Research Database (Denmark)

    Kruuse, Christina Rostrup; Frandsen, E; Schifter, S

    2004-01-01

    whether the pain-inducing effects of sildenafil would be reflected in plasma levels of important signalling molecules in migraine: cGMP, cyclic adenosine monophosphate (cAMP) and calcitonin gene-related peptide (CGRP). Ten healthy subjects (four women, six men) and 12 patients (12 women) suffering from......Sildenafil, a selective inhibitor of the cyclic guanosine monophosphate (cGMP) degrading phosphodiestrase 5 (PDE5), induced migraine without aura in 10 of 12 migraine patients and in healthy subjects it induced significantly more headache than placebo. The aim of the present study was to determine...... migraine without aura were included in two separate double-blind, placebo-controlled, cross-over studies in which placebo or sildenafil 100 mg was administered orally. Plasma levels of CGRP, cAMP and cGMP were determined in blood from the antecubital vein. Despite the ability of sildenafil to induce...

  16. Interstitial cells of Cajal in the striated musculature of the mouse esophagus

    DEFF Research Database (Denmark)

    Rumessen, J J; de Kerchove d'Exaerde, A; Mignon, S

    2001-01-01

    Interstitial cells of Cajal (ICC) are important regulatory cells in the smooth muscle coats of the digestive tract. Expression of the Kit receptor tyrosine kinase was used in this study as a marker to study their distribution and development in the striated musculature of the mouse esophagus...... scarce in both muscle layers of the thoracic esophagus, while their number increased steeply toward the cardia in the striated portion of the intraabdominal esophagus. They did not form networks and had no relationship with intrinsic myenteric ganglia and motor end-plates. They were often close to nerve...... fibers immunoreactive for neuronal nitric oxide synthase (nNOS), vasoactive intestinal polypeptide (VIP) or neuropeptide Y (NPY), but not to fibers immunoreactive for substance P (SP), calcitonin gene related peptide (CGRP), enkephalin, or the capsaicin receptor VRI. They were present in the fetus...

  17. Novel strategies in drug discovery of the calcium-sensing receptor based on biased signaling

    DEFF Research Database (Denmark)

    Thomsen, Alex Rojas Bie; Smajilovic, Sanela; Bräuner-Osborne, Hans

    2012-01-01

    A hallmark of chronic kidney disease is hyperphosphatemia due to renal phosphate retention. Prolonged parathyroid gland exposure to hyperphosphatemia leads to secondary hyperparathyroidism characterized by hyperplasia of the glands and excessive secretion of parathyroid hormone (PTH), which cause...... by virtue of it not affecting calcitonin secretion. The present review will focus on recent advancements in understanding signaling and biased signaling of the CaSR, and how that may be utilized to discover new and smarter drugs targeting the CaSR....... targeting the CaSR and can be used to effectively control and reduce PTH secretion in PTH-related diseases. Cinacalcet is a positive allosteric modulator of the CaSR and affects PTH secretion from parathyroid glands by shifting the calcium-PTH concentration-response curve to the left. One major disadvantage...

  18. Cancer-induced anorexia and malaise are mediated by CGRP neurons in the parabrachial nucleus.

    Science.gov (United States)

    Campos, Carlos A; Bowen, Anna J; Han, Sung; Wisse, Brent E; Palmiter, Richard D; Schwartz, Michael W

    2017-07-01

    Anorexia is a common manifestation of chronic diseases, including cancer. Here we investigate the contribution to cancer anorexia made by calcitonin gene-related peptide (CGRP) neurons in the parabrachial nucleus (PBN) that transmit anorexic signals. We show that CGRPPBN neurons are activated in mice implanted with Lewis lung carcinoma cells. Inactivation of CGRPPBN neurons before tumor implantation prevents anorexia and loss of lean mass, and their inhibition after symptom onset reverses anorexia. CGRPPBN neurons are also activated in Apcmin/+ mice, which develop intestinal cancer and lose weight despite the absence of reduced food intake. Inactivation of CGRPPBN neurons in Apcmin/+ mice permits hyperphagia that counteracts weight loss, revealing a role for these neurons in a 'nonanorexic' cancer model. We also demonstrate that inactivation of CGRPPBN neurons prevents lethargy, anxiety and malaise associated with cancer. These findings establish CGRPPBN neurons as key mediators of cancer-induced appetite suppression and associated behavioral changes.

  19. Effect of adrenomedullin on the cerebral circulation: relevance to primary headache disorders

    DEFF Research Database (Denmark)

    Petersen, K A; Birk, S; Kitamura, K

    2009-01-01

    Adrenomedullin (ADM) is closely related to calcitonin gene-related peptide, which has a known causative role in migraine. Animal studies have strongly suggested that ADM has a vasodilatory effect within the cerebral circulation. For these reasons, ADM is also likely to be involved in migraine....... However, the hypothetical migraine-inducing property and effect on human cerebral circulation of ADM have not previously been investigated. Human ADM (0.08 microg kg(-1) min(-1)) or placebo (saline 0.9%) was administered as a 20-min intravenous infusion to 12 patients suffering from migraine without aura...... Doppler and the diameter of peripheral arteries by transdermal ultrasound (C-scan). ADM did not induce significantly more headache or migraine compared with placebo (P = 0.58). CBF was unaffected by ADM infusion (global CBF, P = 0.32 and rCBF(MCA), P = 0.38) and the same applied for the V(MCA) (P = 0...

  20. Overview of hypercalcemia of malignancy.

    Science.gov (United States)

    Solimando, D A

    2001-11-15

    The etiology, pathophysiology, and diagnosis of hypercalcemia associated with malignant diseases are discussed. In humans, calcium is controlled by three mechanisms: parathyroid hormone, which regulates bone resorption and renal reabsorption of calcium; calcitonin, an antagonist of parathyroid hormone; and cholecalciferol, which regulates calcium absorption from the gastrointestinal tract. Hypercalcemia of malignancy (HCM) results primarily from increased bone resorption by osteoclasts and, to a lesser extent, from increased renal tubular reabsorption. In most tumors, parathyroid hormone-related protein (PTHrP) is the primary mediator of calcium. PTHrP stimulates increased bone resorption by osteoclasts. This stimulation also activates transforming growth factor-beta (TGF-beta), which stimulates tumor cells, thus perpetuating the cycle. Hypercalcemia is usually defined as a serum calcium concentration greater than 12 mg/dL, corrected for the serum albumin concentration. In diagnosing HCM, it is important to rule out other causes of hypercalcemia, such as primary hyperparathyroidism.

  1. PACAP-38 infusion causes sustained vasodilation of the middle meningeal artery in the rat

    DEFF Research Database (Denmark)

    Bhatt, Deepak K; Gupta, Saurabh; Olesen, Jes

    2014-01-01

    BACKGROUND: In healthy human volunteers and in migraineurs, pituitary adenylate cyclase-activating polypeptide-38 (PACAP-38) infusion caused sustained vasodilation of the middle meningeal artery (MMA) and an immediate as well as a delayed headache. All the study subjects experienced facial flushing...... were depleted by chronic treatment with compound 48/80. The effect of 20 minutes' intravenous (i.v.) infusion of calcitonin gene-related peptide (CGRP), PACAP-38, PACAP(6-38) (PAC-1 receptor antagonist) and PACAP-27 on the diameter of the MMA and on mean arterial blood pressure (MABP) in control.......v.) was given 10 minutes prior to PACAP-38 infusion. Increasing doses of PACAP-38, PACAP-27 and VIP were infused through the intracarotid artery (i.c.) in control and MCD rats to see the direct effects of these peptides on MMA diameter change. RESULTS: There was no significant change in CGRP-induced MMA...

  2. The lung as a route for systemic delivery of therapeutic proteins and peptides

    Science.gov (United States)

    Uchenna Agu, Remigius; Ikechukwu Ugwoke, Michael; Armand, Michoel; Kinget, Renaat; Verbeke, Norbert

    2001-01-01

    The large surface area, good vascularization, immense capacity for solute exchange and ultra-thinness of the alveolar epithelium are unique features of the lung that can facilitate systemic delivery via pulmonary administration of peptides and proteins. Physical and biochemical barriers, lack of optimal dosage forms and delivery devices limit the systemic delivery of biotherapeutic agents by inhalation. Current efforts to overcome these difficulties in order to deliver metabolic hormones (insulin, calcitonin, thyroid-stimulating hormone [TSH], follicle-stimulating hormone [FSH] and growth hormones) systemically, to induce systemic responses (immunoglobulins, cyclosporin A [CsA], recombinant-methionyl human granulocyte colony-stimulating factor [r-huG-CSF], pancreatic islet autoantigen) and to modulate other biological processes via the lung are reviewed. Safety aspects of pulmonary peptide and protein administration are also discussed. PMID:11686885

  3. The lung as a route for systemic delivery of therapeutic proteins and peptides

    Directory of Open Access Journals (Sweden)

    Kinget Renaat

    2001-04-01

    Full Text Available Abstract The large surface area, good vascularization, immense capacity for solute exchange and ultra-thinness of the alveolar epithelium are unique features of the lung that can facilitate systemic delivery via pulmonary administration of peptides and proteins. Physical and biochemical barriers, lack of optimal dosage forms and delivery devices limit the systemic delivery of biotherapeutic agents by inhalation. Current efforts to overcome these difficulties in order to deliver metabolic hormones (insulin, calcitonin, thyroid-stimulating hormone [TSH], follicle-stimulating hormone [FSH] and growth hormones systemically, to induce systemic responses (immunoglobulins, cyclosporin A [CsA], recombinant-methionyl human granulocyte colony-stimulating factor [r-huG-CSF], pancreatic islet autoantigen and to modulate other biological processes via the lung are reviewed. Safety aspects of pulmonary peptide and protein administration are also discussed.

  4. Increased arterial compliance in decompensated cirrhosis

    DEFF Research Database (Denmark)

    Henriksen, Jens Henrik; Møller, Søren; Schifter, S

    1999-01-01

    BACKGROUND/AIMS: In patients with cirrhosis, the systemic circulation is hyperdynamic with low arterial blood pressure and reduced systemic vascular resistance. The present study was undertaken to estimate the compliance of the arterial tree in relation to severity of cirrhosis, circulating level...... of the vasodilator, calcitonin gene-related peptide (CGRP) and mean arterial blood pressure (MAP). METHODS: Arterial compliance (COMPart=deltaV/deltaP) was determined as the stroke volume relative to pulse pressure (i.e. systolic minus diastolic blood pressure) during a haemodynamic evaluation of portal hypertension...... of CGRP (r=0.34, pcompliance in cirrhosis is directly related to the severity of the disease and to the elevated level of circulating vasodilator peptide CGRP, and inversely related...

  5. Severe Milk-Alkali Syndrome in a Patient with Hypoparathyroidism Associated with 1,25(OH2D, Hydrochlorothiazide and Anthranoid Laxative Consumption

    Directory of Open Access Journals (Sweden)

    Lorenzo Morini

    2017-10-01

    Full Text Available Background: Milk-alkali syndrome is a life-threatening condition defined by the triad of hypercalcaemia, metabolic alkalosis and acute renal failure, and is associated with consumption of calcium and absorbable alkali. Methods: We report the case of a patient admitted to a step-down unit of a large hospital in Italy. Results: The patient was a 59-year-old woman with hypoparathyroidism and mild chronic kidney insufficiency, treated for a preceding episode of hypocalcaemia with high doses of calcitriol and calcium carbonate, who was also taking hydrochlorothiazide and unreported herbal anthranoid laxatives. The patient was admitted to hospital with severe hypercalcaemia, severe metabolic alkalosis and acute renal insufficiency. The patient was successfully treated with urgent dialysis, loop diuretics and calcitonin administration. Conclusions: This case underlines the need for caution when treating patients with impaired calcium metabolism regulation, and suggests that herbal anthranoid laxatives might act as triggers for milk-alkali syndrome..

  6. Emerging migraine treatments and drug targets

    DEFF Research Database (Denmark)

    Olesen, Jes; Ashina, Messoud

    2011-01-01

    Migraine has a 1-year prevalence of 10% and high socioeconomic costs. Despite recent drug developments, there is a huge unmet need for better pharmacotherapy. In this review we discuss promising anti-migraine strategies such as calcitonin gene-related peptide (CGRP) receptor antagonists and 5......-hydroxytrypamine (5-HT)(1F) receptor agonists, which are in late-stage development. Nitric oxide antagonists are also in development. New forms of administration of sumatriptan might improve efficacy and reduce side effects. Botulinum toxin A has recently been approved for the prophylaxis of chronic migraine....... Tonabersat, a cortical spreading depression inhibitor, has shown efficacy in the prophylaxis of migraine with aura. Several new drug targets such as nitric oxide synthase, the 5-HT(1D) receptor, the prostanoid receptors EP(2) and EP(4), and the pituitary adenylate cyclase receptor PAC1 await development...

  7. Randomized controlled trial of the CGRP receptor antagonist telcagepant for migraine prevention

    DEFF Research Database (Denmark)

    Ho, Tony W; Connor, Kathryn M; Zhang, Ying

    2014-01-01

    a recommendation from the Safety Monitoring Board due to hepatotoxicity concerns. At termination, the planned 660 patients had been randomized, 656 had been treated with ≥ 1 dose of study medication, and 14 had completed the trial. The mean treatment duration was 48-50 days. Thirteen patients, all......OBJECTIVE: To evaluate whether the calcitonin gene-related peptide (CGRP) receptor antagonist telcagepant might be effective for migraine prevention. METHODS: In this randomized, double-blind, placebo-controlled, multicenter trial (ClinicalTrials.gov NCT00797667), patients experiencing 3......-14 migraine days during a 4-week baseline were randomized to telcagepant 140 mg, telcagepant 280 mg, or placebo twice daily for 12 weeks. Efficacy was assessed by mean monthly headache days and migraine/probable migraine days (headache plus ≥ 1 associated symptom). RESULTS: The trial was terminated following...

  8. Vasoactive substances in the circulatory dysfunction of cirrhosis

    DEFF Research Database (Denmark)

    Møller, Søren; Bendtsen, Flemming; Henriksen, Jens Henrik

    2001-01-01

    Patients with cirrhosis and portal hypertension exhibit characteristic haemodynamic changes with a hyperkinetic systemic circulation, abnormal distribution of the blood volume, and neurohumoral dysregulation. Moreover, the circulating levels of several vasoactive substances may be elevated....... Splanchnic vasodilatation is of pathogenic significance for the low systemic vascular resistance and abnormal volume distribution, which are important elements in the development of the concomitant cardiac dysfunction, recently termed cirrhotic cardiomyopathy. The systolic and diastolic functions...... and calcitonin gene-related peptide, are among candidates in the vasodilatation and the increased arterial compliance recently described in advanced cirrhosis. Reflex-induced enhanced sympatho-adrenal activity, activation of the renin-angiotensin-aldosterone system, and elevated circulating vasopressin...

  9. Endocrine cells and nerves in the stomach of the lizard Podarcis hispanica detected by immunocytochemistry.

    Science.gov (United States)

    De Rada, O D; Burrell, M A; García, C; Barrenechea, M A; Sesma, P

    1992-01-01

    The general identification of endocrine cells in the stomach of the lizard Podarcis hispanica was carried out by their response to the Grimelius and Masson-Fontana techniques. 11 immunoreactive cell-types, positive for chromogranin-, serotonin-, caerulein/gastrin/ cholecystokinin (CAER/G/CCK)-, glucagon-like-peptide-1 (GLP-1)-. glucagon-, bombesin-,somatostatin-, pancreatic polypeptide (PP)-, peptide tyrosine tyrosine (PYY)-, neurotensin-and calcitonin gene related peptide (CGRP)- antisera were detected by immunocytochemical methods. Co-existence of glucagon with GLP-1, and PP with PYY were observed in some cells. Furthermore, immunoreactivities for members of gastrin and PP families were also found to co-exist in a few cells. In the muscular layer, vasoactive intestinal peptide (VIP)- and substance P-immunoreactive nerve fibers were also found.

  10. Acute Pancreatitis: Etiology, Pathology, Diagnosis, and Treatment.

    Science.gov (United States)

    Majidi, Shirin; Golembioski, Adam; Wilson, Stephen L; Thompson, Errington C

    2017-11-01

    Acute pancreatitis is a fascinating disease. In the United States, the two most common etiologies of acute pancreatitis are gallstones and excessive alcohol consumption. The diagnosis of acute pancreatitis is made with a combination of history, physical examination, computed tomography scan, and laboratory evaluation. Differentiating patients who will have a benign course of their pancreatitis from patients who will have severe pancreatitis is challenging to the clinician. C-reactive protein, pro-calcitonin, and the Bedside Index for Severity of Acute Pancreatitis appeared to be the best tools for the early and accurate diagnosis of severe pancreatitis. Early laparoscopic cholecystectomy is indicated for patients with mild gallstone pancreatitis. For patients who are going to have a prolonged hospitalization, enteral nutrition is preferred. Total parenteral nutrition should be reserved for patients who cannot tolerate enteral nutrition. Prophylactic antibiotics are not indicated for patients with pancreatic necrosis. Surgical intervention for infected pancreatic necrosis should be delayed as long as possible to improve patient outcomes.

  11. Neuronal hyperplasia in the anal canal

    DEFF Research Database (Denmark)

    Fenger, C; Schrøder, H D

    1990-01-01

    In a consecutive series of minor surgical specimens from the anal canal, neuronal hyperplasia was found in nine of 56 haemorrhoidectomy specimens and in four of 23 fibrous polyps. In an additional series of 14 resections of the anal canal, neuronal hyperplasia was present in six cases, of which...... five showed haemorrhoids. In all cases, neuronal hyperplasia was located in the submucosa beneath squamous epithelium and extended over an area from 5 to 12 mm. Immunohistochemically, the foci of hyperplasia were found to consist of both neuronal and Schwann cell components. Staining for vasoactive...... intestinal peptide, neuropeptide Y and calcitonin gene related peptide, did not demonstrate any increased terminal density. It is suggested that anal neuronal hyperplasia in these cases represents an acquired lesion due to local mechanical influence....

  12. Changes in calcitropic hormones, bone markers and insulin-like growth factor I (IGF-I) during pregnancy and postpartum: a controlled cohort study

    DEFF Research Database (Denmark)

    Streym, Súsanna við; Møller, Ulla Kristine; Mosekilde, Leif

    2012-01-01

    changes in calcium homeostasis, calcitropic hormones and bone metabolism during pregnancy and lactation. METHODS: We studied 153 women planning pregnancy (n = 92 conceived) and 52 non-pregnant, age-matched female controls. Samples were collected prior to pregnancy, once each trimester and 2, 16 and 36......Pregnancy and lactation cause major changes in calcium homeostasis and bone metabolism. This population-based cohort study presents the physiological changes in biochemical indices of calcium homeostasis and bone metabolism during pregnancy and lactation INTRODUCTION: We describe physiological...... weeks postpartum. The controls were followed in parallel. RESULTS: P-estradiol (E(2)), prolactin and 1,25-dihydroxyvitamin D (1,25(OH)(2)D) increased (p pregnancy, whereas plasma levels of parathyroid hormone (P-PTH) and calcitonin decreased (p 

  13. Phase I, Randomized, Double-blind, Placebo-controlled, Single-dose, and Multiple-dose Studies of Erenumab in Healthy Subjects and Patients With Migraine.

    Science.gov (United States)

    de Hoon, Jan; Van Hecken, Anne; Vandermeulen, Corinne; Yan, Lucy; Smith, Brian; Chen, Jiyun Sunny; Bautista, Edgar; Hamilton, Lisa; Waksman, Javier; Vu, Thuy; Vargas, Gabriel

    2017-07-24

    Monoclonal antibodies (mAbs) targeting calcitonin gene-related peptide (CGRP) signaling are being explored as prophylactic treatments for migraine. Erenumab (AMG 334) is the first potent, selective, and competitive human mAb antagonist of the CGRP receptor. We report the data from two phase I studies assessing the safety, pharmacokinetics (PK), and pharmacodynamics of single and multiple administrations of erenumab in healthy subjects and patients with migraine. The results indicate that the PK profile of erenumab is nonlinear from 1 mg to 70 mg and the linear portion of the clearance from 70 mg to 210 mg is consistent with other human immunoglobulin G2 antibodies. Single doses of erenumab resulted in >75% inhibition of capsaicin-induced dermal blood flow, with no apparent dose-dependency for erenumab ≥21 mg. Erenumab was generally well tolerated, with an acceptable safety profile, supporting further clinical development of erenumab for migraine prevention. © 2017 American Society for Clinical Pharmacology and Therapeutics.

  14. [Calcium metabolism after the menopause].

    Science.gov (United States)

    Kanovitch, D; Klotz, H P

    1976-02-16

    The authors recall the antagonism between estradiol and parathormone. Estradiol tends to lower serum calcium and fix calcium in the bones as shown by one of us 25 years ago. The mechanism of this action of estrogen on calcium metabolism has been determined by numerous authors but some points are still not clear, e.g. the interferences between estrogen and calcitonin. Classically, parathormone is known to increase bony reabsorption and raise serum calcium. After the menopause the gradual reduction in estradiol secretion leads to post-menopausal osteoporosis. It is better to administer estrogens prophylactically to women after the menopause provided a cervical smear and mammography have been carried out to eliminate latent carcinoma of the breast or uterine cervix.

  15. Neuropeptides in Lower Urinary Tract (LUT) Function

    Science.gov (United States)

    Arms, Lauren; Vizzard, Margaret A.

    2014-01-01

    Numerous neuropeptide/receptor systems including vasoactive intestinal polypeptide, pituitary adenylate cyclase-activating polypeptide, calcitonin gene-related peptide, substance P, neurokinin A, bradykinin, and endothelin-1 are expressed in the lower urinary tract (LUT) in both neural and non-neural (e.g., urothelium) components. LUT neuropeptide immunoreactivity is present in afferent and autonomic efferent neurons innervating the bladder and urethra and in the urothelium of the urinary bladder. Neuropeptides have tissue-specific distributions and functions in the LUT and exhibit neuroplastic changes in expression and function with LUT dysfunction following neural injury, inflammation and disease. LUT dysfunction with abnormal voiding including urinary urgency, increased voiding frequency, nocturia, urinary incontinence and pain may reflect a change in the balance of neuropeptides in bladder reflex pathways. LUT neuropeptide/receptor systems may represent potential targets for therapeutic intervention. PMID:21290237

  16. The blood-brain barrier in migraine treatment

    DEFF Research Database (Denmark)

    Edvinsson, L; Tfelt-Hansen, P

    2008-01-01

    Salient aspects of the anatomy and function of the blood-barrier barrier (BBB) are reviewed in relation to migraine pathophysiology and treatment. The main function of the BBB is to limit the access of circulating substances to the neuropile. Smaller lipophilic substances have some access...... to the central nervous system by diffusion, whereas other substances can cross the BBB by carrier-mediated influx transport, receptor-mediated transcytosis and absorptive-mediated transcytosis. Studies of drugs relevant to migraine pathophysiology and treatment have been examined with the pressurized...... with special emphasize on the triptans and calcitonin gene-related peptide (CGRP). The human experimental headache model, especially the use of glycerol trinitrate (the nitric oxide model), and experiences with CGRP administrations utilize the systemic administration of the agonists with effects on other...

  17. Splanchnic and systemic hemodynamic derangement in decompensated cirrhosis

    DEFF Research Database (Denmark)

    Møller, Søren; Bendtsen, Flemming; Henriksen, Jens Henrik

    2001-01-01

    Patients with cirrhosis and portal hypertension exhibit characteristic hemodynamic changes with hyperkinetic systemic circulation, abnormal distribution of blood volume and neurohumoral dysregulation. Their plasma and noncentral blood volumes are increased. Splanchnic vasodilation is of pathogenic...... significance to the low systemic vascular resistance and abnormal volume distribution of blood, which are important elements in the development of the concomitant cardiac dysfunction, recently termed 'cirrhotic cardiomyopathy'. Systolic and diastolic functions are impaired with direct relation to the degree...... of liver dysfunction. Significant pathophysiological mechanisms are reduced beta-adrenergic receptor signal transduction, defective cardiac excitation-contraction coupling and conductance abnormalities. Vasodilators such as nitric oxide and calcitonin gene-related peptide are among the candidates...

  18. Supramolecular amplification of amyloid self-assembly by iodination

    Science.gov (United States)

    Bertolani, Arianna; Pirrie, Lisa; Stefan, Loic; Houbenov, Nikolay; Haataja, Johannes S.; Catalano, Luca; Terraneo, Giancarlo; Giancane, Gabriele; Valli, Ludovico; Milani, Roberto; Ikkala, Olli; Resnati, Giuseppe; Metrangolo, Pierangelo

    2015-06-01

    Amyloid supramolecular assemblies have found widespread exploitation as ordered nanomaterials in a range of applications from materials science to biotechnology. New strategies are, however, required for understanding and promoting mature fibril formation from simple monomer motifs through easy and scalable processes. Noncovalent interactions are key to forming and holding the amyloid structure together. On the other hand, the halogen bond has never been used purposefully to achieve control over amyloid self-assembly. Here we show that single atom replacement of hydrogen with iodine, a halogen-bond donor, in the human calcitonin-derived amyloidogenic fragment DFNKF results in a super-gelator peptide, which forms a strong and shape-persistent hydrogel at 30-fold lower concentration than the wild-type pentapeptide. This is remarkable for such a modest perturbation in structure. Iodination of aromatic amino acids may thus develop as a general strategy for the design of new hydrogels from unprotected peptides and without using organic solvents.

  19. Ectopic thyroid tissue in the periaortic area, cardiac cavity and aortic valve in a Beagle dog - a case report.

    Science.gov (United States)

    Roth, Daniel Robert; Perentes, Elias

    2012-03-01

    Microscopic examination of the heart of a clinically normal 14-month-old female Beagle dog revealed the presence of ectopic thyroid tissue at the base of the heart, around the aorta, and intracardially at the level of the left ventricle and the aortic valve. The tissue was composed of well-differentiated follicles lined by a cuboidal epithelium and containing colloid. Follicular cells and colloid exhibited strong thyroglobulin immunoreactivity, while no parafollicular cells were noted and the immunoreactions for calcitonin remained consistently negative. Although in the dog ectopic thyroid tumors represent 1-10% of all heart base neoplasms (Capen, 1978; Bracha et al., 2009), to the best of our knowledge, nonneoplastic ectopic thyroid tissue has not been reported in the heart of the dog itself or within the dog aortic valve. Copyright © 2010 Elsevier GmbH. All rights reserved.

  20. Nerve fibre studies in skin biopsies in peripheral neuropathies. I. Immunohistochemical analysis of neuropeptides in diabetes mellitus

    DEFF Research Database (Denmark)

    Lindberger, M; Schröder, H D; Schultzberg, M

    1989-01-01

    Standardised skin biopsies followed by immunohistochemical examination for the presence of terminal nerve fibres reacting for neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) were evaluated. Healthy subjects regularly displayed free nerve endings of both fibre types...... in the dermis layers. Five type I diabetes patients without clinical or neurophysiological evidence of polyneuropathy also had reduced density of both fibre types, being significant for CGRP fibres when compared with controls. Skin biopsy with immunohistochemical staining for neuropeptides may represent...... in the papillary and reticular dermis. Both fibre types were present close to blood vessels, while CGRP immunoreactive fibres were more often encountered near sweat gland acini compared to SP fibres. Diabetes mellitus complicated by polyneuropathy was accompanied by marked reduction of SP and CGRP reactive fibres...

  1. Recognizing the role of CGRP and CGRP receptors in migraine and its treatment

    DEFF Research Database (Denmark)

    Edvinsson, Lars; Warfvinge, Karin

    2017-01-01

    Premise The brain and the sensory nervous system contain a rich supply of calcitonin gene-related peptide (CGRP) and CGRP receptor components. Clinical studies have demonstrated a correlation between CGRP release and acute migraine headache that led to the development of CGRP-specific drugs...... that either abort acute attacks of migraine (gepants) or are effective as prophylaxis (antibodies). However, there is still much discussion concerning the site of action of these drugs. Problem Here we describe the most recent data related to CGRP in the trigeminal ganglion and its connections to the CNS......, putative key regions involved in migraine pathophysiology. Gepants are small molecules that have limited ability to cross the blood-brain barrier (BBB), whereas CGRP antibodies are 1500 times larger molecules, and are virtually excluded from the brain, with a BBB permeability of 

  2. CGRP, a target for preventive therapy in migraine and cluster headache

    DEFF Research Database (Denmark)

    Khan, Sabrina; Olesen, Astrid; Ashina, Messoud

    2017-01-01

    Introduction Migraine and cluster headache are challenging to manage, with no tailored preventive medications available. Targeting the calcitonin gene-related peptide (CGRP) pathway to treat these headaches may be the first focused therapeutic option to date, with the potential for promising...... efficacy. Methods We systematically searched PubMed and clinicaltrials.gov for randomized controlled trials investigating the preventive potential of monoclonal antibodies against the CGRP pathway in the treatment of migraine and cluster headache. Results The literature search returned a total of 136...... migraine. Multiple phase II and III trials are under way to further determine the efficacy and safety of this new drug class. It may be particularly important to assess the cardiovascular effects of long-term CGRP blockade. Phase III trials are also currently in progress for the preventive treatment...

  3. Unusual Cushing’s Syndrome and Hypercalcitoninaemia due to a Small Cell Prostate Carcinoma

    Directory of Open Access Journals (Sweden)

    Antonio Balestrieri

    2016-01-01

    Full Text Available A 75-year-old man was hospitalized because of severe hypokalaemia due to ACTH dependent Cushing’s syndrome. Total body computed tomography (TBCT and 68 Gallium DOTATATE PET/CT localized a voluminous prostate tumour. A subsequent transurethral prostate biopsy documented a small cell carcinoma positive for ACTH and calcitonin and negative for prostatic specific antigen (PSA at immunocytochemical study; serum prostatic specific antigen (PSA was normal. Despite medical treatments, Cushing’s syndrome was not controlled and the patient’s clinical condition progressively worsened. Surgical resection was excluded; the patient underwent a cycle of chemotherapy followed by febrile neutropenia and fatal intestinal perforation. This case report describes a rare case of Cushing’s syndrome and hypercalcitoninaemia due to a small cell carcinoma of the prostate, a rare tumour with very few therapeutic options and negative prognosis.

  4. Hypoxic mechanisms in primary headaches

    DEFF Research Database (Denmark)

    Britze, Josefine; Arngrim, Nanna; Schytz, Henrik Winther

    2017-01-01

    and cluster headache. Methods This narrative review investigates the current level of knowledge on the relation of hypoxia in migraine and cluster headache based on epidemiological and experimental studies. Findings Epidemiological studies suggest that living in high-altitude areas increases the risk...... of migraine and especially migraine with aura. Human provocation models show that hypoxia provokes migraine with and without aura, whereas cluster headache has not been reliably induced by hypoxia. Possible pathophysiological mechanisms include hypoxia-induced release of nitric oxide and calcitonin gene......-related peptide, cortical spreading depression and leakage of the blood-brain barrier. Conclusion There is a possible link between hypoxia and migraine and maybe cluster headache, but the exact mechanism is currently unknown. Provocation models of hypoxia have yielded interesting results suggesting a novel...

  5. Unusual Cushing's Syndrome and Hypercalcitoninaemia due to a Small Cell Prostate Carcinoma

    Science.gov (United States)

    Magnani, Elena; Nuzzo, Fiorella

    2016-01-01

    A 75-year-old man was hospitalized because of severe hypokalaemia due to ACTH dependent Cushing's syndrome. Total body computed tomography (TBCT) and 68 Gallium DOTATATE PET/CT localized a voluminous prostate tumour. A subsequent transurethral prostate biopsy documented a small cell carcinoma positive for ACTH and calcitonin and negative for prostatic specific antigen (PSA) at immunocytochemical study; serum prostatic specific antigen (PSA) was normal. Despite medical treatments, Cushing's syndrome was not controlled and the patient's clinical condition progressively worsened. Surgical resection was excluded; the patient underwent a cycle of chemotherapy followed by febrile neutropenia and fatal intestinal perforation. This case report describes a rare case of Cushing's syndrome and hypercalcitoninaemia due to a small cell carcinoma of the prostate, a rare tumour with very few therapeutic options and negative prognosis. PMID:28044110

  6. Vasoactive substances in the circulatory dysfunction of cirrhosis

    DEFF Research Database (Denmark)

    Møller, S; Bendtsen, F; Henriksen, Jens Henrik Sahl

    2001-01-01

    . Splanchnic vasodilatation is of pathogenic significance for the low systemic vascular resistance and abnormal volume distribution, which are important elements in the development of the concomitant cardiac dysfunction, recently termed cirrhotic cardiomyopathy. The systolic and diastolic functions...... are impaired with direct relation to the degree of liver dysfunction. Significant pathophysiological mechanisms seem to include a reduced beta-adrenergic receptor signal transduction, defective cardiac excitation-contraction coupling, and conductance abnormalities. Various vasodilators. such as nitric oxide...... and calcitonin gene-related peptide, are among candidates in the vasodilatation and the increased arterial compliance recently described in advanced cirrhosis. Reflex-induced enhanced sympatho-adrenal activity, activation of the renin-angiotensin-aldosterone system, and elevated circulating vasopressin...

  7. Postmenopausal hormone replacement therapy--clinical implications

    DEFF Research Database (Denmark)

    Ravn, S H; Rosenberg, J; Bostofte, E

    1994-01-01

    . This review is based on the English-language literature on the effect of estrogen therapy and estrogen plus progestin therapy on postmenopausal women. The advantages of hormone replacement therapy are regulation of dysfunctional uterine bleeding, relief of hot flushes, and prevention of atrophic changes......The menopause is defined as cessation of menstruation, ending the fertile period. The hormonal changes are a decrease in progesterone level, followed by a marked decrease in estrogen production. Symptoms associated with these hormonal changes may advocate for hormonal replacement therapy...... in the urogenital tract. Women at risk of osteoporosis will benefit from hormone replacement therapy. The treatment should start as soon after menopause as possible and it is possible that it should be maintained for life. The treatment may be supplemented with extra calcium intake, vitamin D, and maybe calcitonin...

  8. Multiple endocrine neoplasia similar to human subtype 2A in a dog: Medullary thyroid carcinoma, bilateral pheochromocytoma and parathyroid adenoma

    Directory of Open Access Journals (Sweden)

    E.A. Soler Arias

    2016-10-01

    Full Text Available Human multiple endocrine neoplasia subtype 2A (MEN 2A is characterized by medullary thyroid carcinoma, pheochromocytoma and parathyroid hyperplasia or adenoma in the same individual. In this report, a case of a female Rottweiler with medullary thyroid carcinoma, bilateral pheochromocytoma and parathyroid adenoma was described. Clinical manifestations of muscle weakness, polydipsia, polyuria, diarrhea and weight loss were observed. Two adrenal neoplasms were identified incidentally by ultrasonography, and tumor in the left thyroid lobe was identified by palpation. Primary hyperparathyroidism was diagnosed by biochemical testing. Histopathology report was consistent with diagnosis of bilateral pheochromocytoma and parathyroid adenoma. Immunohistochemical staining was positive for calcitonin and synaptophysin, and negative for thyroglobulin, which confirmed medullary thyroid carcinoma. This case in a dog is presenting neoplastic characteristics similar to human MEN 2A and emphasizing the importance of using immunohistochemistry for confirmation.

  9. Blocking CGRP in migraine patients - a review of pros and cons

    DEFF Research Database (Denmark)

    Deen, Marie; Correnti, Edvige; Kamm, Katharina

    2017-01-01

    Migraine is the most prevalent neurological disorder worldwide and it has immense socioeconomic impact. Currently, preventative treatment options for migraine include drugs developed for diseases other than migraine such as hypertension, depression and epilepsy. During the last decade, however......, blocking calcitonin gene-related peptide (CGRP) has emerged as a possible mechanism for prevention of migraine attacks. CGRP has been shown to be released during migraine attacks and it may play a causative role in induction of migraine attacks. Here, we review the pros and cons of blocking CGRP...... in migraine patients. To date, two different classes of drugs blocking CGRP have been developed: small molecule CGRP receptor antagonists (gepants), and monoclonal antibodies, targeting either CGRP or the CGRP receptor. Several trials have been conducted to test the efficacy and safety of these drugs...

  10. Further characterisation of the molecular signature of quiescent and activated mouse muscle satellite cells.

    Directory of Open Access Journals (Sweden)

    Viola F Gnocchi

    Full Text Available Satellite cells are the resident stem cells of adult skeletal muscle. To date though, there is a paucity of native markers that can be used to easily identify quiescent satellite cells, with Pax7 probably being the best that is currently available. Here we have further characterized a number of recently described satellite cell markers, and also describe novel ones. Caveolin-1, integrin alpha7 and the calcitonin receptor proved reliable markers for quiescent satellite cells, being expressed by all satellite cells identified with Pax7. These three markers remained expressed as satellite cells were activated and underwent proliferation. The nuclear envelope proteins lamin A/C and emerin, mutations in which underlie Emery-Dreifuss muscular dystrophy, were also expressed in both quiescent and proliferating satellite cells. Conversely, Jagged-1, a Notch ligand, was not expressed in quiescent satellite cells but was induced upon activation. These findings further contribute to defining the molecular signature of muscle satellite cells.

  11. Primary hyperparathyroidism, pregnancy, and neonatal hypocalcemia.

    Science.gov (United States)

    Kaplan, E L; Burrington, J D; Klementschitsch, P; Taylor, J; Deftos, L

    1984-10-01

    Primary hyperparathyroidism in the mother during pregnancy is known to result in a high rate of fetal complications; spontaneous abortions, still births, and neonatal tetany occur in excessive incidence. To understand the pathophysiology of neonatal hypocalcemia that accompanies this disorder, transplacental calcium dynamics were studied in female sheep during the last trimester of pregnancy and in their fetal lambs after hysterotomy. Calcium ion was shown to move rapidly across the placenta. However, this organ blocked the passage of both parathyroid hormone and calcitonin from the maternal and to the fetal circulations. Our studies support the hypothesis that in primary hyperparathyroidism maternal hypercalcemia results in fetal hypercalcemia, which leads to suppression of fetal parathyroid gland function. In such a situation, neonatal hypocalcemia would occur after birth when maternal calcium flow is interrupted. Parathyroidectomy performed in the mother, especially during the second trimester of pregnancy when operation is safest, would break this cycle and permit normal serum calcium homeostasis in the fetus.

  12. Treatment of migraine attacks based on the interaction with the trigemino-cerebrovascular system

    DEFF Research Database (Denmark)

    Link, A.S.; Kuris, A.; Edvinsson, L.

    2008-01-01

    Primary headaches such as migraine are among the most prevalent neurological disorders, affecting up to one-fifth of the adult population. The scientific work in the last decade has unraveled much of the pathophysiological background of migraine, which is now considered to be a neurovascular...... disorder. It has been discovered that the trigemino-cerebrovascular system plays a key role in migraine headache pathophysiology by releasing the potent vasodilator calcitonin gene-related peptide (CGRP). This neuropeptide is released in parallel with the pain and its concentration correlates well...... with the intensity of the headache. The development of drugs of the triptan class has provided relief for the acute attacks but at the cost of, mainly cardiovascular, side effects. Thus, the intention to improve treatment led to the development of small CGRP receptor antagonists such as olcegepant (BIBN4096BS...

  13. Changes in calcitropic hormones, bone markers and insulin-like growth factor I (IGF-I) during pregnancy and postpartum: a controlled cohort study

    DEFF Research Database (Denmark)

    Liendgaard, Ulla Kristine Møller; við Streym, Susanna; Mosekilde, Leif

    2012-01-01

    Pregnancy and lactation cause major changes in calcium homeostasis and bone metabolism. This population-based cohort study presents the physiological changes in biochemical indices of calcium homeostasis and bone metabolism during pregnancy and lactation INTRODUCTION: We describe physiological...... changes in calcium homeostasis, calcitropic hormones and bone metabolism during pregnancy and lactation. METHODS: We studied 153 women planning pregnancy (n = 92 conceived) and 52 non-pregnant, age-matched female controls. Samples were collected prior to pregnancy, once each trimester and 2, 16 and 36...... weeks postpartum. The controls were followed in parallel. RESULTS: P-estradiol (E(2)), prolactin and 1,25-dihydroxyvitamin D (1,25(OH)(2)D) increased (p pregnancy, whereas plasma levels of parathyroid hormone (P-PTH) and calcitonin decreased (p 

  14. Acupuncture and related techniques during perioperative period: A literature review.

    Science.gov (United States)

    Acar, H Volkan

    2016-12-01

    Acupuncture has been used in the Far East for more than 2000 years. Since the early 1970s, this technique has been gaining popularity among Western medical community. A number of studies suggest that its mechanism of effect can be explained in biomedical terms. In this context, a number of transmitters and modulators including beta-endorphin, serotonin, substance P, interleukins, and calcitonin gene-related peptide are released. For that reason, acupuncture can be used in a wide variety of clinical conditions. Studies showed that acupuncture may have beneficial effect in perioperative period. It relieves preoperative anxiety, decreases postoperative analgesic requirements, and decreases the incidence of postoperative nausea and vomiting. In this review article, we examine perioperative use of acupuncture for a variety of conditions. Copyright © 2016 Elsevier Ltd. All rights reserved.

  15. Amplified Mechanically Gated Currents in Distinct Subsets of Myelinated Sensory Neurons following In Vivo Inflammation of Skin and Muscle.

    Science.gov (United States)

    Weyer, Andy D; O'Hara, Crystal L; Stucky, Cheryl L

    2015-06-24

    Primary afferents are sensitized to mechanical stimuli following in vivo inflammation, but whether sensitization of mechanically gated ion channels contributes to this phenomenon is unknown. Here we identified two populations of murine A fiber-type sensory neurons that display markedly different responses to focal mechanical stimuli of the membrane based on their expression of calcitonin gene-related peptide (CGRP). Following inflammation of the hindpaw, myelinated, CGRP-positive neurons projecting to the paw skin displayed elevated mechanical currents in response to mechanical stimuli. Conversely, muscle inflammation markedly amplified mechanical currents in myelinated, CGRP-negative neurons projecting to muscle. These data show, for the first time, that mechanically gated currents are amplified following in vivo tissue inflammation, and also suggest that mechanical sensitization can occur in myelinated neurons after inflammation. Copyright © 2015 the authors 0270-6474/15/359456-07$15.00/0.

  16. Treatment of central giant cell lesions using bisphosphonates with intralesional corticosteroid injections

    Directory of Open Access Journals (Sweden)

    da Silva Newton

    2012-08-01

    Full Text Available Abstract Central giant cell lesions are benign intraosseous proliferative lesions that have considerable local aggressiveness. Nonsurgical treatment methods, such as intralesional corticosteroid injections, systemic calcitonin and interferon have been reported. Recently, bisphosphonates have been used to treat central giant cell lesions. A case of a 36-year-old male with a central giant cell lesion crossing the mandibular midline was treated with intralesional corticosteroids combined with alendronate sodium for the control of systemic bone resorption. The steroid injections and the use of bisphosphonates were stopped after seven months when further needle penetration into the lesion was not possible due to new bone formation. After two years, the bony architecture was near normal, and only minimal radiolucency was present around the root apices of the involved teeth. The patient was followed up for four years, and panoramic radiography showed areas of new bone formation. Thus far, neither recurrence nor side effects of the medication have been detected.

  17. Laksekalcitonin ved osteoporose. Effekten af intranasal applikation på knoglemineralindhold og frakturhyppighed hos postmenopausale kvinder med manifeste osteoporotiske forandringer

    DEFF Research Database (Denmark)

    Ravn, Pernille

    1993-01-01

    was significantly lower in the women treated with Salcatonin (about one third of that in the non-Salcatonin treated women). In conclusion the results suggest that, compared with calcium alone, Salcatonin given intranasally reduces the rate of fracture by two thirds in elderly women with moderate osteoporosis......The objective was to study the dose-related response of intranasal salmon calcitonin (Salcatonin) on bone mass and bone turnover and the effect of salcatonin on rates of fracture in elderly women with moderate osteoporosis. A total of 208 healthy women aged 68-72 years, who had a bone mineral...... mg calcium daily. In the calcium-(placebo)-treated group the BMC of the spine increased 1%, whereas an increase of 3% was seen in the 200 IU Salcatonin treated group. There was a dose-related response to Salcatonin manifested by an increase in BMC of 1.0%/100 IU. The incidence of new fractures...

  18. Neutron diffraction studies of amphipathic helices in phospholipid bilayers

    Energy Technology Data Exchange (ETDEWEB)

    Bradshaw, J.P.; Gilchrist, P.J. [Univ. of Edinburgh (United Kingdom); Duff, K.C. [Univ. of Edinburgh Medical School (United Kingdom); Saxena, A.M. [Brookhaven National Laboratory, Upton, NY (United States)

    1994-12-31

    The structural feature which is thought to facilitate the interaction of many peptides with phospholipid bilayers is the ability to fold into an amphipathic helix. In most cases the exact location and orientation of this helix with respect to the membrane is not known, and may vary with factors such as pH and phospholipid content of the bilayer. The growing interest in this area is stimulated by indications that similar interactions can contribute to the binding of certain hormones to their cell-surface receptors. We have been using the techniques of neutron diffraction from stacked phospholipid bilayers in an attempt to investigate this phenomenon with a number of membrane-active peptides. Here we report some of our findings with three of these: the bee venom melittin; the hormone calcitonin; and a synthetic peptide representing the ion channel fragment of influenza A M2 protein.

  19. Cluster headache: present and future therapy.

    Science.gov (United States)

    Leone, Massimo; Giustiniani, Alessandro; Cecchini, Alberto Proietti

    2017-05-01

    Cluster headache is characterized by severe, unilateral headache attacks of orbital, supraorbital or temporal pain lasting 15-180 min accompanied by ipsilateral lacrimation, rhinorrhea and other cranial autonomic manifestations. Cluster headache attacks need fast-acting abortive agents because the pain peaks very quickly; sumatriptan injection is the gold standard acute treatment. First-line preventative drugs include verapamil and carbolithium. Other drugs demonstrated effective in open trials include topiramate, valproic acid, gabapentin and others. Steroids are very effective; local injection in the occipital area is also effective but its prolonged use needs caution. Monoclonal antibodies against calcitonin gene-related peptide are under investigation as prophylactic agents in both episodic and chronic cluster headache. A number of neurostimulation procedures including occipital nerve stimulation, vagus nerve stimulation, sphenopalatine ganglion stimulation and the more invasive hypothalamic stimulation are employed in chronic intractable cluster headache.

  20. Rational pain management in complex regional pain syndrome 1 (CRPS 1)--a network meta-analysis.

    Science.gov (United States)

    Wertli, Maria M; Kessels, Alphons G H; Perez, Roberto S G M; Bachmann, Lucas M; Brunner, Florian

    2014-09-01

    Guidelines for complex regional pain syndrome (CRPS) 1 advocate several substance classes to reduce pain and support physical rehabilitation, but guidance about which agent should be prioritized when designing a therapeutic regimen is not provided. Using a network meta-analytic approach, we examined the efficacy of all agent classes investigated in randomized clinical trials of CRPS 1 and provide a rank order of various substances stratified by length of illness duration. In this study a network meta-analysis was conducted. The participants of this study were patients with CRPS 1. Searches in electronic, previous systematic reviews, conference abstracts, book chapters, and the reference lists of relevant articles were performed. Eligible studies were randomized controlled trials comparing at least one analgesic agent with placebo or with another analgesic and reporting efficacy in reducing pain. Summary efficacy stratified by symptom duration and length of follow-up was computed across all substance classes. Two authors independently extracted data. In total, 16 studies were included in the analysis. Bisphosphonates appear to be the treatment of choice in early stages of CRPS 1. The effects of calcitonin surpass that of bisphosphonates and other substances as a short-term medication in more chronic stages of the illness. While most medications showed some efficacy on short-term follow-up, only bisphosphonates, NMDA analogs, and vasodilators showed better long-term pain reduction than placebo. For some drug classes, only a few studies were available and many studies included a small group of patients. Insufficient data were available to analyze efficacy on disability. This network meta-analysis indicates that a rational pharmacological treatment strategy of pain management should consider bisphosphonates in early CRPS 1 and a short-term course of calcitonin in later stages. While most medications showed some efficacy on short-term follow-up, only bisphosphonates

  1. Activation of the umami taste receptor (T1R1/T1R3) initiates the peristaltic reflex and pellet propulsion in the distal colon

    Science.gov (United States)

    Kendig, Derek M.; Hurst, Norman R.; Bradley, Zachary L.; Mahavadi, Sunila; Kuemmerle, John F.; Lyall, Vijay; DeSimone, John; Murthy, Karnam S.

    2014-01-01

    Intraluminal nutrients in the gut affect the peristaltic reflex, although the mechanism is not well defined. Recent evidence supports the presence of taste receptors and their signaling components in enteroendocrine cells, although their function is unclear. This study aimed to determine if nutrients modify colonic motility through activation of taste receptors. Colonic sections were immunostained for the umami taste receptor T1R1/T1R3, which mediates the response to umami ligands, such as monosodium glutamate (MSG), in taste cells. Ascending contraction, descending relaxation, and calcitonin gene-related peptide release were measured in three-chamber flat-sheet preparations of rat colon in response to MSG alone or with inosine 5′-monophosphate (IMP). Velocity of artificial fecal pellet propulsion was measured by video recording in guinea pig distal colon. T1R1/T1R3 receptors were present in enteroendocrine cells of colonic sections from human, rat, mouse, and guinea pig. MSG initiated ascending contraction and descending relaxation components of the peristaltic reflex and calcitonin gene-related peptide release in flat-sheet preparations. IMP augmented the MSG-induced effects, suggesting activation of T1R1/T1R3 receptors. In T1R1−/− mice, mucosal stroking, but not MSG, elicited a peristaltic reflex. Intraluminal perfusion of MSG enhanced the velocity of artificial fecal pellet propulsion, which was also augmented by IMP. Propulsion was also increased by l-cysteine, but not l-tryptophan, supporting a role of T1R1/T1R3 receptors. We conclude that T1R1/T1R3 activation by luminal MSG or l-cysteine elicits a peristaltic reflex and CGRP release and increases the velocity of pellet propulsion in distal colon. This mechanism may explain how nutrients regulate colonic propulsion. PMID:25324508

  2. The Acupuncture on Hot Flushes Among Menopausal Women (ACUFLASH) study, a randomized controlled trial.

    Science.gov (United States)

    Borud, Einar Kristian; Alraek, Terje; White, Adrian; Fonnebo, Vinjar; Eggen, Anne Elise; Hammar, Mats; Astrand, Lotta Lindh; Theodorsson, Elvar; Grimsgaard, Sameline

    2009-01-01

    This study compared the effectiveness of individualized acupuncture plus self-care versus self-care alone on hot flashes and health-related quality of life in postmenopausal women. This study involved a multicenter, pragmatic, randomized, controlled trial with two parallel arms. Participants were postmenopausal women experiencing, on average, seven or more hot flashes per 24 hours during seven consecutive days. The acupuncture group received 10 acupuncture treatment sessions and advice on self-care, and the control group received advice on self-care only. The frequency and severity (0-10 scale) of hot flashes were registered in a diary. Urine excretion of calcitonin gene-related peptide was assessed at baseline and after 12 weeks. The primary endpoint was change in mean hot flash frequency from baseline to 12 weeks. The secondary endpoint was change in health-related quality of life measured by the Women's Health Questionnaire. Hot flash frequency decreased by 5.8 per 24 hours in the acupuncture group (n = 134) and 3.7 per 24 hours in the control group (n = 133), a difference of 2.1 (P acupuncture group and 1.8 units in the control group, a difference of 1.4 (P acupuncture group experienced statistically significant improvements in the vasomotor, sleep, and somatic symptoms dimensions of the Women's Health Questionnaire compared with the control group. Urine calcitonin gene-related peptide excretion remained unchanged from baseline to week 12. Acupuncture plus self-care can contribute to a clinically relevant reduction in hot flashes and increased health-related quality of life in postmenopausal women.

  3. Demographic, clinical, and genetic characteristics of patients with medullary thyroid cancer in the past 16 years in Castilla-La Mancha.

    Science.gov (United States)

    Louhibi, Lynda; Marco, Amparo; Pinés, Pedro J; Padillo, José C; Gómez, Inés; Valero, Miguel A; Alramadán, Mubarak; Herranz, Sandra; Aguirre, Miguel; Hernández, Antonio

    2014-10-01

    Medullary thyroid cancer is a rare tumor that is more aggressive and has a worse prognosis than differentiated thyroid cancer. The purpose of this study was to report the demographic, clinical, and genetic characteristics of patients seen in the health care system of the community of Castilla-La Mancha over a 16-year period. Data were collected through a review of patients' medical records. The medical records of 58 patients (mean age at diagnosis, 51 years; range, 6-82 years; 63.8% women) were reviewed. Prevalence rate was 2.84 cases per 100,000 inhabitants, with a high variability between areas (range, 0-5.4 cases per 100,000 inhabitants). Familial cases accounted for 34.5% of all medullary thyroid cancers, and the most common mutation was C634Y. The condition was most commonly diagnosed following palpation of a cervical lump (70.6%). At diagnosis, 56 of 58 patients underwent ultrasound and 8 of 58 patients were tested for serum calcitonin. Tumor multicentricity was reported in 59 and 50% of patients with multiple endocrine neoplasia syndrome type 2A and 2B, respectively, and in no sporadic cases. Fifty-two percent of patients had an advanced stage (iii or iv) at diagnosis. Median follow-up was 36 months (interquartile range, 14-210); 11 patients were lost to follow-up. In Castilla-La Mancha, medullary thyroid cancer is diagnosed by cervical ultrasound, rather than calcitonin assay. There is a high prevalence of both familial and sporadic medullary thyroid cancer, and a significant variability in the type of proto-oncogen rearranged during transfection mutation as compared to the rest of the Spanish population. Copyright © 2013 SEEN. Published by Elsevier Espana. All rights reserved.

  4. Bone biomarkers in patients with chronic traumatic spinal cord injury.

    Science.gov (United States)

    Sabour, Hadis; Norouzi Javidan, Abbas; Latifi, Sahar; Larijani, Bagher; Shidfar, Farzad; Vafa, Mohammad Reza; Heshmat, Ramin; Emami Razavi, Hassan

    2014-07-01

    Bone loss after spinal cord injury (SCI) occurs because of pathologic changes in osteoblastic and osteoclastic activities due to mechanical unloading. Some biochemical changes in bone metabolism after SCI are described before that were related to bone mineral loss. Our purpose was to determine bone markers' changes and related effective factors in patients with chronic traumatic SCI. This investigation was designed as an observational cross-sectional study. All patients with chronic SCI who were referred to Brain and Spinal Injury Research Center and did not meet our exclusion criteria entered the study. Self-reporting measures including patient's demographic features and date of accident were obtained using a questionnaire and physiologic measures including spinal magnetic resonance imaging to determine the level of injury accompanied with physical examination along with dual-energy X-ray absorptiometry were performed. Blood samples were analyzed in the laboratory. Dual-energy X-ray was used to determine bone mineral density in femoral and spinal vertebrae bone sites. Serum level of C-telopeptide cross-linked Type 1 collagen (CTX), parathyroid hormone, calcitonin, osteocalcin, and bone alkaline phosphatase (BALP) were measured. We detected a negative association between CTX level and bone mineral density in femoral and spinal bone sites that confirms that CTX is a bone resorption marker. C-telopeptide cross-linked Type 1 collagen and BALP levels did not show any significant correlation with postduration injury. Patients with spinal injury at lumbar level had the highest calcitonin level (pmarkers also revealed different site of action as osteocalcin level only affected femoral intertrochanteric bone mineral density. Generally, it seems that the coincidental consideration of these factors that influence bone mineral density can lead to a better understanding of bone changes after SCI. Copyright © 2014 Elsevier Inc. All rights reserved.

  5. Deficiency of RAMP1 attenuates antigen-induced airway hyperresponsiveness in mice.

    Directory of Open Access Journals (Sweden)

    Manyu Li

    Full Text Available Asthma is a chronic inflammatory disease affecting the lung, characterized by breathing difficulty during an attack following exposure to an environmental trigger. Calcitonin gene-related peptide (CGRP is a neuropeptide that may have a pathological role in asthma. The CGRP receptor is comprised of two components, which include the G-protein coupled receptor, calcitonin receptor-like receptor (CLR, and receptor activity-modifying protein 1 (RAMP1. RAMPs, including RAMP1, mediate ligand specificity in addition to aiding in the localization of receptors to the cell surface. Since there has been some controversy regarding the effect of CGRP on asthma, we sought to determine the effect of CGRP signaling ablation in an animal model of asthma. Using gene-targeting techniques, we generated mice deficient for RAMP1 by excising exon 3. After determining that these mice are viable and overtly normal, we sensitized the animals to ovalbumin prior to assessing airway resistance and inflammation after methacholine challenge. We found that mice lacking RAMP1 had reduced airway resistance and inflammation compared to wildtype animals. Additionally, we found that a 50% reduction of CLR, the G-protein receptor component of the CGRP receptor, also ameliorated airway resistance and inflammation in this model of allergic asthma. Interestingly, the loss of CLR from the smooth muscle cells did not alter the airway resistance, indicating that CGRP does not act directly on the smooth muscle cells to drive airway hyperresponsiveness. Together, these data indicate that signaling through RAMP1 and CLR plays a role in mediating asthma pathology. Since RAMP1 and CLR interact to form a receptor for CGRP, our data indicate that aberrant CGRP signaling, perhaps on lung endothelial and inflammatory cells, contributes to asthma pathophysiology. Finally, since RAMP-receptor interfaces are pharmacologically tractable, it may be possible to develop compounds targeting the RAMP1/CLR

  6. Complex regional pain syndrome: a review.

    Science.gov (United States)

    Albazaz, Raneem; Wong, Yew Toh; Homer-Vanniasinkam, Shervanthi

    2008-03-01

    Complex regional pain syndrome (CRPS), formerly known as "reflex sympathetic dystrophy," is a chronic neurological disorder characterized by disabling pain, swelling, vasomotor instability, sudomotor abnormality, and impairment of motor function. The disorder usually develops after minor trauma or surgery. No specific diagnostic test is available and, hence, diagnosis is based mainly on history, clinical examination, and supportive laboratory findings. This review gives a synopsis of CRPS and discusses the principles of management based on the limited available literature in the area. A literature search was conducted using electronic bibliographic databases (Medline, Embase, Pubmed, CENTRAL) from 1970 to 2006. Keywords complex regional pain syndrome, reflex sympathetic dystrophy, neuropathic pain, and causalgia were used for the search. Relevant articles from the reference lists in retrieved articles were also studied. There were 3,771 articles published in the area. Seventy-six randomized controlled trials were identified. Most studies were on the role of sympathetic blockade in the treatment of CRPS (n = 13). The role of sympathectomy is unclear, with some studies showing transient benefit and others showing no beneficial effects, with most studies containing only a small number of patients. Nine studies were on bisphosphonates or calcitonin. Studies involving bisphosphonates showed benefit, but studies involving calcitonin showed no definite benefit. Four studies were on cognitive behavioral therapy, physiotherapy, or occupational therapy, all of which demonstrated a potential beneficial effect. Three studies on spinal cord stimulation and two studies each on acupuncture, vitamin C, and steroid all showed a potential beneficial effect in pain reduction. The remaining studies were on miscellanous therapy or combination therapy, making it difficult to draw any conclusions on the effect of treatment. There is very little good evidence in the literature to guide

  7. An ex vivo culture system to study thyroid development.

    Science.gov (United States)

    Delmarcelle, Anne-Sophie; Villacorte, Mylah; Hick, Anne-Christine; Pierreux, Christophe E

    2014-06-06

    The thyroid is a bilobated endocrine gland localized at the base of the neck, producing the thyroid hormones T3, T4, and calcitonin. T3 and T4 are produced by differentiated thyrocytes, organized in closed spheres called follicles, while calcitonin is synthesized by C-cells, interspersed in between the follicles and a dense network of blood capillaries. Although adult thyroid architecture and functions have been extensively described and studied, the formation of the "angio-follicular" units, the distribution of C-cells in the parenchyma and the paracrine communications between epithelial and endothelial cells is far from being understood. This method describes the sequential steps of mouse embryonic thyroid anlagen dissection and its culture on semiporous filters or on microscopy plastic slides. Within a period of four days, this culture system faithfully recapitulates in vivo thyroid development. Indeed, (i) bilobation of the organ occurs (for e12.5 explants), (ii) thyrocytes precursors organize into follicles and polarize, (iii) thyrocytes and C-cells differentiate, and (iv) endothelial cells present in the microdissected tissue proliferate, migrate into the thyroid lobes, and closely associate with the epithelial cells, as they do in vivo. Thyroid tissues can be obtained from wild type, knockout or fluorescent transgenic embryos. Moreover, explants culture can be manipulated by addition of inhibitors, blocking antibodies, growth factors, or even cells or conditioned medium. Ex vivo development can be analyzed in real-time, or at any time of the culture by immunostaining and RT-qPCR. In conclusion, thyroid explant culture combined with downstream whole-mount or on sections imaging and gene expression profiling provides a powerful system for manipulating and studying morphogenetic and differentiation events of thyroid organogenesis.

  8. RAMP1 suppresses mucosal injury from dextran sodium sulfate-induced colitis in mice.

    Science.gov (United States)

    Kawashima-Takeda, Noriko; Ito, Yoshiya; Nishizawa, Nobuyuki; Kawashima, Rei; Tanaka, Kiyoshi; Tsujikawa, Kazutake; Watanabe, Masahiko; Majima, Masataka

    2017-04-01

    Calcitonin gene-related peptide (CGRP) is thought to be involved in the modulation of intestinal motility. CGRP receptor is composed of receptor activity-modifying protein (RAMP) 1 combined with calcitonin receptor-like receptor (CRLR) for CGRP. The study investigated the role of CGRP in mice with experimentally induced colitis. The study used dextran sodium sulfate (DSS) to induce colitis in mice. The study compared the severity of colitis in wild-type (WT) mice, mice treated with a CGRP receptor antagonist (CGRP8-37 ), and RAMP1 knockout (-/- ) mice. Pathological changes in the mucosa were assessed, and inflammatory cells and cytokine levels were measured. The severity of inflammation in DSS-induced colitis increased markedly in CGRP8-37 -treated mice and RAMP1-/- mice compared with WT mice. RAMP1-/- mice showed more severe damage compared with CGRP8-37 -treated mice. The number of periodic acid-Schiff-positive cells decreased in CGRP8-37 -treated mice compared with WT mice and was even further decreased in RAMP1-/- mice. RAMP1 was expressed by macrophages, mast cells, and T-cells. RAMP1-/- mice exhibited excessive accumulation of macrophages and mast cells into the colonic tissue with increased levels of tumor necrosis factor-α and interleukin-1β as compared with WT mice. Infiltration of T-cells into the colonic mucosa, which was associated with the expression of T helper (Th) cytokines including Th1 (interferon gamma) and Th17 (IL-17), was augmented in RAMP1-/- mice. The findings of this study suggest that RAMP1 exerted mucosal protection in DSS-induced colitis via attenuation of recruitment of inflammatory cells and of pro-inflammatory cytokines. © 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

  9. A confocal microscopic study of solitary pulmonary neuroendocrine cells in human airway epithelium

    Directory of Open Access Journals (Sweden)

    Sparrow Malcolm P

    2005-10-01

    Full Text Available Abstract Background Pulmonary neuroendocrine cells (PNEC are specialized epithelial cells that are thought to play important roles in lung development and airway function. PNEC occur either singly or in clusters called neuroepithelial bodies. Our aim was to characterize the three dimensional morphology of PNEC, their distribution, and their relationship to the epithelial nerves in whole mounts of adult human bronchi using confocal microscopy. Methods Bronchi were resected from non-diseased portions of a lobe of human lung obtained from 8 thoracotomy patients (Table 1 undergoing surgery for the removal of lung tumors. Whole mounts were stained with antibodies to reveal all nerves (PGP 9.5, sensory nerves (calcitonin gene related peptide, CGRP, and PNEC (PGP 9.5, CGRP and gastrin releasing peptide, GRP. The analysis and rendition of the resulting three-dimensional data sets, including side-projections, was performed using NIH-Image software. Images were colorized and super-imposed using Adobe Photoshop. Results PNEC were abundant but not homogenously distributed within the epithelium, with densities ranging from 65/mm2 to denser patches of 250/mm2, depending on the individual wholemount. Rotation of 3-D images revealed a complex morphology; flask-like with the cell body near the basement membrane and a thick stem extending to the lumen. Long processes issued laterally from its base, some lumenal and others with feet-like processes. Calcitonin gene-related peptide (CGRP was present in about 20% of PNEC, mainly in the processes. CGRP-positive nerves were sparse, with some associated with the apical part of the PNEC. Conclusion Our 3D-data demonstrates that PNEC are numerous and exhibit a heterogeneous peptide content suggesting an active and diverse PNEC population.

  10. Prospective evaluation of 68Ga-DOTA-NOC PET-CT in patients with recurrent medullary thyroid carcinoma: comparison with 18F-FDG PET-CT.

    Science.gov (United States)

    Naswa, Niraj; Sharma, Punit; Suman Kc, Sudhir; Lata, Sneh; Kumar, Rakesh; Malhotra, Arun; Bal, Chandrasekhar

    2012-07-01

    To prospectively evaluate the role of Ga-labelled [1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid]-1-NaI-octreotide (Ga-DOTA-NOC) PET-CT in patients with recurrent medullary thyroid carcinoma (MTC) and compare the same with F-fluorodeoxyglucose (F-FDG) PET-CT. Fifty-two consecutive patients with recurrent MTC based on raised serum calcitonin levels underwent Ga-DOTA-NOC PET-CT. In addition, 41 patients also underwent F-FDG PET-CT. PET-CT images were evaluated by two experienced nuclear medicine physicians both qualitatively and quantitatively (standardized uptake value). Histopathology (when available), correlation with conventional imaging modalities (ultrasonography/CT/MRI) and subsequent clinical/imaging follow-up were used as reference standard. Serum calcitonin levels were correlated with findings of PET-CT. Overall, Ga-DOTA-NOC PET-CT showed a sensitivity of 80.7% [95% confidence interval (CI) 67.4-90.3] and a positive predictive value of 100% (95% CI 91.5-100) for detecting recurrent MTC. When both were available (n=41), Ga-DOTA-NOC PET-CT proved superior to F-FDG PET-CT with a higher sensitivity (75.61 vs. 63.4%). However, the difference was statistically not significant (P=0.179). Ga-DOTA-NOC PET-CT was superior to F-FDG PET-CT for detecting recurrence in cervical lymph nodes (PNOC or F-FDG PET-CT. Both Ga-DOTA-NOC PET-CT and F-FDG PET-CT are able to localize disease recurrence in patients with MTC, and their role appears to be complementary for this purpose.

  11. Cross-sectional and longitudinal lipid determination studies in pregnant women reveal an association between increased maternal LDL cholesterol concentrations and reduced human umbilical vein relaxation.

    Science.gov (United States)

    Leiva, A; Salsoso, R; Sáez, T; Sanhueza, C; Pardo, F; Sobrevia, L

    2015-08-01

    Maternal hypercholesterolemia and hypertriglyceridemia during pregnancy is correlated with fetoplacental endothelial dysfunction and atherosclerotic lesions in fetal arteries. Few studies have reported the distribution of the concentrations of maternal total cholesterol (TCh), lipoprotein cholesterol and triglycerides during pregnancy. Therefore, we determined maternal lipid concentration during pregnancy and established the percentiles over which fetoplacental endothelial dysfunction is observed. A lipoprotein profile was determined for 249 pregnant Chilean women in each trimester of pregnancy in cross-sectional and longitudinal lipid determination studies. Distribution percentiles for TCh, high-, low- and very-low-density lipoprotein (HDL, LDL, and vLDL, respectively) cholesterol and triglycerides were estimated. The reactivity of human umbilical vein rings to the calcitonin gene-related peptide (0.1-1000 nmol/L, 5 min) and sodium nitroprusside (10 μmol/L, 5 min) was measured (wire myography) in KCl-preconstricted vessels. Maternal lipoproteins and triglyceride concentrations increased over time from preconception to the 3rd trimester of pregnancy. Newborn umbilical blood lipoprotein and triglyceride concentrations were lower than those in maternal circulation. Changes in maternal HDL correlated with newborn HDL concentration; however, no correlation between maternal lipoprotein concentrations and newborn weight was found. Maternal TCh and LDL concentrations were inversely correlated with the maximal dilation, but the >75th percentile of maternal TCh and LDL concentrations (>291 and >169 mg/dL, respectively) correlated with reduced calcitonin gene-related peptide sensitivity of the vein rings. We identified percentiles for maternal TCh and LDL concentrations over which abnormal endothelium-dependent human fetoplacental vascular response is observed. Copyright © 2015 Elsevier Ltd. All rights reserved.

  12. Biochemical and Pharmacological Characterization of a Mice Model of Complex Regional Pain Syndrome.

    Science.gov (United States)

    Das, Vaskar; Kroin, Jeffrey S; Moric, Mario; Buvanendran, Asokumar

    Complex regional pain syndrome is a challenging disease to treat. Recently, a mouse fracture model of complex regional pain syndrome has been developed that has many signs of the clinical syndrome. However, many aspects of the sensory neuron biochemistry and behavioral and pharmacological characterization of this model remain to be clarified. Mice were randomly assigned to fracture/cast or control (naive) groups. Fracture/cast mice underwent a closed distal tibia facture, with hindlimb wrapped in casting tape for 3 weeks. After cast removal, mice were tested for mechanical allodynia, burrowing behavior, and motor ability over a 12-week period. Protein immunohistochemistry was performed for substance P, calcitonin gene-related peptide, tropomyosin receptor kinase A, nerve growth factor, Nav1.7, and transient receptor potential cation-channel V1, colocalized in neurons, in the ipsilateral lumbar dorsal root ganglia (DRGs). Analgesic drugs were tested for pain-relieving efficacy. Mechanical allodynia was greater in the ipsilateral hindpaw (P = 0.0002) in the fracture/cast group versus the control group, over the 3- to 12-week period. The amount of burrowing material removed was decreased (P = 0.0026), and there were deficits in spontaneous motor-rearing behavior (P = 0.018). Immunostaining of substance P, calcitonin gene-related peptide, Trk A receptor, nerve growth factor, Nav1.7, and transient receptor potential cation-channel V1 all demonstrated up-regulation in the DRGs of fracture mice versus controls (all P mouse fracture/cast model with wide-scale DRG up-regulation of pain mediators. Antihyperalgesic drugs reduced mechanical allodynia and improved burrowing.

  13. What is the best balance of benefits and risks among anti-resorptive therapies for postmenopausal osteoporosis?

    Science.gov (United States)

    Miller, P D; Derman, R J

    2010-11-01

    Pharmacologic osteoporosis therapy, particularly anti-resorptives, is recommended in postmenopausal women with clinical risk factors for fracture. Treatment decisions should be made based on the relative benefit-risk profile in different patient populations. Emerging options [e.g., selective estrogen receptor modulators (SERMs) and denosumab] may hold promise for providing protection from bone loss and for fracture risk reduction.Osteoporosis, the most common clinical disorder of bone metabolism, is characterized by low bone mineral density, deterioration of microarchitecture, and a consequent increase in bone fragility and risk of fracture. Pharmacologic therapy is recommended in postmenopausal women with clinical risk factors for fracture and includes anti-resorptive agents such as bisphosphonates, hormone therapy, SERMs, and calcitonin. The anabolic agent teriparatide (parathyroid hormone) is usually reserved for high-risk patients or those with glucocorticoid-induced osteoporosis. Strontium ranelate, available outside the USA, has both anti-resorptive and anabolic properties. Supplementation with calcium and vitamin D is recommended for all women aged 50 years and older. Bisphosphonates are often considered first-line therapy for osteoporosis and have the largest base of clinical trial data showing efficacy for global fracture risk reduction. Low-dose hormone therapy is appropriate for younger women who are experiencing other menopausal symptoms. In women for whom bisphosphonates are not appropriate or not tolerated or in younger postmenopausal women who have a low risk for hip fracture, SERMs are a suitable treatment option. Calcitonin is designated for patients who are unable or unwilling to tolerate other osteoporosis agents. Emerging options, including newer SERMs (e.g., bazedoxifene and lasofoxifene) and the monoclonal antibody denosumab, may hold promise for providing protection from bone loss and for fracture risk reduction. Because no single agent is

  14. Immobilization contributes to exaggerated neuropeptide signaling, inflammatory changes, and nociceptive sensitization after fracture in rats.

    Science.gov (United States)

    Guo, Tian-Zhi; Wei, Tzuping; Li, Wen-Wu; Li, Xiang-Qi; Clark, J David; Kingery, Wade S

    2014-10-01

    A tibia fracture cast immobilized for 4 weeks can induce exaggerated substance P and calcitonin gene-related peptide signaling and neuropeptide-dependent nociceptive and inflammatory changes in the hind limbs of rats similar to those seen in complex regional pain syndrome (CRPS). Four weeks of hind limb cast immobilization can also induce nociceptive and vascular changes resembling CRPS. To test our hypothesis that immobilization alone could cause exaggerated neuropeptide signaling and inflammatory changes, we tested 5 cohorts of rats: 1) controls; 2) tibia fracture and hind limb casted; 3) hind limb casted, no fracture; 4) tibia fracture with intramedullary pinning, no cast; and 5) tibia fracture with intramedullary pinning and hind limb casting. After 4 weeks, the casts were removed and hind limb allodynia, unweighting, warmth, edema, sciatic nerve neuropeptide content, cutaneous and spinal cord inflammatory mediator levels, and spinal c-Fos activation were measured. After fracture with casting, there was allodynia, unweighting, warmth, edema, increased sciatic nerve substance P and calcitonin gene-related peptide, increased skin neurokinin 1 receptors and keratinocyte proliferation, increased inflammatory mediator expression in the hind paw skin (tumor necrosis factor-α, interleukin [IL]-1β, IL-6, nerve growth factor) and cord (IL-1β, nerve growth factor), and increased spinal c-Fos activation. These same changes were observed after cast immobilization alone, except that spinal IL-1β levels were not increased. Treating cast-only rats with a neurokinin 1 receptor antagonist inhibited development of nociceptive and inflammatory changes. Four weeks after fracture with pinning, all nociceptive and vascular changes had resolved and there were no increases in neuropeptide signaling or inflammatory mediator expression. Collectively, these data indicate that immobilization alone increased neuropeptide signaling and caused nociceptive and inflammatory changes similar

  15. Roles of CLR/RAMP receptor signaling in reproduction and development.

    Science.gov (United States)

    Chang, Chia Lin; Hsu, Sheau Yu Teddy

    2013-08-01

    Adrenomedullin (ADM), calcitonin gene-related peptides (α- and β-CGRPs), and intermedin/adrenomedullin 2 (IMD/ADM2) are major regulators of vascular tone and cardiovascular development in vertebrates. Recent research into their functions in reproduction has illuminated the role of these peptides and their cognate receptors (calcitonin receptor-like receptor/receptor activity-modifying protein (CLR/RAMP) receptors) in fetal-maternal blood circulation, fetoplacental development, female gamete development, and gamete movement in the oviduct. Although ADM family peptides function in a temporally and spatially specific manner in various reproductive processes, they appear to act via a similar set of second messengers, including nitric oxide, cyclic GMP, cyclic AMP, and calcium-activated potassium channels in different tissues. These discoveries supported the view that CLR/RAMP receptors were recruited to perform a variety of newly evolved reproductive functions during the evolution of internal reproduction in mammals. These advances also provided insight into how CLR/RAMP receptor signaling pathways coordinate with other physiological adaptions to accommodate the extra metabolic needs during pregnancy, and captured some important details as to how fetal-maternal vascular communications are generated in the first place. Furthermore, these findings have revealed novel, promising opportunities for the prevention and treatment of aberrant pregnancies such as pregnancy-induced hypertension, preeclampsia, and tubal ectopic pregnancy. However, significant efforts are still needed to clarify the relationships between certain components of the CLR/RAMP signaling pathway and aberrant pregnancies before CLR/RAMP receptors can become targets for clinical management. With this understanding, this review summarizes recent progresses with particular focus on clinical implications.

  16. Surgical approach to medullary thyroid carcinoma associated with multiple endocrine neoplasia type 2

    Directory of Open Access Journals (Sweden)

    Marcos R. Tavares

    2012-01-01

    Full Text Available We briefly review the surgical approaches to medullary thyroid carcinoma associated with multiple endocrine neoplasia type 2 (medullary thyroid carcinoma/multiple endocrine neoplasia type 2. The recommended surgical approaches are usually based on the age of the affected carrier/patient, tumor staging and the specific rearranged during transfection codon mutation. We have focused mainly on young children with no apparent disease who are carrying a germline rearranged during transfection mutation. Successful management of medullary thyroid carcinoma in these cases depends on early diagnosis and treatment. Total thyroidectomy should be performed before 6 months of age in infants carrying the rearranged during transfection 918 codon mutation, by the age of 3 years in rearranged during transfection 634 mutation carriers, at 5 years of age in carriers with level 3 risk rearranged during transfection mutations, and by the age of 10 years in level 4 risk rearranged during transfection mutations. Patients with thyroid tumor >5 mm detected by ultrasound, and basal calcitonin levels >40 pg/ml, frequently have cervical and upper mediastinal lymph node metastasis. In the latter patients, total thyroidectomy should be complemented by extensive lymph node dissection. Also, we briefly review our data from a large familial medullary thyroid carcinoma genealogy harboring a germline rearranged during transfection Cys620Arg mutation. All 14 screened carriers of the rearranged during transfection Cys620Arg mutation who underwent total thyroidectomy before the age of 12 years presented persistently undetectable serum levels of calcitonin (<2 pg/ml during the follow-up period of 2-6 years. Although it is recommended that preventive total thyroidectomy in rearranged during transfection codon 620 mutation carriers is performed before the age of 5 years, in this particular family the surgical intervention performed before the age of 12 years led to an apparent

  17. Incorporation of RANKL promotes osteoclast formation and osteoclast activity on β-TCP ceramics.

    Science.gov (United States)

    Choy, John; Albers, Christoph E; Siebenrock, Klaus A; Dolder, Silvia; Hofstetter, Wilhelm; Klenke, Frank M

    2014-12-01

    β-Tricalcium phosphate (β-TCP) ceramics are approved for the repair of osseous defects. In large defects, however, the substitution of the material by authentic bone is inadequate to provide sufficient long-term mechanical stability. We aimed to develop composites of β-TCP ceramics and receptor activator of nuclear factor κ-B ligand (RANKL) to enhance the formation of osteoclasts and promote cell mediated calcium phosphate resorption. RANKL was adsorbed superficially onto β-TCP ceramics or incorporated into a crystalline layer of calcium phosphate by the use of a co-precipitation technique. Murine osteoclast precursors were seeded onto the ceramics. After 15 days, the formation of osteoclasts was quantified cytologically and colorimetrically with tartrate-resistant acidic phosphatase (TRAP) staining and TRAP activity measurements, respectively. Additionally, the expression of transcripts encoding the osteoclast gene products cathepsin K, calcitonin receptor, and of the sodium/hydrogen exchanger NHA2 were quantified by real-time PCR. The activity of newly formed osteoclasts was evaluated by means of a calcium phosphate resorption assay. Superficially adsorbed RANKL did not induce the formation of osteoclasts on β-TCP ceramics. When co-precipitated onto β-TCP ceramics RANKL supported the formation of mature osteoclasts. The development of osteoclast lineage cells was further confirmed by the increased expression of cathepsin K, calcitonin receptor, and NHA2. Incorporated RANKL stimulated the cells to resorb crystalline calcium phosphate. Our in vitro study shows that RANKL incorporated into β-TCP ceramics induces the formation of active, resorbing osteoclasts on the material surface. Once formed, osteoclasts mediate the release of RANKL thereby perpetuating their differentiation and activation. In vivo, the stimulation of osteoclast-mediated resorption may contribute to a coordinated sequence of material resorption and bone formation. Further in vivo studies

  18. Thyroid cancer and co-occurring RET mutations in Hirschsprung disease.

    Science.gov (United States)

    Virtanen, Valtter B; Pukkala, Eero; Kivisaari, Reetta; Salo, Perttu P; Koivusalo, Antti; Arola, Johanna; Miettinen, Päivi J; Rintala, Risto J; Perola, Markus; Pakarinen, Mikko P

    2013-08-01

    The objective of this study was to assess the occurrence of thyroid cancer and co-occurring RET mutations in a population-based cohort of adult Hirschsprung disease (HD) patients. All 156 patients operated for HD in a tertiary center during 1950-1986 were followed for thyroid malignancies up to 2010 through the nationwide Finnish Cancer Registry. Ninety-one individuals participated in clinical and genetic screening, which included serum calcitonin and thyroid ultrasound (US) with cytology. Exons 10, 11, 13, and 16 were sequenced in all, and all exons of RET in 43 of the subjects, including those with thyroid cancer, RET mutations, suspicious clinical findings, and familial or long-segment disease. Through the cancer registry, two cases (aged 35 and 37 years) of medullary thyroid cancer (MTC) were observed; the incidence for MTC was 340-fold (95% CI 52-1600) compared with average population. These individuals had C611R and C620R mutations in exon 10. One papillary thyroid cancer without RET mutations was detected by clinical screening. Four subjects (aged 31-50 years) with co-occurring RET mutations in exons 10 (C609R; n=1) and 13 (Y791F, n=3) had sporadic short-segment HD with normal thyroid US and serum calcitonin. Three novel mutations and five single-nucleotide polymorphisms were found outside exons 10 and 13 without associated signs of thyroid cancer. MTC-associated RET mutations were restricted to exons 10 and 13 affecting ∼5% of unselected adults with HD. Clinical thyroid assessment did not improve accuracy of genetic screening, which should not be limited to patients with familial or long-segment disease.

  19. Enhancement of local bone remodeling in osteoporotic rabbits by biomimic multilayered structures on Ti6Al4V implants.

    Science.gov (United States)

    Huang, Ling; Luo, Zhong; Hu, Yan; Shen, Xinkun; Li, Menghuan; Li, Liqi; Zhang, Yuan; Yang, Weihu; Liu, Peng; Cai, Kaiyong

    2016-06-01

    To enhance long-term survival of titanium implants in patients with osteoporosis, chitosan/gelatin multilayers containing bone morphogenetic protein 2(BMP2) and an antiosteoporotic agent of calcitonin (CT) are deposited on the Ti6Al4V (TC4) implants through layer-by-layer (LBL) electrostatic assembly technique. Here, the obtained titanium alloy implant (TC4/LBL/CT/BMP2) can regulate the release of loaded calcitonin and BMP2 agents in a sustaining manner to accelerate the bone formation and simultaneously inhibit bone resorption. In vitro results show that the bone-related cells on TC4/LBL/CT/BMP2 present the lowest production level of tartrate resistant acid phosphatase (TRAP) but the highest (p < 0.05) level of alkaline phosphatase (ALP) activity, osteocalcin production, mineralization capacity and osteoblast-related gene expression among all groups after treatment for 7 or 21 days, respectively. Besides, in vivo studies of micro-CT analysis, routine histological and immunohistochemical analysis also collectively demonstrate that the TC4/LBL/CT/BMP2 implant can dramatically promote the formation and remodeling of new bone in osteoporotic rabbits after implantation for 30 days and 90 days, respectively. In vivo push-out testing further confirms that the TC4/LBL/CT/BMP2 implant has the highest (p < 0.01) interfacial shear strength and favorable bone-implant osseointegration. Overall, this study establishes a simple and profound methodology to fabricate a biofunctional TC4 implant for the treatment of local osteoporotic fractures in vivo. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 1437-1451, 2016. © 2016 Wiley Periodicals, Inc.

  20. Evolution of secretin family GPCR members in the metazoa

    Directory of Open Access Journals (Sweden)

    Clark Melody S

    2006-12-01

    Full Text Available Abstract Background Comparative approaches using protostome and deuterostome data have greatly contributed to understanding gene function and organismal complexity. The family 2 G-protein coupled receptors (GPCRs are one of the largest and best studied hormone and neuropeptide receptor families. They are suggested to have arisen from a single ancestral gene via duplication events. Despite the recent identification of receptor members in protostome and early deuterostome genomes, relatively little is known about their function or origin during metazoan divergence. In this study a comprehensive description of family 2 GPCR evolution is given based on in silico and expression analyses of the invertebrate receptor genes. Results Family 2 GPCR members were identified in the invertebrate genomes of the nematodes C. elegans and C. briggsae, the arthropods D. melanogaster and A. gambiae (mosquito and in the tunicate C. intestinalis. This suggests that they are of ancient origin and have evolved through gene/genome duplication events. Sequence comparisons and phylogenetic analyses have demonstrated that the immediate gene environment, with regard to gene content, is conserved between the protostome and deuterostome receptor genomic regions. Also that the protostome genes are more like the deuterostome Corticotrophin Releasing Factor (CRF and Calcitonin/Calcitonin Gene-Related Peptide (CAL/CGRP receptors members than the other family 2 GPCR members. The evolution of family 2 GPCRs in deuterostomes is characterised by acquisition of new family members, with SCT (Secretin receptors only present in tetrapods. Gene structure is characterised by an increase in intron number with organismal complexity with the exception of the vertebrate CAL/CGRP receptors. Conclusion The family 2 GPCR members provide a good example of gene duplication events occurring in tandem with increasing organismal complexity during metazoan evolution. The putative ancestral receptors

  1. Inhibitory effects of two G protein-coupled receptor kinases on the cell surface expression and signaling of the human adrenomedullin receptor

    Energy Technology Data Exchange (ETDEWEB)

    Kuwasako, Kenji, E-mail: kuwasako@med.miyazaki-u.ac.jp [Frontier Science Research Center, University of Miyazaki, Miyazaki, 889-1692 (Japan); Sekiguchi, Toshio [Noto Marine Laboratory, Division of Marine Environmental Studies, Institute of Nature and Environmental Technology, Kanazawa University, Ishikawa, 927-0553 (Japan); Nagata, Sayaka [Division of Circulatory and Body Fluid Regulation, Faculty of Medicine, University of Miyazaki, Miyazaki, 889-1692 (Japan); Jiang, Danfeng; Hayashi, Hidetaka [Frontier Science Research Center, University of Miyazaki, Miyazaki, 889-1692 (Japan); Murakami, Manabu [Department of Pharmacology, Hirosaki University, Graduate School of Medicine, Hirosaki, 036-8562 (Japan); Hattori, Yuichi [Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, 930-0194 (Japan); Kitamura, Kazuo [Division of Circulatory and Body Fluid Regulation, Faculty of Medicine, University of Miyazaki, Miyazaki, 889-1692 (Japan); Kato, Johji [Frontier Science Research Center, University of Miyazaki, Miyazaki, 889-1692 (Japan)

    2016-02-19

    Receptor activity-modifying protein 2 (RAMP2) enables the calcitonin receptor-like receptor (CLR, a family B GPCR) to form the type 1 adrenomedullin receptor (AM{sub 1} receptor). Here, we investigated the effects of the five non-visual GPCR kinases (GRKs 2 through 6) on the cell surface expression of the human (h)AM{sub 1} receptor by cotransfecting each of these GRKs into HEK-293 cells that stably expressed hRAMP2. Flow cytometric analysis revealed that when coexpressed with GRK4 or GRK5, the cell surface expression of the AM{sub 1} receptor was markedly decreased prior to stimulation with AM, thereby attenuating both the specific [{sup 125}I]AM binding and AM-induced cAMP production. These inhibitory effects of both GRKs were abolished by the replacement of the cytoplasmic C-terminal tail (C-tail) of CLR with that of the calcitonin receptor (a family B GPCR) or β{sub 2}-adrenergic receptor (a family A GPCR). Among the sequentially truncated CLR C-tail mutants, those lacking the five residues 449–453 (Ser-Phe-Ser-Asn-Ser) abolished the inhibition of the cell surface expression of CLR via the overexpression of GRK4 or GRK5. Thus, we provided new insight into the function of GRKs in agonist-unstimulated GPCR trafficking using a recombinant AM{sub 1} receptor and further determined the region of the CLR C-tail responsible for this GRK function. - Highlights: • We discovered a novel function of GRKs in GPCR trafficking using human CLR/RAMP2. • GRKs 4 and 5 markedly inhibited the cell surface expression of human CLR/RAMP2. • Both GRKs exhibited highly significant receptor signaling inhibition. • Five residues of the C-terminal tail of CLR govern this function of GRKs.

  2. The General Anesthetic Propofol Excites Nociceptors by Activating TRPV1 and TRPA1 Rather than GABAA Receptors*

    Science.gov (United States)

    Fischer, Michael J. M.; Leffler, Andreas; Niedermirtl, Florian; Kistner, Katrin; Eberhardt, Mirjam; Reeh, Peter W.; Nau, Carla

    2010-01-01

    Anesthetic agents can induce a paradox activation and sensitization of nociceptive sensory neurons and, thus, potentially facilitate pain processing. Here we identify distinct molecular mechanisms that mediate an activation of sensory neurons by 2,6-diisopropylphenol (propofol), a commonly used intravenous anesthetic known to elicit intense pain upon injection. Clinically relevant concentrations of propofol activated the recombinant transient receptor potential (TRP) receptors TRPA1 and TRPV1 heterologously expressed in HEK293t cells. In dorsal root ganglion (DRG) neurons, propofol-induced activation correlated better to expression of TRPA1 than of TRPV1. However, pretreatment with the protein kinase C activator 4β-phorbol 12-myristate 13-acetate (PMA) resulted in a significantly sensitized propofol-induced activation of TRPV1 in DRG neurons as well as in HEK293t cells. Pharmacological and genetic silencing of both TRPA1 and TRPV1 only partially abrogated propofol-induced responses in DRG neurons. The remaining propofol-induced activation was abolished by the selective γ-aminobutyric acid, type A (GABAA) receptor antagonist picrotoxin. Propofol but not GABA evokes a release of calcitonin gene-related peptide, a key component of neurogenic inflammation, from isolated peripheral nerves of wild-type but not TRPV1 and TRPA1-deficient mice. Moreover, propofol but not GABA induced an intense pain upon intracutaneous injection. As both the release of calcitonin gene-related peptide and injection pain by propofol seem to be independent of GABAA receptors, our data identify TRPV1 and TRPA1 as key molecules for propofol-induced excitation of sensory neurons. This study warrants further investigations into the role of anesthetics to induce nociceptor sensitization and to foster postoperative pain. PMID:20826794

  3. Pharmacologic interventions for treating phantom limb pain.

    Science.gov (United States)

    Alviar, Maria Jenelyn M; Hale, Tom; Dungca, Monalisa

    2016-10-14

    particular botulinum toxin A (BoNT/A), to the group of medications reviewed previously. Our primary outcome was change in pain intensity. Most studies did not report our secondary outcomes of sleep, depression or mood, quality of life, treatment satisfaction, or withdrawals from the study.BoNT/A did not improve phantom limb pain intensity during the six months of follow-up compared with lidocaine/methylprednisolone.Compared with placebo, morphine (oral and intravenous) was effective in decreasing pain intensity in the short term with reported adverse events being constipation, sedation, tiredness, dizziness, sweating, voiding difficulty, vertigo, itching, and respiratory problems.The N-methyl D-aspartate (NMDA) receptor antagonists ketamine (versus placebo; versus calcitonin) and dextromethorphan (versus placebo), but not memantine, had analgesic effects. The adverse events of ketamine were more serious than placebo and calcitonin and included loss of consciousness, sedation, hallucinations, hearing and position impairment, and insobriety.The results for gabapentin in terms of pain relief were conflicting, but combining the results favoured treatment group (gabapentin) over control group (placebo) (mean difference -1.16, 95% confidence interval -1.94 to -0.38; 2 studies). However, gabapentin did not improve function, depression score, or sleep quality. Adverse events experienced were somnolence, dizziness, headache, and nausea.Compared with an active control benztropine mesylate, amitriptyline was not effective in PLP, with dry mouth and dizziness as the most frequent adverse events based on one study.The findings for calcitonin (versus placebo; versus ketamine) and local anaesthetics (versus placebo) were variable. Adverse events of calcitonin were headache, vertigo, drowsiness, nausea, vomiting, and hot and cold flushes. Most of the studies were limited by their small sample sizes. Since the last version of this review, we identified another study that added another form

  4. The surface characterisation and comparison of two potential sub-micron, sugar bulking excipients for use in low-dose, suspension formulations in metered dose inhalers.

    Science.gov (United States)

    James, Jeff; Crean, Barry; Davies, Martyn; Toon, Richard; Jinks, Phil; Roberts, Clive J

    2008-09-01

    This study compares the surface characteristics and surface energetics of two potential bulking excipients, anhydrous sub-micron alpha-lactose and sub-micron sucrose, for use with low-dose, suspension formulations in pressurised metered dose inhalers (pMDIs). Both sub-micron bulking excipients are processed from parent materials (alpha-lactose monohydrate/alpha-lactose monohydrate and silk grade sucrose, respectively) so the surface characteristics of each material were determined and compared. Additionally, the surface energetics and adhesive interactions between each sub-micron bulking excipient and some chosen active pharmaceutical ingredients (APIs) used in pMDI formulations were also determined. From this data, it was possible to predict the potential degree of interaction between the APIs and each sub-micron bulking excipient, thus determining suitable API-excipient combinations for pMDI formulation optimisation. Salmon calcitonin was also investigated as a potential API due to the current interest in, and the potential low-dose requirements for, the pulmonary delivery of proteins. The size and morphology of each sub-micron excipient (and parent materials) were determined using scanning electron microscopy (SEM) and the crystalline nature of each sub-micron excipient and parent material was assessed using X-ray diffraction (XRD). The surface chemistry of each sub-micron excipient was analysed using X-ray photoelectron spectroscopy (XPS). The surface energies of each sub-micron excipient, along with their respective parent materials and any intermediates, were determined using two techniques. The surface energies of these materials were determined via (a) single particle adhesive interactions using atomic force microscopy (AFM) and (b) 'bulk' material surface interactions using contact angle measurements (CA). From the CA data, it was possible to calculate the theoretical work of adhesion values for each API-excipient interaction using the surface component

  5. Early, Prophylactic Thyroidectomy in Hereditary Medullary Thyroid Carcinoma: A 26-year Monoinstitutional Experience.

    Science.gov (United States)

    Pelizzo, Maria R; Torresan, Francesca; Boschin, Isabella M; Nacamulli, Davide; Pennelli, Gianmaria; Barollo, Susi; Rubello, Domenico; Mian, Caterina

    2015-10-01

    Prophylactic thyroidectomy has been encouraged for children with REarranged during Transfection (RET) germline mutations to prevent the onset, persistence, or recurrence of medullary thyroid carcinoma (MTC). The American Thyroid Association (ATA) recently published guidelines on the timing of prophylactic thyroidectomy. Our aim here was to seek information on the optimal timing of surgery for carriers of RET gene mutations with no clinical evidence of disease, bearing in mind the ATA recommendations. From 1986 to 2012, total thyroidectomy was performed at our institute on 31 carriers of RET gene mutations, 28 of them found on family screening in the post-RET era, and the other 3 under 20 years of age and classified as "early cases" in the pre-RET era. The following parameters were studied: age at surgery, MTC risk, basal calcitonin (bCT) and pentagastrin-stimulated calcitonin (sCT), surgery outcomes, and persistence of disease. By family, the most prevalent mutation was codon 634 (30%) RET mutation. The youngest MTC patient was 5 years old. Overall, MTC was found in 68% of cases; 52% of the sample had a normal bCT and 25% had an sCT unresponsive to pentagastrin. The only factor predicting the risk of MTC at final histology was an ATA-RET risk level C. On receiver oparating curves analysis, a cutoff at age over 24 years predicted (P=0.06) a yield of MTC in the resected specimen. Interestingly, none of the patients with MTC had nodal involvement (0/21 patients with MTC). Yet, none of the patients had permanent nerve palsy, and only 1 patient had permanent hypocalcemia. bCT was normal postoperatively and during the follow-up in all but 3 patients. It is noteworthy that the yield of cancer in removed thyroid was 100% for codon 634 (9/9 patients, 5 families) and for codons 891 and 768 (2/2 patients in each of the 2 families with those codon mutations), followed by 67% for codon 609 (4/6 patients, 1 family), and 60% for codon 618 (3/5 patients in 4 families) RET mutation

  6. First survey and functional annotation of prohormone and convertase genes in the pig

    Directory of Open Access Journals (Sweden)

    Porter Kenneth I

    2012-11-01

    Full Text Available Abstract Background The pig is a biomedical model to study human and livestock traits. Many of these traits are controlled by neuropeptides that result from the cleavage of prohormones by prohormone convertases. Only 45 prohormones have been confirmed in the pig. Sequence homology can be ineffective to annotate prohormone genes in sequenced species like the pig due to the multifactorial nature of the prohormone processing. The goal of this study is to undertake the first complete survey of prohormone and prohormone convertases genes in the pig genome. These genes were functionally annotated based on 35 gene expression microarray experiments. The cleavage sites of prohormone sequences into potentially active neuropeptides were predicted. Results We identified 95 unique prohormone genes, 2 alternative calcitonin-related sequences, 8 prohormone convertases and 1 cleavage facilitator in the pig genome 10.2 assembly and trace archives. Of these, 11 pig prohormone genes have not been reported in the UniProt, UniGene or Gene databases. These genes are intermedin, cortistatin, insulin-like 5, orexigenic neuropeptide QRFP, prokineticin 2, prolactin-releasing peptide, parathyroid hormone 2, urocortin, urocortin 2, urocortin 3, and urotensin 2-related peptide. In addition, a novel neuropeptide S was identified in the pig genome correcting the previously reported pig sequence that is identical to the rabbit sequence. Most differentially expressed prohormone genes were under-expressed in pigs experiencing immune challenge relative to the un-challenged controls, in non-pregnant relative to pregnant sows, in old relative to young embryos, and in non-neural relative to neural tissues. The cleavage prediction based on human sequences had the best performance with a correct classification rate of cleaved and non-cleaved sites of 92% suggesting that the processing of prohormones in pigs is similar to humans. The cleavage prediction models did not find conclusive

  7. Pain perception in schizophrenia: influence of neuropeptides, cognitive disorders, and negative symptoms

    Directory of Open Access Journals (Sweden)

    Urban-Kowalczyk M

    2015-08-01

    Full Text Available Małgorzata Urban-Kowalczyk,1 Justyna Pigońska,2 Janusz Śmigielski3 1Department of Affective and Psychotic Disorders, Medical University of Łódź, Łódź, Poland; 2Department of Neurology and Movement Disorders, Medical University of Łódź, Łódź, Poland; 3Department of Geriatrics, Healthy Ageing Research Centre (HARC, Medical University of Łódź, Łódź, Poland Objectives: The causes and nature of insensitivity to pain in schizophrenia remain unknown. The role of endorphins and the association of cognitive dysfunction and negative symptoms are postulated.Methods: In this study, 43 patients with schizophrenia, five first-degree relatives, and 34 healthy controls were examined. Participants’ plasma concentrations of substance P, β-endorphin, and calcitonin gene-related peptide (CGRP were assessed. In patients, the Trail-Making Test, the Color Reading Interference Test (Stroop test, and the Positive and Negative Syndrome Scale Negative Syndrome subscale (PANSS N test were performed. We also evaluated pain threshold using nociceptive reflex (RTIII testing.Results: The mean β-endorphin concentration was about 20% higher in patients than in healthy controls (P<0.05. CGRP concentrations were significantly higher in patients than in controls (5.34 ng/mL versus 4.16 ng/mL; P<0.01. Subjects treated with antipsychotic polytherapy had higher concentrations of CGRP than did patients treated with second-generation antipsychotic monotherapy (5.92 ng/mL versus 5.02 ng/mL; P<0.05. There were no correlations between any biochemical parameters and Trail-Making Test, Stroop test, and PANSS N scores. There were no differences in RTIII among study groups. Strong negative correlation (P<0.001 was found between PANSS N scores and subjective pain threshold on the right lower limb.Conclusion: The insensitivity to pain in schizophrenia is a complex phenomenon that is probably not related to changes in nociceptive pathways. Increase in β-endorphin level

  8. Tendencias en la prescripción de fármacos preventivos en el distrito de atención primaria de Sevilla (2000-2003 Trends in preventive drug prescription in the Primary Care District of Seville (2000-2003

    Directory of Open Access Journals (Sweden)

    Ana Monroy-Morcillo

    2005-12-01

    Full Text Available Objetivos: Describir las tendencias en las tasas de prescripción de bisfosfonatos, raloxifeno, calcitonina, estatinas y terapia hormonal sustitutiva (THS entre 2000 y 2003, y medir el impacto de la difusión en los medios de la interrupción del ensayo Women's Health Initiative, sobre la prescripción de terapia hormonal. Metodología: Estudio ecológico descriptivo, con el tiempo (mes como unidad de observación. Se midieron las tasas de prescripción mensuales de bisfosfonatos, calcitonina, raloxifeno, estatinas y THS, en dosis diarias definidas por 1.000 personas en la población adscrita a 249 médicos de familia de 27 centros de salud del distrito de Sevilla. Se realizaron gráficas de tendencias y análisis de series temporales. Resultados y discusión: Hay una tendencia al aumento en la prescripción de fármacos preventivos (salvo calcitonina, entre 2000 y 2003. La tasa de prescripción de THS sufrió un descenso a partir de la suspensión del ensayo Women's Health Initiative.Objectives: To describe trends in prescription rates for biphosphonates, raloxifene, calcitonin, statins and hormone replacement therapy (HRT between 2000 and 2003 and to assess the impact of mass media information on the interruption of the Women's Health Initiative trial on HRT prescription rates. Methodology: We performed a descriptive, ecological study, with time (month as the observation unit. Monthly rates of bisphosphonate, calcitonin, raloxifene, statins and HRT prescription, in defined daily doses per 1000 persons, were measured in the population assigned to 249 family physicians in 27 health centers in Seville. Trend graphs and time series analysis were carried out. Results and discussion: The prescription of preventive drugs has tended to increase between 2000 and 2003. The HRT prescription rate has decreased since the interruption of the Women's Health Initiative trial.

  9. Visceral hypersensitivity is provoked by 2,4,6-trinitrobenzene sulfonic acid-induced ileitis in rats

    Directory of Open Access Journals (Sweden)

    Manoj Kumar Shah

    2016-07-01

    Full Text Available Background and Aims: Crohn’s Disease (CD, a chronic Inflammatory Bowel Disease, can occur in any part of the gastrointestinal tract, but most frequently in the ileum. Visceral hypersensitivity contributes for development of chronic abdominal pain in this disease. Currently, the understanding of the mechanism underlying hypersensitivity of Crohn’s ileitis has been hindered by a lack of specific animal model. The present study is undertaken to investigate the visceral hypersensitivity provoked by 2,4,6-trinitrobenzene sulfonic (TNBS-induced ileitis rats.Methods: Male Sprague-Dawley rats were anaesthetized and laparotomized for intraileal injection of TNBS (0.6 ml, 80 mg/kg body weight in 30% ethanol, n = 48, an equal volume of 30% Ethanol (n = 24 and Saline (n = 24, respectively. Visceral hypersensitivity was assessed by visceromotor responses (VMR to 20, 40, 60, 80 and 100 mmHg colorectal distension pressure (CRD at day 1, 3, 7, 14, 21 and 28. Immediately after CRD test, the rats were euthanized for collecting the terminal ileal segment for histopathological examinations and ELISA of myleoperoxidase and cytokines (TNF-α, IL-1β, IL-6, and dorsal root ganglia (T11 for determination of calcitonin gene-related peptide by immunohistochemistry, respectively. Results: Among all groups, TNBS-treatment showed transmural inflammation initially at 3 days, reached maximum at 7 days and persisted up to 21 days. The rats with ileitis exhibited (P < 0.05 VMR to CRD at day 7 to day 21. The calcitonin gene-related peptide-immunoreactive positive cells increased (P < 0.05 in dorsal root ganglia at day 7 to 21, which was persistently consistent with visceral hypersensitivity in TNBS-treated rats.Conclusions: TNBS injection into the ileum induced transmural ileitis including granuloma and visceral hypersensitivity. As this model mimics clinical manifestations of CD, it may provide a road map to probe the pathogenesis of gut inflammation and visceral

  10. Predictive and prognostic value of 18F-DOPA PET/CT in patients affected by recurrent medullary carcinoma of the thyroid.

    Science.gov (United States)

    Caobelli, Federico; Chiaravalloti, Agostino; Evangelista, Laura; Saladini, Giorgio; Schillaci, Orazio; Vadrucci, Manuela; Scalorbi, Federica; Donner, Davide; Alongi, Pierpaolo

    2018-01-01

    Medullary thyroid carcinoma (MTC) is a malignancy accounting for about 5-8% of thyroid cancers. Serum calcitonin and carcinoembryonic antigen (CEA) levels are widely used to monitor disease progression. However, prognostic factors able to predict outcomes are highly desirable. We, therefore, aimed to assess the prognostic role of 18F-DOPA PET/CT in patients with recurrent MTC. 60 patients (mean age 64 ± 13 years, range 44-82) with recurrent MTC were eligible from a multicenter database. All patients underwent a restaging 18F-DOPA PET/CT, performed at least 6 months after surgery. CEA/calcitonin levels, local recurrences, nodal involvement and metastases at PET/CT were recorded. SUVmax, SUVmean (also normalized to mediastinal uptake) and metabolic tumor volume were automatically calculated for each lesion, by placing a volume of interest around the lesion with 40% of peak activity as threshold for the automatic contouring. The patients were clinically and radiologically followed up for 21 ± 11 months. Rate of progression-free survival (PFS), disease-specific survival (DSS) and incremental prognostic value of 18F-DOPA PET/CT over conventional imaging modalities were assessed by Kaplan-Meier curves and Log-Rank test. Cox regression univariate and multivariate analyses were performed for assessing predictors of prognosis. 18F-DOPA PET/CT showed abnormal findings in 27 patients (45%) and resulted unremarkable in 33 (55%). PFS was significantly longer in patients with an unremarkable PET/CT scan (p = 0.018). Similarly, an unremarkable PET/CT study was associated with a significantly longer DSS (p = 0.04). 18F-DOPA PET/CT added prognostic value over other imaging modalities both for PFS and for DSS (p PET parameters nor clinical or laboratory data were predictive of a worse PFS and DSS in patients with recurrent MTC. 18F-DOPA PET/CT scan has an important prognostic value in predicting disease progression and mortality rate.

  11. N-type calcium current, Cav2.2, is enhanced in small-diameter sensory neurons isolated from Nf1+/- mice.

    Science.gov (United States)

    Duan, J-H; Hodgdon, K E; Hingtgen, C M; Nicol, G D

    2014-06-13

    Major aspects of neuronal function are regulated by Ca(2+) including neurotransmitter release, excitability, developmental plasticity, and gene expression. We reported previously that sensory neurons isolated from a mouse model with a heterozygous mutation of the Nf1 gene (Nf1+/-) exhibited both greater excitability and evoked release of neuropeptides compared to wildtype mice. Furthermore, augmented voltage-dependent sodium currents but not potassium currents contribute to the enhanced excitability. To determine the mechanisms giving rise to the enhanced release of substance P and calcitonin gene-related peptide in the Nf1+/- sensory neurons, the potential differences in the total voltage-dependent calcium current (ICa) as well as the contributions of individual Ca(2+) channel subtypes were assessed. Whole-cell patch-clamp recordings from small-diameter capsaicin-sensitive sensory neurons demonstrated that the average peak ICa densities were not different between the two genotypes. However, by using selective blockers of channel subtypes, the current density of N-type (Cav2.2) ICa was significantly larger in Nf1+/- neurons compared to wildtype neurons. In contrast, there were no significant differences in L-, P/Q- and R-type currents between the two genotypes. Quantitative real-time polymerase chain reaction measurements made from the isolated but intact dorsal root ganglia indicated that N-type (Cav2.2) and P/Q-type (Cav2.1) Ca(2+) channels exhibited the highest mRNA expression levels although there were no significant differences in the levels of mRNA expression between the genotypes. These results suggest that the augmented N-type (Cav2.2) ICa observed in the Nf1+/- sensory neurons does not result from genomic differences but may reflect post-translational or some other non-genomic modifications. Thus, our results demonstrate that sensory neurons from Nf1+/- mice, exhibit increased N-type ICa and likely account for the increased release of substance P and

  12. Comparison of {sup 18}F-DOPA, {sup 18}F-FDG and {sup 68}Ga-somatostatin analogue PET/CT in patients with recurrent medullary thyroid carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Treglia, Giorgio; Castaldi, Paola; Villani, Maria Felicia; Perotti, Germano; Giordano, Alessandro; Rufini, Vittoria [Catholic University of the Sacred Heart, Institute of Nuclear Medicine, Policlinico A. Gemelli, Rome (Italy); Waure, Chiara de [Catholic University of the Sacred Heart, Institute of Hygiene, Policlinico A. Gemelli, Rome (Italy); Filice, Angelina; Versari, Annibale [Santa Maria Nuova Hospital, Nuclear Medicine Unit, Reggio Emilia (Italy); Ambrosini, Valentina; Fanti, Stefano [University of Bologna, Nuclear Medicine Unit, Sant' Orsola-Malpighi Hospital, Bologna (Italy); Cremonini, Nadia [Ospedale Maggiore, Unit of Endocrinology, Bologna (Italy); Santimaria, Monica [Catholic University of the Sacred Heart, PET Radiopharmacy Unit, Policlinico A. Gemelli, Rome (Italy)

    2012-04-15

    To retrospectively evaluate and compare {sup 18}F-FDG, {sup 18}F-DOPA and {sup 68}Ga-somatostatin analogues for PET/CT in patients with residual/recurrent medullary thyroid carcinoma (MTC) suspected on the basis of elevated serum calcitonin levels. Included in the study were 18 patients with recurrent MTC in whom functional imaging with the three tracers was performed. The PET/CT results were compared on a per-patient basis and on a per-lesion-basis. At least one focus of abnormal uptake was observed on PET/CT in 13 patients with {sup 18}F-DOPA (72.2% sensitivity), in 6 patients with {sup 68}Ga-somatostatin analogues (33.3%) and in 3 patients with {sup 18}F-FDG (16.7%) (p < 0.01). There was a statistically significant difference in sensitivity between {sup 18}F-DOPA and {sup 18}F-FDG PET/CT (p < 0.01) and between {sup 18}F-DOPA and {sup 68}Ga-somatostatin analogue PET/CT (p = 0.04). Overall, 72 lesions were identified on PET/CT with the three tracers. {sup 18}F-DOPA PET/CT detected 85% of lesions (61 of 72), {sup 68}Ga-somatostatin analogue PET/CT 20% (14 of 72) and {sup 18}F-FDG PET/CT 28% (20 of 72). There was a statistically significant difference in the number of lymph node, liver and bone lesions detected with the three tracers (p < 0.01). In particular, post-hoc tests showed a significant difference in the number of lymph node, liver and bone lesions detected by {sup 18}F-DOPA PET/CT and {sup 18}F-FDG PET/CT (p < 0.01 for all the analyses) and by {sup 18}F-DOPA PET/CT and {sup 68}Ga-somatostatin analogue PET/CT (p < 0.01 for all the analyses). The PET/CT results led to a change in management of eight patients (44%). {sup 18}F-DOPA PET/CT seems to be the most useful imaging method for detecting recurrent MTC lesions in patients with elevated serum calcitonin levels, performing better than {sup 18}F-FDG and {sup 68}Ga-somatostatin analogue PET/CT. {sup 18}F-FDG may complement {sup 18}F-DOPA in patients with an aggressive tumour. (orig.)

  13. Transganglionic transport and binding of the isolectin B4 from Griffonia simplicifolia I in rat primary sensory neurons.

    Science.gov (United States)

    Wang, H; Rivero-Melián, C; Robertson, B; Grant, G

    1994-09-01

    The isolectin B4 from Griffonia simplicifolia I binds to a subpopulation of rat small-diameter dorsal root ganglion neurons, and to fibres and presumed terminals in laminae I-II of the spinal cord dorsal horn. In the present study we investigated B4 and B4 conjugated to horseradish peroxidase as potential transganglionic tracers of somatic primary afferent neurons after injection into a peripheral nerve. We also tried to identify the specific subpopulation of dorsal root ganglion neurons that bind and ganglion neurons that bind and transport B4. Following injection of B4 or B4-horseradish peroxidase into the sciatic nerve, labelled presumed terminals that reached peak labelling at two days were found exclusively in regions of the spinal cord gray matter known to receive unmyelinated primary afferent fibres. Almost all dorsal root ganglion cells that transported B4-horseradish peroxidase also bound B4. Cell counts showed that 51% of the dorsal root ganglion neurons were B4-positive and cell area measurements that these were all in the small size range. An extensive overlap was found between B4 and fluoride-resistant acid phosphatase (85%), and between B4 and calcitonin gene-related peptide (59%). Seventeen per cent of the B4-positive cells were substance P-immunoreactive and 9% were immunoreactive to somatostatin. Minimal overlap was seen between B4-positive cells and cells positive for RT97 (3%), a selective marker of primary afferent neurons with myelinated axons. All somatostatin-immunoreactive cells and almost all (95%) of the fluoride-resistant acid phosphatase-positive cells were contained within the B4-positive population. This comprised also 58% of the cells immunoreactive to calcitonin gene-related peptide and 42% of those immunoreactive to substance P. The results obtained show that B4 binds to a subpopulation of unmyelinated primary afferent neurons, and that B4 and B4-horseradish peroxidase can be used as selective transganglionic tracers of this

  14. Glycemic control and anti-osteopathic effect of propolis in diabetic rats

    Directory of Open Access Journals (Sweden)

    Al-Hariri M, Gamal Eldin T

    2011-11-01

    Full Text Available M Al-Hariri, T Gamal Eldin, B Abu-Hozaifa, A ElnourDepartment of Physiology, College of Medicine, University of Dammam, Dammam, Saudi ArabiaAbstract: The aim of the study was to explore the possibility that propolis can control diabetes mellitus and prevent diabetic osteopathy in rats. The study compared 60 streptozotocin (STZ-induced diabetic rats, with ten nondiabetic rats used as a negative control. The experimental design comprised seven groups (n = 10 rats per group: (1 nondiabetic, used as a negative control; (2 nontreated, used as a positive control; (3 treated with insulin alone; (4 treated with a single dose of propolis alone; (5 treated with a double dose of propolis; (6 treated with insulin and a single dose of propolis; and (7 treated with insulin and a double dose of propolis. After 6 weeks of treatment, the rats were sacrificed. Ratios of femur ash to femur weight and of femur weight to body weight (FW/BW were calculated and calcium (Ca, phosphorus (P, and magnesium (Mg concentrations in femur ash were estimated and analyzed. Fasting blood glucose (FBG, plasma insulin and glucagon, serum thiobarbituric acid reactive substances (TBARS, plasma parathyroid hormone (PTH, and calcitonin levels were also estimated and analyzed. There was significant reduction in FBG in all diabetic treated rats. Similarly, higher plasma insulin levels were observed in diabetic rats treated with propolis and insulin than in nontreated diabetic rats, although plasma insulin was not comparatively higher in diabetic rats treated with insulin alone. Serum TBARS was significantly lower in the propolis treated rats than the diabetic nontreated rats. No differences in PTH and calcitonin levels were observed among treatment groups. The FW/BW ratio was significantly higher in diabetic treated groups than in control groups. Furthermore, diabetic rats treated with propolis and insulin had significantly higher Ca, P, and Mg concentrations in femoral ash than

  15. Hepatocyte Growth Factor and MET Support Mouse Enteric Nervous System Development, the Peristaltic Response, and Intestinal Epithelial Proliferation in Response to Injury.

    Science.gov (United States)

    Avetisyan, Marina; Wang, Hongtao; Schill, Ellen Merrick; Bery, Saya; Grider, John R; Hassell, John A; Stappenbeck, Thaddeus; Heuckeroth, Robert O

    2015-08-19

    Factors providing trophic support to diverse enteric neuron subtypes remain poorly understood. We tested the hypothesis that hepatocyte growth factor (HGF) and the HGF receptor MET might support some types of enteric neurons. HGF and MET are expressed in fetal and adult enteric nervous system. In vitro, HGF increased enteric neuron differentiation and neurite length, but only if vanishingly small amounts (1 pg/ml) of glial cell line-derived neurotrophic factor were included in culture media. HGF effects were blocked by phosphatidylinositol-3 kinase inhibitor and by MET-blocking antibody. Both of these inhibitors and MEK inhibition reduced neurite length. In adult mice, MET was restricted to a subset of calcitonin gene-related peptide-immunoreactive (IR) myenteric plexus neurons thought to be intrinsic primary afferent neurons (IPANs). Conditional MET kinase domain inactivation (Met(fl/fl); Wnt1Cre+) caused a dramatic loss of myenteric plexus MET-IR neurites and 1-1'-dioctodecyl-3,3,3',3'-tetramethylindocarbocyamine perchlorate (DiI) labeling suggested reduced MET-IR neurite length. In vitro, Met(fl/fl); Wnt1Cre+ mouse bowel had markedly reduced peristalsis in response to mucosal deformation, but normal response to radial muscle stretch. However, whole-bowel transit, small-bowel transit, and colonic-bead expulsion were normal in Met(fl/fl); Wnt1Cre+ mice. Finally, Met(fl/fl); Wnt1Cre+ mice had more bowel injury and reduced epithelial cell proliferation compared with WT animals after dextran sodium sulfate treatment. These results suggest that HGF/MET signaling is important for development and function of a subset IPANs and that these cells regulate intestinal motility and epithelial cell proliferation in response to bowel injury. The enteric nervous system has many neuronal subtypes that coordinate and control intestinal activity. Trophic factors that support these neuron types and enhance neurite growth after fetal development are not well understood. We show that

  16. Pharmacological characterization of the relaxant effect induced by adrenomedullin in rat cavernosal smooth muscle

    Energy Technology Data Exchange (ETDEWEB)

    Leite, L.N. [Programa de Pós-Graduação em Farmacologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP (Brazil); Laboratório de Farmacologia, Departamento de Enfermagem Psiquiátrica e Ciências Humanas, Escola de Enfermagem de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP (Brazil); Gonzaga, N.A. [Programa de Pós-Graduação em Farmacologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP (Brazil); Tirapelli, D.P.C.; Tirapelli, L.F. [Departamento de Cirurgia e Anatomia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP (Brazil); Tirapelli, C.R. [Laboratório de Farmacologia, Departamento de Enfermagem Psiquiátrica e Ciências Humanas, Escola de Enfermagem de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP (Brazil)

    2014-08-15

    The aim of the present study was to determine the mechanisms underlying the relaxant effect of adrenomedullin (AM) in rat cavernosal smooth muscle (CSM) and the expression of AM system components in this tissue. Functional assays using standard muscle bath procedures were performed in CSM isolated from male Wistar rats. Protein and mRNA levels of pre-pro-AM, calcitonin receptor-like receptor (CRLR), and Subtypes 1, 2 and 3 of the receptor activity-modifying protein (RAMP) family were assessed by Western immunoblotting and quantitative real-time polymerase chain reaction, respectively. Nitrate and 6-keto-prostaglandin F{sub 1α} (6-keto-PGF{sub 1α}; a stable product of prostacyclin) levels were determined using commercially available kits. Protein and mRNA of AM, CRLR, and RAMP 1, -2, and -3 were detected in rat CSM. Immunohistochemical assays demonstrated that AM and CRLR were expressed in rat CSM. AM relaxed CSM strips in a concentration-dependent manner. AM{sub 22-52}, a selective antagonist for AM receptors, reduced the relaxation induced by AM. Conversely, CGRP{sub 8-37}, a selective antagonist for calcitonin gene-related peptide receptors, did not affect AM-induced relaxation. Preincubation of CSM strips with N{sup G}-nitro-L-arginine-methyl-ester (L-NAME, nitric oxide synthase inhibitor), 1H-(1,2,4)oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, quanylyl cyclase inhibitor), Rp-8-Br-PET-cGMPS (cGMP-dependent protein kinase inhibitor), SC560 [5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethyl pyrazole, selective cyclooxygenase-1 inhibitor], and 4-aminopyridine (voltage-dependent K{sup +} channel blocker) reduced AM-induced relaxation. On the other hand, 7-nitroindazole (selective neuronal nitric oxide synthase inhibitor), wortmannin (phosphatidylinositol 3-kinase inhibitor), H89 (protein kinase A inhibitor), SQ22536 [9-(tetrahydro-2-furanyl)-9H-purin-6-amine, adenylate cyclase inhibitor], glibenclamide (selective blocker of ATP-sensitive K{sup +} channels), and

  17. [Current concepts in pathophysiology of CRPS I].

    Science.gov (United States)

    Nickel, F T; Maihöfner, C

    2010-02-01

    Knowledge about the pathophysiology underlying the complex regional pain syndrome (CRPS) has increased over the last years. Classically, CRPS has been considered to be mainly driven by sympathetic dysfunction with sympathetically maintained pain being its major pathogenetic mechanism. Currently, the disease is understood as result of a complex interplay between altered somatosensory, motor, autonomic and inflammatory systems. Peripheral and central sensitization is a common feature in CRPS as in other neuropathic pain syndromes. One important mechanism is the sensitization of spinal dorsal horn cells via activation of postsynaptic NMDA-receptors by chronic C-fiber input. Differential activity of endogenous pain modulating systems may play a pivotal role in the development of CRPS, too. Neuronal plasticity of the somatosensory cortex accounts for central sensory signs. Also the motor system is subject to central adaptive changes in patients with CRPS. Calcitonin-gene related peptide (CGRP) and substance P mediate neurogenic inflammation. Additionally other proinflammatory cytokines involved in the inflammatory response in CRPS have been identified. In terms of the sympathetic nervous system, recent evidence rather points to a sensitization of adrenergic receptors than to increased efferent sympathetic activity. Particularly the expression of alpha (1)-adrenoceptors on nociceptive C-fibers may play a major role. These pathophysiological ideas do not exclude each other. In fact they complement one another. The variety of the involved systems may explain the versatile clinical picture of CRPS. Georg Thieme Verlag KG Stuttgart, New York.

  18. Lack of genetic association of neutral endopeptidase (NEP) with complex regional pain syndrome (CRPS).

    Science.gov (United States)

    Huehne, Kathrin; Schaal, Ute; Leis, Stefan; Uebe, Steffen; Gosso, M Florencia; van den Maagdenberg, Arn M J M; Maihöfner, Christian; Birklein, Frank; Rautenstrauss, Bernd; Winterpacht, Andreas

    2010-03-12

    Complex regional pain syndrome (CRPS) is a condition that is characterized by severe pain and exaggerated neurogenic inflammation, which may develop after injury or surgery. Neurogenic inflammation is mediated by neuropeptides, such as calcitonin gene-related peptide (CGRP) and substance P (SP) that are released from nociceptors. Genetic factors may play a role in CRPS as was suggested by the occurrence of familial cases and several genetic association studies investigating mainly the human leukocyte antigen (HLA) system. Here we investigated the role of neutral endopeptidase (NEP), a key enzyme in neuropeptide catabolism. NEP dysfunction resulting in reduced inactivation of neuropeptides may be a possible pathomechanism in CRPS. To this end, we tested a GT-repeat polymorphism in the NEP promoter region as well as 18 tag-SNPs in six linkage disequilibrium (LD) blocks in the NEP gene region in 320 CRPS patients and 376 controls. No significant genetic association was observed. Thus, we conclude that the NEP gene does not seem to be a major risk factor for CRPS. Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

  19. [The Treatment of the Complex Regional Pain Syndrome (CRPS 1 and CRPS 2) of the Upper Limb with Repeated Local Anaesthesia to the Stellate Ganglion.].

    Science.gov (United States)

    Pfister, M; Fischer, L

    2009-03-04

    Two female patients were referred to us with a complex regional pain syndrome (CRPS) of the upper limb. One patient developed a CRPS type 1 after a radius fracture, the other presented a CRPS type 2 after a wrist trauma with a nerve injury of N. ulnaris. Both patients had progressive pain in spite of medical treatment (NSAID, Gabapentine, Calcitonine), physiotherapy, occupational therapy and osteopathy. In addition to pain they also showed the typical autonomic symptoms like oedema, hyperhidrosis, disturbances of skin colour and temperature and a severely limited motility of wrist and fingers. The clinical symptoms of both types of CRPS are identical and not restricted to the peripheral nerve distribution. The sympathetic nerve system is not only involved in the pain mechanism with reflectory processes in the segment and with the sympathetic afferent coupling, it also takes part in the neuroplasticity and in the neurogenic inflammation. The logical therapeutic intervention is therefore to normalize the hyperactivity of the sympathetic nerve systems with local anaesthetics. This regulation is done with injections to the stellate ganglion if upper limbs are affected (affections of lower limbs are treated with injections to the lumbar sympathetic trunk). Repeated injections to the stellate ganglion caused immediate improvement of pain and other symptoms in both patients.

  20. Neuropeptides, neurogenic inflammation and complex regional pain syndrome (CRPS).

    Science.gov (United States)

    Birklein, Frank; Schmelz, Martin

    2008-06-06

    This review explains symptoms and nature of neuropeptide signaling and its importance for clinical symptoms of CRPS. Neurogenic inflammation regularly accompanies excitation of primary afferent nociceptors. It has two major components-plasma extravasation and vasodilatation. The most important mediators are the calcitonin gene-related peptide (CGRP) and substance P (SP). After peripheral trauma immune reaction (e.g. cytokines) and the attempts of the tissue to regenerate (e.g. growth factors) sensitize nociceptors and amplify neurogenic inflammation. This cascade of events has been demonstrated in rat models of CRPS. Clinical findings in these animals strongly resemble clinical findings in CRPS, and can be prevented by anti-cytokine and anti-neuropeptide treatment. In CRPS patients, there is meanwhile also plenty of evidence that neurogenic inflammation contributes to clinical presentation. Increased cytokine production was demonstrated, as well as facilitated neurogenic inflammation. Very recently even "non-inflammatory" signs of CRPS (hyperhidrosis, cold skin) have been linked to neuropeptide signaling. Surprisingly, there was even moderately increased neurogenic inflammation in unaffected body regions. This favors the possibility that CRPS patients share genetic similarities. The future search for genetic commonalities will help us to further unravel the "mystery" CRPS.

  1. [Alternatives to hormone replacement therapy for menopause: an epidemiological evaluation].

    Science.gov (United States)

    Ringa, V

    2004-05-01

    Recent results put into question the risks/benefits ratio of hormone replacement therapy and emphasize the importance of precise knowledge of the effects of other treatments that exist for postmenopausal symptoms or diseases. Our aim is to analyze their effect. A review of randomized trials or epidemiological studies was undertaken. Bisphophonates, calcitonin, parathormone, strontium ranelate, calcium and vitamin D have specific effects on bone. The efficacy of bisphophonates for prevention and treatment of osteoporosis has been proven and parathormone and strontium ranelate seem promising. These treatments are useful for women at high risk of osteoporosis who do not suffer from menopausal symptoms. Tibolone, SERMs and phytoestrogens exert effects on various tissues. SERMs are very promising, but they do not improve climacteric symptoms and their long term effects are still unknown. Tibolone has beneficial effects on climacteric symptoms and on bone loss, but recent results concerning its effects on the risk of breast cancer call into question its interest. The beneficial effects of phytoestrogens on bone and on vasomotor symptoms need to be confirmed. At this time, none of the existing treatments for postmenopausal symptoms or diseases is ideal. The existence of several options for treatments of symptoms or diseases of the postmenopause is helpful as it affords several choices for physicians and for women who sometimes need to be treated for many years. However several questions remain unanswered concerning the long term effects of these treatments.

  2. Dolomite supplementation improves bone metabolism through modulation of calcium-regulating hormone secretion in ovariectomized rats.

    Science.gov (United States)

    Mizoguchi, Toshihide; Nagasawa, Sakae; Takahashi, Naoyuki; Yagasaki, Hiroshi; Ito, Michio

    2005-01-01

    Dolomite, a mineral composed of calcium magnesium carbonate (CaMg (CO3)2), is used as a food supplement that supplies calcium and magnesium. However, the effect of magnesium supplementation on bone metabolism in patients with osteoporosis is a matter of controversy. We examined the effects of daily supplementation with dolomite on calcium metabolism in ovariectomized (OVX) rats. Dolomite was administered daily to OVX rats for 9 weeks. The same amount of magnesium chloride as that supplied by the dolomite was given to OVX rats as a positive control. Histological examination revealed that ovariectomy decreased trabecular bone and increased adipose tissues in the femoral metaphysis. Dolomite or magnesium supplementation failed to improve these bone histological features. Calcium content in the femora was decreased in OVX rats. Neither calcium nor magnesium content in the femora in OVX rats was significantly increased by dolomite or magnesium administration. Urinary deoxypyridinoline excretion was significantly increased in OVX rats, and was not affected by the magnesium supplementation. Serum concentrations of magnesium were increased, and those of calcium were decreased, in OVX rats supplemented with dolomite or magnesium. However, there was a tendency toward decreased parathyroid hormone secretion and increased calcitonin secretion in OVX rats supplemented with dolomite or magnesium. Serum 1,25-dihydroxyvitamin D(3) and osteocalcin levels were significantly increased in the supplemented OVX rats. These results suggest that increased magnesium intake improves calcium metabolism in favor of increasing bone formation, through the modulation of calcium-regulating hormone secretion.

  3. Adrenal malignant melanoma masquerading as a pheochromocytoma in a patient with a history of a multifocal papillary and medullary thyroid carcinoma.

    Science.gov (United States)

    Barmpari, Maria E; Savvidis, Christos; Dede, Anastasia D; Markogiannakis, Haridimos; Dikoglou, Christina; Xekouki, Paraskevi; Stratakis, Constantine A; Manouras, Andreas; Malaktari-Skarantavou, Sofia

    2016-04-01

    Adrenal masses usually represent benign and nonfunctional adrenal adenomas; however, primary or metastatic malignancy should also be considered. Discovery of an adrenal mass needs further evaluation in order to exclude malignancy and hormonal secretion. We present a rare case of a possibly primary adrenal malignant melanoma with imaging and biochemical features of a pheochromocytoma. A 61-year-old male farmer was referred for evaluation of a mass in the right supraclavicular region and a left adrenal lesion. The patient had a history of a multifocal papillary and medullary thyroid carcinoma. Laboratory tests revealed increased 24hour urinary dopamine and also increased serum calcitonin and neuron specific enolase. A pathology report of the resected right supraclavicular mass and left adrenal showed a malignant melanoma. This is a case of a possibly primary adrenal malignant melanoma with imaging and biochemical features of a pheochromocytoma. Although this case is very rare and there are rigid diagnostic criteria for the diagnosis of primary adrenal melanoma, it underlines the fact that the differential diagnosis of a dopamine secreting adrenal mass should include primary or metastatic malignant melanoma in order to determine the best diagnostic approach for the patient and select the most appropriate surgical management.

  4. Profound loss of neprilysin accompanied by decreased levels of neuropeptides and increased CRP in ulcerative colitis.

    Directory of Open Access Journals (Sweden)

    Zeynep Gök Sargın

    Full Text Available Neprilysin (NEP, CD10 acts to limit excessive inflammation partly by hydrolyzing neuropeptides. Although deletion of NEP exacerbates intestinal inflammation in animal models, its role in ulcerative colitis (UC is not well explored. Herein, we aimed to demonstrate changes in NEP and associated neuropeptides at the same time in colonic tissue. 72 patients with UC and 27 control patients were included. Patients' demographic data and laboratory findings, five biopsy samples from active colitis sites and five samples from uninvolved mucosa were collected. Substance P (SP, calcitonin gene related peptide (CGRP and vasoactive intestinal peptide (VIP were extracted from freshly frozen tissues and measured using ELISA. Levels of NEP expression were determined using immunohistochemistry and immunoreactivity scores were calculated. GEBOES grading system was also used. We demonstrated a profound loss (69.4% of NEP expression in UC, whereas all healthy controls had NEP expression. Patients with UC had lower neuronal SP; however non-neuronal SP remained similar. UC patients had also lower neuronal and non-neuronal VIP levels. CGRP were low in general and no significant changes were observed. Additionally, CRP positive patients with UC had higher rates of NEP loss (80% vs 51.9% and lower SP levels when compared with CRP negative patients with UC. Concurrent decreases in SP and VIP with profound loss of NEP expression observed in UC is likely to be one of the factors in pathogenesis. Further studies are required to define the role of neuropeptides and NEP in UC.

  5. Management of Minerals and Bone Disorders after Kidney Transplantation

    Science.gov (United States)

    Kalantar-Zadeh, Kamyar; Molnar, Miklos Z; Kovesdy, Csaba P.; Mucsi, Istvan; Bunnapradist, Suphamai

    2012-01-01

    Purpose of review Mineral and bone disorders (MBD), inherent complications of moderate and advanced chronic kidney disease (CKD), occur frequently in kidney transplant recipients. However, much confusion exists about clinical application of diagnostic tools and preventive or treatment strategies to correct bone loss or mineral disarrays in transplanted patients. We have reviewed the recent evidence about prevalence and consequences of MBD in kidney transplant recipients and examined diagnostic, preventive and therapeutic options to this end. Recent findings Low turnover bone disease occurs more frequently after kidney transplantation according to bone biopsy studies. The risk of fracture is high, especially in the first several months after kidney transplantation. Alterations in minerals (calcium, phosphorus and magnesium) and biomarkers of bone metabolism (PTH, alkaline phosphatase, vitamin D and FGF-23) are observed with varying impact on post-transplant outcomes. Calcineurin inhibitors are linked to osteoporosis, whereas steroid therapy may lead to both osteoporosis and varying degrees of osteonecrosis. Sirolimus and everolimus might have a bearing on osteoblasts proliferation and differentiation or decreasing osteoclast mediated bone resorption. Selected pharmacologic interventions for treatment of MBD in transplant patients include steroid withdrawal, the use of bisphosphonates, vitamin D derivatives, calcimimetics, teriparatide, calcitonin and denosumab. Summary MBD following kidney transplantation is common and characterized by loss of bone volume and mineralization abnormalities often leading to low turnover bone disease. Although there are no well-established therapeutic approaches for management of MBD in renal transplant recipients, clinicians should continue individualizing therapy as needed. PMID:22614626

  6. Depicting medullary thyroid cancer recurrence: the past and the future of nuclear medicine imaging.

    Science.gov (United States)

    Skoura, Evangelia

    2013-10-01

    Inherited and sporadic medullary thyroid cancer (MTC) is an uncommon and medically challenging malignancy. Even if the extent of initial surgery is deemed adequate, the recurrence rate remains high, up to 50% in most series. Measurement of serum calcitonin is important in the follow-up of patients with MTC, and reliably reflects the existence of the disease. There is no single sensitive diagnostic imaging method to reveal all MTC recurrences or metastases. Conventional morphologic imaging methods (U/S, CT, and MRI) and several methods of nuclear medicine have been used for this purpose with variable accuracy. The main role of nuclear medicine imaging is the detection of residual or recurrent tumor in the postoperative follow-up. In this review we present the radiopharmaceuticals used in the diagnosis of MTC recurrence, and comparison among them. The most used radiopharmaceuticals labelled with γ emitters are: Metaiodobenzylguanidine (MIBG), labelled with (131)I or (123)I, (111)In-pentetreotide (Octreoscan), 99mTc-pentavalent dimercaptosuccinic acid ((99m)Tc(V)-DMSA), and (99m)Tc-EDDA/HYNIC-Tyr3-Octreotide ( Tektrotyd). The radiopharmaceuticals labelled with a positron-emitting radionuclide (β+), suitable for positron emission tomography (PET) imaging are: (18)F-fluorodeoxyglucose ((18)F-FDG), (18)F-fluorodihydroxyphenylalanine (18F-DOPA), and 68Ga-labelled somatostatin analogues (68Ga-DOTATATE or DOTATOC).

  7. Surgical Treatment, Oral Rehabilitation, and Orthognathic Surgery After Failure of Pharmacologic Treatment of Central Giant Cell Lesion: A Case Report.

    Science.gov (United States)

    Maia Nogueira, Renato Luiz; Osterne, Rafael Lima Verde; Cavalcante, Roberta Barroso; Abreu, Ricardo Teixeira

    2016-12-01

    Although pharmacologic treatments for central giant cell lesions have gained much emphasis, these treatment modalities do not always have successful outcomes, and surgical treatment may be necessary. The purpose of the present study was to report a case of aggressive central giant cell lesion initially treated by nonsurgical methods without satisfactory results, necessitating segmental mandibular resection for definitive treatment and oral rehabilitation. A 20-year-old woman was diagnosed with an aggressive central giant cell lesion in the mandible. The patient was first treated with intralesional corticosteroid injections. Subsequently, the lesion increased in size. Therefore, a second pharmacologic treatment was proposed with salmon calcitonin nasal spray, but no signs of a treatment response were noted. Because of the lack of response, surgical excision was performed, and a mandibular reconstruction plate was installed. At 12 months after surgical resection, the patient underwent mandibular reconstruction with bone grafts. After 6 months, 7 dental implants were installed, and fixed prostheses were made. After installation of the prostheses, the patient experienced persistent mandibular laterognathism, and a mandibular orthognathic surgery was performed to correct the laterognathia. The follow-up examination 4 years after orthognathic surgery showed no signs of recurrence and good facial symmetry. Copyright © 2016 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.

  8. [Thyroid C cells are decreased in experimental CDH].

    Science.gov (United States)

    Martínez, L; De Ceano-Vivas, M; González-Reyes, S; Fernández-Dumont, V; Calonge, W M; Ruiz, E; Rodríguez, J I; Tovar, J A

    2006-04-01

    Experimental CDH is often associated with malformations of neural crest origin. Several of these features are present in human CDH and therefore likely similar pathogenic mechanisms should be explored. The aim of the present study is to examine whether thyroid C-cells, another neural crest derivative, are abnormal in this rat model. Pregnant rats were exposed either to 100 mg of 2-4-dichlorophenyl-p-nitrophenyl ether (nitrofén) or vehicle (controls) on 9.5 day of gestation. Fetuses were recovered on day 21st and the thyroids of those with CDH (68%) were immuno-histochemically stained with anti-calcitonin antibody. The number of positively stained cells per high power field were counted using a computer-assisted image analysis method in at least 5 sections per thyroid. The distribution of the cells within the gland was assessed as well. Comparisons between CDH and control rats were made by non-parametric tests with a significance threshold of pcraneo-facial malformations in some babies with CDH strongly support further research in this field.

  9. Distribution and chemical coding of neurons in intramural ganglia of the porcine urinary bladder trigone.

    Directory of Open Access Journals (Sweden)

    Zenon Pidsudko

    2004-03-01

    Full Text Available This study presents the distribution and chemical coding of neurons in the porcine intramural ganglia of the urinary bladder trigone (IG-UBT demonstrated using combined retrograde tracing and double-labelling immunohistochemistry. Retrograde fluorescent tracer Fast Blue (FB was injected into the wall of both the left and right side of the bladder trigone during laparotomy performed under pentobarbital anaesthesia. Ten-microm-thick cryostat sections were processed for double-labelling immunofluorescence with antibodies against tyrosine hydroxylase (TH, dopamine beta-hydroxylase (DBH, neuropeptide Y (NPY, somatostatin (SOM, galanin (GAL, vasoactive intestinal polypeptide (VIP, nitric oxide synthase (NOS, calcitonin gene-related peptide (CGRP, substance P (SP, Leu5-enkephalin (LENK and choline acetyltransferase (ChAT. IG-UBT neurons formed characteristic clusters (from a few to tens neuronal cells found under visceral peritoneum or in the outer muscular layer. Immunohistochemistry revealed four main populations of IG-UBT neurons: SOM- (ca. 35%, SP- (ca. 32%, ChAT- and NPY- immunoreactive (-IR (ca. 23% as well as non-adrenergic non-cholinergic nerve cells (ca. 6%. This study has demonstrated a relatively large population of differently coded IG-UBT neurons, which constitute an important element of the complex neuro-endocrine system involved in the regulation of the porcine urogenital organ function.

  10. Aerobic exercise training increases neuronal nitric oxide release and bioavailability and decreases noradrenaline release in mesenteric artery from spontaneously hypertensive rats.

    Science.gov (United States)

    Blanco-Rivero, Javier; Roque, Fernanda R; Sastre, Esther; Caracuel, Laura; Couto, Gisele K; Avendaño, María Soledad; Paula, Suliana M; Rossoni, Luciana V; Salaices, Mercedes; Balfagón, Gloria

    2013-05-01

    To study the effect of aerobic exercise training on sympathetic, nitrergic and sensory innervation function in superior mesenteric artery from spontaneously hypertensive rats (SHRs). De-endothelized vascular rings from sedentary and trained SHRs (treadmill 12 weeks) were used. Vasomotor responses to electrical field stimulation (EFS), noradrenaline, nitric oxide donor DEA-NO and calcitonin gene-related peptide (CGRP) were studied. Neuronal nitric oxide synthase (nNOS) expression and nitric oxide, superoxide anions (O(2.-)), noradrenaline and CGRP levels were also determined. Aerobic exercise training decreased vasoconstrictor response to EFS but increased noradrenaline response. Phentolamine decreased while N(ω)-nitro-(L)-arginine methyl ester ((L)-NAME) increased the response to EFS; the effect of both drugs was greater in trained animals. Training also decreased noradrenaline release and O(2.-) production and increased nNOS expression, nitric oxide release and the vasodilator response to DEA-NO. The O(2.-) scavenger tempol increased DEA-NO-induced vasodilation only in sedentary rats. The EFS-induced contraction was increased to a similar extent in both experimental groups by preincubation with CGRP (8-37). CGRP release and vasodilator response were not modified by training. Aerobic exercise training decreases contractile response to EFS in mesenteric artery from SHRs. This effect is the net result of decreased noradrenaline release, increased sensitivity to the vasoconstrictive effects of noradrenaline and increased neuronal nitric oxide release and bioavailability. These modifications might contribute to the beneficial effects of aerobic exercise training on blood pressure.

  11. Slick (Kcnt2 Sodium-Activated Potassium Channels Limit Peptidergic Nociceptor Excitability and Hyperalgesia

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    Danielle L Tomasello

    2017-09-01

    Full Text Available The Slick (Kcnt2 sodium-activated potassium (K Na channel is a rapidly gating and weakly voltage-dependent and sodium-dependent potassium channel with no clearly defined physiological function. Within the dorsal root ganglia (DRGs, we show Slick channels are exclusively expressed in small-sized and medium-sized calcitonin gene–related peptide (CGRP-containing DRG neurons, and a pool of channels are localized to large dense-core vesicles (LDCV-containing CGRP. We stimulated DRG neurons for CGRP release and found Slick channels contained within CGRP-positive LDCV translocated to the neuronal membrane. Behavioral studies in Slick knockout (KO mice indicated increased basal heat detection and exacerbated thermal hyperalgesia compared with wild-type littermate controls during neuropathic and chronic inflammatory pain. Electrophysiologic recordings of DRG neurons from Slick KO mice revealed that Slick channels contribute to outward current, propensity to fire action potentials (APs, and to AP properties. Our data suggest that Slick channels restrain the excitability of CGRP-containing neurons, diminishing pain behavior after inflammation and injury.

  12. Slick (Kcnt2) Sodium-Activated Potassium Channels Limit Peptidergic Nociceptor Excitability and Hyperalgesia

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    Tomasello, Danielle L; Hurley, Edward; Wrabetz, Lawrence; Bhattacharjee, Arin

    2017-01-01

    The Slick (Kcnt2) sodium-activated potassium (KNa) channel is a rapidly gating and weakly voltage-dependent and sodium-dependent potassium channel with no clearly defined physiological function. Within the dorsal root ganglia (DRGs), we show Slick channels are exclusively expressed in small-sized and medium-sized calcitonin gene–related peptide (CGRP)-containing DRG neurons, and a pool of channels are localized to large dense-core vesicles (LDCV)-containing CGRP. We stimulated DRG neurons for CGRP release and found Slick channels contained within CGRP-positive LDCV translocated to the neuronal membrane. Behavioral studies in Slick knockout (KO) mice indicated increased basal heat detection and exacerbated thermal hyperalgesia compared with wild-type littermate controls during neuropathic and chronic inflammatory pain. Electrophysiologic recordings of DRG neurons from Slick KO mice revealed that Slick channels contribute to outward current, propensity to fire action potentials (APs), and to AP properties. Our data suggest that Slick channels restrain the excitability of CGRP-containing neurons, diminishing pain behavior after inflammation and injury. PMID:28943756

  13. Effects of Electroacupuncture Treatment on Bone Cancer Pain Model with Morphine Tolerance

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    Lei Sima

    2016-01-01

    Full Text Available Objective. To explore the efficacy of electroacupuncture treatment in cancer induced bone pain (CIBP rat model with morphine tolerance and explore changes of calcitonin-gene related peptide (CGRP expression in dorsal root ganglion (DRG. Methods. Forty SD rats were divided into five groups: sham, CIBP (B, CIBP + morphine (BM, CIBP + electroacupuncture (BE, and CIBP + morphine + electroacupuncture (BME. B, BM, BE, and BME groups were prepared CIBP model. The latter three groups then accepted morphine, electroacupuncture, and morphine combined electroacupuncture, separately, nine days consecutively (M1 to M9. Mechanical withdraw threshold (MWT was evaluated. Results. BE group only had differences in M1, M2, and M3 compared to B group (P<0.01. From M5, BM group showed significantly decreased MWT. Electroacupuncture could obtain analgesic effects only at early stage (M1 to M5. From M5 to M9, BME had the differences with BM group (P<0.01. IOD value of CGRP in BM and BME was substantially less than in B group. CGRP in BME was significantly lower than that in BM group (P<0.01. Conclusion. When used in combination with electroacupuncture, morphine could result in improving analgesic effects and reducing tolerance. CGRP may be associated with pain behaviors.

  14. Atypical lung carcinoid metastasis to the pituitary gland

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    Xiao-ling YAN

    2017-09-01

    Full Text Available Objective To study clinicopathological features, diagnosis and differential diagnosis of atypical lung carcinoid metastasis to the pituitary gland based on clinical data of one patient. Methods and Results A 81-year-old female presented headache and sudden blindness, and head MRI showed that there was a lesion at the saddle area. The tumor was detected at intrasellar and in grayish red during surgery. The diameter of tumor was 2 cm. The tumor was soft with no envelop at and well-defined margins, and insufficiency in blood supply. The tumor was removed completely along its edge. Under optical microscopy, the tumor was consisted of small round cells of the same size. Tumor cells were distributed around blood vessels in a nest manner or diffuse manner with brisk mitotic activity and focal necrosis. By using immunohistochemical staining, the tumor cells were diffusely positive for synaptophysin (Syn, CD56 and thyoid transcription factor - 1 (TTF - 1, focal positive for cytokeratin (CK and P53, and negative for growth hormone (GH, prolactin (PRL, adrenocorticotropic hormone (ACTH, follicle stimulating hormone (FSH, thyroid stimulating hormone (TSH, luteinizing hormone (LH, S-100 protein (S-100, thyroglobulin (TG and calcitonin. Ki?67 labeling index was about 33%. Conclusions Pituitary metastasis is a rare tumor, and only a few cases of atypical lung carcinoid metastasis to the pituitary gland have been reported. Definite diagnosis could be made by history, typical histopathological characteristics and immunohistochemical expressions. DOI: 10.3969/j.issn.1672-6731.2017.09.010

  15. Effect of topical application of capsaicin and its related compounds on dermal insulin-like growth factor-I levels in mice and on facial skin elasticity in humans.

    Science.gov (United States)

    Harada, Naoaki; Okajima, Kenji

    2007-04-01

    Capsaicin increases calcitonin gene-related peptide (CGRP) release from sensory neurons by stimulating vanilloid receptor-1 (VR-1). Since CGRP increases production of insulin-like growth factor-I (IGF-I) in fetal osteoblasts in vitro, it is possible that sensory neuron activation by capsaicin increases production of IGF-I. In the present study, we attempted to determine whether topical application of capsaicin and related compounds increases dermal IGF-I level in mice and whether it increases facial skin elasticity in humans. Topical application of 0.01% capsaicin significantly increased dermal IGF-I levels from 30 to 180min (pcapsaicinoids (dihydrocapsaicin and nordihydrocapsaicin), 0.01% capsinoids (capsiate, dihydrocapsiate and nordihydrocapsiate), 0.01% anandamide (an endogenous agonist of VR-1), and 0.01% nonylic acid vanillylamide (a synthetic capsaicin) significantly increased dermal IGF-I levels at 30min after topical application in mice (p<0.01). Topical application of 0.01% capsaicin to faces of 17 healthy female volunteers for seven days significantly increased cheek skin elasticity (p<0.01). These observations suggest that topical application of capsaicin and related compounds might be useful in the treatment of detrimental morphological changes of the skin in patients with growth hormone deficiency and those in the elderly by increasing dermal IGF-I levels.

  16. Paclitaxel-induced peripheral neuropathy increases substance P release in rat spinal cord.

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    Chiba, Terumasa; Oka, Yusuke; Kambe, Toshie; Koizumi, Naoya; Abe, Kenji; Kawakami, Kazuyoshi; Utsunomiya, Iku; Taguchi, Kyoji

    2016-01-05

    Peripheral neuropathy is a common adverse effect of paclitaxel treatment. The major dose-limiting side effect of paclitaxel is peripheral sensory neuropathy, which is characterized by painful paresthesia of the hands and feet. To analyze the contribution of substance P to the development of paclitaxel-induced mechanical hyperalgesia, substance P expression in the superficial layers of the rat spinal dorsal horn was analyzed after paclitaxel treatment. Behavioral assessment using the von Frey test and the paw thermal test showed that intraperitoneal administration of 2 and 4mg/kg paclitaxel induced mechanical allodynia/hyperalgesia and thermal hyperalgesia 7 and 14 days after treatment. Immunohistochemistry showed that paclitaxel (4mg/kg) treatment significantly increased substance P expression (37.6±3.7% on day 7, 43.6±4.6% on day 14) in the superficial layers of the spinal dorsal horn, whereas calcitonin gene-related peptide (CGRP) expression was unchanged. Moreover, paclitaxel (2 and 4mg/kg) treatment significantly increased substance P release in the spinal cord on day 14. These results suggest that paclitaxel treatment increases release of substance P, but not CGRP in the superficial layers of the spinal dorsal horn and may contribute to paclitaxel-induced painful peripheral neuropathy. Copyright © 2015 Elsevier B.V. All rights reserved.

  17. A reversible functional sensory neuropathy model.

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    Danigo, Aurore; Magy, Laurent; Richard, Laurence; Sturtz, Franck; Funalot, Benoît; Demiot, Claire

    2014-06-13

    Small-fiber neuropathy was induced in young adult mice by intraperitoneal injection of resiniferatoxin (RTX), a TRPV1 agonist. At day 7, RTX induced significant thermal and mechanical hypoalgesia. At day 28, mechanical and thermal nociception were restored. No nerve degeneration in skin was observed and unmyelinated nerve fiber morphology and density in sciatic nerve were unchanged. At day 7, substance P (SP) was largely depleted in dorsal root ganglia (DRG) neurons, although calcitonin gene-related peptide (CGRP) was only moderately depleted. Three weeks after, SP and CGRP expression was restored in DRG neurons. At the same time, CGRP expression remained low in intraepidermal nerve fibers (IENFs) whereas SP expression had improved. In summary, RTX induced in our model a transient neuropeptide depletion in sensory neurons without nerve degeneration. We think this model is valuable as it brings the opportunity to study functional nerve changes in the very early phase of small fiber neuropathy. Moreover, it may represent a useful tool to study the mechanisms of action of therapeutic strategies to prevent sensory neuropathy of various origins. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  18. Beta-3 adrenergic receptor is expressed in acetylcholine-containing nerve fibers of the human urinary bladder: An immunohistochemical study.

    Science.gov (United States)

    Coelho, Ana; Antunes-Lopes, Tiago; Gillespie, James; Cruz, Francisco

    2017-11-01

    To identify in the human bladder the structures which express the Beta-3 adrenoceptor (β3AR). Human bladders from cadaveric organ donors (equally balanced in sex and age) were collected. Bladders were immediately fixed in paraformaldehyde and further processed for cryostat sectioning. Single and double immunohistochemistry was performed using antibodies against β3AR C-terminal, β3AR N-terminal, a pan-neuronal marker (β3-Tubulin) and markers of cholinergic (Vesicular Acetylcholine Transporter), adrenergic (Tyrosine Hidroxylase), and peptidergic (Calcitonin Gene-Related Peptide) nerve fibers. Nerve fibers expressing immunoreactivity for β3AR were abundantly found in the mucosa and muscular layers of the human bladder. No β3AR-IR was detected on urothelial or smooth muscle cells. The presence of β3AR-IR in nerve fibers was confirmed by co-expression with β3-Tubulin. Nerve fibers expressing β3AR-IR were cholinergic, VAChT(+) , and abundantly observed in the suburothelium. The cholinergic fibers were in close proximity and intermingled with adrenergic TH(+) and peptidergic CGRP(+) fibers. We demonstrated that β3AR is abundantly located in acetylcholine-containing nerve fibers. These findings have important consequences to understand the mechanism of action of β3AR agonists currently used for the treatment of OAB. © 2017 Wiley Periodicals, Inc.

  19. Expression of mRNAs for PPT, CGRP, NF-200, and MAP-2 in cocultures of dissociated DRG neurons and skeletal muscle cells in administration of NGF or NT-3

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    Weiwei Zhang

    2012-07-01

    Full Text Available Both neurotrophins (NTs and target skeletal muscle (SKM cells are essential for the maintenance of the function of neurons and nerve-muscle communication. However, much less is known about the association of target SKM cells with distinct NTs on the expression of mRNAs for preprotachykinin (PPT, calcitonin-gene related peptide (CGRP, neurofilament 200 (NF-200, and microtubule associated protein 2 (MAP-2 in dorsal root ganglion (DRG sensory neurons. In the present study, a neuromuscular coculture model of dissociated dorsal root ganglion (DRG neurons and SKM cells was established. The morphology of DRG neurons and SKM cells in coculture was observed with an inverted phase contrast microscope. The effects of nerve growth factor (NGF or neurotrophin-3 (NT-3 on the expression of mRNAs for PPT, CGRP, NF-200, and MAP-2 was analyzed by real time-PCR assay. The morphology of DRG neuronal cell bodies and SKM cells in neuromuscular coculture at different conditions was similar. The neurons presented evidence of dense neurite outgrowth in the presence of distinct NTs in neuromuscular cocultures. NGF and NT-3 increased mRNA levels of PPT, CGRP, and NF-200, but not MAP-2, in neuromuscular cocultures. These results offer new clues towards a better understanding of the association of target SKM cells with distinct NTs on the expression of mRNAs for PPT, CGRP, NF-200 and MAP-2, and implicate the association of target SKM cells and NTs with DRG sensory neuronal phenotypes.

  20. [Effect of propolis on insulin resistance in fructose-drinking rats].

    Science.gov (United States)

    Zamami, Yoshito; Takatori, Shingo; Koyama, Toshihiro; Goda, Mitsuhiro; Iwatani, Yukiko; Doi, Shima; Kawasaki, Hiromu

    2007-12-01

    Propolis, a honeybee product, contains a variety of biologically active substances. The present study was designed to investigate the effects of propolis on insulin resistance induced by fructose-drinking rats (FDR; type 2 diabetic animal model). Male Wistar rats (6 weeks old) received 15% fructose solution in drinking water for 8 weeks. FDR showed significant increases in plasma levels of insulin, Homeostasis Model Assessment ratio (HOMA-R, an index of insulin resistance), body weight, and systolic blood pressure but not blood glucose levels, when compared with control rats. Brazilian propolis extract (100 and 300 mg/kg, p.o.) treatment for 8 weeks significantly decreased the plasma level of insulin, HOMA-R, and body weight, increased plasma triglyceride levels without affecting blood glucose and total cholesterol levels, and tended to decrease systolic blood pressure. In isolated and perfused mesenteric vascular beds of FDR, propolis treatment resulted in a significant reduction of sympathetic nerve-mediated vasoconstrictor response to periarterial nerve stimulation (PNS; 8 Hz) and tended to increase the calcitonin gene-related peptide (CGRP) nerve-mediated vasodilator response to PNS, compared with those in untreated FDR. However, propolis treatment did not significantly affect norepinephrine-induced vasoconstriction and CGRP-induced vasodilation. These results suggest that propolis could be an effective functional food to prevent the development of insulin resistance.

  1. [Anaplastic carcinoma of the thyroid at the Instituto Nacional de la Nutrición Salvador Zubirán].

    Science.gov (United States)

    Sierra, M; Gamboa-Domínguez, A; Herrera, M F; Barredo-Prieto, B; Alvarado de la Barrera, C; Llorente, L; Pérez-Enriquez, B; Rivera, R; González, O; Rull, J A

    1997-01-01

    Anaplastic thyroid carcinoma (ATC) is a highly aggressive tumor with a median survival rate of 6 months. To analyze presentation, treatment, morphology, immunohistochemistry, and nuclear DNA analysis of a cohort of patients with ATC. Twelve patients with ATC (11 female) with a mean age of 65 years were seen at our hospital from 1970-1995. The data were obtained from the clinical records and the morphology, immunohistochemic studies and DNA pattern were performed in slides obtained from archival specimens. Previous or coexisting thyroide disease was documented in 10 patients (9 multinodular goiters and one Grave's). The most frequent presentation was a rapidly growing tumor associated with dysphagia, cervical pain, hoarseness and dyspnea. A cold thyroid nodule was detected by thyroid scan in 10 patients. The most frequent subtype was the spindle cell variety. Papillary thyroid carcinoma coexisted in eight cases, two of them corresponded to the tall cell variant. Reactivity for S-100 protein and vimentin was studied in six patients: all were positive for S-100 protein and vimentin, 5/6 for epithelial membrane antigen, half for carcinoembriogenic antigen, 2/6 for thyroglobulin and calcitonin, and one for neuronal specific enolase. These six tumors showed a diploid DNA pattern. Tumor resection was achieved in 2/11 and none survived six years after diagnosis. ATC is a highly aggressive tumor coexisting with thyroid pathologies. Spindle cell variant is the most frequent with positive reactivity for S-100 protein, vimentin and epithelial membrane antigen. Most tumors have a diploid DNA content.

  2. Nimodipine down-regulates CGRP expression in the rat trigeminal nucleus caudalis.

    Science.gov (United States)

    Vijayan, Lakshmy; Bansal, Devanshu; Ray, Subrata Basu

    2012-05-01

    L-type calcium channel blockers like verapamil are used in the prophylaxis of migraine. However, their effect on the expression of CGRP in the trigeminal nucleus caudalis (TNC) is unknown. It is important because an earlier study had shown that olcegepant, a CGRP receptor antagonist, acts at the level of the trigeminal spinal nucleus rather than the trigeminal ganglia. Nimodipine was used in the present study as it crosses the blood-brain barrier. The objective of the study was to determine the pattern of expression of calcitonin gene-related peptide (CGRP) in the TNC after administration of nimodipine and/or morphine. Wistar rats were injected with saline, morphine, nimodipine or morphine + nimodipine for 14 days. Subsequently, the lowest part of the medulla oblongata containing the spinal nucleus was removed and processed for immunohistochemical localization of CGRP. The density of expression was quantified using Image J software. The results were statistically analyzed. CGRP expression was noted over the superficial part of the TNC, which decreased significantly after nimodipine administration. Conversely, morphine produced an up-regulation. The expression was unchanged with reference to saline in the morphine + nimodipine treated group. Decreased expression of CGRP in the trigeminal nucleus caudalis after nimodipine is being reported for the first time. Also, whether CGRP expression can be used as a marker for predicting the therapeutic efficacy of an anti-migraine drug is currently being investigated.

  3. The Effects of Tempol on Cyclophosphamide-Induced Oxidative Stress in Rat Micturition Reflexes

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    Eric J. Gonzalez

    2015-01-01

    Full Text Available We hypothesized that cyclophosphamide- (CYP- induced cystitis results in oxidative stress and contributes to urinary bladder dysfunction. We determined (1 the expression of oxidative stress markers 3-nitrotyrosine (3-NT, reactive oxygen species (ROS/reactive nitrogen species (RNS, inflammatory modulators, neuropeptides calcitonin gene-related peptide (CGRP, substance P (Sub P, and adenosine triphosphate (ATP that contribute to the inflammatory process in the urinary tract and (2 the functional role of oxidative stress in urinary bladder dysfunction with an antioxidant, Tempol, (1 mM in drinking water combined with conscious cystometry. In CYP-treated (4 hr or 48 hr; 150 mg/kg, i.p. rats, ROS/RNS and 3-NT significantly (P≤0.01 increased in urinary bladder. CYP treatment increased ATP, Sub P, and CGRP expression in the urinary bladder and cystometric fluid. In CYP-treated rats, Tempol significantly (P≤0.01 increased bladder capacity and reduced voiding frequency compared to CYP-treated rats without Tempol. Tempol significantly (P≤0.01 reduced ATP expression, 3-NT, and ROS/RNS expression in the urinary tract of CYP-treated rats. These studies demonstrate that reducing oxidative stress in CYP-induced cystitis improves urinary bladder function and reduces markers of oxidative stress and inflammation.

  4. Presepsin for the detection of early-onset sepsis in preterm newborns.

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    Montaldo, Paolo; Rosso, Roberto; Santantonio, Alfredo; Chello, Giovanni; Giliberti, Paolo

    2017-02-01

    Early-onset sepsis (EOS) is responsible for an important fraction of neonatal morbidity and mortality all over the world. The aim of this study was to assess whether presepsin (P-SEP) can be a more accurate biomarker of EOS compared with pro-calcitonin (PCT) and C-reactive protein (CRP). Consecutive preterm neonates (sepsis evaluation) were recruited as part of a case-matched control study. We determined CRP, PCT and P-SEP at admission, and then at 12, 24, and 48 h of age. Neonates recruited into the study were divided into the EOS group (n = 32) and the uninfected group (n =38) according to their infection screening. P-SEP values were significantly higher in the EOS group than in the uninfected group at different time intervals. The highest accuracy was achieved by P-SEP at 24 h after birth. The AUC for P-SEP was 0.97. In our sample, P-SEP achieved the best accuracy for prediction of EOS at the cut-off of 788 ng/l with 93% sensitivity and 100% specificity. This study shows that P-SEP is significantly higher in preterm infants with EOS compared with uninfected infants.

  5. Medullary and papillary carcinoma of the thyroid gland occurring as a collision tumor with lymph node metastasis: A case report

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    Sadat Alavi Mehr

    2011-12-01

    Full Text Available Abstract Introduction Papillary thyroid carcinoma and medullary thyroid carcinoma are two different thyroid neoplasia. The simultaneous occurrence of medullary thyroid carcinoma and papillary thyroid carcinoma as a collison tumor with metastases from both lesions in the regional lymph nodes is a rare phenomenon. Case presentation A 32-year-old Iranian man presented with a fixed anterior neck mass. Ultrasonography revealed two separate thyroid nodules as well as a suspicious neck mass that appeared to be a metastatic lesion. The results of thyroid function tests were normal, but the preoperative calcitonin serum value was elevated. Our patient underwent a total thyroidectomy with neck exploration. Two separate and ill-defined solid lesions grossly in the right lobe were noticed. Histological and immunohistochemical studies of these lesions suggested the presence of medullary thyroid carcinoma and papillary thyroid carcinoma. The lymph nodes isolated from a neck dissection specimen showed metastases from both lesions. Conclusions The concomitant occurrence of papillary thyroid carcinoma and medullary thyroid carcinoma and the exact diagnosis of this uncommon event are important. The treatment strategy should be reconsidered in such cases, and genetic screening to exclude multiple endocrine neoplasia 2 syndromes should be performed. For papillary thyroid carcinoma, radioiodine therapy and thyroid-stimulating hormone suppressive therapy are performed. However, the treatment of medullary thyroid carcinoma is mostly radical surgery with no effective adjuvant therapy.

  6. The Study of Mechanisms of Protective Effect of Rg1 against Arthritis by Inhibiting Osteoclast Differentiation and Maturation in CIA Mice

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    Yanqing Gu

    2014-01-01

    Full Text Available Ginsenoside Rg1 is a natural product extracted from Panax ginseng C.A. Although Rg1 protects tissue structure and functions by inhibiting local inflammatory reaction, the mechanism remains poorly understood. In vitro, Rg1 dose-dependently inhibited TRAP activity in receptor activator of nuclear factor-κB ligand- (RANKL- induced osteoclasts and decreased the number of osteoclasts and osteoclast resorption area. Rg1 also significantly inhibited the RANK signaling pathway, including suppressing the expression of Trap, cathepsin K, matrix metalloproteinase 9 (MMP9, and calcitonin receptor (CTR. In vivo, Rg1 dramatically decreased arthritis scores in CIA mice and effectively controlled symptoms of inflammatory arthritis. Pathologic analysis demonstrated that Rg1 significantly attenuated pathological changes in CIA mice. Pronounced reduction in synovial hyperplasia and inflammatory cell invasion were observed in CIA mice after Rg1 therapy. Alcian blue staining results illustrated that mice treated with Rg1 had significantly reduced destruction in the articular cartilage. TRAP and cathepsin K staining results demonstrated a significant reduction of numbers of OCs in the articular cartilage in proximal interphalangeal joints and ankle joints in Rg1-treated mice. In summary, this study revealed that Rg1 reduced the inflammatory destruction of periarticular bone by inhibiting differentiation and maturation of osteoclasts in CIA mice.

  7. Molecular recognition of parathyroid hormone by its G protein-coupled receptor

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    Pioszak, Augen A.; Xu, H. Eric (Van Andel)

    2008-08-07

    Parathyroid hormone (PTH) is central to calcium homeostasis and bone maintenance in vertebrates, and as such it has been used for treating osteoporosis. It acts primarily by binding to its receptor, PTH1R, a member of the class B G protein-coupled receptor (GPCR) family that also includes receptors for glucagon, calcitonin, and other therapeutically important peptide hormones. Despite considerable interest and much research, determining the structure of the receptor-hormone complex has been hindered by difficulties in purifying the receptor and obtaining diffraction-quality crystals. Here, we present a method for expression and purification of the extracellular domain (ECD) of human PTH1R engineered as a maltose-binding protein (MBP) fusion that readily crystallizes. The 1.95-{angstrom} structure of PTH bound to the MBP-PTH1R-ECD fusion reveals that PTH docks as an amphipathic helix into a central hydrophobic groove formed by a three-layer {alpha}-{beta}-{beta}{alpha} fold of the PTH1R ECD, resembling a hot dog in a bun. Conservation in the ECD scaffold and the helical structure of peptide hormones emphasizes this hot dog model as a general mechanism of hormone recognition common to class B GPCRs. Our findings reveal critical insights into PTH actions and provide a rational template for drug design that targets this hormone signaling pathway.

  8. Mining amino acid association patterns in class B GPCRs.

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    Kumari, Tannu; Pardasani, Kamal Raj

    2015-01-01

    Class B GPCR family is a small group of receptors which are activated by peptides of intermediate length that range from 30 to 40 amino acid residues including hormones, neuropeptides and autocrine factors that mediate diverse physiological functions. They are involved in physiological processes like glucose homeostasis (glucagon and glucagon-like peptide-1), calcium homeostasis and bone turnover (parathyroid hormone and calcitonin), and control of the stress axis (corticotropin-releasing factor). Most of the GPCR structures and their functions are still unknown. Thus, the study of amino acid association patterns can be useful in prediction of their structure and functions. In view of above, in this paper, an attempt has been made to explore amino acid association patterns in class B GPCRs and their relationships with secondary structures and physiochemical properties. The fuzzy association rule mining is employed to take care of uncertainty due to variation in length of sequences. The association rules have been generated with the help of patterns discovered in the sequences.

  9. Correlation of RET somatic mutations with clinicopathological features in sporadic medullary thyroid carcinomas

    Science.gov (United States)

    Moura, M M; Cavaco, B M; Pinto, A E; Domingues, R; Santos, J R; Cid, M O; Bugalho, M J; Leite, V

    2009-01-01

    Screening of REarranged during Transfection (RET) gene mutations has been carried out in different series of sporadic medullary thyroid carcinomas (MTC). RET-positive tumours seem to be associated to a worse clinical outcome. However, the correlation between the type of RET mutation and the patients' clinicopathological data has not been evaluated yet. We analysed RET exons 5, 8, 10–16 in fifty-one sporadic MTC, and found somatic mutations in thirty-three (64.7%) tumours. Among the RET-positive cases, exon 16 was the most frequently affected (60.6%). Two novel somatic mutations (Cys630Gly, c.1881del18) were identified. MTC patients were divided into three groups: group 1, with mutations in RET exons 15 and 16; group 2, with other RET mutations; group 3, having no RET mutations. Group 1 had higher prevalence (P=0.0051) and number of lymph node metastases (P=0.0017), and presented more often multifocal tumours (P=0.037) and persistent disease at last control (P=0.0242) than group 2. Detectable serum calcitonin levels at last screening (P=0.0119) and stage IV disease (P=0.0145) were more frequent in group 1, than in the other groups. Our results suggest that, among the sporadic MTC, cases with RET mutations in exons 15 and 16 are associated with the worst prognosis. Cases with other RET mutations have the most indolent course, and those with no RET mutations have an intermediate risk. PMID:19401695

  10. Diagnostic correlation between RET proto-oncogene mutation, imaging techniques, biochemical markers and morphological examination in MEN2A syndrome: case report and literature review.

    Science.gov (United States)

    Sovrea, Alina Simona; Dronca, Eleonora; Galatâr, Mihaela; Radian, Serban; Vornicescu, Corina; Georgescu, Carmen

    2014-01-01

    Multiple endocrine neoplasia type 2 (MEN2) is a rare autosomal dominant monogenic disorder caused mostly by missense mutations in the RET (REarranged during Transfection) proto-oncogene on chromosome 10q11.2. MEN2A represents more than 50% of all MEN2 cases, having a regular pattern with medullary thyroid carcinoma (MTC) incidence of 90-100%, bilateral pheochromocytoma (PCC) incidence of 40-50% and primary hyperparathyroidism (HPT) incidence of 10-25%. Until recently, the diagnosis of MTC was most frequently based on fine-needle aspiration of thyroid nodules, after an ultrasound examination and endocrine evaluation of serum calcitonin levels. Nowadays, RET gene screening (starting with exons 10 and 11) is a mandatory test used for identification of both symptomatic and non-symptomatic MTC carriers or for exclusion of healthy individuals from subsequent periodical clinical/biochemical screening. In this context, and in the idea of PCC preceding MTC, the early detection of germline RET mutations are highly suggestive for hereditary disease. PCC diagnosis is established in classical manner by abdominal ultrasound imaging or computed tomography confirming the presence of adrenal gland masses, elevated plasma metanephrines and normetanephrines values and histopathological examination. Additional HPT diagnosis is acknowledged by serum ionized calcium and parathormone levels. Here we report a hereditary case of MEN2A in a two-generation Romanian family, along with data presenting the importance of correlative plurifactorial diagnostic scheme in this syndrome and a short literature review.

  11. Childhood chronic gastritis and duodenitis: Role of altered sensory neuromediators.

    Science.gov (United States)

    Islek, Ali; Yilmaz, Aygen; Elpek, Gulsum Ozlem; Erin, Nuray

    2016-10-07

    To investigate the roles of the neuropeptides vasoactive intestinal peptide (VIP), substance P (SP), and calcitonin gene-related peptide (CGRP) in chronic gastritis and duodenitis in children. Biopsy samples from the gastric and duodenal mucosa of 52 patients and 30 control subjects were obtained. Samples were taken for pathological examination, immunohistochemical staining, enzyme activity measurements and quantitative measurements of tissue peptide levels. We observed differential effects of the disease on peptide levels, which were somewhat different from previously reported changes in chronic gastritis in adults. Specifically, SP was increased and CGRP and VIP were decreased in patients with gastritis. The changes were more prominent at sites where gastritis was severe, but significant changes were also observed in neighboring areas where gastritis was less severe. Furthermore, the degree of changes was correlated with the pathological grade of the disease. The expression of CD10, the enzyme primarily involved in SP hydrolysis, was also decreased in patients with duodenitis. Based on these findings, we propose that decreased levels of VIP and CGRP and increased levels of SP contribute to pathological changes in gastric mucosa. Hence, new treatments targeting these molecules may have therapeutic and preventive effects.

  12. The 11th quality control survey for radioisotopes in vitro tests in Japan, 1989

    Energy Technology Data Exchange (ETDEWEB)

    1990-10-01

    This report presents the results of the 11th quality control nationwide survey. Of 730 facilities performing radioisotopes in vitro tests in November 1989, 422 facilities (60.5%) participated in the present survey. The following 23 items were examined: adrenocorticotropic hormone (ACTH), albumin, carbohydrate antigen 125 (CA 125), carbohydrate antigen 19-9 (CA 19-9), carcinoembryonic antigen (CEA), calcitonin, cortisol, estradiol, ferritin, free thyroxine (FT{sub 4}), follicle stimulating hormone (FSH), gastrine, cholylglycine, glucagon, insulin, anti-DNA antibody, luteinizing hormone (LH), neuron specific enolase (NSE), parathyroid hormone (PTH), squamous cell carcinoma associated antigen (SCC), thyroxine (T{sub 4}), thyroxine binding globulin (TBG), and antithyroid stimulating hormone (TSH) receptor antibody. 'Within kit variation' between facilities showed large coefficient of variation for ACTH, CA125, CEA, estradiol, ferritin, FSH, glucagon, anti-DNA antibody, LH, PTH, and TSH receptor antibody. Both 'within kit variation' and 'between kit variation' showed small coefficient of variation for cortisol, free T{sub 4}, NSE, SCC, T{sub 4}, and TBG. The present survey was characterized by using immunoradiometric assay (IRMA) and non-isotope techniques, as well as radioimmunoassay. Kits for IRMA greatly varied from facility to facility. (N.K.).

  13. Nitric oxide synthase localized in a subpopulation of vestibular efferents with NADPH diaphorase histochemistry and nitric oxide synthase immunohistochemistry.

    Science.gov (United States)

    Lysakowski, A; Singer, M

    2000-11-27

    Efferent innervation of the vestibular labyrinth is known to be cholinergic. More recent studies have also demonstrated the presence of the neuropeptide calcitonin gene-related peptide in this system. Nitric oxide is one of a new class of neurotransmitters, the gaseous transmitters. It acts as a second messenger and neurotransmitter in diverse physiological systems. We decided to investigate the anatomical distribution of the synthetic enzyme for nitric oxide, nitric oxide synthase (NOS), to clarify the role of nitric oxide in the vestibular periphery. NADPH diaphorase histochemical and NOS I immunohistochemical studies were done in the adult chinchilla and rat vestibular brainstem; diaphorase histochemistry was done in the chinchilla periphery. Retrograde tracing studies to verify the presence of NOS in brainstem efferent neurons were performed in young chinchillas. Our light microscopic results show that NOS I, as defined mainly by the presence of NADPH diaphorase, is present in a subpopulation of both brainstem efferent neurons and peripheral vestibular efferent boutons. Our ultrastructural results confirm these findings in the periphery. NADPH diaphorase is also present in a subpopulation of type I hair cells, suggesting that nitric oxide might be produced in and act locally upon these cells and other elements in the sensory epithelium. A hypothesis about how nitric oxide is produced in the vestibular periphery and how it may interact with other elements in the vestibular sensory apparatus is presented in the discussion. Copyright 2000 Wiley-Liss, Inc.

  14. Comparison of the vascular innervation of the rat cochlea and vestibular system.

    Science.gov (United States)

    Lyon, M J; Payman, R N

    2000-03-01

    In order to gain a better understanding of the neuronal and local control of inner ear blood flow, the vascular innervation to the rat cochlea and vestibular system was examined. Specimens were removed in toto beginning at the basilar artery extending to the anterior inferior cerebellar artery, labyrinthine artery, common cochlear artery, modiolar artery and anterior vestibular artery. When possible the vessels were dissected in continuity through the cribrose area. The vestibular endorgans were also removed. Specimens were examined using immunohistochemical techniques for the presence of vasoactive intestinal peptide, neuronal nitric oxide synthase, neuropeptide-Y, substance P and calcitonin gene related peptide. Results show that the vasculature to the cochlea and vestibular portion of the inner ear receive similar types of nonadrenergic innervation, that within the vestibular endorgans, only CGRP and SP were found in the neuroepithelium or in association with vessels, and that within the vestibular system, the majority of the vascular innervation appears to stop at or near the cribrose area. In the cochlea however, it extends to include the radiating arterioles. These findings suggest that cochlear blood flow is under finer control and that neuronally induced changes in blood flow may have a more global effect in the vestibular periphery.

  15. Different effects of implanting vascular bundles and sensory nerve tracts on the expression of neuropeptide receptors in tissue-engineered bone in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Chen Siyuan; Qin Junjun; Wang Le; Mu Tianwang; Jin Dan; Jiang Shan; Zhao Peiran [Department of Orthopaedic and Trauma, Nanfang Hospital, Southern Medical University, Guangzhou 510515 (China); Pei Guoxian, E-mail: easonfaye_2001@qq.co [Department of Orthopaedic Surgery, Xijing Hospital, The Fourth Military Medical University, Xi' an 710032 (China)

    2010-10-01

    We investigated whether implantation of vascular bundles or sensory nerves affected the expression of calcitonin gene-related peptide type I receptor (CGRP1R) and neuropeptide Y1 receptor (NPY1R) in tissue-engineered bone. We implanted osteogenically induced bone marrow mesenchymal stem cells (BMSCs) with {beta}-tricalcium phosphate ({beta}-TCP) as the scaffold material either with sensory nerve tracts (group I, n = 18), vascular bundles (group II, n = 18) or alone (group III, n = 18) to repair a 1.2 cm femur defect in the rabbit. Better osteogenesis was observed by x-ray and histology in groups I and II than in group III at 4, 8 and 12 weeks. Within the new bone, the mRNA levels of the two neuropeptide receptors determined by real-time PCR increased through week 8, and then gradually decreased (P < 0.05). Expression of the neuropeptide receptors determined by immunohistochemistry was lowest at 4 weeks (P < 0.05) and was higher in group II than in group I (P < 0.05). Expression was significantly higher in groups I and II than in group III at all time points. We conclude that implanting vascular bundles into tissue-engineered bone can significantly improve the early expression of CGRP1R and NPY1R. In contrast, implantation of sensory nerves did not show the same dramatic effect as implantation of vascular bundles.

  16. [The experimental study on melatonin gastro intestinal motility and plasma levels of stress hormones in overtraining rat].

    Science.gov (United States)

    Jing, Hui-feng; Wang, Xiao-mei

    2015-09-01

    To study the effect of melatonin on the gastrointestinal motility and plasma levels of the stress hormone in overtraining rats. Thirty adult SD rats were randomly divided into three groups (n = 10): control group, over-training group, melatonin intervention group. 30 min before each training, rats in the control and over-training groups were fed with normal saline (15 mg/kg) once a day and 5 times per week, while rats in the melatonin intervention group were administrated with melatonin, perfusion in the intervention group (15 mg/kg). Excessive training group and melatonin intervention group rats were subjected to excessive training at 5 times a week for 6 weeks. After 6 weeks, the gastric emptying rate, small intestinal propulsion ratio and levels of plasma motilin (MTL) and calcitonin gene-related peptide (CGRP), cortisol (CORT) and catecholamines (CA) were observed in all groups. Compared with the control group, the gastric emptying rate, small intestinal propulsion ratio and levels of plasma MTL, CORT and CA were increased significantly (P melatonin, this trend was reversed, that was, the gastric emptying rate, small intestinal propulsion ratio and levels of plasma MTL, CORT and CA were surpressed significantly (P Melatonin plays an important role in protecting gastrointestinal tract from dysfunction, in which MTL, CGRP, CORT and CA are all involved.

  17. Denosumab in the treatment of hypercalcemia secondary to malignancy

    Directory of Open Access Journals (Sweden)

    Dalkin AC

    2015-11-01

    Full Text Available Alan C Dalkin,1 Mitchell H Rosner2 1Division of Endocrinology and Metabolism, 2Division of Nephrology, University of Virginia Health System, Charlottesville, VA, USA Abstract: Hypercalcemia secondary to malignancy is associated with serious morbidity and mortality. Current treatment paradigms focus on acute lowering of serum calcium with a combination of intravenous volume repletion and expansion coupled with therapies to decrease bone release of calcium (calcitonin, bisphosphonates. While highly effective, in some cases, patients may be refractory to these existing therapies or may not tolerate them. Recently, the role of receptor activator of nuclear factor-κB ligand in bone modeling has been elucidated and specific therapies to target this pathway have been developed. One of these therapies, denosumab has been effectively used in the management of postmenopausal osteoporosis. Given the important role of bone modeling in the development of malignancy associated hypercalcemia, denosumab has been used to treat this condition. This review focuses on the existing clinical data regarding denosumab for the treatment of hypercalcemia of malignancy. Keywords: denosumab, hypercalcemia, malignancy, therapy

  18. Study on osteogenesis promoted by low sound pressure level infrasound in vivo and some underlying mechanisms.

    Science.gov (United States)

    Long, Hua; Zheng, Liheng; Gomes, Fernando Cardoso; Zhang, Jinhui; Mou, Xiang; Yuan, Hua

    2013-09-01

    To clarify the effects of low sound pressure level (LSPL) infrasound on local bone turnover and explore its underlying mechanisms, femoral defected rats were stabilized with a single-side external fixator. After exposure to LSPL infrasound for 30min twice everyday for 6 weeks, the pertinent features of bone healing were assessed by radiography, peripheral quantitative computerized tomography (pQCT), histology and immunofluorescence assay. Infrasound group showed a more consecutive and smoother process of fracture healing and modeling in radiographs and histomorphology. It also showed significantly higher average bone mineral content (BMC) and bone mineral density (BMD). Immunofluorescence showed increased expression of calcitonin gene related peptide (CGRP) and decreased Neuropeptide Y (NPY) innervation in microenvironment. The results suggested the osteogenesis promotion effects of LSPL infrasound in vivo. Neuro-osteogenic network in local microenvironment was probably one target mediating infrasonic osteogenesis, which might provide new strategy to accelerate bone healing and remodeling. Copyright © 2013 Elsevier B.V. All rights reserved.

  19. Hormonal alterations in PCOS and its influence on bone metabolism.

    Science.gov (United States)

    Krishnan, Abhaya; Muthusami, Sridhar

    2017-02-01

    According to the World Health Organization (WHO) polycystic ovary syndrome (PCOS) occurs in 4-8% of women worldwide. The prevalence of PCOS in Indian adolescents is 12.2% according to the Indian Council of Medical Research (ICMR). The National Institute of Health has documented that it affects approximately 5 million women of reproductive age in the United States. Hormonal imbalance is the characteristic of many women with polycystic ovarian syndrome (PCOS). The influence of various endocrine changes in PCOS women and their relevance to bone remains to be documented. Hormones, which include gonadotrophin-releasing hormone (GnRH), insulin, the leutinizing/follicle-stimulating hormone (LH/FSH) ratio, androgens, estrogens, growth hormones (GH), cortisol, parathyroid hormone (PTH) and calcitonin are disturbed in PCOS women. These hormones influence bone metabolism in human subjects directly as well as indirectly. The imbalance in these hormones results in increased prevalence of osteoporosis in PCOS women. Limited evidence suggests that the drugs taken during the treatment of PCOS increase the risk of bone fracture in PCOS patients through endocrine disruption. This review is aimed at the identification of the relationship between bone mineral density and hormonal changes in PCOS subjects and identifies potential areas to study bone-related disorders in PCOS women. © 2017 Society for Endocrinology.

  20. Medical management of Charcot arthropathy.

    Science.gov (United States)

    Petrova, N L; Edmonds, M E

    2013-03-01

    Charcot arthropathy is a major complication of diabetes and it poses management challenges to health care professionals. Early diagnosis and timely intervention are essential for improved outlook of these patients. Casting therapy has been accepted as the mainstay treatment of the acute Charcot foot, although there are still controversies regarding its duration, the choice of removable and non-removable device and weight-bearing casts vs. non-weight-bearing casts. Two groups of antiresorptive therapies have been evaluated in the treatment of the acute Charcot foot, bisphosphonates (intravenous and oral) and calcitonin. These therapies have clearly shown a reduction of bone turnover, although, they have not shown a significant effect on temperature reduction. Current evidence to support their use is weak. An anabolic agent to speed up clinical resolution and fracture healing may be helpful and a clinical trial to evaluate the possible benefit of 1-84 recombinant human parathyroid hormone on fracture healing in the acute Charcot foot is in progress. This paper summarises the current approach to medical management of acute Charcot arthropathy with specific emphasis on casting and pharmacological therapy. Emerging new studies of the pathogenesis of this condition are also discussed. © 2012 Blackwell Publishing Ltd.

  1. [Long-term steroid therapy in children: is adjunct therapy relevant in nephrotic syndrome?].

    Science.gov (United States)

    Bacchetta, J; Harambat, J; Cochat, P

    2008-11-01

    The impact of glucocorticoids on bone is specifically relevant in children exposed to a long course of treatment. Corticosteroids lead to a decrease in bone formation, mainly by osteoblastic inhibition in trabecular bone. They also play an indirect role in bone metabolism through systemic actions, such as bone maturation delay, hypogonadism, pubertal delay, and IGF1 inhibition. A systematic review of the literature was conducted. We found 12 clinical trials of interventions including calcium, vitamin D, growth hormone, calcitonin, and bisphosphonates for preventing bone disease in children receiving steroid therapy. There were few randomized controlled trials (n=7), with a limited number of patients, so that a meta-analysis could not be performed. Calcium and vitamin D supplementation may, however, have a beneficial effect on bone in children with nephrotic syndrome receiving long-term steroid therapy. We, therefore, recommend routine vitamin D supplementation, use of steroid-sparing protocols, and global prevention of risk to bone (adequate calcium intake, sun exposure, and physical activity).

  2. Hydrogen-rich saline injection into the subarachnoid cavity within 2 weeks promotes recovery after acute spinal cord injury

    Directory of Open Access Journals (Sweden)

    Jian-long Wang

    2015-01-01

    Full Text Available Hydrogen can relieve tissue-damaging oxidative stress, inflammation and apoptosis. Injection of hydrogen-rich saline is an effective method for transporting molecular hydrogen. We hypothesized that hydrogen-rich saline would promote the repair of spinal cord injury induced by Allen′s method in rats. At 0.5, 1, 2, 4, 8, 12 and 24 hours after injury, then once daily for 2 weeks, 0.25 mL/kg hydrogen-rich saline was infused into the subarachnoid space through a catheter. Results at 24 hours, 48 hours, 1 week and 2 weeks after injury showed that hydrogen-rich saline markedly reduced cell death, inflammatory cell infiltration, serum malondialdehyde content, and caspase-3 immunoreactivity, elevated serum superoxide dismutase activity and calcitonin gene-related peptide immunoreactivity, and improved motor function in the hindlimb. The present study confirms that hydrogen-rich saline injected within 2 weeks of injury effectively contributes to the repair of spinal cord injury in the acute stage.

  3. Effect of maternal nicotine/thiocyanate exposure during gestational period upon pituitary, thyroid and parathyroid function/morphology of 1-month-old rat offspring.

    Science.gov (United States)

    Abdelhafez, A M; Eltony, S A; Abdelhameed, S Y; Elgayar, S A

    2014-05-01

    Impact of in utero exposure to nicotine, on the structure of the thyroid-pituitary axis and the parathyroid glands have been examined in 1-month-old rats and compared with that of thiocyanate. Three pregnant female groups were used; control, nicotine and thiocyanate. Treatment started from gestation day (4-20) and the specimens were harvested from the male offspring of all groups at the age of 1 month and processed for light, electronmicroscopic and immunohistochemical examination. Total triiodothyronine (tT3), total thyroxine (tT4) and total thyrotropin (TSH) were quantitatively determined in serum. Both nicotine and thiocyanate activated the thyroid follicular cells, with an increase in height (about 30 %) and a negative feedback on the pituitary thyrotrophs which revealed a reduction in the number of cytoplasmic secretory granules, particularly the thiocyanate group. However, in thiocyanate group there was signs of impaired secretory activity of the thyroid gland. The arbitrary area of parathyroid chief cells, increased (about 45 %) particularly in nicotine group, with signs of reduced activity and a positive feedback on the parafollicular cells which revealed hypertrophy, proliferation (25 %) and increased intensity of positive immunohistochemical reaction for calcitonin. Nicotine impaired chief parathyroid cells activity and consequently activated parafollicular cells. Thiocyanate reduced pituitary thyrotrophs activity, whereas both nicotine and thiocyanate increased thyroid follicular cells activity. This impact of in utero exposure persisted for 1-month postnatal.

  4. Further studies in the developmental hyperserotonemia model (DHS) of autism: social, behavioral and peptide changes.

    Science.gov (United States)

    McNamara, Ilan M; Borella, Alice W; Bialowas, Lynn A; Whitaker-Azmitia, Patricia M

    2008-01-16

    Prior research has reliably found high blood (hyperserotonemia) - but low brain - serotonin levels in autistic individuals. At early stages of development, high levels of serotonin in the blood may enter the brain of a developing fetus, causing a loss of serotonin terminals through negative feedback and thus disrupting subsequent serotonergic function. The current study extends earlier findings in a developmental hyperserotonemia (DHS) model of autism in Sprague-Dawley rats by treating 8 dams of developing rat pups with a serotonergic agonist, 5-methoxytryptamine (5-MT; 1 mg/kg) during development (from gestational day 12 to post-natal day 20; PND 20). DHS pups exhibited post-injection seizures, which were non-existent in saline-treated pups (pDHS pups spent less time with the dam during the active phase on PNDs 15-17 (pDHS animals exhibited greater gnawing reactions to a novel stimulus (p0.05). Post mortem analyses revealed that DHS animals had a loss of oxytocin (OT)-containing cells in the paraventricular nucleus in the hypothalamus (PVN; p<0.05) as well as an increase in calcitonin-gene related peptide (CGRP; p<0.05, one tailed) processes in the central nucleus of the amygdala (CeA) on PND 198. These results may correspond to hypothalamic and amygdalar changes in the human condition and suggest that the hyperserotonemia model of autism may be a valid model which produces many of the social, behavioral, and peptide changes inherent to autism.

  5. Impact of antiepileptic drugs on bone health: Need for monitoring, treatment, and prevention strategies

    Directory of Open Access Journals (Sweden)

    Ekta Arora

    2016-01-01

    Full Text Available Epilepsy is the most common neurological disorder affecting approximately 50 million people worldwide. In India, overall prevalence of epilepsy is reported to be 5.59/1000 population. Antiepileptic drugs (AEDs constitute the main-stay of treatment with a large number of AEDs available in the market. High incidence of adverse effects is a major limitation with AEDs. One of the major concerns is significant metabolic effects on the bone. However, little attention has been paid to this issue because most of the bone effects remain subclinical for a long time and may take years to manifest clinically. The main effects include hypocalcemia, hypophosphatemia, reduced serum levels of Vitamin D, increase in parathormone (PTH levels, and alterations in bone turnover markers. The CYP450 enzyme-inducing AEDs such as phenytoin, phenobarbital, carbamazepine, and primidone are the most common AEDs associated with bone disorders while the data regarding the effect of valproate and newer AEDs such as lamotrigine, gabapentin, vigabatrin, levetiracetam, and topiramate on bone metabolism and bone density are scanty and controversial. Deficiency of Vitamin D is commonly described as a cause for the bone loss in epileptic patients while others being decreased absorption of calcium, increased PTH levels, and inhibition of calcitonin secretion, etc. However, there are no formal practical guidelines for the management of bone disease among those taking AEDs. Evidence-based strategies regarding monitoring, prevention, and treatment of bone diseases in patients on AED therapy are needed.

  6. Immunohistochemical profiling of the ultimobranchial remnants in the rat postnatal thyroid gland.

    Science.gov (United States)

    Vázquez-Román, Victoria; Utrilla, José C; Fernández-Santos, José M; Martín-Lacave, Inés

    2017-08-01

    Ultimobranchial (UB) remnants are a constant presence in the thyroid throughout rat postnatal life; however, the difficulty in identifying the most immature forms from the surrounding thyroid tissue prompted us to search for a specific marker. With that objective, we applied a panel of antibodies reported to be specific for their human counterpart, solid cell nests (SCNs), using double immunohistochemistry and immunofluorescence. Our results demonstrated that cytokeratin 34βE12 and p63 are highly sensitive markers for the immunohistologic screening of UB-remnants, independently of their maturity or size. Furthermore, rat UB-follicles (UBFs) coincided with human SCNs in the immunohistochemical pattern exhibited by both antigens. In contrast, the pattern displayed for calcitonin and thyroglobulin differs considerably but confirm the hypothesis that rat UB-cells can differentiate into both types of thyroid endocrine cells. This hypothesis agrees with recent findings that thyroid C-cells share an endodermic origin with follicular cells in rodents. We suggest that the persistence of p63-positive undifferentiated cells in UB-remnants may constitute a reservoir of basal/stem cells that persist beyond embryogenesis from which, in certain unknown conditions, differentiated thyroid cells or even unusual tumors may arise. © 2017 Wiley Periodicals, Inc.

  7. Letrozole induced low estrogen levels affected the expressions of duodenal and renal calcium-processing gene in laying hens.

    Science.gov (United States)

    Li, Qiao; Zhao, Xingkai; Wang, Shujie; Zhou, Zhenlei

    2017-10-14

    Estrogen regulates the calcium homeostasis in hens, but the mechanisms involved are still unclear fully. In this study, we investigated whether letrozole (LZ) induced low estrogen levels affected the calcium absorption and transport in layers. In the duodenum, we observed a significant decrease of mRNA expressions of Calbindin-28k (CaBP-28k) and plasma membrane Ca(2+)-ATPase (PMCA 1b) while CaBP-28k protein expression was declined in birds with LZ treatment, and the mRNA levels of duodenal transient receptor potential vanilloid 6 (TRPV6) and Na(+)/Ca(2+) exchanger 1 (NCX1) were not affected. Interestingly, we observed the different changes in the kidney. The renal mRNA expressions of TRPV6 and NCX1 were unregulated while the PMCA1b was down-regulated in low estrogen layers, however, the CaBP-28k gene and protein expressions were no changed in the kidney. Furthermore, it showed that the duodenal estradiol receptor 2 (ESR2) transcripts rather than parathyroid hormone 1 receptor (PTH1R) and calcitonin receptor (CALCR) played key roles to down-regulate calcium transport in LZ-treated birds. In conclusion, CaBP-28k, PMCA 1b and ESR2 genes in the duodenum may be primary targets for estrogen regulation in order to control calcium homeostasis in hens. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. Inhibitory effect of chronic oral treatment with fluoxetine on capsaicin-induced external carotid vasodilatation in anaesthetised dogs.

    Science.gov (United States)

    Muñoz-Islas, Enriqueta; González-Hernández, Abimael; Lozano-Cuenca, Jair; Ramírez-Rosas, Martha Beatríz; Medina-Santillán, Roberto; Centurión, David; MaassenVanDenBrink, Antoinette; Villalón, Carlos M

    2015-10-01

    During migraine, capsaicin-sensitive trigeminal sensory nerves release calcitonin gene-related peptide (CGRP), resulting in cranial vasodilatation and central nociception. Moreover, 5-HT is involved in the pathophysiology of migraine and depression. Interestingly, some limited lines of evidence suggest that fluoxetine may be effective in migraine prophylaxis, but the underlying mechanisms are uncertain. Hence, this study investigated the canine external carotid vasodilator responses to capsaicin, α-CGRP and acetylcholine before and after acute and chronic oral treatment with fluoxetine. Forty-eight vagosympathectomised male mongrel dogs were prepared to measure blood pressure, heart rate and external carotid blood flow. The thyroid artery was cannulated for infusions of agonists. In 16 of these dogs, a spinal cannula was inserted (C1-C3) for infusions of 5-HT. The external carotid vasodilator responses to capsaicin, α-CGRP and acetylcholine remained unaffected after intracarotid or i.v. fluoxetine. In contrast, the vasodilator responses to capsaicin, but not those to α-CGRP or acetylcholine, were inhibited after chronic oral treatment with fluoxetine (300 µg/kg; for 90 days) or intrathecal 5-HT. Chronic oral fluoxetine inhibited capsaicin-induced external carotid vasodilatation, and this inhibition could partly explain its potential prophylactic antimigraine action. © International Headache Society 2015.

  9. The role of brain-derived neurotrophic factor (BDNF) in the development of neurogenic detrusor overactivity (NDO).

    Science.gov (United States)

    Frias, Bárbara; Santos, João; Morgado, Marlene; Sousa, Mónica Mendes; Gray, Susannah M Y; McCloskey, Karen D; Allen, Shelley; Cruz, Francisco; Cruz, Célia Duarte

    2015-02-04

    Neurogenic detrusor overactivity (NDO) is a well known consequence of spinal cord injury (SCI), recognizable after spinal shock, during which the bladder is areflexic. NDO emergence and maintenance depend on profound plastic changes of the spinal neuronal pathways regulating bladder function. It is well known that neurotrophins (NTs) are major regulators of such changes. NGF is the best-studied NT in the bladder and its role in NDO has already been established. Another very abundant neurotrophin is BDNF. Despite being shown that, acting at the spinal cord level, BDNF is a key mediator of bladder dysfunction and pain during cystitis, it is presently unclear if it is also important for NDO. This study aimed to clarify this issue. Results obtained pinpoint BDNF as an important regulator of NDO appearance and maintenance. Spinal BDNF expression increased in a time-dependent manner together with NDO emergence. In chronic SCI rats, BDNF sequestration improved bladder function, indicating that, at later stages, BDNF contributes NDO maintenance. During spinal shock, BDNF sequestration resulted in early development of bladder hyperactivity, accompanied by increased axonal growth of calcitonin gene-related peptide-labeled fibers in the dorsal horn. Chronic BDNF administration inhibited the emergence of NDO, together with reduction of axonal growth, suggesting that BDNF may have a crucial role in bladder function after SCI via inhibition of neuronal sprouting. These findings highlight the role of BDNF in NDO and may provide a significant contribution to create more efficient therapies to manage SCI patients. Copyright © 2015 Frias et al.

  10. Evidence for a key role of steroids in the modulation of pain.

    Science.gov (United States)

    Mensah-Nyagan, Ayikoe G; Meyer, Laurence; Schaeffer, Véronique; Kibaly, Cherkaouia; Patte-Mensah, Christine

    2009-12-01

    Neurotransmitters such as glutamate, substance P, serotonin and gamma-aminobutyric acid pivotally control pain mechanisms. It is also well known that inflammatory and/or neuropathic pain may depend on the action of diverse cytokines and other molecules including eicosanoids, endorphins, calcitonin-gene related peptide, free radicals and transcription factors. Because steroids control the development, activities and plasticity of the nervous system, these compounds are of particular interest in the modulation of pain. The paper discusses various data supporting the existence of key regulatory effects of steroids in the control of pain. In particular, we analyzed three categories of observations which historically contributed to demonstrate that endogenous and synthetic steroids play a crucial role in the regulation of neurobiological processes involved in pain sensation. The first series of data, which present the chemical characteristics enabling steroids to act on several tissues, also summarize pertinent results supporting the modulation of pain sensation by steroidal compounds. The second category of data evokes psychosocial, fundamental and clinical results suggesting the existence of sex steroid-based differences in pain perception. Finally, we discuss recent evidence showing the endogenous production of neurosteroids and their effects in the spinal cord which crucially controls pain transmission. Taken together, the data reviewed herein suggest that future investigations aiming to develop effective steroid-based strategies against chronic pain must integrate in a complementary manner anti-inflammatory properties of steroids, sex steroid-induced dimorphism in pain perception and regulatory effects exerted by endogenous neurosteroids in pain neural circuits.

  11. Sensory Neuropeptides and Endogenous Opioids Expression in Human Dental Pulp with Asymptomatic Inflammation: In Vivo Study

    Directory of Open Access Journals (Sweden)

    Daniel Chavarria-Bolaños

    2015-01-01

    Full Text Available Purpose. This study quantified the expression of substance P (SP, calcitonin gene-related peptide (CGRP, β-endorphins (β-End, and methionine-enkephalin (Met-Enk in human dental pulp following orthodontic intrusion. Methods. Eight patients were selected according to preestablished inclusion criteria. From each patient, two premolars (indicated for extraction due to orthodontic reasons were randomly assigned to two different groups: the asymptomatic inflammation group (EXPg, which would undergo controlled intrusive force for seven days, and the control group (CTRg, which was used to determine the basal levels of each substance. Once extracted, dental pulp tissue was prepared to determine the expression levels of both neuropeptides and endogenous opioids by radioimmunoassay (RIA. Results. All samples from the CTRg exhibited basal levels of both neuropeptides and endogenous opioids. By day seven, all patients were asymptomatic, even when all orthodontic-intrusive devices were still active. In the EXPg, the SP and CGRP exhibited statistically significant different levels. Although none of the endogenous opioids showed statistically significant differences, they all expressed increasing trends in the EXPg. Conclusions. SP and CGRP were identified in dental pulp after seven days of controlled orthodontic intrusion movement, even in the absence of pain.

  12. Isolated carcinoid tumor metastatic to the thyroid gland: report of a case initially diagnosed by fine needle aspiration cytology.

    Science.gov (United States)

    Maly, Alexander; Meir, Karen; Maly, Bella

    2006-01-01

    Neuroendocrine tumor metastatic to the thyroid gland is rare and may be difficult to differentiate from primary thyroid neuroendocrine tumors, such as medullary thyroid carcinoma (M/ITC). This report describes an unusual case of bronchial carcinoid metastatic to the thyroid diagnosed by fine needle aspiration cytology (FNAC). A 42-year-old woman with an undiagnosed bronchial carcinoid tumor presented to our clinic with a solitary nodule in the thyroid gland. FNAC of the nodule showed loosely cohesive groups of cuboidal tumor cells with scant, slightly granular cytoplasm; centrally located nuclei with a coarsely granular, salt-and-pepper chromatin pattern and inconspicuous nucleoli. Immunocytochemically the tumor cells were positive for neuron-specific enolase, chromogranin and synaptophysin and negative for thyroglobulin, calcitonin and carcinoembryonic antigen. The cytologic diagnosis of a metastatic neuroendocrine carcinoma was confirmed histologically. Metastasis to the thyroid gland may pose a diagnostic problem, particularly with tumors of neuroendocrine origin, as these have similar cytologic features in various organs. The correct preoperative cytologic diagnosis of metastatic carcinoid tumor in patients without a prior history of cancer and differential diagnosis with MTC are crucial because prognosis, workup and treatment are different in each.

  13. Can migraine aura be provoked experimentally? A systematic review of potential methods for the provocation of migraine aura.

    Science.gov (United States)

    Lindblad, Marianne; Hougaard, Anders; Amin, Faisal Mohammad; Ashina, Messoud

    2017-01-01

    Background The nature of the migraine aura and its role in migraine pathophysiology is incompletely understood. In particular, the mechanisms underlying aura initiation and the causal relation between aura and headache are unknown. The scientific investigation of aura in patients is only possible if aura can be triggered. This paper reviews potential methods for the experimental provocation of migraine aura. Methods We systematically searched PubMed for studies of experimental migraine provocation, including case reports of patients with aura and reports of the occurrence of aura following exposure to any kind of suspected trigger. Results We identified 21 provocation studies, using 13 different prospective provocation methods, and 34 case reports. In the prospective studies, aura were reported following the administration of intravenous and sublingual glyceryl trinitrate, visual stimulation, physical activity, calcitonin gene-related peptide infusion, chocolate ingestion, and the intravenous injection of insulin. In addition, carotid artery puncture has consistently been reported as a trigger of aura. Conclusions No safe and efficient method for aura provocation exists at present, but several approaches could prove useful for this purpose.

  14. Pharmacological interventions for phantom limb pain.

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    Fang, Jun; Lian, Yan-hong; Xie, Kang-jie; Cai, Shu-nü

    2013-02-01

    To review the mechanisms and current clinical application of pharmacological interventions for phantom limb pain. Both Chinese and English language literatures were searched using MEDLINE (1982 - 2011), Pubmed (1982 - 2011) and the Index of Chinese Language Literature (1982 - 2011). Data from published articles about pharmacological management of phantom limb pain in recent domestic and foreign literature were selected. Data extraction Data were mainly extracted from 96 articles which are listed in the reference section of this review. By reviewing the mechanisms and current clinical application of pharmacological interventions for phantom limb pain, including anticonvulsants, antidepressants, local anaesthetics, N-methyl-D-aspartate receptor antagonists, non-steroidal anti-inflammatory drugs, tramadol, opioids, calcitonin, capsaicin, beta-adrenergic blockers, clonidine, muscle relaxants, and emerging drugs, we examined the efficacy and safety of these medications, outlined the limitations and future directions. Although there is lack of evidence-based consensus guidelines for the pharmacological management of phantom limb pain, we recommend tricyclic antidepressants, gabapentin, tramadol, opioids, local anaesthetics and N-methyl-D-aspartate receptor antagonists as the rational options for the treatment of phantom limb pain.

  15. Mechanism of action of ZOT-derived peptide AT-1002, a tight junction regulator and absorption enhancer.

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    Gopalakrishnan, Shobha; Pandey, Niranjan; Tamiz, Amir P; Vere, John; Carrasco, Rosa; Somerville, Robert; Tripathi, Amit; Ginski, Mark; Paterson, Blake M; Alkan, Sefik S

    2009-01-05

    Tight junctions (TJs) are intercellular structures that control paracellular permeability and epithelial polarity. It is now accepted that TJs are highly dynamic structures that are regulated in response to exogenous and endogenous stimuli. Here, we provide details on the mechanism of action of AT-1002, the active domain of Vibrio cholerae's second toxin, zonula occludens toxin (ZOT). AT-1002, a hexamer peptide, caused the redistribution of ZO-1 away from cell junctions as seen by fluorescence microscopy. AT-1002 also activated src and mitogen activated protein (MAP) kinase pathways, increased ZO-1 tyrosine phosphorylation, and rearrangement of actin filaments. Functionally, AT-1002 caused a reversible reduction in transepithelial electrical resistance (TEER) and an increase in lucifer yellow permeability in Caco-2 cell monolayers. In vivo, co-administration of salmon calcitonin with 1 mg of AT-1002 resulted in a 5.2-fold increase in AUC over the control group. Our findings provide a mechanistic explanation for AT-1002-induced tight junction disassembly, and demonstrate that AT-1002 can be used for delivery of other agents in vivo.

  16. Topographical organization of TRPV1-immunoreactive epithelium and CGRP-immunoreactive nerve terminals in rodent tongue

    Directory of Open Access Journals (Sweden)

    M. Kawashima

    2012-05-01

    Full Text Available Transient receptor potential vanilloid subfamily member 1 (TRPV1 is activated by capsaicin, acid, and heat and mediates pain through peripheral nerves. In the tongue, TRPV1 expression has been reported also in the epithelium. This indicates a possibility that sensation is first received by the epithelium. However, how nerves receive sensations from the epithelium remains unclear. To clarify the anatomical basis of this interaction, we performed immunohistochemical studies in the rodent tongue to detect TRPV1 and calcitonin gene-related peptide (CGRP, a neural marker. Strong expression of TRPV1 in the epithelium was observed and was restricted to the apex of the tongue. Double immunohistochemical staining revealed that CGRP-expressing nerve terminals were in close apposition to the strongly TRPV1-expressing epithelium of fungiform papilla in the apex of rodent tongues. These results suggest that the TRPV1-expressing epithelium monitors the oral environment and acquired information may then be conducted to the adjacent CGRPexpressing terminals.

  17. The role of TRPV1 in different subtypes of dorsal root ganglion neurons in rat chronic inflammatory nociception induced by complete Freund's adjuvant

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    Han Ji-Sheng

    2008-12-01

    Full Text Available Abstract Background The present study aims to investigate the role of transient receptor potential vanilloid 1 (TRPV1 in dorsal root ganglion (DRG neurons in chronic pain including thermal hyperalgesia and mechanical allodynia. Chronic inflammatory nociception of rats was produced by intraplantar injection of complete Freund's adjuvant (CFA and data was collected until day 28 following injection. Results Thermal hyperalgesia was evident from day 1 to day 28 with peak at day 7, while mechanical allodynia persisted from day 1 to day 14 and was greatest at day 7. Intrathecal administration of AMG 9810 at day 7, a selective TRPV1 antagonist, significantly reduced thermal hyperalgesia and mechanical allodynia. TRPV1 expression in DRG detected by Western blotting was increased relative to baseline throughout the observation period. Double labeling of TRPV1 with neuronal marker neurofilament 200 (NF200, calcitonin gene-related peptide (CGRP or isolectin B4 (IB4 was used to distinguish different subtypes of DRG neurons. TRPV1 expression was increased in the medium-sized myelinated A fiber (NF200 positive neurons and in small non-peptidergic (IB4 positive neurons from day 1 to day 14 and was increased in small peptidergic (CGRP positive neurons from day 1 to day 28. Conclusion TRPV1 expression increases in all three types of DRG neurons after CFA injection and plays a role in CFA-induced chronic inflammatory pain including thermal hyperalgesia and mechanical allodynia.

  18. The inhibition of subchondral bone lesions significantly reversed the weight-bearing deficit and the overexpression of CGRP in DRG neurons, GFAP and Iba-1 in the spinal dorsal horn in the monosodium iodoacetate induced model of osteoarthritis pain.

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    Degang Yu

    Full Text Available BACKGROUND: Chronic pain is the most prominent and disabling symptom of osteoarthritis (OA. Clinical data suggest that subchondral bone lesions contribute to the occurrence of joint pain. The present study investigated the effect of the inhibition of subchondral bone lesions on joint pain. METHODS: Osteoarthritic pain was induced by an injection of monosodium iodoacetate (MIA into the rat knee joint. Zoledronic acid (ZOL, a third generation of bisphosphonate, was used to inhibit subchondral bone lesions. Joint histomorphology was evaluated using X-ray micro computed tomography scanning and hematoxylin-eosin staining. The activity of osteoclast in subchondral bone was evaluated using tartrate-resistant acid phosphatase staining. Joint pain was evaluated using weight-bearing asymmetry, the expression of calcitonin gene-related peptide (CGRP in the dorsal root ganglion (DRG, and spinal glial activation status using glial fibrillary acidic protein (GFAP and ionized calcium binding adaptor molecule-1 (Iba-1 immunofluorescence. Afferent neurons in the DRGs that innervated the joints were identified using retrograde fluorogold labeling. RESULTS: MIA injections induced significant histomorphological alterations and joint pain. The inhibition of subchondral bone lesions by ZOL significantly reduced the MIA-induced weight-bearing deficit and overexpression of CGRP in DRG neurons, GFAP and Iba-1 in the spinal dorsal horn at 3 and 6 weeks after MIA injection; however, joint swelling and synovial reaction were unaffected. CONCLUSIONS: The inhibition of subchondral bone lesions alleviated joint pain. Subchondral bone lesions should be a key target in the management of osteoarthritic joint pain.

  19. [Effect of intrathecal sufentanil and protein kinase C inhibitor on pain threshold and the expression of NMDA receptor/ CGRP in spinal dorsal horn in rats with neuropathic pain].

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    Wang, Yichun; Guo, Qulian; Wang, Mingde; Wang, E; Zou, Wangyuan; Zhao, Jianghong

    2012-08-01

    To investigate the effect of intrathecal sufentanil and protein kinase C inhibitor on pain threshold and the expression of N-methyl-D-aspartate receaptors (NMDAR)/calcitonin generelated peptide (CGRP) in spinal dorsal horn in rats with neuropathic pain. Fifty-four healthy male Sprague-Dawley rats were randomly divided into 6 groups (9 in each group). The rats in the sham group(Group S) + spared nerve injury (SNI), SP+SNI, and P+SNI were intrathecally injected sufentanil (1 μg), sufentanil (1 μg) and chelerythrine chloride (11 μg), chelerythrine chloride (11 μg) followed by 10 μL normal saline once every day for 14 days postoperatively, respectively. Similarly, rats in the control group (Group C), the sham group (Group S), and SNI model group (Group SNI) were intrathecally injected 20 μL normal saline in the uniform interval. Pain behaviours were measured on Day 1 pre-surgery and on Day 1, 2, 7, and 14 after the intrathecal injection. The expressions of NMDAR and CGRP in the spinal dorsal horn of L5 segment were determined by immunohistochemistry on Day 2, 7, and 14 after the intrathecal injection. Compared with Group C and Group S, mechanical allodynia threshold in group SNI was decreased after the surgery (Phorn was significantly increased (Phorn of SNI rat models.

  20. The vanilloid receptor TRPV1 is activated and sensitized by local anesthetics in rodent sensory neurons

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    Leffler, Andreas; Fischer, Michael J.; Rehner, Dietlinde; Kienel, Stephanie; Kistner, Katrin; Sauer, Susanne K.; Gavva, Narender R.; Reeh, Peter W.; Nau, Carla

    2008-01-01

    Local anesthetics (LAs) block the generation and propagation of action potentials by interacting with specific sites of voltage-gated Na+ channels. LAs can also excite sensory neurons and be neurotoxic through mechanisms that are as yet undefined. Nonspecific cation channels of the transient receptor potential (TRP) channel family that are predominantly expressed by nociceptive sensory neurons render these neurons sensitive to a variety of insults. Here we demonstrated that the LA lidocaine activated TRP channel family receptors TRPV1 and, to a lesser extent, TRPA1 in rodent dorsal root ganglion sensory neurons as well as in HEK293t cells expressing TRPV1 or TRPA1. Lidocaine also induced a TRPV1-dependent release of calcitonin gene–related peptide (CGRP) from isolated skin and peripheral nerve. Lidocaine sensitivity of TRPV1 required segments of the putative vanilloid-binding domain within and adjacent to transmembrane domain 3, was diminished under phosphatidylinositol 4,5-bisphosphate depletion, and was abrogated by a point mutation at residue R701 in the proximal C-terminal TRP domain. These data identify TRPV1 and TRPA1 as putative key elements of LA-induced nociceptor excitation. This effect is sufficient to release CGRP, a key component of neurogenic inflammation, and warrants investigation into the role of TRPV1 and TRPA1 in LA-induced neurotoxicity. PMID:18172555