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1.
Obes Surg ; 22(3): 478-86, 2012 Mar.
Article in English | MEDLINE | ID: mdl-21964795

ABSTRACT

BACKGROUND: Hepatic 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) activity, which converts cortisone (inactive) to cortisol, is downregulated in obesity. However, this compensation fails in obese with metabolic abnormalities, such as diabetes. To further characterize the tissue-specific cortisol regeneration in obesity, we have investigated the mRNA expression of genes related to local cortisol production, i.e., 11ß-HSD1, hexose-6-phosphate dehydrogenase (H6PDH) and cortisol action, glucocorticoid receptor (GR) and a cortisol target gene, phosphoenolpyruvate carboxykinase (PEPCK) in the liver, and visceral (VAT) and subcutaneous (SAT) adipose tissues from morbidly obese patients with and without metabolic syndrome (MS). METHODS: Fifty morbidly obese patients undergoing bariatric surgery, 14 men (mean age, 41.3 ± 3.5 years; BMI, 48.0 ± 3.6 kg/m(2)) and 36 women (mean age, 44.6 ± 1.9 years; BMI, 44.9 ± 1.2 kg/m(2)), were classified as having MS (MS+, n = 20) or not (MS-, n = 30). Tissue mRNA levels were measured by real-time polymerase chain reaction. RESULTS: Hepatic mRNA levels of these genes were higher in obese patients with MS (11ß-HSD1, P = 0.002; H6PDH, P = 0.043; GR, P = 0.033; PEPCK, P = 0.032) and positively correlated with the number of clinical characteristics that define the MS. The expression of the four genes positively correlated among them. In contrast to the liver, these genes were not differently expressed in VAT or SAT, when MS+ and MS- obese patients were compared. CONCLUSIONS: Coordinated liver-specific upregulation of genes involved in local cortisol regeneration and action support the concept that local hepatic hypercortisolism contributes to development of MS in morbidly obese patients.


Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , Hydrocortisone/metabolism , Liver/enzymology , Metabolic Syndrome/enzymology , Obesity, Morbid/enzymology , Phosphoenolpyruvate Carboxykinase (ATP)/metabolism , 11-beta-Hydroxysteroid Dehydrogenase Type 1/genetics , Adipose Tissue/enzymology , Adult , Bariatric Surgery , Cortisone/metabolism , Female , Gene Expression Regulation , Humans , Hydrocortisone/biosynthesis , Hydrocortisone/genetics , Male , Metabolic Syndrome/genetics , Obesity, Morbid/genetics , Obesity, Morbid/surgery , Phosphoenolpyruvate Carboxykinase (ATP)/genetics , RNA, Messenger , Real-Time Polymerase Chain Reaction , Up-Regulation
4.
Brain Res ; 1375: 28-40, 2011 Feb 23.
Article in English | MEDLINE | ID: mdl-21184749

ABSTRACT

Brain derived neurotrophic factor (BDNF) increases the levels of somatostatin (SS) and its mRNA. To test the hypothesis that the regulation of SS synthesis by BDNF occurs at the transcriptional level and requires specific promoter sequences, cerebrocortical and PC12trkB neurons were transiently transfected with different constructs of the SS promoter fused to the luciferase and CAT reporter genes. We demonstrated that BDNF triggered the transcription of the SS gene through the CRE sequence located in the SS promoter. BDNF and SS are genes regulated by K(+)-induced neuronal activity. Using BDNF blocking antibodies, we investigated whether K(+)-induced BDNF was required for K(+)-dependent SS mRNA induction. We found that K(+)-induced SS mRNA was partially prevented when BDNF was blocked. This finding indicated that BDNF mediated the induction of SS mRNA by K(+) depolarization. To identify the mechanisms by which BDNF activates SS gene transcription we first elucidated the signaling pathways activated by BDNF in cerebrocortical cells. We confirmed that BDNF activates the MAPK/ERKs and PI3K/Akt pathways. Both signaling pathways are, in turn, implicated in the activation of CREB by BDNF. In addition we observed that the PKA inhibitors, H89 and Rp-cAMPS decreased BDNF-induced CREB activation. These findings suggested that BDNF-induced CREB activation was also mediated by the cAMP/PKA pathway. We next elucidated the mechanism by which BDNF induces SS mRNA. We observed that H89, PD0998059, KN62 and LY294002 diminished BDNF-induced SS mRNA suggesting that BDNF-induced SS mRNA is mediated by the activation of cAMP/PKA, MAPK/ERKs, CaMK and PI3K pathways.


Subject(s)
Brain-Derived Neurotrophic Factor/pharmacology , Cerebral Cortex/metabolism , Somatostatin/biosynthesis , Animals , Blotting, Western , Brain-Derived Neurotrophic Factor/antagonists & inhibitors , Cells, Cultured , Cerebral Cortex/drug effects , Cyclic AMP Response Element-Binding Protein/metabolism , Cyclic AMP-Dependent Protein Kinases/antagonists & inhibitors , Electric Stimulation , Enzyme Activation/drug effects , Enzyme Inhibitors/pharmacology , Extracellular Signal-Regulated MAP Kinases/metabolism , Female , Gene Expression , Immunoglobulin G/isolation & purification , Mitogen-Activated Protein Kinases/antagonists & inhibitors , Phosphoinositide-3 Kinase Inhibitors , Potassium/pharmacology , Pregnancy , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Rats , Rats, Sprague-Dawley , Regulatory Elements, Transcriptional , Signal Transduction/drug effects , Somatostatin/genetics , Transcription, Genetic/drug effects , Transfection
7.
J Neurosci Res ; 88(4): 825-36, 2010 Mar.
Article in English | MEDLINE | ID: mdl-19859966

ABSTRACT

Ca(2+) influx through L-type voltage-gated Ca(2+) channels (L-VSCC) is required for K(+)-induced somatostatin (SS) mRNA. Increase in intracellular Ca(2+) concentration leads to the activation of cyclic AMP-responsive element binding protein (CREB), a key regulator of SS gene transcription. Several different protein kinases possess the capability of driving CREB upon membrane depolarization. We investigated which of the signalling pathways involved in CREB activation mediates SS gene induction in response to membrane depolarization in cerebrocortical cells exposed to 56 mM K(+). Activity dependent phosphorylation of CREB in Ser(133) was immunodetected. Activation of CREB was biphasic showing two peaks at 5 and 60 min. The selective inhibitors of extracellular signal related protein kinase/mitogen-activated protein kinase (ERK/MAPK) PD098059, cyclic-AMPdependent protein kinase (cAMP/PKA) H89 and RpcAMPS, and Ca(2+)/calmodulin-dependent protein kinases (CaMKs) pathways KN62 and KN93 were used to determine the signalling pathways involved in CREB activation. Here we show that the early activation of CREB was dependent on cAMP/PKA along with CaMKs pathways whereas the ERK/MAPK and CaMKs were implicated in the second peak. We observed that H89, RpcAMPS, KN62 and KN93 blocked K(+)-induced SS mRNA whereas PD098059 did not. These findings indicate that K(+)-induced SSmRNA is mediated by the activation of cAMP/PKA and CaMKs pathways, thus suggesting that the early activation of CREB is involved in the induction of SS by neuronal activity. We also demonstrated, using transient transfections of cerebrocortical cells, that K(+) induces the transcriptional regulation of the SS gene through the cAMP-responsive element (CRE) sequence located in the SS promoter.


Subject(s)
Calcium-Calmodulin-Dependent Protein Kinases/metabolism , Calcium/metabolism , Cyclic AMP-Dependent Protein Kinases/metabolism , Gene Expression Regulation, Developmental/physiology , Signal Transduction/physiology , Somatostatin/genetics , Animals , Cerebral Cortex/cytology , Dose-Response Relationship, Drug , Embryo, Mammalian , Enzyme Inhibitors/pharmacology , Gene Expression Regulation, Developmental/drug effects , Neurons/drug effects , Neurons/metabolism , Potassium Chloride/pharmacology , RNA, Messenger/metabolism , Rats , Signal Transduction/drug effects , Somatostatin/metabolism , Time Factors , Transfection/methods
8.
Brain Res ; 1178: 1-11, 2007 Oct 31.
Article in English | MEDLINE | ID: mdl-17920050

ABSTRACT

The stimulatory effect of insulin-like growth factor I (IGF-I) on myelin basic protein (MBP) expression, a parameter for oligodendrocyte development, is mediated by the MAPK and PI3K signaling pathways. We have previously shown that the second messenger cAMP inhibits IGF-I-induced MAPK activation as well as MBP expression. We also showed that the PKA inhibitor Rp-cAMPS reverted the cAMP effect on IGF-I-induced MBP without affecting the cAMP effect on IGF-I-induced MAPK activation. Here we report that, in contrast to Rp-cAMPS, H89 (a PKA inhibitor structurally non-related to Rp-cAMPS) enhances both the inhibitory effect of cAMP on IGF-I-induced MBP expression and the inhibitory effect of cAMP on IGF-I-induced MAPK activation. Likewise, H89 is capable of inhibiting the IGF-I-induced MAPK activation in the absence of PKA stimulation. Thus, we hypothesize that an unspecific action of H89 on a target located upstream MAPK could account for the discrepancies between the effects elicited by Rp-cAMPS and H89.


Subject(s)
Cyclic AMP-Dependent Protein Kinases/antagonists & inhibitors , Cyclic AMP/pharmacology , Enzyme Inhibitors/pharmacology , Insulin-Like Growth Factor I/antagonists & inhibitors , Insulin-Like Growth Factor I/pharmacology , Oligodendroglia/drug effects , Animals , Animals, Newborn , Blotting, Western , Cell Differentiation/drug effects , Cells, Cultured , Culture Media , Cyclic AMP/analogs & derivatives , Cyclic AMP/metabolism , Enzyme Activation/physiology , Immunohistochemistry , Isoquinolines/pharmacology , Mitogen-Activated Protein Kinases/metabolism , Myelin Basic Protein/biosynthesis , Phosphatidylinositol 3-Kinases/metabolism , Rats , Rats, Sprague-Dawley , Substrate Specificity , Sulfonamides/pharmacology , Thionucleotides/pharmacology
9.
Am J Physiol Endocrinol Metab ; 293(5): E1140-52, 2007 Nov.
Article in English | MEDLINE | ID: mdl-17684105

ABSTRACT

Growth hormone (GH) secretion and serum insulin-like growth factor-I (IGF-I) decline with aging. This study addresses the role played by the hypothalamic regulators in the aging GH decline and investigates the mechanisms through which growth hormone secretagogues (GHS) activate GH secretion in the aging rats. Two groups of male Wistar rats were studied: young-adult (3 mo) and old (24 mo). Hypothalamic growth hormone-releasing hormone (GHRH) mRNA and immunoreactive (IR) GHRH dramatically decreased (P < 0.01 and P < 0.001) in the old rats, as did median eminence IR-GHRH. Decreases of hypothalamic IR-somatostatin (SS; P < 0.001) and SS mRNA (P < 0.01), and median eminence IR-SS were found in old rats as were GHS receptor and IGF-I mRNA (P < 0.01 and P < 0.05). Hypothalamic IGF-I receptor mRNA and protein were unmodified. Both young and old pituitary cells, cultured alone or cocultured with fetal hypothalamic cells, responded to ghrelin. Only in the presence of fetal hypothalamic cells did ghrelin elevate the age-related decrease of GH secretion to within normal adult range. In old rats, growth hormone-releasing peptide-6 returned the levels of GH and IGF-I secretion and liver IGF-I mRNA, and partially restored the lower pituitary IR-GH and GH mRNA levels to those of young untreated rats. These results suggest that the aging GH decline may result from decreased GHRH function rather than from increased SS action. The reduction of hypothalamic GHS-R gene expression might impair the action of ghrelin on GH release. The role of IGF-I is not altered. The aging GH/IGF-I axis decline could be rejuvenated by GHS treatment.


Subject(s)
Aging/physiology , Ghrelin/pharmacology , Growth Hormone/physiology , Insulin-Like Growth Factor I/physiology , Oligopeptides/pharmacology , Aging/drug effects , Animals , Blotting, Northern , Blotting, Western , Gonadotropin-Releasing Hormone/biosynthesis , Gonadotropin-Releasing Hormone/genetics , Gonadotropin-Releasing Hormone/physiology , Hypothalamo-Hypophyseal System/drug effects , Hypothalamo-Hypophyseal System/physiology , Male , Pituitary-Adrenal System/drug effects , Pituitary-Adrenal System/physiology , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Rats , Rats, Wistar , Reverse Transcriptase Polymerase Chain Reaction , Somatostatin/genetics , Somatostatin/physiology , Specific Pathogen-Free Organisms
10.
J Gerontol A Biol Sci Med Sci ; 62(6): 585-97, 2007 Jun.
Article in English | MEDLINE | ID: mdl-17595414

ABSTRACT

Growth hormone (GH) declines during aging. This study investigates whether pituitary constitutive alterations may be involved in the GH decline. Two groups of male Wistar rats were studied (young: 3-month-old; old: 24-month-old). The old rats showed lower pituitary GH messenger RNA (mRNA) levels, immunoreactive rat (IR)-GH content, and GH secretion with no difference in pituitary Pit-1 and cAMP-response element-binding protein (CREB) expression. Pituitary GH releasing hormone receptor (GHRH-R), GH secretagogue receptor (GHS-R), sstr2, and sstr5 mRNA levels were significantly reduced in old rats. The percentage of GH immunoreactive cells was similar in both groups. In vitro, pituitary IR-GH response to GHRH, forskolin (FK), ghrelin, and insulin-like growth factor I (IGF-I) was similar when compared with respective basal secretion and somatostatin-diminished GHRH- and ghrelin-induced IR-GH release in both groups. These results indicate that, as somatotrope function is maintained in aging, the changes observed in GH gene expression and secretion could be reversed by GHS.


Subject(s)
Aging/genetics , Gene Expression/genetics , Growth Hormone/genetics , Pituitary Gland/metabolism , Animals , Cells, Cultured , Colforsin/pharmacology , Cyclic AMP Response Element-Binding Protein/genetics , Ghrelin , Growth Hormone/analysis , Growth Hormone/metabolism , Growth Hormone-Releasing Hormone/pharmacology , Insulin-Like Growth Factor I/pharmacology , Male , Peptide Hormones/pharmacology , Pituitary Gland/drug effects , RNA, Messenger/genetics , Rats , Rats, Wistar , Receptors, G-Protein-Coupled/genetics , Receptors, Ghrelin , Receptors, Neuropeptide/genetics , Receptors, Pituitary Hormone-Regulating Hormone/genetics , Receptors, Somatostatin/genetics , Transcription Factor Pit-1/genetics
12.
Endocrinol. nutr. (Ed. impr.) ; 53(6): 399-404, jun. 2006. tab
Article in Es | IBECS | ID: ibc-046315

ABSTRACT

Entre los puntos controvertidos del tratamiento del carcinoma diferenciado de tiroides (CDT) está la indicación de tratamiento ablativo con radioyodo en microcarcinoma y en carcinoma diferenciado de bajo riesgo. La controversia debe fundamentarse en definiciones precisas de microcarcinoma papilar, microcarcinoma folicular y carcinoma diferenciado de bajo riesgo que quedan aquí definidos. Aunque un 2,8% de los microcarcinomas, según criterio de tamaño, pueda manifestarse con metástasis a distancia iniciales, el mayor número se produce en condiciones predictivas de bajo riesgo: monofocal y unilateral, sin extensión extratiroidea, invasión ni metástasis, encapsulado. Cuando el tumor tenga esas propiedades y no haya historia de radioterapia ionizante previa en cuello, se recomienda la hemitiroidectomía. En el resto de los tumores, se recomienda la tiroidectomía intencionalmente total, que determina menor frecuencia de recurrencia y metástasis que la lobectomía, aunque no menor mortalidad. Con tiroidectomía total y factores predictivos de bajo riesgo, no se recomendaría el tratamiento ablativo con yodo-131 y su seguimiento se realizaría con ecografía de cuello y tiroglobulina (Tg) circulante con autoanticuerpos anti-Tg negativos. El tratamiento ablativo se justificaría sólo para establecer control más preciso evolutivo referido a persistencia o recurrencia de enfermedad. El tratamiento con radioyodo del microcarcinoma y del CDT de bajo riesgo no tiene evidencia científica de que disminuya la mortalidad específica por el tumor, ni la recurrencia locorregional. Puede aumentar el riesgo de segundos tumores primarios, particularmente de leucemias y producir algunos efectos secundarios leves en gonadas, retraso de planificación de fertilidad, leve disfunción transitoria de glándulas salivares y lagrimales y leves trastornos hematológicos transitorios. El tratamiento posquirúrgico con radioyodo de microcarcinoma y CDT de bajo riesgo debe ser selectivo para pacientes con factores predictivos de alto riesgo


Among the controversial issues in differentiated thyroid carcinoma is the indication for radioiodine ablation therapy in microcarcinoma and low-risk differentiated thyroid carcinoma. The controversy should be based on precise definitions of papillary microcarcinoma, follicular microcarcinoma and low-risk differentiated carcinoma, which we define in the present article. When the criterion of size alone is applied, 2.8% of microcarcinomas can manifest with initial distant metastases. However, most are included within the group of low-risk microcarcinomas: monofocal and unilateral, without extrathyroidal extension, invasion, metastases or encapsulation. When tumors have these characteristics and there is no history of ionizing radiotherapy in the neck, hemithyroidectomy is recommended. In the remaining tumors, total thyroidectomy is recommended, which shows a lower rate of recurrences and metastases than lobectomy, although mortality is not reduced. With total thyroidectomy and predictive factors for low risk, 131I ablation therapy is not recommended, and follow-up should include neck ultrasonography and evaluation of circulating Tg with negative anti-Tg antibodies. Ablation therapy is only useful to achieve closer monitoring of disease persistence or recurrence. There is no scientific evidence that radioiodine therapy of microcarcinoma and low-risk differentiated thyroid carcinoma reduces mortality due to the tumor or locoregional recurrence. It may increase the risk of second primary tumors, particularly leukemias, and produce mild secondary effects in the gonads, delayed fertility planning, mild transitory dysfunction of the salivary and tear glands and transitory hematological abnormalities. Postsurgical radioiodine therapy of microcarcinoma and low-risk differentiated thyroid carcinoma should be restricted to patients with factors predicting high risk


Subject(s)
Adult , Adolescent , Middle Aged , Humans , Carcinoma/therapy , 3-Iodobenzylguanidine/therapeutic use , Thyroid Neoplasms/therapy , Thyroidectomy , Radiotherapy
13.
J Neurochem ; 95(4): 1091-107, 2005 Nov.
Article in English | MEDLINE | ID: mdl-16271046

ABSTRACT

Insulin-like growth factor I (IGF-I) is a potent inducer of oligodendrocyte development and myelination. Although IGF-I intracellular signaling has been well described in several cell types, intracellular mechanisms for IGF-I-induced oligodendrocyte development have not been defined. By using specific inhibitors of intracellular signaling pathways, we report here that the MAPK and phosphatidylinositol 3-kinase signaling pathways are required for the full effect of IGF-I on oligodendrocyte development in primary mixed rat cerebrocortical cell cultures. The MAPK activation, but not the phosphatidylinositol 3-kinase activation, leads to phosphorylation of the cAMP response element-binding protein, which is necessary for IGF-I to induce oligodendrocyte development. cAMP, although it does not show any effect on oligodendrocyte development, has an inhibitory effect on IGF-I-induced oligodendrocyte development that is mediated by the cAMP-dependent protein kinase. Furthermore, cAMP also has an inhibitory effect on IGF-I-dependent MAPK activation. This is a cAMP-dependent protein kinase-independent effect and probably contributes to the cAMP action on IGF-I-induced oligodendrocyte development.


Subject(s)
Cell Differentiation/drug effects , Cyclic AMP/pharmacology , Gene Expression Regulation, Developmental/drug effects , Insulin-Like Growth Factor I/pharmacology , Intracellular Space/drug effects , Oligodendroglia/cytology , Animals , Animals, Newborn , Blotting, Western/methods , Cells, Cultured , Cerebellar Cortex/cytology , Cyclic AMP Response Element-Binding Protein/metabolism , Drug Interactions , Embryo, Mammalian , Enzyme Inhibitors/pharmacology , Extracellular Signal-Regulated MAP Kinases/metabolism , Glial Fibrillary Acidic Protein/metabolism , Immunohistochemistry/methods , Models, Biological , Myelin Basic Protein/metabolism , Oligodendroglia/drug effects , Proto-Oncogene Proteins c-akt/metabolism , Rats , Rats, Sprague-Dawley , Time Factors , Tubulin/metabolism
14.
Eur J Endocrinol ; 153(5): 651-9, 2005 Nov.
Article in English | MEDLINE | ID: mdl-16260423

ABSTRACT

OBJECTIVE: To determine, based on published literature and expert clinical experience, current indications for the post-surgical administration of a large radioiodine activity in patients with differentiated thyroid cancer. DESIGN AND METHODS: A literature review was performed and was then analyzed and discussed by a panel of experts from 13 European countries. RESULTS: There is general agreement that patients with unifocal microcarcinomas = 1 cm in diameter and no node or distant metastases have a <2% recurrence rate after surgery alone, and that post-surgical radioiodine confers recurrence and cause-specific survival benefits in patients, strongly suspected of having persistent disease or known to have tumor in the neck or distant sites. In other patients, there is limited evidence that after complete thyroidectomy and adequate lymph node dissection performed by an expert surgeon, post-surgical radioiodine provides clear benefit. When there is any uncertainty about the completeness of surgery, evidence suggests that radioiodine can reduce recurrences and possibly mortality. CONCLUSION: This survey confirms that post-surgical radioiodine should be used selectively. The modality is definitely indicated in patients with distant metastases, incomplete tumor resection, or complete tumor resection but high risk of recurrence and mortality. Probable indications include patients with tumors >1 cm and with suboptimal surgery (less than total thyroidectomy or no lymph node dissection), with age <16 years, or with unfavorable histology.


Subject(s)
Carcinoma, Papillary, Follicular/radiotherapy , Carcinoma, Papillary, Follicular/surgery , Iodine Radioisotopes/therapeutic use , Neoplasm, Residual/surgery , Postoperative Care , Thyroid Neoplasms/radiotherapy , Thyroid Neoplasms/surgery , Consensus , Humans , Radiotherapy, Adjuvant
15.
Eur J Endocrinol ; 151(5): 539-48, 2004 Nov.
Article in English | MEDLINE | ID: mdl-15538930

ABSTRACT

As differentiated (follicular and papillary) thyroid cancer (DTC) may recur years after initial treatment, follow-up of patients with DTC is long term. However, this population has changed, with more individuals being discovered at an earlier stage of disease, so that previous follow-up protocols based mostly on data from high-risk patients no longer apply. We have proposed, in a previous issue of this Journal, an improved protocol for the follow-up of low-risk patients with DTC based on the findings of recent studies. We report here the case of a paradigmatic patient with papillary thyroid carcinoma, with the goal of illustrating the benefits of applying this algorithm in routine clinical practice. We also offer expanded and additional comments on various issues in the management of DTC.


Subject(s)
Carcinoma, Papillary/therapy , Thyroid Neoplasms/therapy , Thyroidectomy , Adult , Algorithms , Carcinoma, Papillary/diagnostic imaging , Carcinoma, Papillary/drug therapy , Carcinoma, Papillary/radiotherapy , Carcinoma, Papillary/surgery , Female , Follow-Up Studies , Humans , Iodine Radioisotopes/therapeutic use , Radionuclide Imaging , Thyroid Neoplasms/diagnostic imaging , Thyroid Neoplasms/drug therapy , Thyroid Neoplasms/radiotherapy , Thyroid Neoplasms/surgery , Thyroxine/therapeutic use
16.
Eur J Endocrinol ; 150(2): 105-12, 2004 Feb.
Article in English | MEDLINE | ID: mdl-14763906

ABSTRACT

OBJECTIVE: Because differentiated (follicular and papillary) thyroid cancer (DTC) may recur years after initial treatment, the follow-up of patients with DTC is long term. However, this population has changed, with more individuals being discovered at an earlier stage of the disease, so that previous follow-up protocols based mostly on data from high-risk patients no longer apply. We sought to develop an improved protocol for the follow-up of low-risk patients with DTC based on the findings of recent studies. METHODS: We analysed recent literature on the follow-up of DTC. RESULTS: Recent large studies have produced three important findings: (i) in patients with low-risk DTC with no evidence of disease up to the 6- to 12-month follow-up, diagnostic whole-body scan adds no information when serum thyroglobulin (Tg) is undetectable and interference from anti-Tg antibodies is absent; (ii) use of recombinant human thyroid-stimulating hormone to aid Tg measurement is effective and provides greater safety, quality-of-life and work productivity than does levothyroxine withdrawal with its attendant hypothyroidism; and (iii) ultrasonography performed by an experienced operator is the most sensitive means of detecting neck recurrences of DTC. CONCLUSIONS: We present a revised follow-up protocol for low-risk patients taking into account the above findings. This protocol should help clinicians enter a new era of monitoring characterized by greater safety, simplicity, convenience and cost savings.


Subject(s)
Adenocarcinoma, Follicular/diagnosis , Carcinoma, Papillary/diagnosis , Thyroglobulin/blood , Thyroid Neoplasms/diagnosis , Adenocarcinoma, Follicular/blood , Adenocarcinoma, Follicular/secondary , Adenocarcinoma, Follicular/therapy , Carcinoma, Papillary/blood , Carcinoma, Papillary/secondary , Clinical Protocols/standards , Decision Trees , Europe , Follow-Up Studies , Lymphatic Metastasis , Neoplasm Recurrence, Local/blood , Neoplasm Recurrence, Local/diagnostic imaging , Practice Guidelines as Topic , Recombinant Proteins , Risk , Thyroid Neoplasms/blood , Thyroid Neoplasms/therapy , Treatment Outcome , Ultrasonography
17.
Biol Reprod ; 70(2): 348-55, 2004 Feb.
Article in English | MEDLINE | ID: mdl-14561652

ABSTRACT

Appropriate expression of the GnRH receptor (GnRH-R) in gonadotrophs is critical for GnRH signaling and hence for gonadotropin secretion and sexual development. In the present work, we have studied the ontogeny of the steady-state GnRH-R mRNA levels in pituitaries of female rats from Day 5 to Day 55, when sexual maturity is attained. Developmental changes of gonadotropin subunit (alpha, FSHbeta, and LHbeta) mRNA levels were also assessed. In addition, the role of the endogenous GnRH on the maturational changes of GnRH-R and gonadotropin subunit gene expression was investigated. Messenger RNA levels were determined by Northern blot analysis of total RNA from anterior pituitaries. Amounts of the most abundant (5.0 kilobase [kb]) GnRH-R mRNA increased slowly from Day 5 through the infantile period, to peak at Day 20 ( approximately 4-fold increase vs. Day 5). Thereafter the levels of the GnRH-R mRNA decline abruptly by Day 25 (75% decrease vs. Day 20) and then fell slightly until Day 35. Parallel changes were observed on the 4.5-kb transcript of the GnRH-R gene. Alpha subunit mRNA was easily detected at Day 5 and its levels increased quickly through the beginning of the infantile period to peak at Day 10 (3.2-fold increase vs. Day 5); then it decreased by 85% at Day 35. FSHbeta and LHbeta mRNA levels rose slowly until Days 15-20, a short time before GnRH-R. Thereafter, the levels of both mRNAs fell until Day 35 (90% decrease vs. Day 15 for FSHbeta and 50% decrease vs. Day 20 for LHbeta). To ascertain whether developmental activation of the GnRH-R and gonadotropin subunit gene expression is GnRH dependent, we have studied the effect of blocking the endogenous GnRH action by treating developing female rats with the specific GnRH antagonist cetrorelix (1.5 mg/kg body weight/wk, s.c.) through the infantile (Days 5-20) and the juvenile period (Days 20-35). Cetrorelix completely blocked the rise of levels of the two most abundant species, 5.0 kb and 4.5 kb, of GnRH-R mRNA during the infantile phase and dropped them to almost undetectable levels during the juvenile prepubertal period. Cetrorelix also abolished the developmental rise of gonadotropin beta subunit mRNAs during the two periods of the study. In contrast, alpha subunit gene expression tended to decrease, but not significantly, with cetrorelix treatment during the two periods. These data demonstrate that sexual maturation of female rats is advanced by an early and strong induction of GnRH-R and gonadotropin subunit gene expression during the infantile period, followed by weaker persistent activation during puberty. Developmental GnRH-R and gonadotropin beta subunit gene expression is almost entirely GnRH dependent, not only in the juvenile prepubertal stage but also during the infantile period.


Subject(s)
Gonadotropin-Releasing Hormone/analogs & derivatives , Receptors, LHRH/genetics , Sexual Maturation/physiology , Animals , Estradiol/blood , Female , Follicle Stimulating Hormone, beta Subunit/blood , Follicle Stimulating Hormone, beta Subunit/genetics , Gene Expression Regulation, Developmental/drug effects , Gene Expression Regulation, Developmental/physiology , Gonadotropin-Releasing Hormone/pharmacology , Hormone Antagonists/pharmacology , Luteinizing Hormone, beta Subunit/blood , Luteinizing Hormone, beta Subunit/genetics , RNA, Messenger/analysis , Rats , Rats, Wistar
18.
Neuroendocrinology ; 77(5): 341-52, 2003 May.
Article in English | MEDLINE | ID: mdl-12806180

ABSTRACT

In previous studies we demonstrated that insulin-like growth factor I (IGF-I) induces pituitary vasoactive intestinal peptide (VIP) gene expression and secretion, and that IGF-I-induced prolactin (PRL) release is mediated by VIP. In this study, we investigate the mitotropic action of IGF-I and VIP on pituitary lactotropes, and their possible interplay in this effect. Cultured male rat pituitary cells were treated with rhIGF-I (10(-7)M) and/or VIP (10(-7)M) for 48 h. 5-Bromo-2'-deoxyuridine (BrdU) (10 microM) was added for labeling proliferation of pituitary cells. BrdU-labeling indices indicative of the proliferation rate of lactotropes were determined by double-labeling immunofluorescence staining for PRL and BrdU. Treatment with either IGF-I or VIP increased BrdU-labeling indices of lactotropes, but there was no further increase upon combined incubation with both factors, suggesting an interaction between the signal transduction pathways of IGF-I and VIP. VIP antiserum partially suppressed IGF-I-induced BrdU-labeling indices of lactotropes. We also investigated the intracellular signal transduction pathways in the action of IGF-I and VIP on the proliferation of lactotropes. Treatment of pituitary cells with an inhibitor of the mitogen-activated protein kinase (MAPK) pathway completely abolished IGF-I-induced lactotrope proliferation, whereas it partially suppressed VIP-induced BrdU-labeling indices. The protein kinase A (PKA) inhibitor, which abolished the mitogenic action of VIP, markedly suppressed IGF-I-induced lactotrope proliferation. These results indicate that both IGF-I and VIP stimulate lactotrope proliferation, and that IGF-I-induced lactotrope proliferation is partially mediated by VIP produced locally. Also, this study suggests that interactions between MAPK and cyclic adenosine 3',5'-monophosphate-PKA signaling pathways are implicated in the lactotrope proliferation induced by IGF-I and VIP.


Subject(s)
Insulin-Like Growth Factor I/metabolism , Pituitary Gland, Anterior/metabolism , Signal Transduction/physiology , Vasoactive Intestinal Peptide/metabolism , Animals , Cell Division/physiology , Cells, Cultured , Gene Expression Regulation , Male , Pituitary Gland, Anterior/cytology , Protein Kinases/metabolism , Rats , Rats, Sprague-Dawley
19.
Nat Genet ; 33(4): 463-5, 2003 Apr.
Article in English | MEDLINE | ID: mdl-12627230

ABSTRACT

We took advantage of overlapping interstitial deletions at chromosome 8p11-p12 in two individuals with contiguous gene syndromes and defined an interval of roughly 540 kb associated with a dominant form of Kallmann syndrome, KAL2. We establish here that loss-of-function mutations in FGFR1 underlie KAL2 whereas a gain-of-function mutation in FGFR1 has been shown to cause a form of craniosynostosis. Moreover, we suggest that the KAL1 gene product, the extracellular matrix protein anosmin-1, is involved in FGF signaling and propose that the gender difference in anosmin-1 dosage (because KAL1 partially escapes X inactivation) explains the higher prevalence of the disease in males.


Subject(s)
Extracellular Matrix Proteins , Kallmann Syndrome/genetics , Mutation , Receptor Protein-Tyrosine Kinases/genetics , Receptors, Fibroblast Growth Factor/genetics , Cell Adhesion Molecules/metabolism , Chromosome Deletion , Chromosomes, Human, Pair 8 , Chromosomes, Human, X , Exons , Extracellular Matrix/metabolism , Family Health , Female , Genes, Dominant , Humans , Introns , Male , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Pedigree , Receptor, Fibroblast Growth Factor, Type 1 , Sex Factors , Signal Transduction
20.
Endocrinology ; 144(3): 1086-97, 2003 Mar.
Article in English | MEDLINE | ID: mdl-12586785

ABSTRACT

To define the role of GH during central nervous system development, we performed studies in cultured rat cerebral cortical cells from 14- (E14) and 17-d-old embryos (E17). The expression of GH receptor, IGF-I receptor, and IGF-I mRNAs was confirmed. In E17, GH increased total cell number (3.9-fold), [(3)H]-thymidine incorporation (3.5-fold), proliferating cell nuclear antigen levels (2.5-fold), and bromodeoxyuridine (BrdU)-positive cells (2.5-fold). GH action on nestin/BrdU-positive cells was increased in E14 cells at 3 d in vitro (80-fold) but not at 7 d in vitro. In E14 cells, GH increased (9.5-fold) beta-tubulin/BrdU cells. In E17 cells, GH induced neuronal differentiation, as indicated by the absence of beta-tubulin/BrdU-positive cells and the 5.9-fold increment of beta-tubulin protein, and increased glial fibrillary acidic protein/BrdU-positive cells (2.5-fold) and glial fibrillary acidic protein expression (4.5-fold). GH-induced proliferation and differentiation was blocked by IGF-I antiserum. GH increased IGF-binding protein-3 (IGFBP-3), IGF-I receptor protein and its phosphorylation. This study shows that GH promotes proliferation of neural precursors, neurogenesis, and gliogenesis during brain development. These responses are mediated by locally produced IGF-I. GH-induced IGFBP-3 may also have a role in these responses. Therefore, GH is able to activate the IGF-I/IGFBP-3 system in these cerebral cells and induce a physiological action of IGF-I.


Subject(s)
Cell Differentiation/drug effects , Cell Division/drug effects , Cerebral Cortex/cytology , Cerebral Cortex/embryology , Growth Hormone/pharmacology , Animals , Astrocytes/cytology , Cells, Cultured , Cerebral Cortex/chemistry , Female , Gene Expression , Gestational Age , Glial Fibrillary Acidic Protein/analysis , Insulin-Like Growth Factor Binding Protein 3/genetics , Insulin-Like Growth Factor I/genetics , Neurons/cytology , Phosphorylation , Pregnancy , RNA, Messenger/analysis , Rats , Rats, Wistar , Receptor, IGF Type 1/genetics , Receptor, IGF Type 1/metabolism , Receptors, Somatotropin/genetics , Tubulin/analysis
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