bluuebunny/crossref_metadata_2025_split huggingface dataset:
Involvement of γ-Aminobutyric Acid in the Control of GTH-1 and GTH-2 Secretion in Male and Female Rainbow Trout
Authors: Mañanos Evaristo L. , Anglade Isabelle , Chyb Jaroslaw , Saligaut Christian , Breton Bernard , Kah Olivier 
Published: April 2003

The potential role of the neurotransmitter γ-aminobutyric acid (GABA) in the control of the secretion of the two pituitary fish gonadotropins (GTH-1 and GTH-2) was investigated in male and female rainbow trout (Oncorhynchus mykiss). The presence of glutamate decarboxylase-positive fibers in the neurohypophyseal digitations adjacent to the gonadotropic cells was demonstrated by means of double immunohistochemistry, providing a morphofunctional support for potential GABA-gonadotropin interactions in both sexes. In spermiating males, in vivo treatment with GABA did not affect basal gonadotropin release, but stimulated GTH-1 release when coadministered with a gonadotropin-releasing hormone analogue (GnRHa), and potentiated GnRHa-stimulated GTH-2 release. In vitro, using dispersed pituitary cells, GABA stimulated basal GTH-1 and GTH-2 secretion, in a dose-dependent manner, and potentiated salmon GnRH effect on both hormones. In mature females, GABA induced in vivo a strong elevation of plasma GTH-2 levels after 2– 6 h of injection, but had no effect in vitro. GABA treatment in vivo was also stimulatory in recrudescent females, slightly increasing plasma GTH-2 levels in both saline- and GnRHa-treated fish (GnRHa alone has no effect at this stage). Immature fish were unresponsive to GABA/GnRHa treatments but, after steroid implantation [testosterone (T) or estradiol] for 13 days, injection of GABA stimulated GTH-2 release in vivo (also GTH-1 slightly in T-implanted fish). In conclusion, GABA has an overall stimulatory action on GTH-1 and GTH-2 secretion in rainbow trout, which depends on the sex and the reproductive stage of the fish. The stimulatory action of GABA might be exerted, at least in part, directly onto the gonadotropes, as it stimulates basal and GnRH-induced GTH-1 and GTH-2 secretion from dispersed pituitary cells.
Monensin and Hypo-Osmolar Medium Cause Calcium-Independent β-Endorphin Secretion from Melanotropes
Authors: Bäck Nils , Soinila Seppo , Törnquist Kid 
Published: April 2003

Monensin has been shown to cause nonexocytotic release of catecholamines from adrenal medullary and PC12 cells. We examined the effect of monensin on peptide secretion with cultured melanotropes from the rat pituitary as a model. 1 µ<i>M</i> monensin caused an immediate, transient increase in β-endorphin secretion. The effect was still seen in a calcium-free medium, but was totally abolished in a sodium-free medium. Intracellular calcium concentration was measured with Fura 2: no increase was observed during monensin stimulation. Hypo-osmolar medium mimicked the effect of monensin, causing a 12-fold transient increase in β-endorphin secretion. This effect was not abolished in either calcium-free or sodium-free medium. No increase in the number of exocytotic figures captured by tannic acid incubation was observed during 5 min of incubation with 1 µ<i>M</i> monensin or hypo-somolar medium. We thus show that monensin causes β-endorphin secretion from the melanotrope and that this effect is due to sodium influx and resultant cell swelling. The calcium independency and lack of increase of exocytotic figures suggest that swelling-induced secretion is nonexocytotic, possibly via transient exocytotic pore opening.
Influence of Different Serotonin Receptor Subtypes On Growth Hormone Secretion
Authors: Valverde Ignacio , Peñalva Angela , Dieguez Carlos 
Published: April 2003

The role of serotonin (5-HT) in the regulation of growth hormone (GH) secretion remains unclear due to the existence of many different receptors that mediate the 5-HT actions, and the lack of suitable specific agonist and antagonist drugs. In the present work we have taken advantage of the recent development of new selective 5-HT drugs in order to clarify the role played by different 5-HT receptor types and subtypes on GH secretion. The experiments were carried out on beagle dogs. GH-releasing hormone (GHRH) increased basal canine GH (cGH) levels from 0.8 ± 0.2 to 8.8 ± 1.7 µg/l at 15 min. Administration of 5-HT<sub>1D</sub> receptor agonist sumatriptan (SUM) induced a cGH peak at 30 min of 12.9 ± 2.7 µg/l. The combined administration of GHRH plus SUM strikingly potentiated cGH release with a peak of 36.9 ± 6 µg/l at 30 min (p < 0.05). Pretreatment with the muscarinic receptor antagonist atropine completely abolished the cGH response to SUM, while the cholinergic agonist pyridostigmine (PYR) did not modify this response (15.3 ± 5 µg/l PYR plus SUM vs. SUM alone 12.9 ± 2.7 µg/l). On the other hand, administration of drugs with activity at 5-HT<sub>2A/C</sub> receptors showed a stimulatory role for the 5-HT<sub>2C</sub> receptor subtype, since LY-53857 (antagonist 5-HT<sub>2A/C</sub>) and DOI agonist (5-HT<sub>2A/C</sub>) both modified the GH response stimulated by GHRH (AUC 88.5 ± 30.4 and 400 ± 64.6 vs. 267.3 ± 52.6 respectively), while ketanserin (antagonist 5-HT<sub>2A</sub>) did not modify this response. The 5-HT<sub>3</sub> antagonist ICS-205–930 failed to modify either basal or GHRH induced GH responses. In conclusion, our data show that 5-HT<sub>1D</sub> receptors play a stimulatory role on GH secretion in the dog, possibly by acting through a decrease in hypothalamic somatostatin release. Similarly, the 5-HT<sub>2C</sub> receptor subtypes also appear to play a stimulatory role. However, 5-HT<sub>2A</sub> and 5-HT<sub>3</sub> receptors do not appear to be involved in the control of basal and GHRH-induced GH secretion.
Estradiol Attenuates the Forskolin-Induced Increase in HypothalamicTyrosine Hydroxylase Activity
Authors: Arbogast Lydia A. , Hyde James F. 
Published: April 2003

The purpose of this study was to evaluate interactions between estradiol and the 3′,5′ cyclic adenosine monophosphate (cAMP) signaling pathway to regulate tyrosine hydroxylase (TH) activity in hypothalamic dopaminergic neurons. The first experiment examined the ability of forskolin to activate TH in the tuberoinfundibular dopaminergic neurons of adult ovariectomized rats with or without estradiol treatment. Estradiol treatment reduced both basal and forskolin-stimulated TH activity in the median eminence. The second group of experiments examined the effect of estradiol on the forskolin-induced activation of TH in fetal hypothalamic cells cultures. Estradiol decreased basal TH activity in the hypothalamic cell cultures to 80% of control levels. Forskolin treatment for 1 h increased TH activity in a concentration-dependent manner in control and estradiol-treated cells, but estradiol attenuated the stimulatory response to 0.01–10 µ<i>M</i> forskolin. The suppressive effect of estradiol on cAMP-dependent activation of TH was evident with 1–12 h of forskolin treatment. The responses to other activators of the cAMP- protein kinase A pathway, including dibutyryl cAMP and 8-bromo-cAMP, and to a depolarizing stimulus were blunted in estradiol-treated cultures. Forskolin treatment for 1 h increased radiolabeled phosphate incorporation into TH protein in control but not estradiol-treated cells, suggesting that estradiol interferes with the ability of the cAMP pathway to phosphorylate TH. Forskolin caused a time-dependent increase in TH mRNA signal levels in control cultures. The magnitude of the forskolin-induced increase in TH mRNA levels was less in the estradiol-treated cells after 6 h of forskolin treatment, indicating that estradiol hinders cAMP-regulated TH gene expression. These data indicate that estradiol attenuates the ability of hypothalamic dopaminergic neurons to respond to cAMP-dependent stimulation by interfering with phosphorylation mechanisms in the short term and control of TH mRNA levels in the long term.
Maternal Behavior Stimulates <i>c-fos</i> Activity within Estrogen Receptor Alpha-Containing Neurons in Lactating Rats
Authors: Lonstein Joseph S. , Gréco Béatrice , De Vries Geert J. , Stern Judith M. , Blaustein Jeffrey D. 
Published: April 2003

Estradiol and other hormones are thought to be critical for the onset, but not maintenance, of maternal behavior in rats. Maternal behavior is instead maintained postpartum by tactile stimulation that dams receive during interactions with pups, and many neural sites implicated in the control of maternal behavior show elevated <i>c-fos</i> activity in response to this stimulation. Many of these sites also contain neurons that express the alpha subtype of the estrogen receptor (ERα). Because of possible interactions between tactile stimulation from pups, <i>c-fos,</i> and ERα in the lactating rat brain, we determined if populations of cells that show increased <i>c-fos</i> activity after maternal behavior in lactating rats also contain ERα. Dams were separated from their pups for 48 h beginning on day 5 postpartum. On day 7 postpartum, experimental dams were reunited with pups and mother-litter interactions were observed for 60 min. Control dams received no pup stimulation. Subjects were sacrificed 60 min later and brain sections were double immunolabeled for the Fos and ERα proteins. As expected, the number of ERα-immunoreactive (ERα-ir) neurons did not differ between the two groups in the eight areas analyzed (lateral region of the lateral septum, posterodorsal medial amygdala, dorsal and ventral medial preoptic area, dorsal and ventral bed nucleus of the stria terminalis, lateral habenula, and ventrolateral caudal periaqueductal gray). Consistent with previous reports, maternal dams had 2- to 7-fold more Fos-immunoreactive (Fos-ir) neurons in these sites compared with nonstimulated controls. Maternal dams had significantly more Fos-ir neurons that also contained ERα-ir in all sites, with the greatest increases in the ventral medial preoptic area, lateral habenula, and ventral bed nucleus of the stria terminalis. Between ∼25 and 45% of the Fos-ir cells in the sites examined also expressed ERα. Thus, a substantial number of neurons that are genomically activated during maternal behavior contain ERα, raising the possibility that the postpartum display of maternal behavior can be influenced by ERα activity.
Antagonist of Pituitary Adenylate Cyclase Activating Polypeptide Suppresses Prolactin Secretion without Changing the Activity of Dopamine Neurons in Lactating Rats
Authors: Tohei Atsushi , Matsuzaki Minako , Kogo Hiroshi 
Published: April 2003

Pituitary adenylate cyclase activating polypeptide (PACAP) is a relatively new neuropeptide, and it has a potent stimulatory effect on adenylate cyclase activity in rat pituitary cells. However, the role of PACAP in the physiological control of prolactin (PRL) secretion is still unclear. In the present study, we investigated the physiological significance of endogenous PACAP on PRL secretion in lactating rats. On lactation days 7–8, pups were separated from their mother rats for 5 h before the onset of suckling and PACAP<sub>6–38</sub> (16 µg), a receptor antagonist, was injected through the lateral ventricle cannula just after the removal of pups. The effects of PACAP<sub>6–38</sub> on PRL and oxytocin secretion, and on the activity of tyrosine hydroxylase (TH), were examined after the onset of suckling. Administration of PACAP<sub>6–38</sub> inhibited PRL levels in response to suckling, but it did not affect the activity of TH, as measured by DOPA accumulation at 15 min after administration of NSD 1015 (25.0 mg/kg), an <i>L</i>-aromatic amino acid decarboxylase inhibitor, or the plasma concentrations of oxytocin in lactating rats. Injection of α-methyl-<i>p</i>-tyrosine (α-MT; 50 mg/kg), an inhibitor of dopamine synthesis, increased PRL levels, and suckling caused a further increase in the plasma concentrations of PRL. An injection of PACAP<sub>6–38</sub> (i.c.v.) also inhibited the PRL response to suckling under dopamine depletion. These results suggest that endogenous PACAP acts as a neurotransmitter or neuromodulator within the hypothalamus and plays an important role for PRL secretion in lactating rats. Endogenous PACAP may regulate PRL secretion, possibly mediated by PRL-releasing factors such as vasoactive intestinal polypeptide or vasopressin.
Hypothalamic Circuitry of Neuropeptide Y Regulation of Neuroendocrine Function and Food Intake via the Y5 Receptor Subtype
Authors: Campbell Rebecca E. , ffrench-Mullen Jarlath M.H. , Cowley Michael A. , Smith M. Susan , Grove Kevin L. 
Published: April 2003

Neuropeptide Y (NPY) displays diverse modes of action in the CNS including the modulation of feeding behavior, gonadotropin releasing hormone release, and stress responses. Many of the above physiological actions have been at least partially attributed to actions of NPY on the NPY Y5 receptor subtype. We utilized an antibody directed against the NPY Y5 receptor to characterize the distribution of this receptor in the rat brain. Using Western blot analysis, this antibody recognized a single major band at approximately 57 kD. To further verify the specificity of the antibody, animals were treated for 5 days with antisense oligonucleotides for the Y5 receptor. The antisense treatment significantly reduced food intake and body weight. Furthermore, the Y5 antibody detected a significant decrease in Y5 receptor protein. Y5-like immunoreactivity (-ir) was observed throughout the hypothalamus, thalamus, hippocampus and cortex. Double-label immunofluorescence demonstrated that Y5-ir was colocalized with the following neuronal phenotypes in the hypothalamus, gonadotropin-releasing hormone, neurophysins, corticotropin-releasing hormone, and γ-amino butyric acid. In addition, functional interactions were demonstrated by the presence of close appositions of NPY fibers with Y5-ir expressing cells. The wide distribution of the Y5 receptor-ir, as well as the colocalization within specific neuronal populations, agrees with the distribution of the Y5 receptor mRNA and the known physiological roles of the NPY/Y5 system. The role of the NPY/Y5 receptor system as a mediator between signals of peripheral energy availability and reproductive neuroendocrine function is discussed.
Delay between Stroke Onset and Emergency Department Evaluation
Authors: Goldstein L.B. , Edwards M.G. , Wood D.P. 
Published: April 2003

<i>Background:</i> Public educational programs have been developed to reduce delays between the onset of ischemic stroke symptoms and emergency department evaluation. An increase in the proportion of patients presenting soon after stroke would reflect the effectiveness of these efforts. <i>Methods:</i> All patients (n = 506) with ischemic stroke admitted to an academic medical center located within the ‘Stroke Belt’ of the USA were prospectively identified over 2 years (1998–1999). Demographics, stroke characteristics and time from symptom onset to arrival in the emergency department were recorded. <i>Results:</i> A higher proportion of ischemic stroke patients presented within 3 h of symptoms in 1998 than in 1999 (18% of 234 vs. 8% of 272, p = 0.0001). Those with less severe strokes (Canadian Neurological Scale score; Spearman r = 0.18, p < 0.0001) and younger patients (r = –0.09, p = 0.04) had greater delays. There was no difference in time to presentation based on race (13% of whites and blacks presented within 3 h, p = 0.70) or sex (16% of women vs. 9% of men, p = 0.10). Logistic regression showed that time to presentation was independently related to both stroke severity and year. <i>Conclusions:</i> These data show that, after accounting for other variables, the proportion of stroke patients presenting within 3 h of symptom onset to one academic medical center decreased by 10% between 1998 and 1999. Revision of public stroke-related educational programs may need to be considered.
Large Vestibular Aqueduct Syndrome Presenting with Mixed Hearing Loss and an Intact Mobile Ossicular Chain
Authors: Mamıkoğlu Bülent , Bentz Brandon , Wiet Richard J. 
Published: April 2003

The majority of patients with large vestibular aqueduct syndrome (LVAS) present with progressive sensorineural hearing loss. Some patients with LVAS also have a mixed hearing loss with conduction components ranging from 15 to 40 dB. In this paper, we report a child with LVAS who presented with a moderate mixed hearing loss which appeared following a head trauma. Exploration of the middle ear revealed an intact and mobile ossicular chain. Opening of the inner ear showed a moderate gusher. Aspects of the issue that LVAS might present with a combined sensorineural and conductive hearing loss are discussed.
Increase in Amino Acids in the Pons after Sleep Deprivation: A Pilot Study Using Proton Magnetic Resonance Spectroscopy
Authors: Murck Harald , Struttmann Tobias , Czisch Michael , Wetter Thomas , Steiger Axel , Auer Dorothee P. 
Published: April 2003

Total sleep deprivation (TSD) is an efficient method to relieve depression. An involvement of GABAergic and glutamatergic neurotransmission in the pathophysiology of depression and the mechanism of action of TSD has been suggested. To directly assess the content of GABA, glutamate (Glu) and glutamine (Gln) before and after TSD, we estimated their concentrations in four brain regions in six healthy subjects using proton magnetic resonance spectroscopy. The unresolved estimate of GABA, Glu and Gln, as well as GABA and Gln were increased in the pons after 24 h of TSD, the effect being prominent in three subjects. There were no significant changes in the hypothalamus, thalamus or parietooccipital cortex. These preliminary data support earlier animal data and indirect findings in humans suggesting that GABA and Gln, especially in the pontine structures, may play a key role in the mechanism of TSD.
Topotecan and Gemcitabine in Platinum/Paclitaxel-Resistant Ovarian Cancer
Authors: Greggi Stefano , Salerno M. Giovanna , D’Agostino Giuseppe , Ferrandina Gabriella , Lorusso Domenica , Manzione Luigi , Mancuso Salvatore , Scambia Giovanni 
Published: April 2003

24 patients were enrolled into a phase I–II study conducted to determine the maximum tolerated doses of topotecan-gemcitabine in sequential combination and the response rate in platinum/paclitaxel resistant ovarian cancer patients. A total of 83 courses are evaluable, with a median number of three cycles administered per patients (range 2–7). Topotecan was administered on days 1–5 by 30 min i.v. infusion immediately after gemcitabine given by 30 min i.v. on days 1 and 3; cycles were repeated every 28 days. The starting doses were topotecan 0.7 mg/m<sup>2</sup> and gemcitabine 200 mg/m<sup>2</sup>. Following dose levels were 08/400; 0.9/600; 0.9/800 for topotecan and gemcitabine, respectively. The maximum tolerated dose (MTD) was reached at dose level 3, the dose-limiting toxicity being represented by febrile neutropenia and thrombocytopenia. After the MTD was reached, granulocyte-colony-stimulating factor was administered in 27% of cycles. Mild and manageable was non hematological toxicity. All patients are so far evaluable for response. Among them 2 complete responses (8.3%; 95% CI: 2.6–19), 1 partial response (4.2%; 95% CI: 3.8–12), 9 no change (37.5%; 95% CI: 18–56.8) and 12 progressions (50%; 95% CI: 30–70) have been registered. Based on these data, there is no evidence that combining topotecan and gemcitabine is better than using either of the two drugs used separately
Vinorelbine-Based Regimens as Salvage Treatment in Patients with Advanced Non-Small Cell Lung Cancer: Two Parallel Multicenter Phase II Trials
Authors: Agelaki Sophia , Bania Helen , Kouroussis Charalambos , Blazoyiannakis George , Souglakos John , Tsiafaki Xanthi , Harpidou Adriani , Kalbakis Kostas , Rapti Ageliki , Androulakis Nikos , Sarra Evi , Georgoulias Vassilis , Papadakis Emmanuel 
Published: April 2003

Two parallel phase II trials were conducted in order to evaluate the efficacy and toxicity of vinorelbine-ifosfamide (VNB-IFX) and vinorelbine-carboplatin (VNB-C) combinations as salvage treatment in patients with advanced non-small cell lung cancer (NSCLC). <i>Patients and Methods:</i> Patients failing platinum-based front-line chemotherapy were enrolled in the VNB-IFX trial while patients failing non-platinum-containing chemotherapy were treated with VNB-C. Twenty-nine patients were treated with VNB-IFX [median age: 59 years; performance status, PS (WHO) 0–1: 72% and disease stage IV: 79%] and 37 with VNB-C [median age: 61 years; PS (WHO) 0–1: 51% and stage IV: 84%]. Patients received vinorelbine 25 mg/m<sup>2</sup> i.v. on days 1 and 8 and ifosfamide 1.6 g/m<sup>2</sup> i.v. on days 8–10 with uroprotective mesna, in cycles of 28 days. G-CSF (5 µg/kg/day s.c.) was administered prophylactically on days 11–16 or until hematological recovery. The VNB-C regimen consisted of carboplatin 300 mg/m<sup>2</sup> on day 1 and vinorelbine 30 mg/m<sup>2</sup> on days 1 and 8 every 28 days. <i>Results: </i>Twenty-six patients were evaluable for response in the VNB-IFX trial and 29 in the VNB-C. Overall response rates (intent-to-treat analysis) were 3% (1 patient; duration of response: 3 months) for the VNB-IFX and 16% (median duration of response: 7.5 months) for the VNB-C combination. The median time to progression and survival for patients receiving VNB-IFX were 4.5 and 6 months (1-year survival: 19%), respectively; the corresponding values for VNB-C were 9.0 and 8.5 months (1-year survival: 38%). The median survival of patients achieving stable disease was 10 (VNB-IFX) and 14.5 (VNB-C) months. Grade 3–4 neutropenia occurred in 4 (13%) of the patients treated with VNB-IFX; all cases were complicated with fever. Grade 3–4 neutropenia was documented in 13 (35%) patients in the VNB-C trial; 6 (16%) developed neutropenic fever. There were no treatment-related deaths. Non-hematologic toxicity for the VNB-IFX and VNB-C regimens was mild with grade 2–3 peripheral neurotoxicity occurring in 3 (10%) and 7 (19%) patients, and grade 2–3 asthenia in 11 (38%) and 18 (48%) patients, respectively. <i>Conclusion: </i> Both combinations were associated with a tolerable toxicity profile. VNB-C demonstrated notable activity in patients previously treated with a taxane-based regimen, whilst VNB-IFX failed to produce a significant response rate in patients treated with platinum-containing chemotherapy. Stabilization of disease was associated with a favorable survival in both studies.
First-Line Herceptin<sup>®</sup> Monotherapy in Metastatic Breast Cancer
Authors: Vogel Charles L. , Cobleigh Melody A. , Tripathy Debu , Gutheil John C. , Harris Lyndsay N. , Fehrenbacher Louis , Slamon Dennis J. , Murphy Maureen , Novotny William F. , Burchmore Michael , Shak Steven , Stewart Stanford J. 
Published: April 2003

The pivotal phase II and III Herceptin<sup>®</sup> trials proved the efficacy and safety of second- or third-line single-agent Herceptin and first-line Herceptin in combination with chemotherapy, respectively. In the current trial, 114 patients were randomized to one of two dose groups of first-line Herceptin monotherapy: standard dose of 4 mg/ kg initial dose followed by 2 mg/kg intravenous (i.v.) weekly; or high dose of 8 mg/kg initial dose followed by 4 mg/kg i.v. weekly. The regimen was generally well tolerated. A similar incidence of adverse events was demonstrated in the two dose groups with the possible exception of acute infusion-related events such as fever and chills as well as rash and dyspnea, which appear to be more prevalent in the higher dose group. The overall response rate was 26% and response rates were similar between the two dose groups (24% for the standard Herceptin dose group and 28% for the high Herceptin dose group). Subgroup analysis determined a higher response rate in IHC 3+ patients (35%) and FISH-positive patients (41%). When women with stable disease for ≧6 months were included with responders, the clinical benefit rate in IHC 3+ patients was 47%. Median survival was 24.4 months, which is comparable with the survival rate seen in the pivotal phase III combination trial (25 months). Therefore, single-agent Herceptin is an important new option for the first-line treatment of HER2-positive metastatic breast cancer patients.