bluuebunny/crossref_metadata_2025 huggingface dataset:
Viral Inhibition of Interferon Signal Transduction
Authors: Cebulla Colleen M. , Miller Daniel M. , Sedmak Daniel D.
Published: April 2003

The type I and II interferons (IFNs) are potent stimulators of antigen processing and presentation and are essential in antiviral immunity. IFNs upregulate the transcription of major histocompatibility complex (MHC) class I and II molecules, associated antigen-processing proteins, and induce the production of direct antiviral effector molecules such as 2′,5′-oligoadenylate synthetase, double-stranded-RNA-dependent protein kinase and Mx proteins. It is increasingly evident that viruses have evolved mechanisms to globally inhibit the actions of IFNs through disruption of their signal transduction pathways. Herein, we review the ability and novel mechanisms of several diverse viruses to inhibit IFN-induced JAK/STAT signal transduction.
Low-Molecular-Weight Heparins in Acute Unstable Coronary Artery Disease – An Update
Authors: Turpie Alexander G.G.
Published: April 2003

Low-molecular-weight heparins (LMWHs) have been rigorously evaluated in the management of acute coronary ischaemia. The results of clinical trials suggest that the LMWHs (enoxaparin, dalteparin and nadroparin) are effective and safe in the treatment of unstable angina and non-Q-wave myocardial infarction. Two studies have shown enoxaparin to be more effective than unfractionated heparin in this setting. Furthermore, the pharmacologic and pharmacokinetic characteristics of LMWHs result in them having practical and economic advantages. Data on the benefits of long-term therapy with LMWHs are conflicting.
Can All Patients with Deep Vein Thrombosis Receive Low-Molecular-Weight Heparin in an Outpatient Setting?
Authors: Lindmarker Per
Published: April 2003

Studies have shown subcutaneous low- molecular-weight heparin (LMWH) to be at least as safe and efficacious as intravenous unfractionated heparin (UFH) for the treatment of venous thromboembolism (VTE). Furthermore, unlike UFH, LMWH is administered on a once- or twice-daily basis without monitoring in uncomplicated cases. Consequently, it has been suggested that the large majority of patients with VTE could be treated on an outpatient basis. Exceptions include patients with an increased risk of haemorrhage, pregnant women, children and those with renal insufficiency. Outpatient management would offer economic advantages and be more convenient for both the patient and the hospital staff.
von Willebrand Factor Antigen as a Prognostic Marker in Posttraumatic Acute Lung Injury
Authors: Siemiatkowski Andrzej , Kloczko Janusz , Galar Marzenna , Czaban Slawomir
Published: April 2003

The specific endothelial cell product von Willebrand factor antigen (vWf:Ag) was measured in plasma and lung function tests were carried out and the following lung injury parameters measured: PaO2/FiO2 ratio, static respiratory compliance and Murray’s lung injury score (LIS) in a follow-up study of 36 severely traumatized patients. Injury severity score (ISS) and APACHE II scores were calculated. Patients were classified according to the presence or absence of acute respiratory distress syndrome (ARDS) complications and survival versus death. Data collection was performed on admission to hospital and after 1–3, 5, 7, 10 days of ICU stay. On all of the occasions investigated, plasma vWf:Ag levels in ARDS patients and nonsurvivors were significantly greater than those in patients without ARDS and survivors, respectively. Significant correlations were observed between initial vWf:Ag concentration and ISS, APACHE II, LIS. Our study suggests that increased concentrations of vWf:Ag in plasma are predictive of the development of ARDS and signal poor prognosis in patients following severe trauma.
Characteristics of Heparin-Induced Platelet Aggregates in Chronic Hemodialysis with Long-Term Heparin Use
Authors: Matsuo Takefumi , Matsuo Miyako , Kario Kazuomi , Suzuki Shunji
Published: April 2003

This study investigated the usefulness of a new platelet aggregometer with a laser-scattering method for detection of heparin-induced small platelet aggregates in chronic hemodialysis patients. Using this device, small platelet aggregates (particle size 9–25 µm) were detectable, but these aggregates could not be detected using a conventional light transmittance aggregometer. The laser-scattering intensity of the small aggregates was increased with an increasing dosage of heparin as agonist. These aggregates were disaggregated by heparin neutralization with protamine sulfate. Induction of small platelet aggregates by heparin was inhibited by preincubation with nafamostat mesilate, a synthetic protease inhibitor, and cilostazol, a platelet phosphodiesterase inhibitor, but not by the therapeutic doses of aspirin or argatroban, a selective thrombin inhibitor. The dialysis patients with long-term heparin use could be divided into two groups: responders to heparin, who formed small aggregates with a scattering intensity over 0.51 × 105 V after addition of 0.5 IU/ml of heparin obtained from normal platelet-rich plasma without inductor, and nonresponders, who showed an intensity under 0.51 × 105 V. The rate of heparin responders among dialysis patients was significantly higher than the rate among normal subjects. Heparin-induced small aggregates were detected in 13 (36.1%) of 36 normal subjects with no history of heparin infusion and in 37 (62.7%) of 59 dialysis patients who received heparin anticoagulation during each dialysis session. Dialysis patients with coronary heart disease did not have a significantly higher rate of heparin responders than patients without complications. There was no significant difference in the positivity rate between cases complicated by diabetes and those without diabetes. In patients who had more than 2 episodes of thrombotic occlusions of an arteriovenous fistula, the rate of responders and the enhancement of scattering intensity of small aggregates by heparin were significantly increased compared with these in patients without occlusions during the preceding 2 years. Moreover, dialysis patients with a positive heparin response showed a marked increase in scattering intensity of small aggregates after heparin infusion in each dialysis session. Determination of the response to heparin prior to heparin use in dialysis patients with repeated thromboembolic complication may be useful in choosing anticoagulant regimens.
Effect of Oral Anticoagulant Treatment on Markers for Calcium and Bone Metabolism
Authors: Knapen M.H.J. , Hellemons-Boode B.S.P. , Langenberg-Ledeboer M. , Knottnerus J.A. , Hamulyák K. , Price P.A. , Vermeer C.
Published: April 2003

Vitamin K-dependent proteins regulate blood coagulation as well as bone growth and calcification. Here, we have compared the effects of oral anticoagulants on circulating vitamin K-dependent proteins and on markers for calcium and bone metabolism. Patients with a clinical indication for antithrombotic therapy were randomized into three groups and treated with either aspirin, regular-intensity anticoagulation [target international normalized ratio (INR) values: 2.5–3.5] or low-intensity anticoagulation (target INR values: 1.1–1.6). At the start and after 1 year of treatment, various biochemical markers were assessed. Both the circulating levels and the degree of carboxylation of the various γ-carboxyglutamate (Gla)-containing proteins were affected differently by oral anticoagulant treatment. Circulating osteocalcin was more sensitive to poor vitamin K status than other Gla proteins. From the fact that – except for osteocalcin – neither markers for osteoblast nor osteoclast function were affected by oral anticoagulant treatment, we conclude that bone turnover remained unaltered, which is indicative of an unchanged rate of bone loss. Whether the long-term production of undercarboxylated bone Gla proteins may have a negative effect on the quality of bone (e.g. bone strength) cannot be concluded from this study.
Risk Assessment and Prophylaxis of Venous Thromboembolism in Non-Surgical Patients: Cancer as a Risk Factor
Authors: Otten Hans-Martin M.B. , Prins Martin H. , Smorenburg Susanne M. , Hutten Barbara A.
Published: April 2003

It is well documented that cancer patients undergoing surgery are at a sufficiently high risk of developing venous thromboembolism (VTE) to justify the routine use of prophylactic anticoagulant therapy. However, despite many studies showing an increased incidence of VTE associated with the use of chemotherapy in patients with breast carcinoma and with the use of indwelling venous access catheters in patients with various kinds of cancer, thromboprophylactic strategies are not yet widely used.
Risk Assessment and Prophylaxis of Venous Thromboembolism in Acutely and/or Critically Ill Patients
Authors: Davidson Bruce L.
Published: April 2003

Both undetected and clinically evident venous thrombosis and venous thromboembolism (VTE) can seriously impact the prognosis of acutely and/or critically ill patients. Pulmonary embolism (PE) is harder to diagnose in the acutely and/or critically ill, many of whom also have developed respiratory failure for other reasons. Deep vein thrombosis (DVT) of the upper and lower extremities can subsequently complicate insertion of central venous catheters, leading to PE, sepsis and septic shock. Recovery from the original critical illness (e.g. weaning from mechanical ventilation) can be adversely affected by these complications. There are recent data suggesting that, for prophylaxis, low-molecular-weight heparin (LMWH) is more effective than unfractionated heparin (UFH) in critically ill trauma patients, and that high-dose LMWH is more effective than placebo or low-dose LMWH in seriously ill medical patients. In both populations, LMWH appeared safe. While LMWH appears superior to UFH in acute stroke patients to prevent venographically-proven lower-extremity DVT, whether it provides a superior long-term outcome after acute stroke is uncertain. One study found that a high dosage of the LMWH dalteparin was more effective than placebo in preventing left ventricular thrombi after acute myocardial infarction, but there was a significant safety cost. Current questions surrounding prophylaxis of VTE and the use of LMWH in acutely and/or critically ill patients include whether monitoring levels and dosage adjustment in some of these patients would improve outcome, and whether the diagnosis of VTE can be improved so that treatment can be instituted when prophylaxis has failed.
Involvement of Renal Nerves and Endothelins in the Regulation of Renal Water Excretion in Diabetes insipidus Rats
Authors: Girchev Radoslav , Markova Petia , Mikhov Dimitar , Avramova Tatiana , Nattcheff Natcho
Published: April 2003

The interaction between renal nerves, endothelins acting via endothelin-A receptors and vasopressin in the regulation of renal excretory function was investigated. In conscious intact and renal denervated diabetes insipidus (DI) Brattleboro rats, as well as their controls, Long-Evans (LE) rats, an infusion of 16.4 nmol/kg/min ETA receptor antagonist BQ-123 was performed in the course of 50 min. Femoral artery blood pressure, heart rate, Ccr, V · UNa, V · UK and V · UCl did not alter in any of the groups. Urine flow rate diminished by 38.1% (p < 0.02), while urine osmolality increased by 30.3% (p < 0.05) as a result of BQ-123 infusion in the intact LE rats but neither urine flow rate nor urine osmolality changed in the DI rats. In contrast to intact LE rats, BQ-123 infusion in renal denervated LE rats did not alter urine flow rate or urine osmolality. However, urine flow rate in renal denervated DI rats surprisingly decreased by 71.1% (p < 0.01) while urine osmolality increased by 161% (p < 0.001) as a result of BQ-123 infusion. Endogenous endothelins can regulate renal water excretion through ETA receptor activation. Renal sympathetic nerves participate in the modulation of renal water excretion influencing the ETA receptor-mediated effects of endothelins in the kidney.
Different Levels of Hypertension Induce Opposite Diuretic Behaviors from the Nonclipped Kidney in the Rat Two-Kidney, One-Clip Model
Authors: Al-Qattan K.K.
Published: April 2003

This study was carried out on conscious two-kidney, one-clip (2K1C) rats to establish whether different levels of hypertension induced opposite diuretic behaviors from the nonclipped kidney. Mildly hypertensive rats and severely hypertensive rats were produced by, respectively, constricting their right renal arteries with 0.3-mm and 0.15-mm clips. On the 11th day of the study, the systolic blood pressure (SBP) of the 0.3-mm clip rats was 150 ± 2 mm Hg, the water intake was 24 ± 1 ml, and the urine output was 7 ± 1 ml. The SBP of the 0.15-mm clip rats was 231 ± 10 mm Hg, the water intake was 46 ± 4 ml, and the urine output was 27 ± 6 ml. The data from the two groups are significantly different. On the 19th day half of the mildly hypertensive (0.3-mm clip) rats that received cilazapril from day 15 had, with respect to their water-treated counterparts, a SBP of 140 ± 8 as compared with 159 ± 7 mm Hg, the water intake was 37 ± 5 as compared with 26 ± 4 ml, and the urine output was 18 ± 4 as compared with 12 ± 1 ml. In contrast, half of the severely hypertensive (0.15-mm clip) rats that received cilazapril had, with respect to their water-treated counterparts, a SBP of 143 ± 4 as compared with 227 ± 10 mm Hg, the water intake was 30 ± 2 as compared with 51 ± 9 ml, and the urine output was 8 ± 2 as compared with 29 ± 4 ml. All changes induced by cilazapril are significant in both groups. The data of this study suggest that different levels of hypertension in the rat 2K1C model induce opposite water elimination modes from the nonclipped kidney. This conclusion is supported by the different shift in the water intake and urine output among the cilazapril-treated rats of the two groups. This contrast in the response to cilazapril seems to be dependent on the magnitude of the resulting hypotension. Thus, it seems that in this model, when the hypertension is mild, the antidiuretic effect of angiotension II on the nonclipped kidney is exhibited, whereas, when the hypertension is severe, the diuretic influence of the blood pressure is evident. Irrespective of these different characteristics of the submodels of 2K1C, angiotensin I converting enzyme inhibitors, such as cilazapril, are effective in normalizing the blood pressure.
Renal Hemodynamic Effects of Captopril and Doxazosin during Slight Physical Activity in Hypertensive Patients with Type-1 Diabetes mellitus
Authors: Svarstad Einar , Gerdts Eva , Omvik Per , Ofstad Jarle , Iversen Bjarne M.
Published: April 2003

Angiotensin-converting enzyme inhibitors are renoprotective in diabetes mellitus through their intrarenal hemodynamic effects. Alpha-1 blockade has variable pre- and postglomerular vasodilatory effects dependent upon the stimulation of the sympathetic nervous system. We tested the hypothesis that the two different classes of drugs have similar renal hemodynamic effects when the patients are examined in an upright position where the sympathetic nervous system is activated. Mean blood pressure (MAP), glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were examined in 28 hypertensive type-1 diabetic patients with variable degree of nephropathy treated for a mean period of 7.6 ± 0.4 months with captopril (n = 13) or doxazosin (n = 15). Average treatment doses were 112 ± 7 mg/day in the captopril group and 8 ± 1 mg/day in the doxazosin group. Sitting MAP decreased from 118 ± 3 to 106 ± 4 mm Hg after captopril (p < 0.05), and from 117 ± 4 to 110 ± 3 mm Hg after doxazosin (p = 0.07). GFR and ERPF were unchanged in both groups. The filtration fraction (FF) decreased from 0.27 ± 0.02 to 0.25 ± 0.02 after captopril (p < 0.05) and from 0.26 ± 0.01 to 0.25 ± 0.01 after doxazosin (p = 0.08). Calculation of 95% confidence intervals of the difference between the post-treatment values as well as the difference between pre- and post-treatment values of MAP, GFR, ERPF and FF of the two drugs indicates no difference in renal hemodynamic response between the drugs. In conclusion, captopril and doxazosin have similar renal hemodynamic responses when the patients are examined in a situation where the sympathetic nervous system is stimulated, and this suggests that doxazosin has a renoprotective effect beyond the blood pressure-lowering effect.
Factor Analysis, Including Antihypertensive Medication, of the Outcome of Pregnancy in Pregnancy-Associated Hypertension
Authors: Hussein Magdi M. , Mooij Jaap M.V. , Roujouleh Haysam
Published: April 2003

Aim: To study the influence of different maternal factors, inlcuding antihypertensive medication, on the outcome of pregnancy in primi- and multiparas with pregnancy-associated hypertension. Methods: A retrospective, multiple-variate analysis was undertaken of the influence of several maternal factors, including antihypertensive medication, on fetal death and Apgar scores and the correlation between the medication and the number of caesarean sections in 127 episodes of pregnancy-associated hypertension was studied for the whole group as well as for primi- and multiparas separately. Of the multiparas, 40.8% had a history of preeclampsia, 19.7% of chronic hypertension and 9.2% of diabetes mellitus. Antihypertensive treatment aimed at achieving a blood pressure of 140/90 mm Hg. Forty-one patients (32.3%) received intravenous hydralazine, 25 (19.7%) received nifedipine per os and 44 (34.6%) received labetalol per os. Results:  The maximum systolic and diastolic blood pressure in the patients given intravenous hydralazine, nifedipine per os or labetalol per os did not differ, whereas in the multiparas, the number of patients who reached the target blood pressure while using labetalol was higher than with the two other medications, especially in comparison with intravenous hydralazine. For the primiparas, the time of delivery was the only factor with a significant impact on the Apgar scores. In the multiparas, there was an additional negative influence of the use of intravenous hydralazine. This was not seen in the patients using nifedipine and labetalol. Conclusion: The results suggest that in multiparas, intravenous hydralazine is possibly associated with more fetal distress when compared to primiparas.
Technetium-99m-Tetrofosmin Scintimammography in Suspected Breast Cancer Patients: A Comparison with Technetium-99m-MIBI
Authors: Kim Seong Jang , Kim In Ju , Kim Yong Ki , Bae Young Tae
Published: April 2003

Objective: To investigate the diagnostic role of 99mTc-tetrofosmin in the detection of primary breast cancer and axillary lymph node metastasis and to compare the findings with those of 99mTc-MIBI. Methods: Forty-eight patients with clinically palpable masses or abnormal radiologic findings had 99mTc-MIBI and 99mTc-tetrofosmin scintimammographies (SMMs) after intravenous injections of 925 MBq of radiopharmaceuticals. The SMMs were correlated with histopathologic findings. Results: Thirty-three patients were diagnosed with breast cancer and 15 patients with benign breast diseases. The number of true positive, true negative, false positive, and false negative cases of 99mTc-tetrofosmin SMM were 31, 10, 5, and 2, respectively. The sensitivity, specificity, positive predictive value and negative predictive value of 99mTc-tetrofosmin SMM were 93.9, 66.7, 86.1 and 73.3%, respectively. The number of true positive, true negative, false positive, and false negative cases of 99mTc-MIBI SMM was 29, 10, 5, and 4, respectively. The sensitivity, specificity, positive predictive value, and negative predictive value of 99mTc-MIBI SMM were 87.8, 66.7, 85.3 and 73.3%, respectively. In assessment of axillary lymph node involvement, 99mTc tetrofosmin SMM demonstrated 31.8, 100, 100, and 42.3% sensitivity, specificity, positive and negative predictive values, respectively. The sensitivity and specificity of 99mTc-MIBI SMM was 22.7 and 100%. Positive and negative predictive values were 100 and 39.3%, respectively. One patient was false negative in both 99mTc-MIBI and 99mTc-tetrofosmin SMMs with a tumor size of 0.5 cm. Conclusion:99mTc-tetrofosmin and 99mTc-MIBI SMMs were noninvasive and useful in the detection of primary breast cancer and 99mTc tetrofosmin was comparable to 99mTc-MIBI in the detection of primary breast cancer. However, both radiopharmaceuticals had limited values in the assessment of axillary lymph node involvement.
Suppression of NK Cell Activity and of Resistance to Metastasis by Stress: A Role for Adrenal Catecholamines and β-Adrenoceptors
Authors: Ben-Eliyahu Shamgar , Shakhar Guy , Page Gayle G. , Stefanski Volker , Shakhar Keren
Published: April 2003

Although acute stress has been reported to suppress natural killer cell activity (NKA) and host resistance to metastasis, it is unclear whether the sympathetic nervous system (SNS) has a role in these effects. The current study in Fischer 344 rats assessed the involvement of adrenal catecholamines and β1- and β2-adrenoceptors in mediating these deleterious effects of swim stress. In addition to assessing the number and activity of NK cells following swim stress, we used a tumor model based on the MADB106 mammary adenocarcinoma line: this syngeneic tumor metastasizes only to the lungs, and its lung tumor retention (LTR) and metastatic colonization are highly sensitive to NKA. The findings indicate that stress increased both LTR, assessed 24 h after inoculation, and the number of lung metastases, counted 3 weeks later. These effects were attenuated or completely abolished by the ganglionic blocker chlorisondamine (3 mg/kg i.p.), by adrenal demedullation, by a selective β-adrenergic antagonist (nadolol, 0.4 mg/kg), and additively by a selective β1- (atenolol, 1–6 mg/kg) and a selective β2-antagonist (either butoxamine 4–32 mg/kg or ICI-118,551 0.3–8 mg/kg). Stress also suppressed NKA, and adrenal demedullation prevented this suppression. Administration of adrenaline (0.1–1 mg/kg) or of a β-adrenergic agonist (metaproterenol, 0.8 mg/kg), in physiologically relevant doses, suppressed NKA in a dose-dependent manner, and increased LTR to levels characteristic of swim stress. Taken together, these findings suggest that acute stress, by releasing catecholamines from the adrenal glands and activating β1- and β2-adrenoceptors, suppresses NKA and consequently compromises resistance to NK-sensitive metastasis.
Patients with Premenstrual Syndrome Have a Different Sensitivity to a Neuroactive Steroid during the Menstrual Cycle Compared to Control Subjects
Authors: Sundström Inger , Andersson Agneta , Nyberg Sigrid , Ashbrook Donald , Purdy Robert H. , Bäckström Torbjörn
Published: April 2003

We have evaluated the functional sensitivity to a neuroactive steroid in 12 women with and 12 women without premenstrual syndrome (PMS) at two stages of the menstrual cycle, by comparing the effects of three increasing doses of intravenous pregnanolone (3α-hydroxy-5β-pregnan-20-one) on saccadic eye velocity (SEV) and self-rated sedation. Control subjects in the follicular and luteal phase showed a significant reduction in SEV after pregnanolone injections compared to vehicle. In PMS patients, pregnanolone injections induced a significant dose-related decrease in SEV compared to vehicle only in the follicular phase, not in the luteal phase. After pregnanolone injections, sedation scores increased significantly from vehicle among control subjects in the luteal phase but not among PMS patients in either cycle phase. High-severity PMS patients responded with less decrease in SEV and less increase in sedation scores following pregnanolone injections compared to low-severity patients. Control subjects increased their SEV response to pregnanolone in the luteal phase compared to the follicular phase, whereas PMS patients did not. These findings are compatible with a decreased GABAA-receptor sensitivity in brain areas controlling saccadic eye movements among PMS patients in the late luteal phase.
Calcium/Calmodulin-Dependent Protein Kinase II Involvement in Release of Gonadotropin-Releasing Hormone
Authors: Waters Wendy W. , Chen Pat L. , McArthur Newell H. , Moreno Pete A. , Harms Paul G.
Published: April 2003

Involvement of calcium/calmodulin-dependent protein kinase II (CaM kinase II) in regulation of GnRH release was tested by determining the effect of CaM kinase II antagonists (KN-62 or KN-93) on GnRH release from rat or cattle infundibular (stalk median eminence) explants. Preincubation of male rat infundibular explants for 30 min with KN-62 (0.5, 1, 5 or 10 µM) 1.5 h prior to the addition of 59.3 mM (high) K+ resulted in a dose-dependent suppression of GnRH release. A longer pretreatment period (2 h) of rat infundibular explants with KN-62 (1 or 10 µM) appeared to enhance the suppressive effect of the CaM kinase II antagonist. Exposure (2 h) of rat infundibular explants to 10 µM, but not 0.1 µM KN-93, resulted in a complete inhibition of high K+-induced GnRH release. Exposure of steer infundibular explant halves to KN-62 (50 or 100 µM) or KN-93 (50 µM) inhibited high K+-induced GnRH release. Likewise, treatment of heifer infundibular explant halves with KN-93 (50 µM) abolished high K+-induced GnRH release. The period of exposure required for KN-62 to elicit its effect was relatively short since exposure of KN-62 (100 µM) for only 91–150 min of incubation was sufficient to block high K+-induced GnRH release from steer infundibular explant halves. In conclusion, these results: (1) support the hypothesis that CaM kinase II is involved in GnRH release from the rat and cattle infundibulum, (2) demonstrate that the effect of CaM kinase II on GnRH release from cattle infundibula is independent of reproductive state, (3) confirm previous reports supporting Ca2+ and CaM involvement in GnRH release from rat and cattle infundibula and (4) establish that infundibular explants incubated in vitro are useful for studying selected mechanisms regulating hypothalamic neurohormone release from neuron terminals.
A Naturally Occurring Basically Charged Human Follicle-Stimulating Hormone (FSH) Variant Inhibits FSH-Induced Androgen Aromatization and Tissue-Type Plasminogen Activator Enzyme Activity in vitro
Authors: Timossi Carlos M. , Barrios de Tomasi Jorgelina , Zambrano Elena , González Roberto , Ulloa-Aguirre Alfredo
Published: April 2003

It is well known that deglycosylation of gonadotropins by enzymatic or chemical procedures or by deletion of sites for N-linked glycosylation produces antagonistic analogs which are able to interact strongly with the receptor and to inhibit binding of the wild-type hormone. In the present study, we analyzed the antagonistic properties of a naturally occurring basic follicle-stimulating hormone (FSH) charge isoform obtained after high-resolution chromatofocusing of human anterior pituitary glycoprotein extracts. Coincubation of increasing amounts of this isoform with a highly purified human pituitary FSH preparation or with recombinant human FSH at doses equivalent to their corresponding ED50 for estradiol and tissue-type plasminogen activator (tPA) production, inhibited FSH-induced estrogen production and tPA enzyme activity by cultured rat granulosa cells in a dose-dependent manner. These inhibitory effects were apparently exerted at steps following 3′,5′-cyclic adenosine monophosphate (cAMP) formation and did not involve activation of the protein kinase C pathway since: (a) at low doses, this basic FSH isoform moderately increased FSH-induced cAMP production by cultured rat granulosa cells; (b) coincubation of the antagonist isoform with dibutyryl cAMP completely inhibited the effects of this cAMP analog on estrogen and tPA production; (c) the isoform was able to stimulate production of cAMP in a human fetal cell line expressing the recombinant human FSH receptor, and (d) the inhibitory effects of the isoform were not affected by staurosporine, a protein kinase C inhibitor. The effects of this isoform upon dibutyryl cAMP-induced estrogen and tPA production were blocked by the addition of a highly specific antibody directed against human FSH, further demonstrating that the antagonistic effects observed were due to FSH-like molecules. In contrast to the inhibitory effects exhibited by this basic FSH isoform, a more acidic FSH charge variant consistently acted as an agonist of pituitary and recombinant FSH on both estrogen production and induction of tPA enzyme activity. These results indicate that the anterior pituitary gland normally produces FSH isoforms which act as either agonists or antagonists of FSH at the target cell level.
Is GnRH Reduced at the Midcycle Surge in the Human?
Authors: Martin Kathryn A. , Welt Corrine K. , Taylor Ann E. , Smith Julie A. , Crowley Jr. William  F. , Hall Janet E.
Published: April 2003

Recent studies indicate that the midcycle gonadotropin surge in the human occurs without an increase in hypothalamic gonadotropin-releasing hormone (GnRH) pulse frequency. In addition, previous studies employing a GnRH antagonist to provide a semiquantitative estimate of endogenous GnRH secretion suggest that the overall amount of GnRH secreted is decreased at the time of the surge. To investigate the hypothesis that a normal gonadotropin surge can be generated in the human with a decreased amount of GnRH at the midcycle, 7 GnRH-deficient subjects underwent two cycles of a physiologic regimen of intravenous pulsatile GnRH therapy. In the control cycle, 75 ng/kg/bolus of GnRH, a dose known to be sufficient for folliculogenesis, was administered throughout the cycle, using physiological frequencies. In a second cycle, the bolus dose of GnRH was decreased by one-half log order to 25 ng/kg just prior to the luteinizing hormone surge and returned to 75 ng/kg after documented ovulation. All cycles were ovulatory. The peak luteinizing hormone level (77.4±9.7 vs. 67.5±17.6 IU/l) did not differ between the control and decreased GnRH cycles. There was no difference in the peak serum estradiol level (475.8±144.1 vs. 493.2±93.0 pg/ml), follicular phase length (15.0±1.3 vs. 14.8±0.6 days), or progesterone level (22.4±5.1 vs. 34.8±5.7 ng/ml) on day 6 of the luteal phase in the control and decreased GnRH cycles, respectively. Three pregnancies were achieved in each of the control and reduced GnRH cycles. We conclude that a decreased overall amount of GnRH generates a normal midcycle gonadotropin surge and has no significant impact on luteal phase adequacy or fertility. These results provide further evidence that a decrease in endogenous hypothalamic GnRH secretion may occur at the midcycle in normal women. This study also provides evidence that the GnRH requirements for normal follicular and luteal phase dynamics may well be greater than those required for generation of a normal midcycle gonadotropin surge and ovulation in women.
Arcuate Nucleus Ablation Prevents Fasting-Induced Suppression of ProTRH mRNA in the Hypothalamic Paraventricular Nucleus
Authors: Legradi Gabor , Emerson Charles H. , Ahima Rexford S. , Rand William M. , Flier Jeffrey S. , Lechan Ronald M.
Published: April 2003

Fasting results in reduced thyroid hormone levels and inappropriately low or normal thyroid-stimulating hormone (TSH), partly attributed to central hypothyroidism due to suppression of pro TRH gene expression in the hypothalamic paraventricular nucleus. Recently, we demonstrated that the systemic administration of leptin to fasting animals restores plasma thyroxine (T4) and proTRH mRNA in the paraventricular nucleus to normal, suggesting that the fall in circulating leptin levels during fasting acts as a signal to hypophysiotropic neurons in the paraventricular nucleus to reset the set point for feedback regulation of pro TRH mRNA by thyroid hormone. To determine whether the effect of fasting on the hypothalamic-pituitary-thyroid axis is mediated through the hypothalamic arcuate nucleus where leptin receptors are highly concentrated, we studied the effect of fasting and exogenous leptin administration on plasma thyroid hormone levels and proTRH mRNA concentration in the paraventricular nucleus in adult animals with arcuate nucleus lesions induced pharmacologically by the neonatal administration of monosodium L-glutamate (MSG). In normal animals, fasting reduced plasma T4 and TSH levels and the concentration of proTRH mRNA in the hypothalamic paraventricular nucleus. In contrast, neither fasting nor leptin administration to fasting MSG-treated animals had any significant effects on plasma thyroid hormone and TSH levels and proTRH mRNA in the paraventricular nucleus. These studies suggest that during fasting, the arcuate nucleus is essential for the normal homeostatic response of the hypothalamic-pituitary-thyroid axis and may serve as a critical locus to mediate the central actions of leptin on proTRH gene expression in the paraventricular nucleus.
Cytokine-Mediated Growth Hormone Release from Cultured Ovine Pituitary Cells
Authors: Fry Christa L. , Gunter David R. , McMahon Christopher D. , Steele Barbara , Sartin James L.
Published: April 2003

Previous studies have demonstrated that intravenous lipopolysaccharide (LPS) will increase concentrations of growth hormone (GH). One possible explanation for this may reside in the response of the pituitary to specific cytokines. This study sought to determine the effects of recombinant bovine tumor necrosis factor α (TNF), recombinant ovine (ro) interleukin-1α (IL-1α), roIL-1β, ro interleukin-2 (IL-2), and ro γ-interferon (INT) on GH release from cultured sheep pituitary cells. Sheep were sacrificed and pituitary cells cultured in DMEM with 10% fetal bovine serum for 3 days. On day 4, cells were washed and serum-free DMEM added to cells. IL-1α and IL-1β were used at 0.2, 2 and 20 ng/ml and the remaining cytokines at 2, 20 and 200 ng/ml. Neither IL-2 nor INT had effects on basal or on GH-releasing hormone (GRH)-stimulated GH release. TNF inhibited GRH-stimulated GH release (p < 0.05). Both IL-1α and IL-1β stimulated GH release from cultured pituitary cells at all doses tested (p < 0.01). Neither IL-1α nor IL-1β had an effect on GRH-stimulated GH release. IL-1 effects were inhibited by H-89 (p < 0.05; a protein kinase A inhibitor) and by nifedipine (p < 0.05; a calcium channel blocker). Both of these mechanisms are central signal transduction mechanisms mediating GRH-stimulated GH release. IL-1-stimulated GH release is partially inhibited (p < 0.05) by lipoxygenase pathway blockers. Phorbol myristate acetate downregulation of protein kinase C did not alter IL-1-stimulated GH release. IL-1β increased the content of both GH and GH mRNA in cultured sheep pituitary cells. We conclude that IL-1 produces a strong stimulus to GH release, which is mediated by calcium entry and protein kinase A activation. IL-1 also activates lipoxygenase pathways. This latter pathway as well as calcium entry were shown to mediate LPS stimulation of GH release from cultured pituitary cells. The similarity between IL-1 and LPS signal transduction suggests that LPS may activate pituitary production of IL-1 to produce the stimulus to GH. The lack of inhibitory effects of INT, TNF and IL-2 as opposed to what is seen in the rat may suggest a partial mechanism to explain the different effects of LPS on GH release between sheep and that seen in cattle and rats.
Sexual Dimorphism in Growth as Measured by Microknemometry: Different Responses to GH Deficiency and Exogenous GH Administration
Authors: Rol de Lama M. Angeles , Pérez-Romero Angel , Hermanussen Michael , Ariznavarreta Carmen , Tresguerres Jesus A.F.
Published: April 2003

To monitor growth, a novel noninvasive leg length measurement technique, called microknemometry, which allows daily observation of tibial growth rate, was used. The rat exhibits a striking sex-related difference in postpubertal growth. Exogenous GH administration results in a sexually dimorphic response, affecting growth in normal young female rats but not in males. Here we investigated how chronic GH deficiency affects male and female rat growth patterns. The degree of growth rate recovery was investigated after exogenous GH administration to chronically deficient males and females. The deficiency was induced by neonatal monosodium glutamate (MSG) treatment. Since the neonatal gonadal environment plays an important role in the dimorphic growth pattern, neonatal androgenization of female rats with testosterone or neonatal feminization of male rats by castration was performed and the growth pattern monitored. MSG treatment decreased pituitary GH content and plasma IGF I levels in both sexes, but caused a less marked reduction of female rat tibial growth and body weight gain than in males. Additionally, only MSG-treated males showed decreased pituitary LH content, so that the dimorphic action of MSG on the gonadal axis may contribute to the observed differences in growth rate. GH administration was able to increase leg length in all MSG-treated rats but was more effective in females, despite a similar restoration of plasma IGF I levels in both sexes. Although neonatal castration of male rats resulted in a reduction of tibial growth rate and body weight, and neonatal testosterone administration to female rats caused a slight increase in body weight, a complete modification of the gender-dependent growth pattern was not achieved, indicating that appropriate steroid environment is also needed in puberty and adulthood.
Stress-Induced Release of Anterior Pituitary Hormones: Effect of H3 Receptor-Mediated Inhibition of Histaminergic Activity or Posterior Hypothalamic Lesion
Authors: Knigge Ulrich , Søe-Jensen Peter , Jørgensen Henrik , Kjær Andreas , Møller Morten , Warberg Jørgen
Published: April 2003

The effect of stress- or lipopolysaccharide (LPS) endotoxin-induced release of ACTH, β-endorphin (β-END) and prolactin (PRL) was investigated in two groups of conscious male rats: (1) Rats pretreated with different H3 receptor agonists, which inhibit neuronal histamine (HA) synthesis and release, and (2) rats with bilateral posterior hypothalamic lesion, which destroys the histaminergic perikarya exclusively localized in the mammillary nuclei. The H3 receptor agonists R(α)methyl-HA, BP 2-94 or imetit injected intraperitoneally (ip) had no effect on basal secretion of ACTH or PRL but inhibited the ACTH and PRL responses to restraint stress and the ACTH response to LPS endotoxin. LPS had no effect on PRL secretion. The inhibitory effect of the agonists was prevented by prior ip administration of the H3 receptor antagonist thioperamide. Bilateral lesion of the posterior hypothalamus inhibited the ACTH, β-END and PRL responses to restraint stress, ether stress and LPS endotoxin, whereas sham operation had no effect compared to nonoperated control rats. In addition, posterior hypothalamic lesion inhibited the PRL response but not the ACTH and β-END responses to activation of serotonergic neurons induced by ip administration of the 5-HT precusor 5-hydroxytryptophan in combination with the 5-HT re-uptake inhibitor fluoxetine. Thus, serotonergic pathways were not damaged by the lesions. The present results support our previous findings that inhibition of neuronal HA synthesis by α-fluoromethylhistidine as well as blockade of H1 or H2 receptors inhibit the ACTH, β-END and PRL responses to stress and LPS endotoxin and further substantiate an important role of histaminergic neurons in the mediation of the stress-induced release of pituitary stress hormones. Furthermore, in accordance with our previous findings, the lesion experiments indicated the existence of an interaction between the histaminergic and serotonergic system in regulation of the stress- and LPS-induced PRL release.
Effect of Serotonin Inhibition on Glucocorticoid and Mineralocorticoid Expression in Various Brain Structures
Authors: Semont Alexandra , Fache Marie-Pierre , Ouafik L’Houcine , Hery Micheline , Faudon Maxime , Hery Francis
Published: April 2003

Many studies have shown the existence of functional interactions between central neurotransmitter systems and the hypothalamo-pituitary adrenal axis. Mineralocorticoid receptors (MR) and glucocorticoid receptors (GR) are regulated by multiple factors including glucocorticoids themselves. Neurotransmitters such as serotonin (5-hydroxytryptamine: 5-HT) can regulate brain corticosteroid receptors in a complex way. The present study examined the short-term (48 h) effects of parachlorophenylalanine (PCPA), a drug which specifically inhibits 5-HT synthesis, on corticosteroid receptor levels and on the expression of their respective messenger ribonucleic acids (mRNA) in the rat hippocampus, hypothalamus and brain stem. The study was performed in bilaterally adrenalectomized animals, in order to avoid potential drug-induced changes in plasma corticosterone levels, which could secondarily regulate MR and GR. Short-term inhibition of 5-HT synthesis by PCPA significantly increased the number of hippocampal MR-binding sites. PCPA treatment did not alter the number of GR-binding sites in the hippocampus, hypothalamus and brain stem. We observed no change in the affinities of GR and MR sites in all the structures studied. In PCPA-treated rats, restoration of control 5-HT levels by injection of its immediate precursor, 5-hydroxytryptophan (5-HTP) brings the number of hippocampal MR-binding sites back to control levels. It can therefore be concluded that the increase in number of MR-binding sites induced by acute PCPA treatment is dependent on the decrease in 5-HT levels. The increase in hippocampal MR binding sites was correlated with an induction of their messengers, suggesting that 5-HT modulates the synthesis of MR protein. Although PCPA did not modify the number of hippocampal GR-binding sites, a decrease in hippocampal GR mRNA expression was observed. This study shows that 5-HT inhibits hippocampal mineralocorticoid receptor synthesis and that this effect is not mediated by changes in corticosterone hormone secretion, and illustrates the existence of complex mechanisms for corticosteroid receptor regulation in the hippocampus.
A Comparative Study of the Effects of Nitric Oxide and Carbon Monoxide on the in vivo Release of Gonadotropin-Releasing Hormone and Neuropeptide Y from Rat Hypothalamus during the Estradiol-Induced Luteinizing Hormone Surge: Estimation by Push-Pull Perfusion
Authors: Kohsaka Akira , Watanobe Hajime , Kakizaki Yoshifumi , Suda Toshihiro
Published: April 2003

Recent evidence suggests that nitric oxide (NO), a free radical gas, plays an important role in regulating the function of a variety of neuroendocrine systems. With respect to the hypothalamo-pituitary-gonadal axis, a stimulatory effect of NO on the release of gonadotropin-releasing hormone (GnRH) from rat hypothalamus has been demonstrated in vitro. However, no previous study has reported NO-stimulated secretion of GnRH from in vivo hypothalamus, and also the precise cellular site of action of NO within the GnRH neuronal system remains to be elucidated. In the present study, utilizing the push-pull perfusion technique of rat hypothalamus, we examined the effect of L-arginine (L-Arg), an NO donor, on the release of GnRH, neuropeptide Y and cyclic GMP (c-GMP), which is a pivotal second messenger molecule of the NO system. For comparison, we also examined the effect of carbon monoxide (CO), another putative gaseous neurotransmitter, using hematin, a CO donor. During the period of 11.00–18.00 h, we collected blood and hypothalamic perfusates from ovariectomized adult rats that had been implanted with an estradiol capsule 2 days before. During the entire period of observation, L-Arg (1.0 or 10 mM), hematin (10 or 100 µM) or artificial cerebrospinal fluid alone (as the control) was infused into the medial preoptic area (MPOA) where there are cell bodies of GnRH neurons, or the median eminence-arcuate nucleus complex (ME-ARC) where axon terminals of GnRH neurons are localized. Although 10 mM of L-Arg significantly stimulated GnRH and c-GMP, but not neuropeptide Y, levels in both the MPOA and ME-ARC, GnRH and c-GMP in the ME-ARC were already increased by 1.0 mM of L-Arg. By contrast, both concentrations of hematin were without effect at either site of the hypothalamus. This study is the first to demonstrate that NO is capable of stimulating GnRH release from rat hypothalamus in vivo. Our data also suggests that both cell bodies and axon terminals of GnRH neurons may be sites of action of NO. Our data do not support a previous study by other investigators that reported a stimulatory effect of CO on the GnRH release.
GABA Exerts Stimulatory and Inhibitory Influences on Gonadotropin II Secretion in the Atlantic Croaker (Micropogonias undulatus)
Authors: Khan IzharA. , Thomas Peter
Published: April 2003

Possible involvement of γ-aminobutyric acid (GABA) in the control of gonadotropin II (GTH II) secretion was investigated during different phases of the seasonal gonadal cycle of the Atlantic croaker (Micropogonias undulatus). Intraperitoneal administration of GABA (100 µg/g) elicited a significant increase in plasma GTH II levels in croaker with regressed or pre-recrudescence phase gonads, whereas it did not significantly affect GTH II levels during the early- to mid-recrudescence phase of the gonadal cycle in this species. On the other hand, GABA induced a dose-related inhibition of GTH II secretion in fish with fully recrudesced gonads. Similar opposite changes in GTH II levels were observed when croaker with regressed and fully recrudesced gonads were injected with the GABA transaminase inhibitor, γ-vinyl GABA (10 and 100 µg/g). This suggests an involvement of endogenous GABA in the control of GTH II secretion. GABA (1–100 µM) did not significantly alter GTH II release from pituitary fragments from regressed or fully recrudesced fish incubated in vitro, suggesting the lack of a major direct influence at the pituitary level. Muscimol (GABAA receptor agonist, 1 µg/g) treatment mimicked both the stimulatory and inhibitory effects of GABA, whereas injection of baclofen (GABAB receptor agonist, 1 µg/g) had no significant effect on basal or a gonadotropin-releasing hormone (GnRH) analog-induced GTH II secretion. Pretreatment of fish with bicuculline (1 µg/g), a GABAA antagonist, completely blocked the stimulatory influence of GABA on GTH II secretion in croaker with regressed gonads and partially blocked the inhibitory effect in individuals with fully recrudesced gonads. The results demonstrate that GABA exerts opposite influences on GTH II secretion at two different stages of the gonadal cycle of croaker, and acts primarily via GABAA type receptors. Thus, GABAergic pathways may be important in mediating seasonal influences on GTH II secretion in this species.