bluuebunny/crossref_metadata_2025 huggingface dataset:
Immortalized Gonadotropin-Releasing Hormone Neurons (GT1-7 Cells) Exhibit Synchronous Bursts of Action Potentials
Authors: Funabashi Toshiya , Suyama Kumiko , Uemura Tsuguo , Hirose Makiko , Hirahara Fumiki , Kimura Fukuko
Published: April 2003

Although it has been assumed that synchronized firing of gonadotropin-releasing hormone (GnRH) neurons is necessary for pulsatile GnRH secretion, there is no clear evidence for this. In the present study we simultaneously recorded spontaneous action potentials from multiple cells. Immortalized GnRH neurons (GT1-7 cells) were cultured on a multi-electrode dish (MED) and action potentials recorded by an extracellular recording method. One to two weeks after the beginning of culture, spontaneous action potentials appeared, exhibiting bursts composed of 5–10 action potentials. Burst activity was intermittent and periodic with mean burst intervals of 13.3 s. Furthermore, burst activity was recorded almost simultaneously from several micro-electrodes, suggesting that electrical activities of GT1-7 cells were synchronized with each other. Periodic bursts were completely and reversibly blocked by 1–5 µM tetrodotoxin, indicating that voltage-dependent Na+ channels are involved in their generation. γ-Aminobutyric acid (GABA) given at a 10-µM concentration shortened inter-burst intervals, whereas 10 µM bicuculline lengthened them. Finally, the gap junctional blockers n-octyl alcohol (1 mM) and carbenoxolone (100 µM) reversibly blocked periodic burst activity. The present study provides direct evidence that the electrical activity of GT1-7 cells exhibits synchronous and periodic bursts composed of action potentials. In addition, endogenous GABA is involved in GT1-7 cells in determining burst frequency. Although the precise mechanism of synchronized burst activities needs to be clarified, gap junctional communications among GT1-7 cells are at least partially involved.
Appetite-Suppressing Effects of Urotensin I and Corticotropin-Releasing Hormone in Goldfish (Carassius auratus)
Authors: Bernier Nicholas J. , Peter Richard E.
Published: April 2003

Fish urotensin I (UI), a member of the corticotropin-releasing hormone (CRH) family of peptides, is a potent inhibitor of food intake in mammals, yet the role of UI in the control of food intake in fish is not known. Therefore, to determine the acute effects of UI on appetite relative to those of CRH, goldfish were given intracerebroventricular (i.c.v.) injections of carp/goldfish UI and rat/human CRH (0.2–200 ng/g) and food intake was assessed for a 2-hour period after the injection. UI and CRH both suppressed food intake in a dose-related manner and UI (ED50 = 3.8 ng/g) was significantly more potent than CRH (ED50 = 43.1 ng/g). Pretreatment with the CRH receptor antagonist, α-helical CRH(9–41), reversed the reduction in food intake induced by i.c.v. UI and CRH. To assess whether endogenous UI and CRH modulate fish appetite, goldfish were given intraperitoneal implants of the glucocorticoid receptor antagonist, RU-486 (50 and 100 µg/g), or the cortisol synthesis inhibitor, metyrapone (100 and 200 µg/g), and food intake was monitored over the following 72 h. Fish treated with either RU-486 or metyrapone were characterized by a sustained and dose-dependent reduction in food intake. Pretreatment with i.c.v. implants of α-helical CRH(9–41) partially reversed the appetite-suppressing effects of RU-486 and metyrapone. In a parallel experiment, the effects of RU-486 (100 µg/g) and metyrapone (200 µg/g) intraperitoneal implants on brain UI and CRH gene expression were assessed. Relative to sham-implanted controls, fish treated with RU-486 or metyrapone had elevated UI mRNA levels in the hypothalamus and CRH mRNA levels in the telencephalon-preoptic brain region. Together, these results suggest that UI is a potent anorectic peptide in the brain of goldfish and that endogenous CRH-related peptides can play a physiological role in the control of fish appetite.
Differential Inhibition of Growth Hormone Secretion by Analogs Selective for Somatostatin Receptor Subtypes 2 and 5 in Human Growth-Hormone-Secreting Adenoma Cells in vitro
Authors: Tulipano Giovanni , Bonfanti Carlo , Milani Gabriella , Billeci Bruno , Bollati Angelo , Cozzi Renato , Maira Giulio , Murphy William A. , Poiesi Claudio , Turazzi Sergio , Giustina Andrea
Published: April 2003

Somatostatin (SRIH), a cyclic tetradecapeptide hormone originally isolated from mammalian hypothalamus, is a potent suppressor of pituitary growth hormone (GH) secretion. SRIH acts through a family of G-protein-coupled membrane receptors containing seven transmembrane domains. Five genes encoding distinct SRIH receptor (SSTR) subtypes have so far been cloned in human and other species and termed SSTR1–5. In human somatotrophe pituitary adenomas GH secretion is controlled by both SSTR2 and SSTR5. However, in clinical practice only somatostatin analogs selective for SSTR2 (octreotide and lanreotide) are available. This may explain why clinical and in vitro responses to these analogs in acromegaly are only partial. In this study, we investigated the inhibitory effect of two new SRIH analogs with high selectivity for SSTR2 (NC-4-28B) and SSTR5 (BIM-23268) and compared it to that of native somatostatin (SRIH-14) on a large number of GH-secreting adenomas obtained by transphenoidal neurosurgery. Tissues from 16 adenomas were enzymatically dispersed and plated in 24-well dishes at 50,000 cells/well. After 3 days, groups of three wells were incubated for 4 h with medium alone, SRIH-14 or analogs NC-4-28B or BIM-23268, at the concentrations of 0.01, 0.1 and 1 µM. Our results show that 9 out of 16 adenomas were responsive (GH suppression: 20–40% vs. control, p < 0.05) to SRIH. In this group only 4 adenomas showed similar responses to both selective analogs, with 2 nonresponders (expression of other SRIH receptor subtypes) and 2 responders (concomitant expression of SSTR2 and SSTR5) to both analogs. GH release was selectively inhibited by NC-4-28B in 3 adenomas and by BIM-23268 in the remaining 2 adenomas, suggesting predominant expression of SSTR2 and SSTR5, respectively. SRIH failed to inhibit GH release in 7 adenomas (43%). Interestingly, in that group a better inhibitory effect was obtained with BIM-23268 (5 out of 7 adenomas) than with NC-4-28B, suggesting expression of a few SSTR5 receptors only, or of both SSTR2 and SSTR5, respectively. We conclude that the availability of somatostatin analogs selective for SSTR5 will enhance the treatment potency and spectrum in acromegaly.
Somatostatin Inhibits Alpha-2-Adrenergic-Induced Secretion of Growth Hormone-Releasing Hormone
Authors: McMahon Christopher D. , Chapin Larry T. , Radcliff Roy P. , Lookingland Keith J. , Tucker H. Allen
Published: April 2003

The purpose of this experiment was to determine the role of growth hormone-releasing hormone (GHRH) and somatostatin (SRIH) neurons in mediating α2-adrenergic receptor-induced stimulation of growth hormone (GH) secretion in cattle. Our first objective was to determine if stimulation of α2-adrenergic receptors increases activity of GHRH neurons in the arcuate nucleus (ARC) and/or decreases activity of SRIH neurons in periventricular (PeVN) and ARC nuclei. Clonidine (an α2-adrenergic agonist) or vehicle (saline) were injected i.v. into steers and dual-label immunohistochemistry was performed to quantify the number of GHRH and SRIH neurons expressing Fos and Fos-related antigens (Fos/FRA) as markers of neuronal activity. Clonidine increased concentrations of GH in serum and decreased activity of SRIH neurons in the PeVN, but not in the ARC. Clonidine did not alter activity of GHRH neurons in the ARC. Our second objective was to determine if clonidine decreases secretion of SRIH from perifused slices of hypothalami, which contain perikarya and terminals of GHRH and SRIH neurons, and from explants of hypophysial stalk alone, which contain only terminals of GHRH and SRIH neurons. Clonidine failed to alter release of GHRH or SRIH from hypothalamic slices, but stimulated release of GHRH from explants of hypophysial stalk. Blockade of SRIH receptors enabled clonidine to stimulate release of GHRH from slices of hypothalami, but also stimulated release of SRIH. These results suggest that α2-adrenergic-induced secretion of GH occurs via a dual mechanism involving inhibition of SRIH neurons in the PeVN and direct stimulation of GHRH release from axon terminals in the median eminence.
Effects of Loperamide and Other Opioid-Related Substances on the Transcriptional Regulation of the Rat Pro-Opiomelanocortin Gene in AtT20 Cells
Authors: Nomura Atsushi , Iwasaki Yasumasa , Aoki Yoshiaki , Yamamori Etsuko , Mutsuga Noriko , Yoshida Masanori , Asai Masato , Oiso Yutaka , Saito Hidehiko
Published: April 2003

Although opioid peptides are involved in the regulation of the hypothalamic-pituitary-adrenal axis, their role in pro-opiomelanocortin (POMC) gene expression at the pituitary level is not known. We therefore examined the effects of opioid receptor agonists, including recently discovered endogenous opioid peptides, on POMC gene expression using the AtT20PL cell line, a subclone of AtT20 in which the rat POMC 5′-promoter-luciferase fusion gene was stably incorporated. The endogenous µ-opioid receptor agonists endomorphin 1 and 2 had no effect on either basal or corticotropin-stimulating-hormone-induced POMC expression. This was also the case with the δ-agonist BUBUC, the ĸ-agonist U50488H and the orphan receptor agonist orphanin FQ. In contrast, the synthetic µ-agonist loperamide significantly inhibited basal and yet enhanced cAMP-induced POMC expression. The inhibitory effect of loperamide was mimicked by the calmodulin antagonist W7 and antagonized by the calcium channel blocker nifedipine, whereas neither the inhibitory nor the enhancing effect of loperamide was influenced by the opioid antagonist naloxone. These results suggest that the synthetic µ-agonist loperamide has a modulatory effect on the 5′-promoter activity of the POMC gene. This effect does not seem to be mediated through the classical µ-opioid receptor but rather in part through a calcium/calmodulin-related mechanism.
Structure and Biological Activity of Gonadotropin-Releasing Hormone Isoforms Isolated from Rat and Hamster Brains
Authors: Montaner Alejandro D. , Mongiat Lucas , Lux-Lantos Victoria A.R. , Park Min Kyu , Fischer Wolfgang H. , Craig A. Grey , Rivier Jean E. , Lescheid David , Lovejoy David , Libertun Carlos , Sherwood Nancy M. , Somoza Gustavo M.
Published: April 2003

Rat and hamster brain tissues were used to investigate the possible existence of a follicle stimulating hormone (FSH)-releasing factor with similar characteristics to the lamprey gonadotropin-releasing hormone III (lGnRH-III) form proposed in previous reports. The present studies involved isolation and purification of the molecule by high-performance liquid chromatography (HPLC), identification by radioimmunoassay, sequence analysis by automated Edman degradation, mass spectrometry and examination of biological activity. Hypothalamic extracts from both species contained an HPLC fraction that was immunoreactive to GnRH and coeluted with lGnRH-III and 9-hydroxyproline mGnRH ([Hyp9]GnRH). Determination of primary structure from purified total brain material demonstrated that the isolated molecule was [Hyp9]GnRH. This is the first report showing the presence of the posttranslationally modified form already known as [Hyp9]GnRH by primary sequence analysis. The biological activity of distinct GnRH peptides was also tested in vitro for gonadotropin release using rat pituitary primary cell cultures. The results showed that [Hyp9]GnRH stimulated both luteinizing hormone and FSH release, as already reported, whereas lGnRH-III had no action on the secretion of either gonadotropin.
Involvement of Nitric Oxide in the Regulation of Growth Hormone Secretion in Dogs
Authors: Valverde Ignacio , Peñalva Angela , Ghigo Ezio , Casanueva Felipe F. , Dieguez Carlos
Published: April 2003

Nitric oxide (NO) is a highly reactive gas that has been suggested to function as a neurotransmitter in the neuroendocrine system. In this work, we have evaluated the role of NO pathways in growth hormone (GH) secretion by assessing the effect of L-arginine infusion, a precursor of NO formation, and L-NAME, a nitric oxide synthase (NOS) inhibitor. The experiments were carried out on 7 adult beagle dogs. A saline infusion was carried out on all the dogs as a control test. L-arginine (infusion i.v. 10 g in 100 ml of saline, from t = 0 to 30 min) and L-nitro-arginine-methyl ester, L-NAME (infusion of 300 µg/kg in 120 ml of saline, from t = –30 to 45 min) were administered alone and together with growth hormone-releasing hormone (GHRH) (i.v. bolus at 0 min, at a dose of 100 µg), the synthetic GH secretagogue GHRP-6 (i.v. bolus at 0 min, at a dose of 90 µg), and the 5-HT1D serotonin receptor agonist sumatriptan, SUM (s.c. injection at the dose of 3 mg). Plasma cGH was determined by RIA. Results were evaluated by one-way analysis of variance, followed by the Newman-Keuls test for multiple comparisons. L-arginine administration resulted in a slight increase in plasma cGH in comparison with saline controls. Combined administration of L-arginine and GHRH enhanced cGH release in comparison with GHRH alone. L-NAME alone did not modify baseline cGH levels, but completely suppressed the GH release induced by GHRH or GHRP-6. It also strongly reduced, but did not abolish the effect of the two peptides (GHRH plus GHRP-6) administered together. Finally, administration of the 5-HT1D agonist SUM induced a significant cGH secretion in all dogs, a response which was not modified when L-NAME was administered in combination with SUM. In conclusion, our data show that inhibition of NO blunts both GHRH or GHRP-6-induced cGH release, and are compatible with the hypothesis that it acts by decreasing hypothalamic somatostatin release.
Profiling γ-Aminobutyric Acid (GABAA) Receptor Subunit mRNA Expression in Postnatal Gonadotropin-Releasing Hormone (GnRH) Neurons of the Male Mouse with Single Cell RT-PCR
Authors: Pape Jean-Rémi , Skynner Michael J. , Sim Joan A. , Herbison Allan E.
Published: April 2003

The present investigation has examined which subunits of the GABAA receptor are expressed by gonadotropin-releasing hormone (GnRH) neurons in the juvenile and adult male mouse. Cells of defined morphology, located in the medial septum (MS) and rostral preoptic area (POA), were patch-clamped in the acute brain slice preparation and their cell contents extracted. A reverse transcriptase polymerase chain reaction (RT-PCR) procedure using nested primers was used to establish individual GnRH mRNA-expressing cells which were then evaluated for eleven GABAA receptor (α1–5, β1–3, γ1–3) subunit transcripts. Single and multiple GABAA receptor subunit mRNAs were detected in approximately 70% of all GnRH neurons. A range of different subunit mRNAs (α1, α2, α5, β1, β2, β3, γ2) were found in juvenile GnRH neurons, with the α1γ2 and α5γ2 combinations encountered most frequently within individual cells. The expression profile in adult GnRH neurons was more extensive than that detected in juveniles with α1, α2, α3, α5, β1, β2, β3, γ1 and γ2 subunits all being detected. The major difference in subunit profile between GnRH neurons located in the MS and POA involved the β subunits. The principal postnatal developmental change was one of increasing overall subunit heterogeneity in maturing POA GnRH neurons. The profile of GABAA receptor subunit mRNAs detected in male GnRH neurons was quite different to that reported by us for female GnRH neurons in the mouse using the same RT-PCR approach. Together, these findings indicate that postnatal GnRH neurons are likely to express a range of GABAA receptor subunit mRNAs in a sexually dimorphic and developmentally-regulated manner.
Differential Neonatal Imprinting and Regulation by Estrogen of Estrogen Receptor Subtypes α and β and of the Truncated Estrogen Receptor Product (TERP-1) mRNA Expression in the Male Rat Pituitary
Authors: Tena-Sempere Manuel , Barreiro M. Luz , González Lucas C. , Pinilla Leonor , Aguilar Enrique
Published: April 2003

Two distinct nuclear estrogen receptors (ERs) have been identified, the classical one, renamed ERα, and the more recently cloned ERβ. In a variety of tissues, gene expression of both receptor subtypes results in the generation of multiple transcripts encoding the full-length as well as several alternately spliced isoforms. In the rat pituitary, a truncated, tissue-specific variant of ERα, called TERP-1, has been identified and found able to modulate ERα and ERβ activity. So far, its pattern of expression and hormonal regulation have been mostly studied in females. The present study was designed to analyze the pattern of expression of TERP-1 mRNA in the male rat pituitary at different stages of postnatal development, and to evaluate the impact of neonatal imprinting and estrogen treatment upon TERP-1 expression in the male pituitary. Assessment of TERP-1 mRNA levels by semi-quantitative RT-PCR, using a variant-specific primer pair, revealed that TERP-1 is also expressed in the male rat pituitary. Relative mRNA expression levels changed markedly during postnatal development, with moderate expression of the TERP-1 transcript at birth, barely detectable levels during the infantile-prepubertal period, and maximal values in adulthood. Expression of TERP-1 was sensitive to neonatal estrogen exposure, which resulted in a significant, persistent increase in mRNA levels from the infantile period until puberty. This phenomenon was not mimicked by neonatal blockade of endogenous GnRH. In addition, estrogen was able to acutely up-regulate pituitary TERP-1 mRNA expression levels in prepubertal (30-day-old) and adult (75-day-old) males. Interestingly, neonatal imprinting as well as acute estrogen treatment resulted in opposite effects on TERP-1 and full-length ERα and ERβ transcripts, the latter being decreased under both conditions. In conclusion, our data indicate that TERP-1 mRNA is expressed in a developmentally regulated manner in the male rat pituitary, and is affected by neonatal estrogen imprinting and acute estrogen treatment. Regulation of TERP-1 expression by neonatal or acute estrogen treatment may thus represent an additional tuning mechanism for estrogen actions in the male rat pituitary.
Food Deprivation Decreases Blood Galanin-Like Peptide and Its Rapid Entry into the Brain
Authors: Kastin Abba J. , Akerstrom Victoria , Hackler Laszlo
Published: April 2003

Galanin-like peptide (GALP) was recently isolated from the hypothalamus, where its expression is influenced by leptin and food deprivation. Since leptin crosses the blood-brain barrier (BBB) by a saturable transport system that is downregulated by fasting, we examined the effect of leptin and fasting on the entry of GALP into mouse brain. Multiple-time regression analysis showed that the basal influx of 125I-GALP from blood was rapid (Ki = 9.49 ± 0.72 × 10–4 ml/g·min). This influx was not affected by leptin but was significantly decreased by food deprivation for 24 or 48 h, accompanied by decreased immunoreactive plasma GALP at 48 h, but not at 24 h. By contrast, pretreatment of mice fasted for 24 h with glucose resulted in a significant increase in the blood-to-brain influx of GALP that was not accompanied by increased immunoreactive plasma GALP. HPLC showed that most of the GALP crossed the BBB in an intact form, and capillary depletion studies showed that more than 93% of the GALP crossing entered the parenchyma of the brain rather than being bound to the endothelial cells of the capillaries composing the BBB or being reversibly associated with the vasculature. Efflux of 125I-GALP occurred at the rate of the normal reabsorption of CSF, and the octanol-buffer partition coefficient showed insufficient lipophilicity to explain the fast rate of influx. When 125I-GALP was perfused in blood-free buffer, the self-inhibition characteristic of a saturable transport system was evident even though capillary gel electrophoresis showed GALP aggregating as a trimer. Capillary zone electrophoresis showed protein binding of GALP in serum, perhaps facilitating its interactions at the BBB. In particular, these studies show for the first time (1) that immunoreactive GALP is present in blood where (2) its concentrations are reduced by food deprivation, and (3) that there is a rapid blood-to-brain influx of intact GALP (4) which is decreased by fasting and (5) increased by pretreatment with glucose.
Clinical Effect of Intravenous Calcitriol Administration on Secondary Hyperparathyroidism
Authors: Koshikawa S. , Akizawa T. , Kurokawa K. , Marumo F. , Sakai O. , Arakawa M. , Morii H. , Seino Y. , Ogata E. , Ohashi Y. , Akiba T. , Tsukamoto Y. , Suzuki M.
Published: April 2003

Background/Aims: Although the PTH-suppressive effect of intravenous calcitriol has already been demonstrated by various studies, the precise dose-response to calcitriol has not been fully determined for uremic secondary hyperparathyroidism (2HPT). In order to investigate in detail the dose-response of intravenous calcitriol and the adequate initial dose against 2HPT, a randomized prospective double-blind study was conducted. Method: One-hundred and sixty-two patients with 2HPT undergoing hemodialysis three times per week were randomly assigned to four calcitriol (Ro21-5535) treatment groups, 0 (placebo), 1, 1.5 or 2 µg. Calcitriol or placebo was given intravenously after each dialysis for 12 weeks under double-blind conditions. Results: Calcitriol dose-dependently reduced both intact-PTH and high-sensitivity assay mid-terminal (HS)-PTH levels. The rate of per-week change in intact-PTH was 0.0% in the placebo group, –7.8% in the 1-µg group, –18.9% in the 1.5-µg group and –24.1% in the 2-µg group. Calcitriol dose-dependently increased the rate of increase in serum Ca adjusted by albumin level. The per-week increases in adjusted serum Ca were –0.01, 0.08, 0.23 and 0.35 mg/dl in the placebo, 1-, 1.5- and 2-µg groups, respectively. Although the degree of PTH suppression was correlated with the adjusted serum Ca increase, by-patients investigation revealed that the number of patients with suppression of PTH despite of no or slight elevation of adjusted serum Ca level was largest in the 1-µg group among the three calcitriol groups. Conclusion: Intravenous calcitriol was found to have a clear dose-dependent effect on PTH reduction in patients with 2HPT, and the appropriate initial dose of this agent was determined to be 1 µg per dialysis session.
GLEPP1 Receptor Tyrosine Phosphatase (Ptpro) in Rat PAN Nephrosis
Authors: Kim Yeong Hoon , Goyal Meera , Wharram Bryan , Wiggins Jocelyn , Kershaw David , Wiggins Roger
Published: April 2003

Glomerular epithelial protein 1 (GLEPP1) is a podocyte receptor membrane protein tyrosine phosphatase located on the apical cell membrane of visceral glomerular epithelial cell and foot processes. This receptor plays a role in regulating the structure and function of podocyte foot process. To better understand the utility of GLEPP1 as a marker of glomerular injury, the amount and distribution of GLEPP1 protein and mRNA were examined by immunohistochemistry, Western blot and RNase protection assay in a model of podocyte injury in the rat. Puromycin aminonucleoside nephrosis was induced by single intraperitoneal injection of puromycin aminonucleoside (PAN, 20 mg/100g BW). Tissues were analyzed at 0, 5, 7, 11, 21, 45, 80 and 126 days after PAN injection so as to include both the acute phase of proteinuria associated with foot process effacement (days 5–11) and the chronic phase of proteinuria associated with glomerulosclerosis (days 45–126). At day 5, GLEPP1 protein and mRNA were reduced from the normal range (265.2 ± 79.6 × 106 moles/glomerulus and 100%) to 15% of normal (41.8 ± 4.8 × 106 moles/glomerulus, p < 0.005). This occurred in association with an increase in urinary protein content from 1.8 ± 1 to 99.0 ± 61 mg/day (p < 0.001). In contrast, podocalyxin did not change significantly at this time. By day 11, GLEPP1 protein and mRNA had begun to return towards baseline. By day 45–126, at a time when glomerular scarring was present, GLEPP1 was absent from glomerulosclerotic areas although the total glomerular content of GLEPP1 was not different from normal. We conclude that GLEPP1 expression, unlike podocalyxin, reflects podocyte injury induced by PAN. GLEPP1 expression may be a useful marker of podocyte injury.
Environmental Risk Factors for Amyotrophic Lateral Sclerosis
Authors: Armon Carmel
Published: April 2003

In order to evaluate reported associations of environmental risk factors with amyotrophic lateral sclerosis (ALS), consideration is given first to robust clinical and epidemiologic observations. These are observations which have persisted in time, have been replicated consistently and likely reflect the reality of the disease. Sporadic, familial and Western Pacific ALS are considered. In contrast, other associations appear to have emerged due to chance, sometimes compounded by faulty study design, and have dissipated once greater attention was given to methodological rigor. Current data suggest that there are no robust environmental risk factors for sporadic ALS.
Aspirin Use and Risk of Stroke in the Elderly: The Rotterdam Study
Authors: Vokó Zoltán , Koudstaal Peter J. , Bots Michiel L. , Hofman Albert , Breteler Monique M.B.
Published: April 2003

The objective of the study was to assess the association between aspirin use and the risk of stroke in a population-based study in the elderly. The study was carried out within the framework of the Rotterdam Study, a prospective population-based cohort study. In the total study population there was a weak, nonsignificant association between aspirin use and the risk of stroke (adjusted relative risk 1.29, 95% CI 0.91–1.83). Stratification by history of vascular diseases revealed that aspirin considerably increased the risk of first-ever stroke in subjects free from vascular disease (adjusted relative risk 1.80; 95% CI 1.03–3.13). In persons with vascular disease, no association was observed between aspirin use and risk of stroke (adjusted relative risk 0.99, 95% CI 0.56–1.73). Our findings suggest that aspirin use may increase the risk of stroke in elderly subjects free from vascular disease.
Assessing the Clinical Importance of Statistically Significant Improvement in Anti-Dementia Drug Trials
Authors: Rockwood Kenneth , MacKnight Chris
Published: April 2003

A strategy for assessing the clinical importance of statistically significant treatment benefits in recent dementia drug trials is proposed. Traditional criteria for the assessment of valid inferences are helpful: the more likely the treatment effects are valid, the greater the chance that they will be clinically important. The role of the Clinician’s Interview-Based Impression of Change is also of some importance. Progress in this area faces the special challenge that the ‘new’ disease entity of partial treatment of Alzheimer’s disease has not been well described. Large, systematic clinical studies of treated patients remain necessary to define reliable guides to successful treatment.
Combination Therapies and the Theoretical Limits of Evidence-Based Medicine
Authors: Saver Jeffrey L. , Kalafut Mary
Published: April 2003

Background: Advances in molecular pharmacology and surgical, endovascular, and radiation techniques have yielded multiple effective or promising, and potentially complementary, classes of treatments for virtually every major medical disorder. Consequently, determining the optimum combination of therapies for a condition is a burgeoning challenge to clinical trialists and practicing physicians. Methods: General phase III trial strategies for testing combination regimens are described, and then applied to two illustrative conditions, Alzheimer disease and ischemic stroke. Results: Strategies for testing combination regimens include: head to head trials of all combinations, which lead to unwieldy trial numbers; very large multi-arm trials, which impractically delay interval information on regimen utility; and hierarchical, serial clinical trials. Systematic literature review revealed seven classes of agents already approved or in late phase III testing for preventing the development or slowing the progression of Alzheimer disease and five for ischemic stroke prevention. Possible combination regimens number 128 (27) for Alzheimer disease and 32 (25) for ischemic stroke. Hierarchical, serial clinical trials would permit identification of the optimum combination of these agent classes for Alzheimer disease through 127 trials, enrolling 63,500 patients, requiring 286 years; for ischemic stroke through 31 trials, enrolling 186,000 patients, requiring 155 years. Conclusions: Marked limitations in the ability of clinical trials to interrogate varied treatment combinations to determine the most effective ensemble exist, and their scope is widely underappreciated. Steps that may attenuate, though not eliminate, the challenge of a surfeit of combination treatment regimens include preclinical testing to identify the most promising regimens, use of surrogate outcome measures in exploratory clinical trials, and use of hierarchical, serial and factorial phase III trials.
Proportion of Older People in the Community as a Predictor of Increasing Stroke Incidence
Authors: Marini Carmine , Triggiani Leonardo , Cimini Nicola , Ciancarelli Irene , De Santis Federica , Russo Tommasina , Baldassarre Massimo , di Orio Ferdinando , Carolei Antonio
Published: April 2003

Objectives: To compare stroke incidence rates among comparable registries and to make correlations with aging of the resident populations. Methods: This correlation study included all comparable stroke registries maintained in industrialized countries (Italy, France, United Kingdom, Denmark, Norway, United States, and Australia). Eleven community-based stroke registries with similar high proportions of radiologically confirmed diagnoses based on standard definitions were identified. Incidence rates of first-ever stroke from the prospective L’Aquila registry and from the other registries were compared after age and sex standardization to the 1996 European population. The rates were then correlated with the proportion of individuals aged 65 and over in the corresponding resident populations by means of the Poisson regression analysis. Results: In the L’Aquila registry, the crude annual incidence of first-ever stroke was 281/100,000 (95% confidence interval 271–293) based on 2,515 patients included during a 3-year period. The rate standardized to the European population was 249/100,000. Standardized incidence ratios indicated a significant excess of first-ever strokes in the L’Aquila registry up to 51% with respect to most of the compared studies. A significant correlation was also found between crude (p < 0.0001) and standardized (p = 0.0012) stroke incidence rates and proportions of individuals aged 65 and over in the different populations. Conclusions: The L’Aquila experience suggests that any further aging of a population will increase the stroke occurrence for both the reasons of a direct and predictable effect of the growing proportion of elderly individuals within that population and a disproportionately increased stroke risk in the older age groups.
Pilot Study of Prevalence of Parkinson’s Disease in Australia
Authors: Chan D.K.Y. , Dunne M. , Wong A. , Hu E. , Hung W.T. , Beran R.G.
Published: April 2003

Parkinson’s disease is a common neurological disease and its prevalence increases with age. Because of an ageing population and changing environment compared to the last epidemiological study done in Australia over 30 years ago, we have conducted a door-to-door pilot survey which looked at the latest prevalence as well as putative risk factors in a random population. We used a two-phase investigation method (screening followed by detailed examination) in a random community sample of 2,820 households (with 527 individuals aged 55 and over) along with 203 residents in aged care facilities (single-phase examination for residents aged 55 and above) in the Randwick area of Sydney, New South Wales. We had a 75% participation rate in the community and a 94% in the aged care facilities. The results of the survey in this sample of 730 subjects indicated that the crude prevalence of Parkinson’s disease was between 3.6 and 4.9% (higher in the aged care facilities). The putative risk factors positively identified using chi-square method were ‘family history’ (p < 0.01) and ‘exposure to chemicals at work or in surrounding environment’ (p < 0.05). The age-adjusted prevalence rate of Parkinson’s disease revealed at least a 42.5% increase in the disease compared to 1966. We conclude that there may be an increase in the disease in Australia due to ageing and other risk factors.
The Incidence of Vascular Dementia in Canada: A Comparison with Europe and East Asia
Authors: Dubois Marie-France , Hébert Réjean
Published: April 2003

Vascular dementia (VaD) is the second commonest subtype of dementia after Alzheimer’s disease (AD). However, its incidence has been studied much less extensively than that of AD. This article reviews the incidence data for VaD reported in the international literature. Results from 10 incidence studies are compared to those of the Canadian Study of Health and Aging using age-standardized incidence ratios (SIR). SIRs vary from 0.42 to 2.68, indicating that geographical variation is still present after taking into account the countries’ differential age distributions. It is still unclear if these differences are due to genetic and/or environmental factors since a large part reflects methodological differences between studies.
Prevalence of Parkinson’s Disease in Bulgaria
Authors: Milanov I. , Kmetska K. , Karakolev B. , Nedialkov E.
Published: April 2003

Despite some publications on Parkinson’s disease prevalence in Bulgaria, its frequency in the country still remains uncertain. Earlier studies in Bulgaria were carried out on large population groups and were based on medical records without further diagnostic confirmation. The aim of the present study was to perform an epidemiological investigation on Parkinson’s disease in Bulgaria, using strict diagnostic criteria in an attempt to obtain a more accurate estimate of its frequency in this country. We studied the prevalence of Parkinson’s disease in two small regions of Bulgaria. Cases were ascertained by the medical records and confirmed by personal examination. The prevalence of Parkinson’s disease was found to be 164.2 per 100,000 with 47 cases in the first region and 169.8 per 100,000 with 155 cases in the second region. Based on two small population studies, the prevalence ratio in different parts of Bulgaria is not significantly different and is similar to other European countries.
Accuracy of Death Certificates for Motor Neuron Disease and Multiple Sclerosis in the Province of Palermo in Southern Italy
Authors: Ragonese Paolo , Salemi Giuseppe , Aridon Paolo , Conte Silvia , Cuccia Giovanni , Lupo Innocenzo , Savettieri Giovanni
Published: April 2003

Mortality studies based on death certificates (DCs) are relatively inexpensive and easy to conduct. Therefore, they are frequently used to evaluate variations of geographical and temporal patterns, particularly in uncommon diseases. Recent surveys of motor neuron disease (MND) and multiple sclerosis (MS) based on official mortality statistics in Italy showed a decreasing trend of mortality from northern to southern Italy. To evaluate if DCs are homogeneously recorded in Italy and whether or not they can be considered a good instrument for mortality studies, we assessed the accuracy of DCs for MND and MS in the province of Palermo, Italy, and compared our results with those reported in other studies. We searched the archives of the neurological clinic of the University of Palermo for patients affected by one of the two diseases who were residents and were diagnosed in Palermo province. We found 157 patients with definite MND and 360 with clinically definite MS. Seventy-eight out of the 157 MND patients and 43 out of the 360 MS patients had died. Considering the underlying cause of death, the true-positive rate was 48% [95% confidence interval (CI) 36–60%] for MND and 46% (95% Cl 30–62%) for MS. The rates we found for MND were lower than those reported either in Italy or worldwide. This result suggests caution in formulating gradient hypotheses for MND. Concerning MS, the rate we found was low, but similar to that found by others. This indicates that a mortality survey of MS based on DCs is unlikely to be contributory.
Bilateraler Küttner-Tumor
Authors: Thomaser E.G. , Laeng R. Hubert
Published: April 2003

Fragestellung: Was sind die Gründe für die Seltenheit bilateraler, simultaner chronischer sklerosierender Sialadenitis der Glandula submandibularis (Küttner-Tumor)? Patienten und Methoden: Wir berichten über eine Patientin mit gleichzeitig auftretenden bilateralen Küttner-Tumoren der Glandulae submandibulares und führten auf der Suche nach weiteren Beispielen eine Literaturrecherche durch; ferner diskutieren wir die Histomorphologie und Pathogenese des Leidens. Resultate: Wir fanden einschliesslich unserer eigenen Patientin 5 Fälle bilateraler Küttner-Tumoren. Anhaltspunkte für ein systemisches Leiden fehlten mit einer Ausnahme, nur 1 Patient litt an einer chronischen Polyarthritis und hatte Xerostomie; bei allen andern bestand keine Autoimmunsialadenitis. Unsere Patientin war nach bilateraler Submandibulektomie, die in zwei Sitzungen vorgenommen wurde, beschwerdefrei, was bisher in den Nachkontrollen zu bestätigen war. Schlussfolgerung: Die Gründe für die grosse Seltenheit bilateraler Küttner-Tumoren sind in deren Pathogenese zu suchen: Es handelt sich um eine drüsenspezifische Elektrolytsialadenopathie, die oft mit Lithiasis assoziiert ist und zu einer lokalisierten destruierenden Immunreaktion führt.
Das Merkel-Zell-Karzinom – kasuistische Darstellung eines seltenen Tumors im Kopf-Hals-Bereich
Authors: Koscielny S. , Krüger J.
Published: April 2003

Hintergrund: Das Merkel-Zell-Karzinom ist ein seltener maligner Tumor der Hautanhangsgebilde, der vornehmlich in der lichtexponierten Haut der Kopf-Hals-Region vorkommt. Kennzeichnend für den Tumor ist seine hohe Neigung zu lokoregionalen Rezidiven und Fernmetastasen. Fallbeschreibung: In unserer Klinik behandelten wir im Januar 1996 eine 62jährige Patientin mit einem Merkel-Zell-Karzinom der rechten Wange erstmalig durch eine lokale Tumorresektion. Die vorgeschlagene Nachbestrahlung wurde von der Patientin abgelehnt. Ein lokoregionales Rezidiv, das 4 Monate später auftrat, therapierten wir kombiniert chirurgisch-radiologisch. Ergebnisse und Schlussfolgerungen: Die Patientin ist seit 40 Monaten tumorfrei. Im jährlichen Abstand durchgeführte Ganzkörperszintigramme, um das Vorhandensein von somatostatinrezeptorpositiven Strukturen abzuklären, ergaben auch keine Hinweise auf ein Rezidivgeschehen. Das Merkel-Zell-Karzinom ist ein seltener subkutaner Tumor der Kopf-Hals-Region mit einer hohen Rezidivneigung und einem hohen Metastasierungspotential. Die optimale Therapie ist eine Kombination von grosszügiger Resektion und Nachbestrahlung. In der Nachsorge hat sich die nuklearmedizinische Untersuchung auf somatostatinpositive Strukturen mit 111In-Octreosan für die Rezidiv- und Metastasensuche bewährt.
Welches System für den Stimmprothesenwechsel – Provox 1 oder Provox 2?
Authors: Koscielny S. , Bräuer B.
Published: April 2003

Hintergrund: Für den Wechsel von Stimmprothesen des Typs Provox stehen heute zwei unterschiedliche Systeme zur Verfügung. Während der Wechsel mit Provox 1 unter Einsatz eines Führungsmandrins retrograd via Mundhöhle/Pharynx erfolgt, wird Provox 2 komplett antegrad über das Tracheostoma eingesetzt. Aufgrund des notwendigen Führungsmandrins ist der Wechsel mit Provox 1 für Patienten und Operateur mit erheblichen Unannehmlichkeiten verbunden. Mit dem über das Tracheostoma einzuführenden System Provox 2 ist der Wechsel deutlich einfacher und komfortabler geworden. In dieser Studie teilen wir unsere Erfahrungen mit beiden Wechselsystemen mit. Patienten und Methode: 45 laryngektomierte Patienten mit Stimmprothesen aus unserer Tumornachsorge wurden bezüglich der Stimmprothesenwechsel ausgewertet. Ergebnisse: Es wurden 177 Stimmprothesenwechsel (69-mal Provox 1, 108-mal Provox 2) durchgeführt. Die Indikation zum Stimmprothesenwechsel ergab sich hauptsächlich aufgrund einer Aspiration. Deutlich weniger häufig waren erhöhter Widerstand beim Sprechen, Weitung der tracheoösophagealen Fistel, notwendige Änderung der Prothesenlänge und Prothesenverlust Gründe zum Wechsel. Provox 1 liess sich in 68% der Fälle problemlos wechseln, jedoch war in 23% der Fälle eine Führung des Mandrins in Oropharynx/Mundhöhle nur unter endoskopischer Kontrolle möglich. Provox 2 wurde in 94% der Fälle problemlos gewechselt. In 2% der Fälle ersetzten wir die Provox-2-Stimmprothese aufgrund eines unsicheren Sitzes im Ösophagus bei Granulationen durch eine Provox 1. Durchschnittlich musste alle 6 Monate die Stimmprothese gewechselt werden. Einen Unterschied in der Lebensdauer zwischen Provox 1 und 2 fanden wir nicht. In einer Patientenbefragung empfanden nahezu alle Patienten den Wechsel mit Provox 2 im Vergleich zu Provox 1 als deutlich angenehmer. Schlussfolgerungen: Provox 2 sollte heute das Standardsystem sein. Provox 1 sollte bei unsicherem ösophagealem Sitz aufgrund von Granulationen zur Anwendung kommen.
Dermoid Cyst of the Lateral Neck: Report of a Case
Authors: Ferekidis Eleftherios , Dinopoulou Dimitra , Yiotakis Ioannis , Kandiloros Dimitrios , Ferekidou Elisabeth , Adamopoulos George
Published: April 2003

Dermoid cysts of the floor of the mouth and submandibular space represent an unusual clinical entity. A case of an enlarged dermoid cyst in the left submandibular space in a 19-year-old female is reported, along with a review of the literature.
Differential Efficacy of Lithium and Carbamazepine in the Prophylaxis of Bipolar Disorder: Results of the MAP Study
Authors: Kleindienst Nikolaus , Greil Waldemar
Published: April 2003

In a randomized clinical trial with an observation period of 2.5 years, the differential efficacy of lithium versus carbamazepine was compared in 171 bipolar patients (DSM-IV). In order to investigate the efficacy of the two drugs in clearly defined subsamples, a series of subgroup analyses was carried out. First, patients with a bipolar I disorder (n = 114) were analyzed separately. In these patients, lithium was superior to carbamazepine. In contrast, carbamazepine was at least equally as efficacious as lithium in the subsample of patients with bipolar II disorder or bipolar disorder not otherwise specified (n = 57). In a second analysis on differential efficacy, the whole sample was subdivided into a classical subgroup (bipolar I patients without mood-incongruent delusions and without comorbidity; n = 67) and a nonclassical subgroup including all other patients (n = 104). Classical bipolar patients had a significantly lower hospitalization rate under lithium than under carbamazepine prophylaxis (26 vs. 62%, p = 0.012). For the nonclassical group, a tendency in favor of carbamazepine was found. In a third step, we analyzed the impact of episode sequence on differential efficacy. In a global view, the episode sequence prior to the index episode was not correlated to differential efficacy. Our results might, however, indicate that patients with an episode sequence of mania-depression-free interval responded better to lithium. Besides differential efficacy, suicidal behavior and patients’ satisfaction with treatment were investigated. Regarding suicidal behavior, a trend in favor of lithium was found. The data on patients’ satisfaction were significantly in favor of carbamazepine. In conclusion, lithium appears to be superior to carbamazepine in classical bipolar cases and might have additional impact on proneness to suicide. The distinctly larger group of patients with nonclassical features might profit more from carbamazepine which seems to be well accepted by the patients. Hence, treatment alternatives to lithium are desirable for the majority of bipolar patients.
Association Studies of Candidate Genes in Bipolar Disorders
Authors: Heiden Angela , Schüssler Petra , Itzlinger Ulrike , Leisch Friedrich , Scharfetter Joachim , Gebhardt Christian , Fuchs Karoline , Willeit Matthäus , Nilsson Linda , Miller-Reiter Ellenore , Stompe Thomas , Meszaros Kurt , Sieghart Werner , Hornik Kurt , Kasper Siegfried , Aschauer Harald N.
Published: April 2003

The aim of the investigation was to test genes for predisposition to bipolar affective disorder. Therefore, we studied candidate genes in a sample of unrelated patients (n = 102) and healthy controls (n = 79) of Austrian origin, searching for a possible association between polymorphic DNA markers of 5 candidate genes (serotonin transporter, 5-HTT; serotonin 2a receptor, 5-HT2a; dopamine D2 receptor, DRD2; dopamine D3 receptor, DRD3; dopamine transporter, DAT1) and bipolar disorder. There was an association between allelic and genotypic frequencies of 5-HTT and affection status (p = 0.014 and p = 0.017, respectively). However, after correction for multiple comparisons (Bonferroni), these results did not remain significant. Nevertheless, the findings might suggest that alterations in the structure of 5-HTT are involved in the pathogenesis of bipolar disorder, which could have major implications in treatment. No association between 5-HT2a, DRD2, DRD3, DAT1 and bipolar disorder was found.
Monoamine Compounds in Cerebrospinal Fluid of Healthy Subjects Punctured without Preceding Strict Bed Rest: A Pilot Study
Authors: Eklundh Thomas , Gunnarsson Tove , Nordin Conny
Published: April 2003

The interpretation of data on compounds in the lumbar cerebrospinal fluid (CSF) is limited by several confounding factors, e.g. motor activity for which strict bed rest prior to lumbar puncture is recommended for standardisation. Now we report data from 14 healthy males employing the standardised procedure except for the requirement of strict bed rest. The levels of serotonin, noradrenaline, 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid and 4-hydroxy-3-methoxyphenylglycol in the second CSF fraction (7–12 ml) were significantly higher than those in the first fraction (0–6 ml), indicating the presence of concentration gradients. 5-HIAA was negatively influenced by age and the neuraxis distance in the lying position and positively by atmospheric pressure. Storage time and atmospheric pressure contributed to the variance in dopamine. Both tyrosine, tryptophan and dopamine were linearly correlated with storage time. We also found a significant curvilinear correlation between tapping time and atmospheric pressure. On comparing with previous studies, the results support the notion that the issue of strict bed rest or not prior to lumbar puncture might have to be taken into consideration when interpreting lumbar monoamine CSF data.