bluuebunny/crossref_metadata_2025 huggingface dataset:
Rapid Stimulatory Effects of Brain-Derived Neurotrophic Factor and Neurotrophin-3 on Somatostatin Release and Intracellular Calcium Rise in Primary Hypothalamic Cell Cultures
Authors: Marmigère Frédéric , Choby Cécile , Rage Florence , Richard Sylvain , Tapia-Arancibia Lucia
Published: April 2003

Although the long-lasting effects of neurotrophins have been extensively studied, less data are available on their rapid effects, especially on peptide release. In the present report, we investigated rapid effects of neurotrophins on somatostatin release and on intracellular calcium concentration ([Ca2+]i) in primary cultures of hypothalamic neurons. RT-PCR experiments revealed mRNA expression of the three high-affinity neurotrophin receptors tyrosine kinase (Trk) TrkA, TrkB and TrkC, indicating potential responses to their preferential ligands: nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin 3 (NT-3), respectively. We demonstrated that BDNF, and to a lesser extent NT-3, induced significant time- and concentration-dependent somatostatin release, while NGF was devoid of any effect. BDNF or NT-3 induction of somatostatin release was inhibited by the Trk inhibitors K-252a and genistein, whereas K-252b, a less effective inhibitor, had no effect. BDNF- and NT-3-induced somatostatin release depended upon extra- and intracellular Ca2+ since it was completely abolished in the presence of the Ca2+ chelators BAPTA (bis-(α-aminophenoxy)-ethane-N,N,N′,N′-tetraacetic acid) or BAPTA-AM (bis-(α-aminophenoxy)-ethane-N,N,N′,N′-tetraacetoxymethylester), respectively. In addition, BDNF and NT-3 induced a sustained and rapid increase in [Ca2+]i which depended on the extracellular Ca2+ concentration. MK-801 (dizocilpine) and tetrodotoxin (TTX) entirely blocked neurotrophin-evoked somatostatin release and [Ca2+]i rise in response to BDNF and NT-3 application in most neurons. Neurotrophin-induced [Ca2+]i rise was completely blocked by K-252a. The present results are consistent with: (1) an indirect effect of neurotrophins on somatostatin release via endogenous glutamate release and subsequent NMDA receptor activation, (2) a major indirect effect of neurotrophins on Ca2+ rise in hypothalamic neurons which very likely occurs through NMDA receptor activation. Taken altogether, these results indicate that BDNF and NT-3 can rapidly affect the activity of hypothalamic neurons.
A Role of Ghrelin in Neuroendocrine and Behavioral Responses to Stress in Mice
Authors: Asakawa Akihiro , Inui Akio , Kaga Toshihiro , Yuzuriha Hideki , Nagata Toshiaki , Fujimiya Mineko , Katsuura Goro , Makino Susumu , Fujino Masayuki A. , Kasuga Masato
Published: April 2003

Ghrelin, an endogenous ligand of the growth hormone secretagogue receptor, was recently identified in the rat stomach. Previous studies have shown that ghrelin potently increases growth hormone release and food intake. We examined the effects of the gastric peptide ghrelin on anxiety-like behavior in association with the hypothalamic-pituitary-adrenal axis in mice. Both intra-third cerebroventricular and intraperitoneal administration of ghrelin potently and significantly induced anxiogenic activities in the elevated plus maze test. Ghrelin gene expression in the stomach was increased by tail pinch stress as well as by starvation stress. Administration of a corticotropin-releasing hormone (CRH) receptor antagonist significantly inhibited ghrelin-induced anxiogenic effects. Peripherally administered ghrelin significantly increased CRH mRNA, but not urocortin mRNA expression in the hypothalamus. Furthermore, intraperitoneal injection of ghrelin produced a significant dose- dependent increase in serum corticosterone levels. These findings suggest that ghrelin may have a role in mediating neuroendocrine and behavioral responses to stressors and that the stomach could play an important role, not only in the regulation of appetite, but also in the regulation of anxiety.
Ciliary Neurotrophic Factor, a gp130 Cytokine, Regulates Preovulatory Surges of Luteinizing Hormone and Prolactin in the Rat
Authors: Watanobe Hajime , Habu Satoshi
Published: April 2003

Ciliary neurotropic factor (CNTF) is a neuroregulatory cytokine belonging to the interleukin-6 type cytokine superfamily. Although a few studies have reported a facilitatory action of CNTF on the reproductive axis in rodents, information along this line is still very limited. In this study, we examined a possible role of CNTF in the generation of ovarian steroid-induced luteinizing hormone (LH) and prolactin (PRL) surges in the rat, a crucial physiological event in mammalian reproduction. Experiments were performed on both normally-fed and 3-day-fasted rats, ovariectomized and primed with estradiol and progesterone. Blood was collected every 30 min between 11:00 and 18:00 h, to measure LH and PRL. Drugs were given intracerebroventricularly at 11:00 h. Compared to control serum, undiluted as well as threefold dilutions of anti-CNTF serum caused partial but significant suppression of LH surges. Both concentrations of the antibody also delayed the onset of PRL surge to a comparable degree. Fasted rats did not exhibit significant surges of the hormones, while 0.3 and 1.0 nmol, but not 0.1 nmol, recombinant human CNTF led to a dose-dependent recovery of both LH and PRL surges. These results demonstrate for the first time a significant role of CNTF in the generation of preovulatory LH and PRL surges in the rat. CNTF may thus be another humoral signal linking nutrition and reproductive function.
In vivo Release of Prolactin-Releasing Peptide in Rat Hypothalamus in Association with Luteinizing Hormone and Prolactin Surges
Authors: Watanobe Hajime
Published: April 2003

Prolactin (PRL)-releasing peptide (PrRP) is a novel hypothalamic peptide reported to be a potent and specific stimulator of PRL secretion. This author recently reported that PrRP might play a significant role in mediating the steroid-induced PRL surge in the rat. In order to examine the secretory profile of PrRP in the rat hypothalamus before and during the luteinizing hormone (LH) and PRL surges, this study employed the push-pull perfusion technique and determined the in vivo release of PrRP and also of gonadotropin-releasing hormone (GnRH) in ovariectomized rats primed with estradiol and progesterone. In the medial preoptic area (MPOA) where the GnRH neuronal perikarya exist, GnRH release was increased prior to the initiation of the LH surge, and PrRP also started rising even earlier than GnRH. In the median eminence-arcuate nucleus complex (ME-ARC), where GnRH neuronal fibers terminate, GnRH secretion started increasing before the commencement of the LH surge, but the release of PrRP did not change significantly. These results suggest that PrRP may play a role in mediating the steroid-induced LH surge by activating GnRH neurons in the MPOA. A possible involvement of PrRP in the PRL surge was not suggested from the present data. The lack of a significant alteration in PrRP release in the ME-ARC may argue against a direct hypophysiotropic action of the peptide.
Restraint Stress Modulates Brain, Pituitary and Adrenal Expression of Angiotensin II AT1A, AT1B and AT2 Receptors
Authors: Leong Darren S. , Terrón José A. , Falcón-Neri Alicia , Armando Ines , Ito Takeshi , Jöhren Olaf , Tonelli Leonardo H. , Hoe Kwang-Lae , Saavedra Juan M.
Published: April 2003

Angiotensin II (Ang II) AT1 receptors are involved in the regulation of the stress response. In adult male rats, acute restraint increased AT1A mRNA in paraventricular nucleus. Repeated restraint increased AT1A mRNA and AT1 binding in paraventricular nucleus and AT1 binding in subfornical organ and median eminence. AT1B and AT2 receptors were not expressed in brain areas involved in the stress response. Acute restraint increased anterior pituitary AT1A mRNA and AT1 binding and decreased AT1B mRNA. During repeated restraint, the increase in AT1A mRNA in the anterior pituitary was maintained, but AT1B mRNA and AT1 binding returned to normal levels. In adrenal zona glomerulosa, AT1B mRNA, AT1 binding, AT2 mRNA and AT2 binding decreased during acute restraint. Receptor mRNA and binding returned to normal after repeated stress, with the exception of rebound increase in adrenal zona glomerulosa AT2 mRNA. In adrenal medulla, AT1A mRNA increased and AT2 mRNA decreased during acute restraint. AT1A mRNA remained increased during repeated restraint, while alterations in AT2 mRNA were no longer present. Expression of AT1A, AT1B and AT2 receptors in the hypothalamic-pituitary-adrenal axis is tissue specific and is different in acute and repeated stress. Increased brain, pituitary and adrenomedullary AT1A receptor expression correlates with hypothalamic-pituitary-adrenal axis stimulation, supporting the hypothesis of Ang II, through selective AT1A receptor stimulation, as an important determinant of the acute and repeated stress response. Decreased adrenal zona glomerulosa and anterior pituitary AT1B receptors during acute stress can be interpreted as compensatory to increased stimulation by Ang II. There may be additional roles for adrenal AT2 receptors during acute stress, possibly related to interaction or cross-talk with AT1 receptors.
Marked Increases in Macrophage Colony-Stimulating Factor and Interleukin-18 in Maintenance Hemodialysis Patients: Comparative Study of Advanced Glycation End Products, Carboxymethyllysine and Pentosidine
Authors: Uchimura Tomonori , Motomiya Yoshihiro , Okamura Haruki , Hashiguchi Teruto , Miura Masakazu , Uji Yoshinori , Iwamoto Hisahiko , Maruyama Ikuro
Published: April 2003

Background: Recent studies have demonstrated the crucial involvement of advanced glycation end products (AGEs) in major complications of long-term hemodialysis (HD) patients. HD, in a clinical setting, is characterized by increased production of proinflammatory cytokines. AGEs and cytokines are presumed to be responsible for the development of major complications in long-term HD. We therefore investigate here the relationship between a newly identified cytokine, interleukin-18 (IL-18), and two AGEs, carboxymethyllysine-hemoglobin (CML-Hb) and pentosidine. Methods: CML-Hb, pentosidine macrophage colony-stimulating factor (M-CSF), and IL-18 were evaluated in 35 patients undergoing stable maintenance HD. CML-Hb and pentosidine were measured by a dot blot and competitive ELISA. Cytokines were measured with a cytokine-specific ELISA. Results: Circulating levels of CML-Hb and pentosidine were elevated in HD patients as compared to controls. The serum values of M-CSF and IL-18 were significantly increased in the HD patients in comparison to controls. Moreover, these two AGEs and serum values of M-CSF, M-CSF and IL-18 showed significant correlation by simple and multiple regression analysis. Conclusion: Elevation of circulating IL-18 levels was demonstrated in maintenance HD patients relative to controls. A correlative increase in M-CSF and IL-18 suggests the presence of a primed state of monocytes/macrophages in HD patients.
A Latent Variable Approach to Studying Risk Factors for Alzheimer’s Disease
Authors: Liu Susan J. , Crum Rosa M. , Anthony James C.
Published: April 2003

The objective of this study is to investigate and to improve measurements for the study of suspected animal and occupational exposure risk factors for Alzheimer’s disease (AD). A subsample (n = 200) of a longitudinal study sample from research on risk factors for Alzheimer’s disease was selected by systematic probability sampling. Participants were men born between 1917 and 1927, selected from the National Academy of Sciences-National Research Council (NAS-NRC) Registry of white male twins who served in the United States Armed Forces during the World War II Korean Conflict era. A questionnaire was administered via telephone interview. A total of 25 animal exposure items and 28 occupational exposure items were selected from the risk factor questionnaire administered to the men. Measurement for animal or occupational exposure was ascertained based upon the participants’ responses to the survey questions. Latent variable analyses extracted 3 animal exposure factor scales: pet, farm/livestock and exposure to wild animals (e.g. while hunting). The occupational exposure data led to extraction of 2 factor scales: medical exposures and manual work involving metal. Latent variable analysis revealed that many items (potential risk factors) are highly correlated with each other and can be conceptualized as correlated observable manifestations of more unitary underlying constructs. In future research, it may be advantageous to assess correlated items such as these in relation to an underlying dimension of exposure, rather than as discrete exposures.
Frequency of Multiple Sclerosis in Menorca, Balearic Islands, Spain
Authors: Casquero Pilar , Villoslada Pablo , Montalbán Xavier , Torrent Matías
Published: April 2003

Objective: To establish prevalence and incidence of multiple sclerosis (MS) in Menorca (Balearic Islands, Spain; population: 67,009). Methods: An extensive epidemiological study was undertaken using all available information sources. Patients were classified according to Poser’s criteria. Results: The prevalence rate of definite and probable MS was 68.6/100,000 (95% confidence interval 50.3–91.6). The incidence rate was 3.4/100,000/year (95% CI 2.2–5.3). The time lag between the first symptom and diagnosis was 10.2 years for patients with disease onset before 1987 and 2.1 years for patients with onset between 1987 and 1996. Conclusion: Menorca’s population has a moderately high MS risk, with a prevalence rate the highest reported for a Spanish region.
The Cochrane Collaboration in Neurology: Acquisitions, Research, and New Initiatives
Authors: Tonini Clara , Beghi Ettore , Telaro Elena , Candelise Livia
Published: April 2003

The Cochrane Collaboration (CC) is an international organization involving 16 national centers around the world, set up in response to the need for collecting all randomized controlled trials on health care interventions, with the aim of facilitating and coordinating the preparation, maintenance and dissemination of periodic systematic reviews of these trials. These are prepared by Collaborative Review Groups (CRGs) working together in an area of common interest under the guidance of an editorial team, supported by national Cochrane centers. Nine CRGs are involved in each neurological field, with more than 300 reviewers and members of editorial teams. For a review to be called a ‘Cochrane review’, it must be structured in the format outlined in the Cochrane Handbook. It is then published and disseminated through the Cochrane Database of Systematic Reviews (CDSR) in the Cochrane Library (CL). Each Cochrane review is prepared using the Review Manager software distributed to CRGs by CC. The editorial team is responsible for assembling an edited module of reviews prepared by CRGs for incorporation and dissemination using electronic media through the CDSR located in the CL. The CL contains information about the CC and 4 other databases: the Database of Abstracts of Reviews of Effectiveness, the Cochrane Controlled Trials Register, the Cochrane Review Methodology Database and the NHS Economic Evaluation Database. The authors use an example of Cochrane reviews about cerebrovascular disorders to illustrate that the CL is a powerful source of evidence for answering clinical questions and providing information as a basis for therapeutic decisions, for the improvement of neurological practice. A new initiative, the Cochrane Neurological Network, has recently been set up with the aim of improving communication among neurological CRGs, and between them and health care professionals interested in neurological diseases so as to update neurologists on the activity of the CC.
Estimation of Mortality and Morbidity due to Strokes in India
Authors: Anand K. , Chowdhury D. , Singh K.B. , Pandav C.S. , Kapoor S.K.
Published: April 2003

In order to control the stroke problem, its magnitude should be assessed. India is ranked among the countries where the information on stroke is minimal. We decided to review the information available in order to estimate the mortality and morbidity due to stroke in India. Information was collected through electronic search, hand search and contact with experts. Each article was reviewed for relevance and epidemiological rigor. The demographic data were as derived from published government figures. The prevalence from individual studies was pooled and weighted based on sample size. Analysis was done separately for males and females at 10-year intervals (20 years onwards). A total of 7 studies was located, but 2 were discarded. All were done in rural areas except 2 which also included urban areas. The prevalence was estimated as 203 per 100,000 population above 20 years amounting to a total of about 1 million cases. The male to female ratio was 1.7. Around 12% of all strokes occurred in population below 40 years. The estimation of stroke mortality was seriously limited by the method of classification of cause of death in the country. The best estimate derived was 102,000 deaths; which represented 1.2% of total deaths in the country. There is need to initiate steps to collect data on morbidity and mortality due to stroke in the country as a first step towards control measures.
Fish Consumption and Stroke: A Community Case-Control Study in Asturias, Spain
Authors: Caicoya M.
Published: April 2003

Background: The relationship between fish consumption and stroke is controversial. Actually, a low fish consumption may protect against ischemic stroke, while a fish diet is ecologically associated with an increased risk of hemorrhagic stroke. Objective: This study seeks to examine the relationship between fish consumption and stroke in a population with a high fish consumption and stroke incidence. Methods: A population-based case-control study was performed, lasting from September 1990 to December 1991. The study comprised 440 incident cases of stroke and 473 controls between the ages of 40 and 85. Cases were defined following WHO criteria, and controls were randomly selected from the study base population. Information on fish consumption was obtained with a food frequency questionnaire. Results: After controlling for age, energy intake and several stroke risk factors, the risk of stroke increased with the consumption of fish, χ2 4.12, p = 0.04. Those in the highest quintile of consumption (46 g of fish/day) had a multivariate adjusted odds ratio (OR) of 1.95 (95% CI: 1.14–3.33) as compared to those in the lowest quintile of fish consumption (11 g/ day). The risk of cerebral infarction also increased with the consumption of fish, showing an OR of 1.98 (95% CI: 1.08–3.47). Those in the highest quintile of n–3 fatty acid consumption (660 mg/day) were at borderline higher risk of stroke, with an OR of 1.76 (95% CI: 0.95–3.26), and also of cerebral infarction (OR: 1.89, 95% CI: 0.95–3.75), as compared to those in the lower quintile of n–3 fatty acids consumption (115 mg/day). Conclusion: Although misclassification of exposure and residual confounding by unmeasured factors cannot be ruled out, a high fish consumption was associated with an increased risk of stroke and cerebral infarction in this study. More studies should be done to clarify the effect of fish consumption on stroke and stroke subtype in order to issue recommendations regarding the consumption of fish and the risk of stroke.
Dreidimensionale Navigation mit dem EasyGuide®-System im Kopf-Hals-Bereich
Authors: Heermann R. , Husstedt H. , Schwab B. , Tyra G. , Becker H. , Lenarz T.
Published: April 2003

Fragestellung: Die Verbreitung der minimal invasiven Operationstechniken hat zu neuen chirurgischen Herausforderungen geführt. Insbesondere bei veränderter Anatomie und fehlenden anatomischen Landmarken kann die Orientierung auch für den erfahrenen Chirurgen schwierig sein. Hier haben die intraoperativen Navigationssysteme in den letzten Jahren neue Möglichkeiten eröffnet. Methode/Patienten: Das Navigationssystem EasyGuide® Neuro (Philips Medizinische Systeme, Best, Niederlande) basiert auf einem dreidimensionalen optoelektronischen Messsystem. Infrarotemittierende Dioden an verschiedenen Pointerinstrumenten sowie der Patientenkopfhalterung werden durch ein Kamerasystem erfasst. Mittels weiterer mathematischer Transformation wird die Position der Instrumente in Bezug zum Patienten berechnet und mit den präoperativ gewonnenen radiologischen Datensätzen korreliert. Durch Studien an verschiedenen Phantomen wurden zunächst die technische Genauigkeit und die Grenzen der optischen Detektion evaluiert. Dann erfolgte bei 38 Patienten der operative Eingriff im Bereich der vorderen und seitlichen Schädelbasis mit Unterstützung des Navigationssystems. Hierbei wurden klinische Genauigkeit, Praktikabilität, Vorteile und Probleme des Systems untersucht. Ergebnisse: Am Phantom bot das System eine Abweichung von unter 1 mm. Im klinischen Einsatz konnte nur mit Kopffixierung und knochenverankerten Referenzmarkern eine Genauigkeit von etwa 1,5 mm erreicht werden. Bei Hautklebereferenzmarkern und flexibler Kopflagerung waren aufgrund der unzuverlässigen Kopfnachführung Abweichungen von bis zu 28 mm möglich. Die präoperative Vorbereitungszeit betrug 20–30 min, je nach Aufwand der Operationsplanung. Schlussfolgerungen: Das intraoperative Orientierungssystem stellt insbesondere bei untypischen anatomischen Verhältnissen eine deutliche Orientierungshilfe dar. HNO-spezifische Veränderungen sind jedoch notwendig, um den routinemässigen Einsatz im Bereich der Nasennebenhöhlenchirurgie zu gewährleisten.
Is There a Loss of Efficacy of Lithium in Patients Treated for Over 20 Years?
Authors: Berghöfer Anne , Müller-Oerlinghausen Bruno
Published: April 2003

Diminishing efficacy of lithium prophylaxis in initially well-responding patients during long-term treatment as well as after interruption of prophylaxis has been described repeatedly in the past. For the present analysis, 22 patients with bipolar and unipolar affective disorder continuously treated and documented in a specialized lithium outpatient clinic over at least 20 years were included. The cumulative affective morbidity of the first 10 years versus the second 10 years of prophylactic treatment was subjected to statistical and single-case (life chart method) analysis. There was no statistical evidence for diminishing efficacy of lithium prophylaxis. The increase in the Morbidity Index in single patients in a case-related individual approach could be revealed as not necessarily due to an alleged loss of efficacy of lithium, but more likely to be due to the atypical features in the psychopathology and course of illness.
mRNA Expression of Serotonin Receptors of Type 2C and 5A in Human Resting Lymphocytes
Authors: Marazziti Donatella , Ori Michela , Nardini Martina , Rossi Alessandra , Nardi Irma , Cassano Giovanna B.
Published: April 2003

We investigated the presence of mRNA for serotonin receptors of type 2C (5-HT2C) in resting lymphocytes by means of RT-PCR and Southern blotting analyses, given their possible role in the pathophysiology of anxiety and eating disorders. At the same time, we explored also the presence of the specific mRNA for 5-HT5A receptors, a novel subtype for which still no functional data exist. Healthy subjects and patients with obsessive-compulsive or bipolar disorders were included in the study. The results showed the presence of the specific mRNAs for both 5-HT2C and 5-HT5A receptors in resting lymphocytes of the three groups of subjects. An additional band was also observed after the amplification of the 5-HT5A cDNA in each sample. These findings, while revealing the presence of 5-HT2C and 5-HT5A receptor mRNAs in an easily available tissue, can be considered preliminary for future quantitative analyses in patients with different psychiatric conditions.
Dehydroepiandrosterone Sulphate and Corticotropin Levels Are High in Young Male Patients with Conduct Disorder: Comparisons for Growth Factors, Thyroid and Gonadal Hormones
Authors: Dmitrieva T.N. , Oades R.D. , Hauffa B.P. , Eggers C.
Published: April 2003

Childhood conduct disorder (CD) may originate in a stressful upbringing, and be associated with unusual physical or sexual development and thyroid dysfunction. We therefore explored circulating levels of hormones from adrenal, gonadal and growth hormone axes associated with stress, aggression and development in 28 CD patients and 13 age-matched healthy children (10–18 years old). The CD group had higher levels of dehydroepiandrosterone sulphate (DHEA-S), corticotropin (ACTH) and free tri-iodothyronine (fT3) if under 14 years. There were no differences for gonadal hormones or maturity ratings which were not associated with aggression. Smaller physical measures in CD children correlated with DHEA-S and growth factors (e.g. insulin-like growth factor I) increased ACTH and fT3 correlated with restless-impulsive ratings, and DHEA-S with ‘disruptive behaviour’. Imbalances in the adrenal and growth axes may have neurotropic repercussions in development.
Mania Resulting from Continuous Positive Airways Pressure in a Depressed Man with Sleep Apnea Syndrome
Authors: Hilleret Henriette , Jeunet Eric , Osiek Christian , Mohr Sylvia , Blois Robert , Bertschy Gilles
Published: April 2003

The authors report the case of a 50-year-old man, with no previous history of bipolar illness, hospitalized with a very severe depression and who was resistant to a 7-weeks treatment of venlafaxine and trazodone (the respective daily doses were 300 and 50 mg which were stable during the last 4 weeks). A diagnosis of sleep apnea syndrome led to the use of the continuous positive airways pressure technique (CPAP). A few days after starting CPAP, he presented a mood switch, first hypomanic, then mixed. The authors discuss the contribution of the sleep apnea syndrome to the appearance and the maintenance of the depressive disorder.
Short-Term Rivastigmine Treatment Reduces EEG Slow-Wave Power in Alzheimer Patients
Authors: Adler Georg , Brassen Stefanie
Published: April 2003

The effects of a 5-day treatment with rivastigmine on the resting EEG power spectrum were studied in 15 mildly to moderately ill Alzheimer patients. In these patients, beta power was positively correlated with cognitive performance and negatively correlated with functional impairment. Rivastigmine produced a decrease in delta and theta power with no effect of hemisphere and electrode position. Delta power decrease reflects the cerebral cholinergic action of rivastigmine and may thus allow a quantitative assessment of its CNS effects.
Consensus on the Practical Use of Amisulpride, an Atypical Antipsychotic, in the Treatment of Schizophrenia
Authors: Lecrubier Yves , Azorin Michel , Bottai Thierry , Dalery Jean , Garreau Gérard , Lempérière Thérèse , Lisoprawski Agnès , Petitjean François , Vanelle Jean-Marie
Published: April 2003

Clinical expectations in schizophrenia treatment have greatly increased since the introduction of new atypical antipsychotics, but the choice of therapeutic strategy has become more complex and reference guidelines are scarce. This paper summarizes the consensus of a broad range of professionals after long-term commercialization in France of an atypical antipsychotic, amisulpride. Participants were from psychiatric hospitals, private clinics, out-patients settings and research; all were experienced with the drug. Discussions focused on the practical use of amisulpride, as, in addition to the double-blind trials information, it may be useful for psychiatrists of other countries to intuitively understand the therapeutic properties of amisulpride. The topics selected include acute psychotic episodes, short- and long-term follow-up, feasibility of treating the initial phase, the elderly and switching treatments. The French experience emphasizes the central role of amisulpride as a first-line treatment of schizophrenia.
Neurotrophic Factor S100beta in Major Depression
Authors: Grabe Hans Jörgen , Ahrens Norbert , Rose Hans-Joachim , Kessler Christof , Freyberger Harald Jürgen
Published: April 2003

Disturbances in the serotonergic system are considered to be implicated in the pathophysiology of depressive disorders. The possible role of the neurotrophic factor S100 beta, which is suspected to regulate regeneration of serotonergic synapses, has not been investigated in depressive disorders. The S100beta concentration in the cerebrospinal fluid was measured in 11 patients with the current diagnosis of mild or moderate depressive episodes (DSM-IV) and in 11 matched control patients. Using the t test for paired samples, the presence of a depressive episode was significantly associated with an elevation of the cerebrospinal fluid concentration of S100beta (t = 2.6, d.f. = 10, p = 0.024). Replications of this finding in severely depressed patients are necessary to confirm the association between neurotrophic factor S100beta and depressive disorders.
Seed Finding in Golden Hamsters: A Potential Animal Model for Screening Anxiolytic Drugs
Authors: King Jean A. , Messenger Tara , Ferris Craig F.
Published: April 2003

Fasting hamsters overnight, followed by temporary isolation in a novel environment are stressful conditions that hamper their ability or motivation to find hidden sunflower seeds when returned to their home environment. Studies were done to test whether treatment with antianxiety drugs would reduce stress and shorten the latency to find the hidden seeds. Prior to testing, the animals were fasted for 18–20 h. Ninety minutes after intraperitoneal injection of test drugs (fluoxetine, buspirone, chlordiazepoxide, clozapine, desipramine, yohimbine), the animals were taken from their home cage and placed into a novel holding cage for 2 min. During their absence, 6 sunflower seeds were buried under the bedding in one corner of their home cage. The animals were placed back into their home cage and timed for their latency to find the seeds in a 5-min observation period. Treatment with anxiolytics caused a dose-dependent reduction in the latency to find the sunflower seed, while treatment with other psychotherapeutics were ineffective. Seed finding is an extremely sensitive bioassay, responding to anxiolytics given in doses as low as 1 µg/kg. These data provide evidence that seed finding in hamsters may serve as an animal model for screening potential anxiolytic drugs.
Endocrine Therapy in Pancreatic Carcinoma
Authors: Yamashita Jun-ichi , Abe Michio , Ogawa Michio
Published: April 2003

There are indications of the possible effects of sex hormones on pancreatic carcinoma. Estrogen receptor (ER) has been demonstrated in pancreatic tumors in experimental animals and in humans and it has been suggested that endocrine manipulation may be effective in the treatment of pancreatic carcinoma. However, it is still controversial whether this lethal cancer can potentially benefit from endocrine therapy. One explanation for the conflicting data on the benefit of hormonal manipulation in the treatment of pancreatic carcinoma may stem from the fact that there is no adequate marker to assess estrogen dependency of the pancreatic tumors. In this article, we review our work on tissue plasminogen activator as a prognostic guide to evaluate the efficacy of hormonal therapy in human pancreatic carcinoma, and also suggest that a selected subgroup of patients with this lethal cancer may have a potential clinical benefit from endocrine therapy, especially medroxyprogesterone acetate treatment.
Aromatase and Intracrinology of Estrogen in Hormone-Dependent Tumors
Authors: Harada Nobuhiro
Published: April 2003

Aromatase (estrogen synthetase) has been shown to occur in various extragonadal tissues as well as gonadal tissues, to be tissue-specifically regulated by various factors, and to play important roles in physiological functions in various tissues. The human gene is revealed to contain multiple variants of exon 1 which are tissue-specifically selected. Each exon 1 is flanked with a unique promoter region, which may explain tissue-specific transcription. All results strongly support an idea of intracrinology of estrogen. The validity of this concept is verified in connection with plasma levels of various steroid hormones and association constants of aromatase and estrogen receptor. 17β-Estradiol is locally produced through several metabolic pathways. In this context, aromatase, steroid sulfatase, estrogen sulfotransferase, and 17β-hydroxysteroid dehydrogenases I and II are considered to be important factors in the development of hormone-dependent tumors.
Oral Combination of Cyclophosphamide, Uracil plus Tegafur and Estramustine for Hormone-Refractory Prostate Cancer
Authors: Nishimura K. , Nonomura N. , Ono Y. , Nozawa M. , Fukui T. , Harada Y. , Imazu T. , Takaha N. , Sugao H. , Miki T. , Okuyama A.
Published: April 2003

Objective: To evaluate the clinical usefulness of an oral combination of cyclophosphamide, uracil plus tegafur (UFT) and estramustine in the treatment of patients with hormone-refractory prostate cancer (HRPC). Methods: Twenty-one patients were treated with oral administration of cyclophosphamide (100 mg/day), UFT (400 mg/day) and estramustine phosphate (560 mg/day). The median age of the patients was 70 years. Twelve patients had symptomatic bone metastasis, 6 had asymptomatic bone metastasis, 5 had lymph node metastasis, while 2 had only biochemical progression evaluated by prostate-specific antigen (PSA). Results: Twelve (57%) out of 21 patients showed a PSA decline of 50% or greater. The median response duration was 7 months (range 2–15 months). Among the 20 patients assessable for bone pain, 2 (10%) improved, 12 (60%) remained stable and 6 (30%) progressed. Among the 10 patients assessable for bone metastasis, 1 (10%) improved, 5 (50%) were stable and 4 (40%) progressed on bone scan. Among 3 patients assessable for measurable disease (lymph node metastasis), 2 (67%) showed partial response and 1 (33%) progression. Most toxicities were mild. Conclusions: The combination of cyclophosphamide, UFT and estramustine is an active and well-tolerated regimen for HRPC. To evaluate the survival benefit, further randomized studies are required.
Phase II Trial of a Paclitaxel-Carboplatin Combination in Recurrent Squamous Cell Carcinoma of the Head and Neck
Authors: Pivot X. , Cals L. , Cupissol D. , Guardiola E. , Tchiknavorian X. , Guerrier P. , Merad L. , Wendling J.L. , Barnouin L. , Savary J. , Thyss A. , Schneider M.
Published: April 2003

Objective: Twenty-seven patients with recurrent squamous cell carcinoma of the head and neck were entered in a multicenter study to determine the efficacy of the paclitaxel-carboplatin association. Methods: Standard eligibility criteria applied, i.e. measurable disease, and chemotherapy given as induction treatment or concomitant chemoradiotherapy was allowed if completed more than 6 months prior to the study. Every 21 days, paclitaxel 175 mg/m2 and carboplatin AUC 6 were administered. The patient group included 3 females and 24 males with a median age of 61 years (range 39–75 years). Results: All patients were assessable for toxicity and 24 for responses. Main grade 3–4 toxicities were: neutropenia (62.9%), febrile neutropenia (18.5%), anemia (11.1%), thrombocytopenia (14.8%), mucositis (7.4%) and vomiting (7.4%). Among the intent-to-treat population, 29.6% of patients had an objective response, with a median response duration of 4.2 months (range 1–5.7 months). Stable and progressive disease were observed in 11.1 and 48.1% of patients, respectively. The median overall survival was 7.2 months (range 0.5–10.9 months). Conclusion: From these data, paclitaxel-carboplatin seems to have an activity in recurrent squamous cell carcinoma of the head and neck, but the high level of toxicity highlights the need to search for a safer chemotherapy combination.
Tumor ‘Flare’ Hypercalcemia – An Additional Indication for Bisphosphonates?
Authors: Nikolić-Tomašević Zorica , Jelic Svetislav , Popov Ivan , Radosavljević Davorin , Mitrović Labuda
Published: April 2003

The most serious, potentially life-threatening manifestation of ‘flare’ is hypercalcemia, registered in 4–5% of breast cancer patients with bone metastases, usually during the first few weeks of tamoxifen treatment. There are no specific treatment recommendations for flare hypercalcemia, except tamoxifen withdrawal. There are no reports on the use of bisphosphonates in the treatment of flare hypercalcemia. Among 87 hypercalcemic patients with metastatic breast cancer observed during a 7-year period, 10 patients had tamoxifen-induced hypercalcemia. Diagnosis of flare hypercalcemia was based on the normal pretreatment values of serum calcium and the development of hypercalcemia within a maximum of 6 weeks of hormonal drug initiation. The median time from hormonal drug initiation to flare hypercalcemia was 14 days, the median duration 8.5 days, and the median calcium level was 3.09 mmol/l (range 2.79–4.46 mmol/l). All patients were treated with hydration, and 7 patients with calcium levels above 3.0 mmol/l were also treated with disodium pamidronate in various single doses (30–90 mg/24 h). Normocalcemia was achieved in all patients, and tamoxifen was continued without relapse of hypercalcemia. Median survival was 177 days (range 12–570 days). It seems that the use of bisphosphonates in the treatment of flare hypercalcemia could allow safe readministration of tamoxifen and prevent premature and unjustified tamoxifen discontinuation. Flare hypercalcemia might represent one more indication for the use of bisphosphonates.
The Evolving Role of Gemcitabine in the Management of Breast Cancer
Authors: Seidman Andrew D.
Published: April 2003

Despite the common clinical use of numerous active cytotoxic agents for breast cancer therapy, and the combinations that are derived from them, the median survival for patients with metastatic breast cancer has not been dramatically improved over the past two decades. Furthermore, when the expected outcome of treatment is not cure, optimizing the dynamic equilibrium between chemotherapy-induced side effects and the benefits attributable to chemotherapy-mediated relief of cancer-related symptomatology becomes paramount. The search for active agents to this end has recently included the clinical evaluation of the novel nucleoside analogue gemcitabine (2′,2′-difluorodeoxycytidine). This review summarizes the recent and current development of this agent.
Expression and Clinical Significance of the G1-S Modulators in Intrahepatic Cholangiocellular Carcinoma
Authors: Ito Yasuhiro , Takeda Tsutomu , Sasaki Yo , Sakon Masato , Yamada Terumasa , Ishiguro Shingo , Imaoka Shingi , Tsujimoto Masahiko , Matsuura Nariaki
Published: April 2003

Objective: To elucidate the clinical roles of G1-S modulators in cholangiocellular carcinoma (CCC). Methods: We performed immunohistochemistry using antibodies against the retinoblastoma gene product (pRb), p16, p21, p27, p53 and cyclin D1 for 41 cases of CCC as well as normal bile ducts. Results: The p27 labeling index (LI) was significantly higher in cases without lymph node metastasis than in normal bile ducts, but it decreased greatly in cases with lymph node metastasis. It was inversely related to the Ki-67 LI. The p16 LI also showed a relationship with lymph node metastasis, but not with the Ki-67 LI. The p21 LI was even higher in poorly differentiated cases and showed a direct relationship with the Ki-67 LI, although it is a negative regulator of the cell cycle. pRb expression did not correlate with any clinicopathological features. Cyclin D1 overexpression was more frequently observed in cases with poor or moderate differentiation and with lymph node metastasis. Cyclin D1 overexpression and aberrant p53 expression showed direct relationships with the Ki-67 LI. Conclusions: These results suggest that in CCC: (1) p27 expression reflects the biological character of the carcinoma and may regulate its progression; (2) cyclin D1 plays a crucial role in cell cycle progression, and (3) aberrant p53 expression has some effect on CCC cell proliferating activity.
Insulin-Like Growth Factor Binding Protein-3 Predicts Survival from Acute Childhood Leukemia
Authors: Petridou Eleni , Skalkidou Alkistis , Dessypris Nick , Moustaki Maria , Mantzoros Christos , Spanos Evagelos , Trichopoulos Dimitrios
Published: April 2003

Objective: To investigate whether the three principal components of the insulin-like growth factor (IGF) system, IGF-1, IGF-2 and IGF binding protein-3 (IGFBP-3), are associated with survival from childhood leukemia. Patients and Methods: 116 children, 0–14 years old, with newly diagnosed and bone-marrow-biopsy-confirmed acute childhood leukemia between 1993 and 1996 were followed up until death or March 31, 1998. IGF-1, IGF-2 and IGFBP-3 were measured at diagnosis and clinical data, including presence of hepatosplenomegaly and number of white blood cells, were available. Results: After controlling for gender, age, indicators of clinical severity and the other measured components of the IGF system there was a statistically significant (p < 0.05) inverse association of IGFBP-3 with survival. An increment of one standard deviation in IGFBP-3 was associated with a 65% reduction of the death hazard among the children with leukemia. Neither IGF-1 nor IGF-2 was associated with survival in this data set. Conclusion: The presented empirical evidence in conjunction with the fact that IGFBP-3 modulates IGF-1 and IGF-2 bioavailability and is likely to have proapoptotic effects makes this compound a plausible independent predictor of survival from childhood leukemia.
Evaluation of TGF-α and EGFR Expression in Oral Leukoplakia and Oral Submucous Fibrosis by Quantitative Immunohistochemistry
Authors: Srinivasan Mythily , Jewell Scott D.
Published: April 2003

Objective: Oral leukoplakia (OL) and oral submucous fibrosis (OSMF) are clinically distinct preneoplastic states that precede the development of oral squamous cell carcinoma. Recently, attempts are being made to identify specific molecular event(s) as prognostic markers to identify oral precancerous lesions with higher malignant potential. The goal of the present study was to evaluate the expression of EGFR and its ligand TGF-α in OL with dysplasia and OSMF as intermediate markers of malignancy by quantitative immunohistochemistry. Methods: Oral tissues were stained with monoclonal antibodies to TGF-α and EGFR. The results were analyzed with Photoquant image analysis software. Results: The expression of TGF-α and EGFR was upregulated in OL, OSMF and oral squamous cell carcinomas relative to normal oral mucosa. The area and intensity of staining of TGF-α in the proliferative layers (stratum germinativum) increased linearly in OL with mild, moderate and severe dysplasia as compared to control mucosa (p < 0.05). EGFR levels increased linearly in the stratum spinosum in OL with increasing degrees of dysplasia (p < 0.05). In general, the expression of both proteins in OSMF was similar to that in OL with moderate dysplasia. Conclusions: EGFR and TGF-α represent early markers of malignancy in OL with dysplasia. Quantitative measurement of these proteins may provide intermediate endpoints in prospective chemopreventive trials.
Quantitative Analysis of Estrogen Receptor-α and -β Messenger RNA Expression in Normal and Malignant Thyroid Tissues by Real-Time Polymerase Chain Reaction
Authors: Egawa Chiyomi , Miyoshi Yasuo , Iwao Kyoko , Shiba Eichi , Noguchi Shinzaburo
Published: April 2003

Objectives: We have conducted a quantitative analysis of estrogen receptor-α (ER-α) and -β (ER-β) mRNA expression in normal thyroid and tumor tissues. Methods: Normal thyroid tissues (n = 10) and tumor tissues [(follicular adenoma (n = 14), follicular carcinoma (n = 8), papillary carcinoma (n = 14), anaplastic carcinoma (n = 3) and medullary carcinoma (n = 6)] were obtained at surgery from 45 female patients. ER-α and ER-β mRNA expression has been studied by a quantitative polymerase chain reaction. Results: ER-α mRNA levels in the normal thyroid were not significantly different from those in follicular adenomas, papillary carcinomas and medullary carcinomas but were marginally (p = 0.08) higher than those in follicular and anaplastic carcinomas. ER-β mRNA levels in the normal thyroid tissues were not significantly different from those in any other tumor tissues. ER-β to ER-α mRNA ratios were significantly (p < 0.05) higher in the normal thyroid tissues than in follicular adenomas. Proportions of ER-β mRNA variants (ER-β 1, 2, 5, and 5′) did not significantly differ among the normal and tumor tissues. Conclusions: A downregulation of ER-α mRNA in follicular and anaplastic carcinomas seems to suggest that estrogens are unlikely to play an important role in the carcinogenesis and progression of these carcinomas. On the other hand, a significant decrease in ER-β to ER-α mRNA ratios in follicular adenomas suggests a possible involvement of estrogens in the pathogenesis of this disease since the same phenomenon has been reported on estrogen-dependent breast cancers.
Complete Response of Highly Advanced Gastric Cancer with Peritoneal Dissemination after New Combined Chemotherapy of S-1 and Low-Dose Cisplatin: Report of a Case
Authors: Iwahashi Makoto , Nakamori Mikihito , Tani Masaji , Yamaue Hiroki , Sakaguchi Satoru , Nakamura Masaki , Ueda Kentaro , Ichiro Matsuura , Nishino Eisei , Tanimura Hiroshi
Published: April 2003

TS-1® (S-1) has been developed as a new oral anticancer drug based on the biological modulation of 5-fluorouracil. We treated a patient with highly advanced gastric carcinoma with a new combination chemotherapy of S-1 and low-dose cisplatin. Remarkable tumor reduction was observed after two cycles of this therapy in the primary tumor and metastatic lymph nodes, and the ascites disappeared. This was concluded to be a partial response. The only adverse effect was skin pigmentation of the fingers (grade 1), leading to early timing of operation after chemotherapy. The gastric tumor showed evident invasion to the serosa. Lymph nodes around the stomach were swollen. Peritoneal dissemination was also recognized in the omentum and mesocolon. Total gastrectomy with regional lymph node dissection was performed. Disseminated tumors were all resected. Histological examination showed that no tumor cells were detected in the gastric primary lesion, metastatic lymph nodes or disseminated peritoneal tumors, suggesting pathological complete remission. It was suggested that this regimen could be a potent combined therapy for the treatment of patients with highly advanced gastric carcinoma, and it could be useful as neoadjuvant chemotherapy. Further studies are necessary to evaluate the efficacy of this therapy.