bluuebunny/crossref_metadata_2025 huggingface dataset:
Natriuretic Peptide Receptors of Type A in Human Neuroblastomas
Authors: Forgeur Annick , Willems Fabienne , Winand Jacques , Robberecht Patrick , Delporte Christine
Published: April 2003

Functional natriuretic peptide receptors of type A (NPR-A) were detected in the human neuroblastoma NB-OK-1, SK-N-SH and SK-N-BE, but not the SH-SY5Y, cell lines. Also, NPR-A mRNA was detected in 19 of the 25 tumor neuroblastoma samples tested in this study. Five of the eight tumor neuroblastoma samples that were assayed for atrial natriuretic peptide (ANP) binding revealed the presence of ANP-binding sites. In the human neuroblastoma NB-OK-1 cell line, [3H] thymidine incorporation was increased in response to ANP, decreased in response to pituitary adenylate cyclase-activating polypeptide (PACAP-27), and the stimulatory effect of ANP was inhibited by PACAP-27. Tissue transglutaminase activity was decreased by ANP and PACAP-27, and their effects were additive. However, neither cell cycle phases, cell growth, or cell apoptosis were modified by ANP or PACAP-27 treatments.
Transcriptional Properties of Ptx1 and Ptx2 Isoforms
Authors: Tremblay Jacques J. , Goodyer Cynthia G. , Drouin Jacques
Published: April 2003

The Ptx (Pitx) family of homeobox transcription factors comprises Ptx1, Ptx2 and Ptx3. Ptx1 and Ptx2 are expressed in the stomodeum and its derivatives including the pituitary, as well as in mesodermal derivatives, whereas Ptx3 is expressed in one neuronal lineage of the brain and in the eyes. A large set of downstream target genes have been identified for Ptx1 in the pituitary gland where it acts as a pan-pituitary regulator of transcription. In particular, Ptx1 contributes to promoter- and lineage-specific transcription by interaction with cell-restricted factors such as SF-1, Egr-1, Pit1, and the basic helix-loop-helix heterodimer NeuroD1/Pan1. We describe the cloning from pituitary cells and the characterization of a Ptx1 isoform, named Ptx1b, generated by alternative promoter usage. The two Ptx1 and two Ptx2 isoforms have similar in vitro DNA binding specificities and they all activate transcription driven by a panel of pituitary promoters, including those for proopiomelanocortin, αGSU, LHβ, FSHβ, GnRH-R, TSHβ, PRL, and GH. Also like Ptx1, the Ptx1b, Ptx2a, and Ptx2b transcription factors synergize with the structurally unrelated factors SF-1, Egr-1, Pit1, and NeuroD1/Pan1 to activate promoter-specific transcription. In conclusion, the pituitary transcriptional activities of the four Ptx isoforms do not appear to be dependent on the variant N-termini of these factors.
Progesterone Prevents Estradiol-Induced Dendritic Spine Formation in Cultured Hippocampal Neurons
Authors: Murphy Diane D. , Segal Menahem
Published: April 2003

Estradiol has been shown to cause an increase in dendritic spine density in cultured hippocampal neurons, an effect mediated by downregulation of brain-derived neurotrophic factor (BDNF) and glutamic acid decarboxylase (GAD), and the subsequent phosphorylation of cAMP response element binding protein (CREB) in response to enhanced activity levels. Interestingly, progesterone was shown to counteract the effects of estradiol on dendritic spine density in vivo and in vitro. The present study examined how progesterone may act to block the effects of estradiol in the molecular cascade of cellular events leading to formation of dendritic spines. Progesterone did not affect the estradiol-induced downregulation of BDNF or GAD, but it did block the effect of estradiol on CREB phosphorylation. The latter effects of progesterone on the pCREB response and spine formation were reversed by indomethacin, which prevents the conversion of progesterone to the neurosteroid tetrahydroprogesterone (THP). We therefore examined if the progesterone effects were caused by its active metabolite THP. Progesterone treatment caused a 60-fold increase in THP in the culture medium. THP itself enhanced spontaneous GABAergic activity in patch-clamped cultured neurons. Finally, THP blocked the estradiol-induced increase in spine density. These results suggest that progesterone, through conversion to THP, blocks the effects of estradiol on dendritic spines not via a direct nuclear receptor interaction but by counteracting the enhanced excitability produced by estradiol in the cultured network.
Gene Therapy in the Neuroendocrine System: Its Implementation in Experimental Models Using Viral Vectors
Authors: Bolognani Federico , Goya Rodolfo G.
Published: April 2003

Gene therapy, the transfer of genetic material for therapeutic purposes, has undergone an explosive development in the last few years. Within this context, development of gene therapy approaches for the neuroendocrine system, while incipient, has already generated a core of results which emerge as a promising area of research in neuroendocrinology. The present review presents a brief description of the viral vector-based gene delivery systems being currently used in neuroendocrinology, namely the adenoviral and herpes simplex type-1 (HSV-1)-derived vector systems, as well as an updated account of neuroendocrine pathologies for which gene therapy approaches in animal models are being implemented is provided. Current research efforts include treatment of experimental pituitary tumors by adenoviral vector-mediated transfer of the suicide gene for the HSV-1 thymidine kinase, which converts the prodrug ganciclovir into a toxic metabolite. An adenoviral vector encoding the human retinoblastoma suppressor oncogene has also been successfully used to rescue the phenotype of spontaneous pituitary tumors of the pars intermedia in mice. At the hypothalamic level, an adenovirus harboring the cDNA for arginine vasopressin has been used in Brattleboro rats to correct diabetes insipidus for several weeks. The last part of the review outlines the potential of gene therapy to correct age-associated neurodegenerative processes at the neuroendocrine level. Although effective implementation of gene therapy strategies still faces significant technical obstacles, these are likely to be progressively overcome as gene delivery systems are being improved.
Rat Strains that Differ in Corticotropin-Releasing Hormone Production Exhibit Different Sleep-Wake Responses to Interleukin 1
Authors: Opp Mark R. , Imeri Luca
Published: April 2003

Corticotropin-releasing hormone (CRH) is a mediator of responses to a variety of stressors, including immune challenge. CRH and the hypothalamic-pituitary-adrenal (HPA) axis constitute a negative feedback mechanism for actions of immunomodulators, such as interleukin (IL) 1. CRH is a potent inducer of waking, whereas IL-1 induces slow-wave sleep (SWS). We hypothesize that the complex changes in sleep-wake behavior during immune challenge are mediated in part by CRH and its antagonism of IL-1-induced enhancement of SWS. To further explore this hypothesis, we administered IL-1β intracerebroventricularly into rats of genetically related strains that differ in CRH/HPA axis responsiveness to IL-1 and determined subsequent alterations in their sleep-wake behavior. Sprague-Dawley rats responded to central administration of IL-1 with alterations in sleep-wake behavior as previously reported; SWS increased, and rapid eye movement sleep (REMS) and waking decreased. CRH and the HPA axis of Lewis rats are reported to be hyporesponsive to challenge; the onset of the IL-1-induced increase in SWS was quicker and the peak magnitude of the response greater than in Sprague-Dawley rats. In contrast, Fischer 344 rats exhibit greater CRH release and HPA axis activation in response to IL-1. IL-1 induced a profound and transient increase in waking of Fischer 344 rats before SWS increased. The febrile responses to IL-1 of Fischer 344 and Lewis rats were identical and of greater magnitude than those observed in Sprague-Dawley rats. Pretreatment with the CRH receptor antagonist α-helical CRH(9–41) blocked the initial IL-1-induced increase in waking of Fischer 344 rats. CRH receptor blockade did not affect the IL-1-induced alterations in sleep-wake behavior of Lewis or Sprague-Dawley rats or brain temperature of any rat strain. These observations support the hypothesis that CRH is both a modulator of responses to IL-1 and is involved in the regulation of waking.
Both Substance P and Its Receptor Are Expressed in Mouse Intestinal T Lymphocytes
Authors: Qian Bi-Feng , Zhou Guang-Qian , Hammarström Marie-Louise , Danielsson Åke
Published: April 2003

Substance P (SP), one of the most prevalent neuropeptides in gut, has been reported to have potent immune modulatory effects as a proinflammatory agent. The synthesis of SP and SP receptor expression in intraepithelial and lamina propria T lymphocytes of mouse intestine was investigated. Using RT-PCR analysis, it was demonstrated that SP receptor mRNA was exclusively expressed in intraepithelial and lamina propria T lymphocytes as well as their purified CD4+, CD8+ and CD4–CD8–CD3+ subsets. Messenger RNAs (mRNAs) for the two precursors of SP, β and γ-preprotachykinin-A, were also detected. These results were consistent in lymphocytes from both epithelium and lamina propria of small and large intestines, although the frequencies and/or intensities of mRNA expression varied. However, none of the findings could be repeated in splenic T lymphocytes. Activation of splenocytes with anti-CD3Ε-chain mAb and PMA did not induce expression of SP or its receptor mRNAs. Furthermore, both cytoplasmic and surface-bound SP was demonstrated in intestinal T lymphocytes using dual color immunocytochemistry and immunoflow cytometry. In vitro treatment with SP did not significantly change the size of the SP-immunoreactive T cell population, indicating the presence of SP receptor on intestinal T lymphocytes as well as in vivo binding of endogenously released SP. Our data suggest that SP production and SP receptor expression are distinctive for mouse intestinal mucosal immunity and that SP may act as a modulator of an ongoing controlled inflammation in normal gut, by acting through its specific receptor on T lymphocytes in an autocrine and/or paracrine pattern.
Aging-Related Increased Expression of Inducible Nitric Oxide Synthase and Cytotoxicity Markers in Rat Hypothalamic Regions Associated with Male Reproductive Function
Authors: Ferrini Monica , Wang Christina , Swerdloff Ronald S. , Sinha Hikim Amiya P. , Rajfer Jacob , Gonzalez-Cadavid Nestor F.
Published: April 2003

We have previously demonstrated that the inducible nitric oxide synthase (iNOS) protein and total NOS activity increase in the hypothalamus and other regions of the male rat brain during aging. We have now tested the hypothesis that increased iNOS results in excessive nitric oxide (NO) and peroxynitrite production, and leads to increased apoptosis in CNS cells, including the GnRH and oxytocin hypothalamic neurons involved in the control of male reproductive function. Young (3-month-old) and old (24-month-old) male Brown Norway rats (n = 6) were perfused with 4% formalin. Adjacent coronal paraffin-embedded sections (5 µm) of preoptic area (POA), supraoptic nucleus (SON), paraventricular nucleus (PVN), and arcuate nucleus (ARC) of the hypothalamus were immunostained with antibodies for iNOS, neuronal NOS (nNOS), and nitrotyrosine (a marker of peroxynitrite formation). The intensity of immunostaining was measured using a densitometric image analysis system. Apoptosis was determined by the TUNEL assay. Double immunofluorescence staining with confocal laser scanning microscopy was used for co-localization studies. A significant increase in the iNOS immunostaining measured as optical density (OD) was found in the old compared to the young animals (SON: 0.32 ± 0.02 vs. 0.23 ± 0.03, p < 0.05; PVN: 0.34 ± 0.03 vs. 0.07 ± 0.05, p < 0.001; POA: 0.18 ± 0.02 vs. 0.01 ± 0.02, p < 0.001). Aging did not affect nNOS expression. Nitrotyrosine was elevated in the hypothalamic regions of old compared to young rats (SON: 0.32 ± 0.05 vs. 0.10 ± 0.04, p < 0.05; PVN: 0.32 ± 0.04 vs. 0.13 ± 0.03, p < 0.01; POA: 0.72 ± 0.06 vs. 0.03 ± 0.003, p < 0.001). Increased nitrotyrosine was accompanied by an elevation of the apoptotic index in the old rats (SON: 11.01 ± 3.33 vs. 0.57 ± 0.50, p < 0.001; PVN: 3.08 ± 1.12 vs. 0.42 ± 0.32; POA: 6.60 ± 1.93 vs. 0.18 ± 0.17, p < 0.01; ARC: 0.001 ± 0.0001 vs. 4.33 ± 2.33). iNOS staining co-localized with GnRH and oxytocin staining. In conclusion: The aging-related iNOS increased expression in the hypothalamus of the male rat affects regions known to control the synthesis and release of GnRH (POA, ARC) and oxytocin (PVN, SON), and the factors regulating penile erection (POA, and PVN). These observations suggest that iNOS may play a role in the reduction in GnRH and oxytocin neuronal secretion resulting in reproductive dysfunctions such as lowered serum testosterone, hypospermatogenesis, and diminished copulatory function in the aging male animal.
Estrogen Modulation of the Cyclic AMP Response Element-Binding Protein Pathway
Authors: Carlstrom Luke , Ke Zun-ji , Unnerstall James R. , Cohen Rochelle S. , Pandey Subhash C.
Published: April 2003

Actions of estrogen include mechanisms leading to alterations in gene transcription that may be independent of nuclear estrogen receptors, as well as those involving direct action of the estrogen receptor on the genome. Also, the influence of estrogen in the brain appears to extend well beyond areas associated with reproduction and may include forebrain areas linked to affective and cognitive behaviors. We investigated the effects of acute and long-term estradiol benzoate (E2) treatment on total and phosphorylated cyclic AMP responsive element-binding (CREB) protein levels and on cyclic AMP response element (CRE)-DNA binding in forebrain areas of ovariectomized (OVX) rats. Long-term E2 treatment increased CRE-DNA binding in the amygdala but not in hippocampus, frontal cortex, or cerebellum. The increase in CRE-DNA binding in the amygdala was associated with increased levels of total and phosphorylated CREB (pCREB) protein during protracted E2 exposure. To localize the estrogenic effect in the amygdala and determine if an effect in one hippocampal region was masked by a lack of effect in another subregion, we performed immunolabeling of pCREB in brain structures of chronically treated OVX animals with or without E2. This treatment resulted in a significant increase in relative total immunolabeled nuclei in the anteroventral subdivision of the medial amygdala. In the hippocampus, a significant increase in relative total immunolabeled nuclei was seen in the CA1 and CA3 regions, but not in the dentate gyrus or hilus of the dentate gyrus. Acute E2 treatment resulted in increased CRE-DNA binding in the frontal cortex but not in amygdala, hippocampus, or cerebellum. However, no changes in levels of total CREB or pCREB protein were observed in the frontal cortex under E2 treatment. No changes were observed either in basal or cAMP-stimulated protein kinase A (PKA) activity or in PKA-α catalytic subunit immunoreactivity in the amygdala or the frontal cortex. Our study indicates that both long-term and acute treatments with estrogens influence the function of CREB in specific brain structures.
Regulation of Dexras1 Expression by Endogenous Steroids
Authors: Brogan Michelle D. , Behrend Ellen N. , Kemppainen Robert J.
Published: April 2003

Dexras1, a newly identified member of the Ras superfamily of proteins, was discovered in AtT-20 corticotrope cells because its expression was induced in response to glucocorticoids (dexamethasone; Dex). As yet, the function of Dexras1 is unknown, but its rapid induction in response to glucocorticoids suggests the possibility that it may be involved in negative feedback regulation of corticotropin secretion. To better understand the control of Dexras1 expression, possible effects of other steroid hormones on its expression were studied in both AtT-20 cells and in mouse pituitaries. AtT-20 cells were treated with each of 6 steroids [aldosterone, corticosterone (Cort), Dex, β-estradiol (E2), progesterone and testosterone] for 2 h. Dexras1 expression was assessed using both reverse transcription polymerase chain reaction (RT-PCR) and Northern analysis. Expression of the gene was only induced in response to glucocorticoid treatment (Dex or Cort). The 6 steroids were also injected into mice, pituitaries were harvested and total RNA was obtained for RT-PCR analysis. Surprisingly, treatment with E2, not only injection of glucocorticoids, induced Dexras1 expression in mouse pituitary. Other steroids were without effect. The results suggest that in AtT-20 corticotropes, Dexras1 expression is only induced by glucocorticoid-type steroids. In pituitary glands of mice, the gene’s expression is also responsive to E2. We conclude that either Dexras1 expression in corticotropes from normal mice is regulated differently from that in AtT-20 cells, or that Dexras1 is also expressed in other pituitary cells than corticotropes.
Role of Nitric Oxide in Inflammatory Conditions
Authors: Blantz Roland C. , Munger Karen
Published: April 2003

Nitric oxide (NO) plays an important regulatory/modulatory role in a variety of inflammatory conditions. NO is a small, short-lived molecule that is released from a variety of cells in response to homeostatic and pathologic stimuli. It may act as a vasodilator and a platelet inhibitor and may interfere with adhesion molecules to prevent neutrophil adhesion. NO release may also lead to the formation of highly reactive species such as peroxynitrite and stable nitrosothiols and may cause mitochondrial damage and nitration of protein tyrosine residues. In addition, NO inhibits cell proliferation via inhibition of polyamine synthesis and cell uptake and may well act as a ‘brake’ on the proliferative response following cytokine exposure. All three isoforms of nitric oxide synthases are found in the kidney during inflammation. The site of NO release impacts significantly on its net function and structural impact. NO plays a protective role in many forms of immune injury, such as nephrotoxic serum-induced glomerulonephritis, autoimmune tubular interstitital nephritis, and experimental allergic encephalomyelitis. NO overproduction in sepsis, after cytokine exposure, inducible NO synthase transcription, and local inflammation can autoinhibit endothelial NO synthase, leading to selective renal and mesenteric vasoconstriction.
Nutritional Factors in Cerebral Aging and Dementia: Epidemiological Arguments for a Role of Oxidative Stress
Authors: Deschamps Valérie , Barberger-Gateau Pascale , Peuchant Evelyne , Orgogozo Jean Marc
Published: April 2003

There is increasing evidence that oxidative stress is involved in cerebral aging and dementia. The objective of this review is to give a progress report on the more recent results of the various epidemiologic cohorts studied for the association between nutrition of older people, the evolution of cognitive performances and the risk of later occurrence of dementia or stroke. The oxidative theory of pathological brain ageing is supported by animal laboratory experiments. Furthermore, experimental research has consistently suggested that diet-related factors play an important role in cognitive functions in ageing. In humans, a number of epidemiological case-control and prospective studies analyzed the association between nutrition, particularly fatty acids and antioxidant molecules (vitamins A, E, C, β-carotene and polyphenols) and cognition. In the context of evidence already available, further studies are needed to identify the specific role of various nutrients, their interactions and the influence of genetic factors and living habits on cerebral aging and dementia. Vascular dementia and Alzheimer’s disease, that share several risk factors, might be targets for primary prevention through nutritional recommendations and/or supplementation.
Regional Variation in Multiple Sclerosis Prevalence in Australia and Its Association with Ambient Ultraviolet Radiation
Authors: van der Mei Ingrid A.F. , Ponsonby Anne-Louise , Blizzard Leigh , Dwyer Terence
Published: April 2003

The aim of this study was to conduct an ecological analysis of the extent to which ultraviolet radiation (UVR) levels might explain the regional variation of multiple sclerosis (MS) in Australia. MS prevalence data for six Australian regions were compared with UVR levels of the largest city in each region, with some other climatic variables and with the melanoma incidence in the same regions. A close association was found between the theoretical MS prevalence predicted from UVR levels and the actual prevalence. Furthermore, the negative correlation between UVR and MS prevalence (r = –0.91, p = 0.01) was higher than the positive correlation observed for UVR and malignant melanoma incidence (r = 0.75, p = 0.15 for males and r = 0.80, p = 0.10 for females). This study demonstrated that the regional variation in MS prevalence in the continent of Australia could be closely predicted by regional UVR levels. It is consistent with the hypothesis that UVR exposure may reduce the risk of MS possibly via T-lymphocyte-mediated immunosuppression. Analytical epidemiology studies are required to investigate this specific hypothesis.
Serum Contents of the Free Forms of α1-Microglobulin and Ulinastatin: Relation to Diseased States in Patients with Mood Disorders
Authors: Shikimi Tadahiro , Kaku Koichi , Uegaki Jun , Inagaki Takuji , Seno Haruo , Ishino Hiroshi , Takaori Shuji
Published: April 2003

We have found previously that the relationship between the urinary contents of α1-microglobulin (α1M) and ulinastatin (UT) in patients with mood disorder differs from that of age-matched healthy subjects. However, it has yet to be determined whether or not the difference in the relation correlates with the contents of the free forms of α1M and UT in serum and whether changes in the existing forms of α1M and UT in serum reflect the actual disease states. The relation between serum contents of the free forms of α1M and UT in 10 patients with mood disorders was different from that of 17 age-matched healthy subjects. The regression plot between scores of the Hamilton Rating Scale for Depression and ratios of the free form content to total content (F/T ratio) of UT was more informative on the depressive state than that of α1M. The F/T ratios of UT may afford a useful objective index in monitoring the diseased state of a patient with mood disorder.
EEG Alpha Rhythm and Glucose Metabolic Rate in the Thalamus in Schizophrenia
Authors: Danos Peter , Guich Steve , Abel Lennart , Buchsbaum Monte S.
Published: April 2003

Positron emission tomography with uptake of [18F]fluorodeoxyglucose (FDG) and quantitative EEG were simultaneously performed in 18 medication-free patients with schizophrenia and in 13 normal volunteers. Subjects performed the Continuous Performance Task (CPT) during FDG uptake. Correlations were calculated between alpha power during the CPT and glucose metabolic rate (GMR) in thalamic regions and between alpha power during the CPT and GMR in occipital cortices. Regression analyses were used to describe the prediction of GMR in the occipital cortices and in the thalamic regions of occipital alpha power. In normal controls, we found (1) significant negative correlations between absolute alpha power and GMR in the left occipital cortex, (2) significant positive correlations between normalized alpha power and GMR in the right and left lateral thalamus and (3) combined effects of GMR in the thalamic regions and the occipital cortices on alpha power, which accounted for 98% of the variance of alpha power. In patients with schizophrenia, we found no significant correlations between alpha power and GMR in the occipital cortices or between alpha power and GMR in the thalamic regions. Correlation coefficients between absolute alpha power and GMR in the left occipital cortex and between normalized alpha power and GMR in the left lateral thalamus were significantly different in normal subjects compared to schizophrenic patients. The present findings provide evidence for involvement of the thalamus in the generation of alpha rhythm in humans. Furthermore, the present results suggest differences in thalamocortical circuits between normal controls and schizophrenic subjects.
Study of Family History in Seasonal Affective Disorder
Authors: Stamenkovic M. , Aschauer H.N. , Riederer F. , Schindler S.D. , Leisch F. , Resinger E. , Neumeister A. , Hornik K. , Kasper S.
Published: April 2003

Objective: In our investigation we assessed the risk of morbidity for psychiatric disorders among the first-degree relatives of patients with seasonal affective disorders (SAD) and compared it with a control group of patients suffering from nonseasonal mood disorders (NSMD). Methods: Over a period of 12 months (June 1994 to May 1995) we recruited patients consecutively admitted to our psychiatric university outpatient clinic in a prospective study. All patients were diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, revised 4th edition. A total of 344 patients presented themselves with a diagnosis of affective disorder. Out of these, 36 were diagnosed as having SAD. From the same group of 344 patients, we selected a matched control group of 36 patients suffering from NSMD. The experimental and control groups were matched according to sex, age, severity of illness and number of siblings. Results: There was no significant difference concerning the lifetime prevalences for psychiatric disorders among the fist-degree relatives in both groups (SAD = 16.5% and NSMD = 19%). Conclusion: It seems that there is no difference in familiarity for psychiatric disorders between SAD and NSMD.
Caudate Nucleus Dopamine D2 Receptors in Depressed Suicide Victims
Authors: Allard Per , Norlén Maria
Published: April 2003

Several lines of evidence indicate the involvement of the dopamine system in depressive states. In this post-mortem study, the binding of [3H]raclopride to dopamine D2 receptors in the caudate nucleus was investigated in 13 depressed suicide victims and 19 controls. There were no differences in Bmax or Kd between the two groups. A subgroup consisting of individuals with major depression, however, had significantly higher Kd values than controls. Previous findings regarding changes in dopamine metabolism in depression and antidepressant effects of dopamine agonists seem, according to the present study, not to be reflected by alterations in density or affinity of dopamine D2 receptors in depressed suicide victims.
EEG Source Localization and Global Dimensional Complexity in High- and Low- Hypnotizable Subjects: A Pilot Study
Authors: Isotani Toshiaki , Lehmann Dietrich , Pascual-Marqui Roberto D. , Kochi Kieko , Wackermann Jiri , Saito Naomi , Yagyu Takami , Kinoshita Toshihiko , Sasada Kyohei
Published: April 2003

Individuals differ in hypnotizability. Information on hypnotizability-related EEG characteristics is controversial and incomplete, particularly on intracerebral source localization and EEG dimensionality. 19-channel, eyes-closed resting EEGs from right-handed, healthy, 8 high- and 4 low-hynotizable subjects (age: 26.7 ± 7.3 years) were analyzed. Hypnotizability was rated after the subjects’ ability to attain a deep hypnotic stage (amnesia). FFT Dipole Approximation analysis in seven EEG frequency bands showed significant differences (p < 0.04) of source gravity center locations for theta (6.5–8 Hz, more posterior and more left for highs), beta-1 and beta-2 frequencies (12.5–18 and 18.5–21 Hz; both more posterior and more right for highs). Low Resolution Electromagnetic Tomography (LORETA) specified the cortical anteriorization of beta-1 and beta-2 in low hypnotizables. Power spectral analysis of Global Field Power time series (curves) showed no overall power differences in any band. Full-band Global Dimensional Complexity was higher in high-hypnotizable subjects (p < 0.02). Thus, before hypnosis, high and low hypnotizables were in different brain electric states, with more posterior brain activity gravity centers (excitatory right, routine or relaxation left) and higher dimensional complexity (higher arousal) in high than low hypnotizables.
Genetic and Epigenetic Alterations of the Estrogen Receptor Gene and Hormone Independence in Human Breast Cancer
Authors: Iwase Hirotaka , Omoto Yoko , Iwata Hiroji , Hara Yasuo , Ando Yoshiaki , Kobayashi Shunzo
Published: April 2003

The existence of hormone-independent tumors is a substantial problem for the present endocrine treatment of breast cancers. Estrogen receptor (ER) gene mutation can change the biochemical activity of the protein and can affect hormone responsiveness. However, quite a few mutations of significance have been described in breast cancer. Recently, numerous variant ERs have been detected at the mRNA level with alternative splicing, yielding deletion of exon 3, 5, or 7. The truncated ER protein induced from variant mRNA could mainly be exhibited as a repressor through dominant negative effects on normal ER protein. The mechanism of the loss of hormone dependency is, however, still very complex. Further work to assess the correlation between clinical behavior and ER variants is required to determine whether these variants play a role in hormone-resistant disease. Additionally, the DNA methylation of the ER gene itself may control ER expression. These epigenetic changes can play an important role in the loss of hormone dependence in breast cancer.
Role of Estrogen and Estrogen-Related Growth Factor in the Mechanism of Hormone Dependency of Endometrial Carcinoma Cells
Authors: Hata Hiroki , Hamano Mieko , Watanabe Jun , Kuramoto Hiroyuki
Published: April 2003

The role of estrogen and estrogen-related growth factors in the mechanism of hormone dependency of endometrial adenocarcinoma cells was investigated. The proliferation of hormone-responsive human endometrial adenocarcinoma cells (Ishikawa cells), which possess both estrogen and progesterone receptors, was optimally stimulated by 10 nM estradiol. Both transforming growth factor (TGF)-α and epidermal growth factor (EGF), added to the culture media, stimulated the proliferation of Ishikawa cells in a dose-dependent manner. Anti-TGF-α antibody completely eliminated the stimulatory effects of TGF-α. Anti-EGF receptor antibody inhibited the proliferation of these cells. The production of TGF-α into culture media was 5–40 pg/10 cells/24 h in 9 human endometrial adenocarcinoma cells. Ten nanomoles of estradiol increased the TGF-α production of Ishikawa cells by approximately 2.5-fold of the control level. In contrast, the production of TGF-α in hormone-unresponsive HEC-50 cels was not influenced by estradiol. C-erbB-2 oncoprotein expression of human endometrial adenocarcinoma cells, detected by both immunocytochemical staining and Western blot analysis, was associated with the tumor grade of the original tumor tissues. Ten nanomoles of estradiol clearly increased the c-erbB-2 oncoprotein levels at an optimal incubation period of 72 h, whereas estradiol did not affect the expression in HEC-50 cells.
Gemcitabine: Progress in the Treatment of Pancreatic Cancer
Authors: Heinemann Volker
Published: April 2003

Unresectable pancreatic cancer has a dismal prognosis with a median survival of 3–5 months in untreated disease. Since the introduction of gemcitabine, pancreatic cancer may no longer be regarded a chemotherapy-resistant tumor. Treatment with single-agent gemcitabine achieved clinical benefit and symptoms improvement in 20–30% of patients. While 1-year survival was observed in 2% of 5-fluorouracil (5-FU)-treated patients, it was raised to 18% by single-agent gemcitabine. Good treatment tolerability and low incidence of side effects are clear advantages of single-agent gemcitabine. Improvement of efficacy is, however, expected from combination treatment. Gemcitabine and cisplatin given as first-line treatment in three studies achieved a median survival of 7.4–8.3 months. One-year survival was raised to 28% as reported in one study. Comparable activity was obtained by a combination of gemcitabine with 5-FU. Nine studies using gemcitabine in combination with standard-dose or high-dose 5-FU reported a median survival ranging from 5.5 to 13 months. Notwithstanding these promising results, recommendations regarding palliative chemotherapy of pancreatic cancer remain tentative and still need confirmation by presently ongoing phase III trials. Inclusion of pancreatic cancer patients into clinical trials should be a major goal. Outside clinical trials, patients should present with an adequate PS (Karnofsky-performance index ≧70) to qualify for chemotherapy.
Early Postoperative Intraperitoneal Chemotherapy with Mitomycin C, 5-Fluorouracil and Cisplatin for Advanced Gastric Cancer
Authors: Noh Sung Hoon , Yoo Chang Hak , Chung Hyun Cheol , Roh Jae Kyung , Shin Dong Woo , Min Jin Sik
Published: April 2003

Objective: The long-term survival of patients who undergo surgery for stage IV gastric cancer is poor, due to metastatic spread of the tumor. Intraperitoneal chemotherapy (IPT) as a possible treatment for peritoneal dissemination has been investigated in a number of different tumors. The aim of this study was to investigate the toxicity and impact of early postoperative IPT on the survival of patients with advanced gastric cancer. Methods: Between 1993 and 1997, a total of 91 patients with stage IV gastric cancer who underwent potentially curative or palliative resection received intraperitoneal mitomycin C before closure of the abdominal wound. 5-Fluorouracil and cisplatin were administered intraperitoneally on postoperative days 1–4, and this was repeated at 4-week intervals. Results: All patients received a median of 3 IPT perfusions. There were 24 (26.4%) postoperative complications and 1 (1.1%) mortality. The most frequent hematologic toxicity (grade 3–4) was leukopenia. The major nonhematologic toxicities (grade 3–4) were emesis and nephrotoxicity. After a median follow-up period of 26 months, 14 patients remain alive without evidence of recurrence, whereas 75 patients died due to recurrence or progression of disease. The median survival period for all 91 patients was 15.4 months. When survival according to the residual tumor was analyzed, median survival was 36.0 months in the R0 (curative resection) group, 20.6 months in the R1 group (margins of resected specimens showing microscopic residual tumor or diameter of each residual tumor less than 3 mm) and 9.0 months in the R2 group (macroscopic residual tumor larger than 3 mm) (p < 0.001). Conclusions: IPT was found to be safe, and it appears to improve the prognosis in patients with minimal residual tumors. However, complete cytoreductive surgery is mandatory for achieving the beneficial effect of IPT.
Is Forequarter Amputation Justified for Palliation of Intractable Cancer Symptoms?
Authors: Merimsky Ofer , Kollender Yehuda , Inbar Moshe , Lev-Chelouche Dina , Gutman Mordechai , Issakov Josephine , Mazeh Doron , Shabat Shai , Bickels Jacob , Meller Isaac
Published: April 2003

Background: Limb-sparing surgery has replaced the radical surgical approach for treating limb sarcomas in most cases. Amputation has been advocated as a palliative procedure for symptomatic locally advanced disease that has already failed to respond to radiation therapy, chemotherapy and limited surgery. Methods: Twelve patients with advanced malignant tumors involving the shoulder girdle or the proximal humerus underwent forequarter amputation (FQA) for palliative purposes. The tumor-related local problems were severe pain, limb dysfunction, tumor fungation, bleeding (requiring emergency FQA in one case) and infection. The preoperative Karnofsky performance status (KPS) in our series ranged from 30 to 70%. Results: No perioperative mortality was observed. The morbidity was well tolerated by the patients. The KPS improved in most of the patients, and was assessed as 90–100% in 9 of the 12 patients. Overall, quality of life was reported to be at least moderately improved by 2 out of 3 patients. Survival was measured in months (3–24 months), but ultimately had no meaning since the procedure was palliative. Lung metastases were the dominant cause of death in our patients. Conclusions: The results of FQA in our series point to its feasibility and the gain in quality of life and performance status in severely ill patients with advanced malignancies. Local symptoms and signs were controlled, and quality of life was restored.
Genetic Changes in Contralateral Bronchioloalveolar Carcinomas of the Lung
Authors: Shin Sang Won , Breathnach Oscar S. , Linnoila R. Ilona , Williams John , Gillespie John W. , Kelley Michael J. , Johnson Bruce E.
Published: April 2003

Objective: The pattern of metastases and recurrence of bronchioloalveolar carcinoma (BAC) differs from adenocarcinoma of the lung, occurring more frequently within the lung without extrapulmonary involvement. Analyses of genetic differences of contralateral BACs may help to explain these clinical differences. Methods: We compared paired tumors from 5 patients with contralateral metachronous BACs for loss of heterozygosity (LOH) on 6 chromosomal arms (2q, 3p, 5q, 9p, 13q and 17p) and mutational analysis of p53 and K-ras. Results: Two patients, patients 1 and 2, had discordant patterns of LOH on 2 and 3 of the chromosome arms, respectively. In addition, patient 2 had a detectable K-ras mutation in his initial tumor but not in his second. These results suggest that in patients 1 and 2, the contralateral tumors were clonally unrelated. Patient 3 had no mutations in the K-ras or p53 gene and no LOH on any of the 5 informative chromosome arms. Patient 4 had LOH of 9p and mutated K-ras in both the first and the second tumor, with a mutation in the p53 gene in the first but not in the second tumor. Patient 5 had LOH of 17p and the same p53 mutations in both the first and the second tumor, with a mutation of K-ras in the first tumor but not in the second. Conclusions: The preponderance of evidence suggests that in patients 3, 4 and 5, the paired tumors were clonally related. The different patterns of LOH and mutations in clinically similar contralateral metachronous BACs provide evidence of genetic heterogeneity in the tumors of this patient group.
Paclitaxel by 72-Hour Continuous Infusion Followed by Bolus Intravenous Ifosfamide or Epirubicin: Results of Two Phase I Studies
Authors: Miglietta L. , Marenghi C. , Nizzo R. , Foglia G. , Ragni N. , Boccardo F.
Published: April 2003

Study Purposes: To determine the maximum-tolerated dose (MTD) of paclitaxel administered by 72-hour continuous infusion followed by bolus intravenous ifosfamide on days 4 and 5 or epirubicin on day 4, every 21 days. To assess the toxicity and preliminary activity in patients with advanced refractory solid tumors. Patients and Methods: Sixteen patients with progressive disease after standard chemotherapy for advanced disease were treated with the combination paclitaxel-ifosfamide and 10 patients with the combination paclitaxel-epirubicin. Results: In the first phase I study the MTDs were: paclitaxel 135 mg/m2 and ifosfamide 2.5 mg/m2/day; hematologic toxicity was the dose-limiting toxicity (DLT) during the first cycle of therapy at dose level 4. Paclitaxel administered at 135 mg/m2 and epirubicin 50 mg/m2 were the MTDs in the second phase I study; grade 4 stomatitis was the DLT of this combination. Conclusions: Paclitaxel by 72-hour continuous infusion followed by bolus ifosfamide was a manageable regimen with an acceptable hematologic toxicity in the absence of neurotoxicity. Preliminary activity of this combination was encouraging in a group of patients with ovarian cancer. The optimal way to combine paclitaxel and epirubicin and the best schedule relative to such a long paclitaxel infusion time in this combination regimen remain to be determined.
Different Response to the Long-Acting Somatostatin Analogues Lanreotide and Octreotide in a Patient with a Malignant Carcinoid
Authors: Raderer Markus , Kurtaran Amir , Scheithauer Werner , Fiebiger Wolfgang , Weinlaender Georg , Oberhuber Georg
Published: April 2003

Introduction: Somatostatin (SST) analogues are cornerstones in the symptomatic management of patients suffering from carcinoid tumors, and antiproliferative activity has also been reported for these agents. The most commonly applied SST analogues are octreotide (OCT) and lanreotide (LAN), which are both available in a slow release formulation. To the current knowledge, both OCT and LAN are thought to be equally effective for the management of various disorders. We report the case of a patient with a disseminated carcinoid, who progressed during dose-intensified treatment with slow-release LAN in combination with interferon-α, but developed a pronounced response after treatment was switched to the application of a depot formulation of OCT. Case Report: A 46-year-old woman was admitted to our department for the evaluation of persistent flushing, diarrhea and dyspnea. After a diagnosis of metastatic carcinoid had been established, treatment with LAN (30 mg i.m. every 10 days) along with interferon-α 3 × 5 MU/week was initiated. In spite of successful blocking of tumoral SST receptors as judged by SST receptor scintigraphy and subjective improvement of symptoms, the patient had progressive disease. As she refused chemotherapy, treatment was switched to a depot formulation of OCT (20 mg i.m. every 4 weeks), resulting both in a disappearance of symptoms as well as tumor regression as seen on CT scanning. Conclusion: To our knowledge, this is the first case demonstrating both a symptomatic as well as objective response to OCT following progression during therapy with LAN in a patient with a carcinoid tumor. Our results suggest that refractoriness to treatment including a long-acting SST analogue does not automatically imply resistance to a related agent and should alert clinicians to the potential of non-cross-resistance between SST analogues in neuroendocrine malignancies.
Evaluation of Methods to Detect p53 Mutations in Ovarian Cancer
Authors: Meinhold-Heerlein Ivo , Ninci Elena , Ikenberg Hans , Brandstetter Thomas , Ihling Christian , Schwenk Ildiko , Straub Alexander , Schmitt Beate , Bettendorf Herta , Iggo Richard , Bauknecht Thomas
Published: April 2003

Objective: The p53 status is increasingly regarded as a marker predictive of response to particular cancer therapies, but for this approach it is self-evident that the p53 status must be determined correctly. Methods: We have tested ovarian cancers with single-strand conformation polymorphism analysis (SSCP), immunohistochemical staining with DO-1 anti-p53 antibody (IHC), and yeast p53 functional assay (FASAY). Results: These techniques commonly used to detect p53 mutations showed important differences in their sensitivity. Of 53 tumors tested with three indirect techniques, 27 (50%), 33 (62%) and 41 (77%) were positive by SSCP, IHC, and FASAY, respectively. In a subset of 32 tumors strongly suspected of containing mutations, 25 (78%), 26 (81%), 29 (91%) and 30 (94%) were positive by SSCP, immunostaining, DNA sequencing and yeast assay, respectively. Conclusions: Under comparable routine conditions, the FASAY reached the highest sensitivity. Since no single technique detected all mutations, we recommend the use of at least two different techniques in situations where the p53 status will affect patient management.
Hormone Replacement Therapy after Treatment of Breast Cancer: Effects on Postmenopausal Symptoms, Bone Mineral Density and Recurrence Rates
Authors: Beckmann Matthias W. , Jap David , Djahansouzi Sirus , Nestle-Krämling Carolin , Kuschel Bettina , Dall Peter , Brumm Carsten , Bender Hans Georg
Published: April 2003

Purpose: Breast cancer (BC) is the most frequent female carcinoma and the major cause of death in women aged 35–50 years. The total number of patients surviving BC and especially the morbidity rate of patients below the age of 55 years has increased significantly in the last several years. As a consequence, the number of BC patients suffering from the long-term effects of estrogen deficiency due to adjuvant treatment is increasing. At present, hormone replacement therapy (HRT) following BC treatment is applied individually and mainly depends on the severity of postmenopausal symptoms (PMS) experienced by these patients. Patients and Methods: In a retrospective study (total n = 185 BC patients, 64 with and 121 without HRT), the effect of HRT during or after adjuvant therapy [chemotherapy and/ or (anti-) hormonotherapy] has been investigated. The surveillance period was up to 60 months. Evaluated were HRT effects on (1) PMS measured by a comprehensive life quality questionnaire, (2) bone mineral density (BMD) measured by osteodensitometry and (3) morbidity as well as mortality rates. Results: Both groups did not differ with regard to tumor stage, lymph node involvement, metastasis, grading, and steroid hormone receptor status. A reduction in PMS was significant in women taking HRT (p < 0.001), especially in the subgroup of women ≤50 years (p < 0.0001). For both age groups, the median reduction in BMD (z-score) was less in women receiving HRT (≤50 years: without HRT –1.99 vs. with HRT –0.95, p < 0.05; >50 years: without HRT –2.29 vs. with HRT –1.19, p < 0.01). There were no statistically significant differences regarding morbidity and mortality (p = 0.29). Conclusion: In this study of BC patients, the use of HRT shows positive effects on PMS and BMD. There was no significant influence on morbidity or mortality. However, a reevaluation of HRT in the routine management of BC patients should await the results of prospective randomized trials.
A Phase I Clinical Trial of Topotecan Given Every 2 Weeks in Patients with Refractory Solid Tumors
Authors: Kakolyris S. , Kouroussis Ch. , Souglakos J. , Mavroudis D. , Agelaki S. , Kalbakis K. , Androulakis N. , Vardakis N. , Vamvakas L. , Georgoulias V.
Published: April 2003

Objectives: Topotecan, a potent inhibitor of the enzyme topoisomerase I, has shown an interesting activity against several types of solid tumors, most notably small cell lung cancer (SCLC) and ovarian cancer. We conducted a phase I study to evaluate the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of topotecan given in a novel schedule of administration in patients with refractory solid tumors. Patients and Methods: Twenty-six patients with histologically confirmed diagnosis of solid tumors refractory to all known forms of effective therapy were enrolled. The patients’ median age was 61 years, 15 were male, and 18 had a performance status of (WHO) 0–1. Seven patients suffered from ovarian cancer, 11 from SCLC, 4 from non-SCLC, 2 from melanoma and 2 from cervical cancer. Topotecan was given for 3 consecutive days as a 30-min intravenous infusion, at doses ranging from 0.75 to 1.2 mg/m2. Treatment was repeated every 2 weeks. Results: At dose level 5 with topotecan 1.2 mg/m2, both study patients presented DLTs (1 patient grade 4 neutropenia and the other grade 3 fatigue), and the recommended doses for future phase II studies are topotecan 1.1 mg/m2 for 3 consecutive days every 2 weeks. A total of 60 treatment cycles were administered, with a median of 2 cycles per patient. Grade 3/4 neutropenia was observed in 11 (18%) cycles and 2 of them were complicated by fever requiring patient hospitalization. Grade 3/4 thrombocytopenia was seen in 2 (3%) cycles and grade 3 anemia in 3 (5%). Although non-hematologic toxicity was generally mild, grade 2/3 fatigue complicated 12 (20%) cycles and grade 4 one (1.5%) requiring treatment interruption in 4 patients. Among 18 evaluable patients, no objective response to treatment was observed. Conclusion: This phase I study demonstrates that topotecan given at the dose of 1.1 mg/m2 for 3 consecutive days every 2 weeks is a safe and tolerable regimen and possibly permits the combination of the drug with other cytotoxic agents at clinically relevant doses.