bluuebunny/crossref_metadata_2025 huggingface dataset:
Lesions of the Dorsomedial Hypothalamic Nucleus Do Not Influence the Daily Profile of Pineal Metabolism in Rats
Authors: Mota Sandra Regina , Canteras Newton Sabino , Bartol Ione , Skorupa Ana Lúcia , Scialfa Julieta Helena , Terra Ilza Mingarini , Afeche Solange Castro , Cipolla-Neto José
Published: April 2003

The present study attempted to characterize the effects of electrolytic lesions of the hypothalamic dorsomedial nucleus on the daily profile of pineal metabolism as well as on the inhibition of pineal melatonin synthesis induced by acute light exposure during the night. Adult male Wistar rats (n = 107, 12:12 h light-dark cycle) were left intact (n = 47) or lesioned (n = 60). Lesioned rats and their respective controls were killed at six time points distributed throughout the light-dark cycle. At ZT (zeitgeber time) 18 the animals were killed either in the dark or after 15 min of light stimulation. Pineal glands were assayed using high-performance liquid chromatography with electrochemical detection (HPLC-ED). There was no difference in the amounts of pineal indoles between lesioned and control rats under any of the experimental situations tested. These results suggest that in rats, the hypothalamic dorsomedial nucleus does not participate in either the neural control of daily pineal metabolism or the nocturnal light-induced inhibition of the pineal metabolism.
Lactation Alters γ-Aminobutyric Acid Neuronal Activity in the Hypothalamus and Cerebral Cortex in the Rat
Authors: Kornblatt Joseph J. , Grattan David R.
Published: April 2003

γ-Aminobutyric acid (GABA) neurons terminating in the hypothalamus have been implicated in the neuroendocrine regulation of reproductive hormones, particularly luteinizing hormone (LH) and prolactin. The aim of this study was to examine whether GABAergic neuronal activity in the hypothalamus was modified during lactation, and whether any observed changes correlated with changes in secretion of these hormones. Animals were divided into three experimental groups: diestrous controls, lactating with pups present (with pups), and lactating with pups removed for 4 h (without pups). Animals were decapitated either without treatment, or 60 min after inhibition of GABA degradation by aminooxyacetic acid (AOAA) (100 mg/kg, i.p.). The rate of GABA accumulation in the tissue after AOAA is a measure of GABA turnover. GABA turnover was estimated in 13 microdissected brain regions, and serum prolactin and LH measured by radioimmunoassay. Suckling was associated with significantly increased prolactin and significantly decreased LH compared with diestrous rats. In lactating rats with pups, GABA turnover was significantly increased in the cingulate cortex compared with diestrous rats. GABA turnover was significantly increased in the ventrolateral preoptic nucleus of lactating rats with pups compared with diestrous rats or lactating rats without pups. There was significantly lower GABA turnover in the anterior hypothalamic area, ventromedial and dorsomedial hypothalamic nuclei in lactating rats without pups compared with diestrous rats. There were no significant changes in other brain regions examined. The results demonstrate that activity of GABAergic neurons in specific parts of the hypothalamus and cerebral cortex is altered during lactation.
Glucocorticoid and Mineralocorticoid Receptors Are Involved in the Facilitation of Anxiety-Like Response Induced by Restraint
Authors: Calvo Nelson , Volosin Marta
Published: April 2003

In previous studies, we have shown that male Wistar rats exposed to a single inescapable stressor session (15 min restraint) exhibited 24 h later an anxiogenic-like behavior in the elevated plus-maze (EPM), which was reversed by inhibition of corticosterone (CS) synthesis with metyrapone (75 mg/kg i.p.) 3 h before stress. Since CS binds to two central corticosteroid receptors, the mineralocorticoid (MR) and the glucocorticoid (GR) receptors, involvement of MR and GR in the modulation of anxiogenic responses was assessed in the EPM. Administration of the GR agonist dexamethasone (Dex, 1.25 µg/kg s.c.) to metyrapone-pretreated rats 1 h before restraint restored the anxiogenic-like response induced by the stressor. Removal of the adrenals also inhibited the anxiogenic-like effect, which was restored by either Dex (1.25 µg/kg s.c.), the MR agonist deoxycorticosterone (0.8 mg/kg s.c.) or CS, the common endogenous agonist of MR and GR (5 mg/kg s.c.) administered 1 h before stress. Intracerebroventricular infusion to intact animals 15 min before restraint of either a selective GR antagonist (A-GR, RU 38486, 100 ng/2 µl), a selective MR antagonist (A-MR, RU 28318, 100 ng/2 µl) or a combination of A-GR and A-MR (100 ng of each one/2 µl), abolished the stress-induced anxiogenic-like effect. The present findings indicate that both MR and GR are involved in the long-term CS modulation of the anxiety response induced by restraint. Both receptors mediate CS effects in an independent manner.
Effects of Estradiol on Glucoprivic Transactivation of Catecholaminergic Neurons in the Female Rat Caudal Brainstem
Authors: Briski Karen P. , Marshall Edith S. , Sylvester Paul W.
Published: April 2003

Hyperphagic and hypothalamic neuroendocrine responses to acute glucose deprivation are modified by the ovarian steroid estradiol (E). Observations of genomic activation of catecholaminergic (CA) neurons in the hindbrain lateral reticular nucleus, nucleus of the solitary tract, and area postrema (AP) by glucopenia support their potential function in pathways mediating regulatory effects of this metabolic challenge within the brain. Expression of E receptors by these cells suggests that their activity may be sensitive to steroid modulation during glucopenia. The present studies investigated the role of E on transcriptional activation of caudal brainstem CA neurons by the glucose antimetabolite, 2-deoxy-D-glucose (2DG). Ovariectomized rats were implanted with s.c. Silastic capsules containing E (30 or 250 µg/ml) or sesame oil, and injected i.p. 7 days later with 400 mg 2DG/kg or saline. Tyrosine hydroxylase (TH)-immunoreactive (-ir) neurons in the C1/A1, C2, C3, A2, A5, and A6 cell groups and AP were colabeled for Fos following antimetabolite administration, whereas vehicle injection resulted in negligible nuclear staining of these cells. With the exception of A2, A6, and AP cells, mean numbers of Fos- and TH-/Fos-ir-positive neurons in these brain sites did not differ between E- and sesame oil-implanted groups. Numbers of TH-positive A2 and A6 neurons that expressed Fos in response to 2DG were significantly greater in rats implanted with the high E dose vs. either the low steroid dose or sesame oil. These results show that the magnitude of cellular Fos labeling within discrete hindbrain CA neuron populations varies in accordance with circulating E levels. These findings suggest that E may exert potential modulatory effects on glucoprivic activation of the Fos stimulus/transcription cascade and consequent compensatory genomic responses within specific areas of the female rat caudal brainstem.
Homologous Upregulation of sst2 Somatostatin Receptor Expression in the Rat Arcuate Nucleus in vivo
Authors: Tannenbaum Gloria S. , Turner Joel , Guo Fang , Videau Catherine , Epelbaum Jacques , Beaudet Alain
Published: April 2003

In vitro studies using various cell systems have provided conflicting results regarding homologous regulation of somatostatin (SRIH) receptors, and information on whether SRIH regulates the expression of its own receptors in vivo is lacking. In the present study we examined, by in situ hybridization, the effects of pretreatment with the sst2-preferring SRIH analog, octreotide, in vivo, on mRNA levels of two SRIH receptor subtypes, sst1 and sst2, in rat brain and pituitary. 125I-[DTrp8]-SRIH binding was also measured in these regions. Three hours after the iv injection of 50 µg octreotide to conscious adult male rats, there was a 46% increase (p < 0.01) in the labeling density of sst2 mRNA-expressing cells in the hypothalamic arcuate nucleus compared to normal saline-pretreated controls, but not in any of the other brain regions examined. Computer-assisted image analysis revealed that 3 h exposure to octreotide significantly (p < 0.01) augmented both the number and labeling density of sst2 mRNA-expressing cells in the arcuate nucleus, compared to those in saline-treated controls. By contrast, within the anterior pituitary gland, in vivo exposure to octreotide did not affect the expression of sst2 mRNA. No changes in sst1 mRNA-expressing cells were observed after octreotide treatment in any of the regions measured, indicating that the observed effects were homologous, i.e. specific of the receptor subtype stimulated. Octreotide pretreatment was also without effect on the density of 125I-[DTrp8]-SRIH binding in either the arcuate nucleus or pituitary. These results demonstrate, for the first time, that SRIH preexposure in vivo upregulates the expression of a subtype of its own receptors, sst2, within the central nervous system. They further suggest that pretreatment with SRIH in vivo does not cause sst2 receptor desensitization in arcuate nucleus and pituitary. Such homologous regulatory mechanisms may play an important role in the neuroendocrine control of growth hormone (GH) secretion by the arcuate nucleus.
Serotonin 5-HT1A Receptor mRNA Expression in Dorsal Hippocampus and Raphe Nuclei after Gonadal Hormone Manipulation in Female Rats
Authors: Birzniece Vita , Johansson Inga-Maj , Wang Ming-De , Seckl Jonathan R. , Bäckström Torbjörn , Olsson Tommy
Published: April 2003

Female ovarian steroids influence mood and cognition, an effect presumably mediated by the serotonergic system. A key receptor in this interplay may be the 5-HT1A receptor subtype. We gave adult ovariectomized female rats subcutaneous pellets containing different dosages of 17β-estradiol alone or in combination with progesterone, or placebo pellets, for 2 weeks. 5-HT1A receptor mRNA levels were analyzed by in situ hybridization in the dorsal hippocampus, dorsal and median raphe nuclei, and entorhinal cortex. Estradiol treatment alone reduced 5-HT1A gene expression in the dentate gyrus and the CA2 region (17 and 19% decrease, respectively). Estradiol combined with progesterone supplementation increased 5-HT1A gene expression versus placebo in the CA1 and CA2 subregions of the dorsal hippocampus (16 and 30% increase, respectively). Concomitantly, 5-HT1A mRNA expression was decreased by 13% in the ventrolateral part of the dorsal raphe nuclei, while no changes were found in the median raphe nucleus and entorhinal cortex. Chronic effects of ovarian hormones on 5-HT1A receptor mRNA expression appear tissue-specific and involve hippocampal subregions and the raphe nuclei. Modulation of 5-HT1A receptor gene expression may be of importance for gonadal steroid effects on mood and cognition.
Improving Influence of Insulin on Cognitive Functions in Humans
Authors: Kern Werner , Peters Achim , Fruehwald-Schultes Bernd , Deininger Eva , Born Jan , Fehm Horst L.
Published: April 2003

Insulin receptors have been identified in limbic brain structures, but their functional relevance is still unclear. In order to characterize some of their effects, we evaluated auditory evoked brain potentials (AEP) in a vigilance task, behavioral measures of memory (recall of words) and selective attention (Stroop test) during infusion of insulin. The hormone was infused at two different rates (1.5 mU/kg × min, ‘low insulin’, and 15 mU/kg × min, ‘high insulin’), inducing respectively serum levels of 543 ± 34 and 24,029 ± 1,595 pmol/l. This experimental design allowed to compare cognitive parameters under two conditions presenting markedly different insulin levels, but with minimal incidence on blood glucose concentrations since these were kept constant by glucose infusion. A ‘no insulin treatment’ group was not included in order to avoid leaving patients infused with glucose without insulin treatment. Measures were taken during a baseline phase preceding insulin infusion and every 90 min during the 360 min of insulin infusion. Compared with ‘low insulin’, ‘high insulin’ induced a slow negative potential shift in the AEP over the frontal cortex (average amplitude, high insulin: 0.27 ± 0.48 µV; low insulin: 1.87 ± 0.48 µV, p < 0.005), which was paralleled by enhanced memory performance (words recalled, high insulin: 22.04 ± 0.93; low insulin: 19.29 ± 0.92, p < 0.05). Also, during ‘high insulin’ subjects displayed enhanced performance on the Stroop test (p < 0.05) and expressed less difficulty in thinking than during ‘low insulin’ (p < 0.03). Results indicate an improving effect of insulin on cognitive function, and may provide a frame for further investigations of neurobehavioral effects of insulin in patients with lowered or enhanced brain insulin, i.e., patients with Alzheimer’s disease or diabetes mellitus.
Basal Hypothalamo-Pituitary-Adrenal Axis Activity and Corticotropin Feedback in Young and Older Men: Relationships to Magnetic Resonance Imaging-Derived Hippocampus and Cingulate Gyrus Volumes
Authors: Wolf Oliver T. , Convit Antonio , de Leon Mony J. , Caraos Conrado , Qadri Syed F.
Published: April 2003

Alterations in basal cortisol secretion and feedback sensitivity are reported in aging. However, it is not known whether these hypothalamus-pituitary-adrenal (HPA) axis alterations are related to structural brain changes. This study was designed to investigate these relationships in the human. Nine young (24.0 ± 1.2 years; mean ± SE; range: 19–30) and 11 older (69.0 ± 1.8 years; range: 59–76) men, in addition to having standardized magnetic resonance imaging of their brains, were given 0.5 mg/kg cortisol or placebo intravenously in a double-blind, crossover study. As expected, older men had significantly smaller volumes for all brain regions. Although the groups did not differ in baseline HPA axis activity, there were significant and specific relationships between the brain volumes and the baseline measures of HPA activity. Namely, for young and older subjects combined and after controlling for age and cerebral vault size, hippocampal volumes were inversely associated with 24-hour urinary cortisol and basal corticotropin (ACTH) levels, and the anterior cingulate gyrus volume was negatively correlated with baseline ACTH. Elderly subjects had a slower decrease in ACTH levels (percent of baseline level) during the first 30 min after cortisol administration. However, no associations were observed between the ACTH feedback indices and any brain measure. This report, although based on a small number of subjects, supports previous studies showing a blunted ACTH fast feedback during normal aging. Hippocampal atrophy appears to be related to increased basal measures of HPA axis activity, but not to fast ACTH feedback. It remains possible that age-associated changes in fast feedback may be related to changes to other brain sites, such as hypothalamus or pituitary.
Hyperthermia Preconditioning Induces Renal Heat Shock Protein Expression, Improves Cold Ischemia Tolerance, Kidney Graft Function and Survival in Rats
Authors: Redaelli Claudio A. , Tien Ying-Hua , Kubulus Darius , Mazzucchelli Luca , Schilling Martin K. , Wagner Andreas C.C.
Published: April 2003

Background: Evidence indicates that hyperthermia preconditioning (HP) can be protective in kidney transplantation, possibly through increased heat shock protein (HSP) expression. A detailed study about individual HSPs and functional preservation is lacking, however. Therefore, we studied the effects of HP on kidney graft survival, function and HSP expression. Methods: Male Lewis rats were or were not subjected to whole-body hyperthermia 24 h prior to kidney procurement. Kidneys were stored in UW solution at 4°C for 32, 40 or 45 h. Recipient kidneys were both removed and single isografts transplanted orthotopically. Results: HP strongly induced HSP72 and HSP32 expression. Following 32-hour cold ischemia, most animals survived even without prior HP. However, HP strongly reduced functional impairment induced by cold ischemia. Following 40-hour cold ischemia, kidneys from donors without HP did not recover function and all animals died within 3 days. In contrast, HP-exposed kidneys tolerated 40-hour storage significantly better, with 44% of rats surviving until sacrifice on day 7. In these animals, renal function was still better compared to animals with 32-hour-stored kidneys without HP. Histological alterations were also diminished following HP. Conclusion: Our data show that HP induces renal HSP72 and, for the first time, HSP32. HP increases survival following transplantation and acts by improving several parameters of kidney function including proteinuria, volume output and creatinine clearance.
Association of Hemostatic Variables with MRI-Detected Cerebral Abnormalities: The Atherosclerosis Risk in Communities Study
Authors: Knuiman Matthew W. , Folsom Aaron R. , Chambless Lloyd E. , Liao Duanping , Wu Kenneth K.
Published: April 2003

Objectives: Population-based and clinical prospective studies have shown independent associations of several hemostatic factors with ischemic heart disease and stroke. MRI-detected cerebral infarcts and white matter lesions are often detected in elderly individuals without clinical disease. It has been hypothesized that these types of lesions are often the consequence of cerebral ischemic damage and may be the precursors of clinical stroke. Methods: This study examined the relation between a range of hemostatic factors measured at baseline in middle-aged participants who were free of diagnosed cardiovascular disease in the Atherosclerosis Risk in Communities Study and MRI-detected cerebral abnormalities at a 6-year follow-up examination. Results: Plasma fibrinogen and perhaps von Willebrand factor were associated positively, and protein C was associated negatively, with cerebral infarctions. Adjusted for other risk factors, the odds ratio for cerebral infarction was 1.21 (95% confidence interval, CI = 1.02–1.44) per standard deviation increment for fibrinogen, 1.15 (95% CI = 0.97–1.37) per standard deviation increment for von Willebrand factor, and 0.77 (95% CI = 0.62–0.95) per standard deviation increment for protein C. No hemostatic factor, however, was associated with white matter disease. Conclusions: This study has only a follow-up MRI, and it is likely that some MRI lesions were present at baseline. Nevertheless, increased levels of fibrinogen and von Willebrand factor and reduced levels of protein C appear to be associated with cerebral infarction identified by MRI.
Reliability of Information Collected by Proxy in Family Studies of Alzheimer’s Disease
Authors: Demissie Serkalem , Green Robert C. , Mucci Lorelei , Tziavas Sophia , Martelli Kathy , Bang Kaitlin , Coons Lisa , Bourque Sylvie , Buchillon Dina , Johnson Kris , Smith Tamisson , Sharrow N. , Lautenschlager Nicola , Friedland Robert , Cupples L. Adrienne , Farrer Lindsay A.
Published: April 2003

The study evaluated the reliability of data obtained from proxy informants. The index subjects in this study were 81 nondemented participants in the Multi-Institutional Research in Alzheimer Genetic Epidemiology (MIRAGE) study. These index subjects and 159 proxy informants, identified by the index subjects, participated in the study. The ĸ statistic with multiple raters per subject (for dichotomous variables) and the intraclass correlation coefficient (for continuous variables) were used to measure reliability. Among proxy respondents who provided answers, there was excellent agreement between proxy responses and the responses of the index subjects (0.7 ≤ ĸ ≤0.9), with the exception of questions about head injury (ĸ = 0.4). A large proportion (>90%) of the proxy informants in this study were able to provide information on most items. Higher nonresponse rates (as high as 30%) were observed for medication history and women’s health questions. This study supports the reliability of proxy responses for most categories of questions that are elicited in typical epidemiological studies, including the MIRAGE study.
Risk Factors for Parkinson’s Disease: The Leisure World Cohort Study
Authors: Paganini-Hill Annlia
Published: April 2003

We conducted a case-control study nested within a prospective cohort study of 13,979 residents of Leisure World Laguna Hills, a retirement community in southern California, for etiologic clues for Parkinson’s disease (PD). Between 1981 (when first mailed a health survey) and 1998, we identified 395 PD cases from death certificates, hospital discharge diagnoses and a 1992 follow-up questionnaire. Six controls were individually matched on sex, birth date (±2 years), vital status and, if dead, death date (±1 year) to each case. Baseline characteristics of the 395 cases and 2,320 controls were analyzed as potential PD risk factors. The risk of PD was significantly reduced among smokers, hypertensives, coffee drinkers and alcohol consumers, and significantly increased among those with 3 or more children and with a high intake of total vitamin A and dietary vitamin C. The multivariate odds ratios (95% confidence intervals) were 0.42 (0.22–0.80) for current cigarette smokers of 1+ pack/day, 0.62 (0.48–0.80) for current users of hypertensive medication, 0.71 (0.52–0.95) for coffee drinkers of 2+ cups/day and 0.77 (0.58–1.03) for drinkers of 2+ alcoholic drinks/day. Risk increased with increasing number of children (1.25 for 1, 1.34 for 2 and 1.90 for 3+ children; p for trend = 0.0003). The increased risks among individuals in the highest third of total vitamin A intake and of dietary vitamin C intake were no longer statistically significant after adjusting for the other variables. These findings suggest several environmental factors that may be related to the development of PD and support a multifactorial etiology.
Renal Failure in Patients with Neurogenic Lower Urinary Tract Dysfunction
Authors: Lawrenson Ross , Wyndaele Jean-Jacques , Vlachonikolis Ioannis , Farmer Christopher , Glickman Scott
Published: April 2003

People with multiple sclerosis, paraplegia and neural tube defects typically have neurogenic lower urinary tract dysfunction (NLUTD). This encompasses detrusor hyperreflexia with or without detrusor sphincter dyssynergia and hypo- or acontractility. Their effects undermine safe, effective and controlled storage and voiding of urine and predispose to reflux nephropathy. Therefore, patients in these diagnostic groups with NLUTD would be expected to have increased risk of renal failure. The aim of this study was to quantify this risk using the General Practice Research Database (GPRD). All patients registered in the database between 1994 and 1997 and aged 10–69 were included in the study. The prevalence and incidence of renal failure and renal replacement therapy in the general population was ascertained, as was the prevalence of multiple sclerosis, paraplegia and neural tube defects. The prevalence of renal failure in each of the special populations was then compared with the prevalence in the unaffected general population. The age-standardised prevalence of renal failure in the GPRD population aged 10–69 years was 14 per 10,000. The rate ratio of renal failure compared with the general population in each of the years 1994–1997 for neural tube defects ranged between males (M) 6.8–9.0 and females (F) 9.2–11.5, for paraplegia M 4.1–9.0, F 4.0–7.0, and for multiple sclerosis M 0.4–1.3, F 0.5–2.2. As expected, people with paraplegia or neural tube defects were found to have a substantially increased risk of renal failure compared with the general population. We could not demonstrate an increased risk of renal failure in people with multiple sclerosis. We believe this finding requires further study, but may reflect a problem in the recognition of renal failure in this group of patients. We recommend that all three patient groups should be regularly screened so that renal impairment may be detected prior to the development of renal failure.
Prognosis of Alzheimer’s Disease: The Rotterdam Study
Authors: Ruitenberg A. , Kalmijn S. , de Ridder M.A.J. , Redekop W.K. , van Harskamp F. , Hofman A. , Launer L.J. , Breteler M.M.B.
Published: April 2003

The aim of this study was to construct a prognostic model to predict the progression of Alzheimer’s disease (AD). Prevalent and incident cases with AD came from the Rotterdam Study, a population-based prospective cohort study of persons aged 55 years and older, including those living in institutions. Rate of cognitive decline, as measured by the Mini Mental State Examination (MMSE score), was predicted by a random effects model. Risk of institutionalization and death were estimated with polytomous logistic regression analysis. At baseline, 306 subjects were diagnosed with prevalent AD and had complete data on living conditions and cognitive function. After a mean follow-up of 2.1 years, 95 subjects with incident AD had been diagnosed. Prevalent patients showed a slower decline in cognitive function than incident patients (p = 0.004). For prevalent and incident AD patients, high age and low cognitive performance were the strongest predictors for institutionalization and death. These prognostic risk functions can provide information on the decline of Alzheimer patients and might be used to better evaluate the effect of treatments for AD.
Stroke in the Urban Population of Calcutta – An Epidemiological Study
Authors: Banerjee T.K. , Mukherjee C.S. , Sarkhel A.
Published: April 2003

A population-based cluster survey on stroke disorders was conducted for the first time in the city of Calcutta, India. The population surveyed totaled 50,291. The crude prevalence rate of stroke was 147/100,000 (age-adjusted prevalence 334/100,000). The annual incidence rate of stroke for the year 1998–1999 was 36/100,000 (age-adjusted annual incidence rate 105/100,000). Women outnumbered men regarding stroke prevalence in all age groups except in the 50- to 69-year age group. There were relatively more cases of cerebral haemorrhage in our study, compared to those in the western countries. Case-control analysis found hypertension to be the most significant risk factor for stroke.
Cause-Specific Mortality in Adults with Unprovoked Seizures
Authors: Rafnsson Vilhjálmur , Ólafsson Elias , Hauser W. Allen , Gudmundsson Gunnar
Published: April 2003

Purpose: To determine the cause-specific mortality relative to that expected in a population-based incidence cohort of people with unprovoked seizures. Methods: The cohort comprises 224 inhabitants of Iceland first diagnosed as suffering from unprovoked seizures during a 5-year period from 1960 to 1964. The expected number of deaths was calculated by multiplying person-years of observation within 5-year age categories for each year from diagnosis through 1995 by cause-specific and sex-specific national death rates for those aged 20 years and above. The standardized mortality ratio (SMR) and 95% confidence intervals (95% CI) were calculated. Results: All-cause mortality was increased among men (SMR 2.25, 95% CI 1.56–3.14) but not women (SMR 0.79, 95% CI 0.38–1.46). Among men, there were 8 deaths from accidents, poisoning and violence observed versus 2.82 expected (SMR 2.84, 95% CI 1.22–5.59) and 4 deaths from suicide versus 0.69 expected (SMR 5.80, 95% CI 1.56–14.84). All-cause mortality for men was still elevated after restriction of analysis to those with seizures of unknown etiology (SMR 1.73, 95% CI 1.05–2.67) with the excess deaths attributable to suicide (SMR 5.26, 95% CI 1.06–15.38). Both males and females with remote symptomatic unprovoked seizures had an increase in all-cause mortality due to excess mortality from all cancers, cerebrovascular disease and accidents. Conclusion: When compared with the age-, time-period- and gender-specific mortality in the general population, there is excess mortality in men but not women. The increased mortality for men is partly attributable to excess mortality from accidents and suicides.
Risk Factors for Epilepsy in a Rural Area in Tanzania
Authors: Matuja W.B.P. , Kilonzo G. , Mbena P. , Mwango’mbola R.L. , Wong P. , Goodfellow P. , Jilek-Aall L.
Published: April 2003

Background and Methods: The high prevalence of epilepsy detected in rural Tanzania by Dr. Jilek-Aall since 1960, was verified by the World Health Organization (WHO) survey on neurological and seizure disorders. Neurologists and psychiatrists further interviewed both patients and controls using standard methods. The presence of possible risk factors was complemented by corroborative evidence through interviewing close relatives and scrutinizing medical records. Seizures were classified based on clinical symptoms and the use of EEG. Results: A family history of epilepsy in first-degree relatives was found in 46.6% of patients, but in only 19.6% of controls. The odds ratio for family history with epilepsy was 3.52 (95% confidence interval, CI 2.4–5.74, p < 0.001). A past history of febrile convulsion was found in 44% of patients in comparison to 23% of the control group which was significant (odds ratio 2.4, 95% CI 1.5–3.8; p < 0.001). A history of intrapartum complications was found in 12.1% of patients and 1.8% of controls (odds ratio 7.3, 95% CI 2.5–25.2; p < 0.002). Head injury was not a significant risk factor for epilepsy in this rural community. Conclusion: The results indicated a strongly independent association between four factors and the risk of developing epilepsy. It would seem more likely that previous brain insults/diseases play a significant major role in the cause of epilepsy in the Mahenge area. However, a genetic predisposition to low threshold for convulsions cannot be excluded.
Validation of Symptoms Related to Excessive Daytime Sleepiness
Authors: Rinaldi Rita , Vignatelli Luca , D’Alessandro Roberto , Bassein Leona , Sforza Emiliana , Plazzi Giuseppe , Provini Federica , Lugaresi Elio
Published: April 2003

The aim of this study was to validate some recurring definitions of excessive daytime sleepiness (EDS) obtained from descriptive epidemiological studies. We devised questions concerning concepts such as ‘tiredness’, ‘resistible sleepiness’, ‘irresistible sleepiness’ and ‘sudden sleep attacks’. The validation was done by comparing the answers with the results of the Multiple Sleep Latency Test (MSLT), considered the gold standard, or criterion measure, for the diagnosis of EDS. The sample study comprised 73 subjects, 57 outpatients referred to our Sleep Center complaining of daytime sleepiness, snoring or sleep apnea and 16 inpatients admitted to our Neurological Institute for causes other than sleep disorders. A moderate correlation (p = –0.38, 95% confidence interval –0.57 to –0.19) was found between ‘irresistible sleepiness’ and mean sleep latency (MSL). The best combinations of sensitivity and specificity in identifying EDS, for 5- and 8-min MSL cutoffs, were observed for the questions concerning ‘sudden sleep attacks’ and ‘irresistible sleepiness’ (areas under the receiver-operating characteristic curves = 66 and 67%, respectively). The subitems exploring the frequency and situations of occurrence of these symptoms improved the validity in identifying EDS. The items regarding ‘tiredness’ and ‘resistible sleepiness’ were not related to the results of the MSLT. In subgroup analysis, irresistible sleepiness failed to identify pathologic MSLT in sleep-disordered breathing subjects. According to previous observations, we suggest that the concept of sleepiness includes various domains heterogeneously related with MSL and that questionnaires must be tailored to the different populations studied.
Psychometric Properties of the Center for Epidemiologic Studies-Depression Scale in Multiple Sclerosis
Authors: Verdier-Taillefer M.-H. , Gourlet V. , Fuhrer R. , Alpérovitch A.
Published: April 2003

The factorial structure of the Center for Epidemiologic Studies-Depression (CES-D) scale has been examined on a large sample of multiple sclerosis (MS) subjects (n = 696), general practice patients (n = 1,308) and healthy workers (n = 342). The aim of this study was to verify if the CES-D is a valid and reliable scale to assess depressive symptomatology in MS. As previously reported in the literature, we found four factors that measure depressed affect, positive affect, somatic complaints or retarded activity and interpersonal relationships. The percent of total variance explained by the four factors was greater than 50% in each group. Cronbach’s α coefficients were 0.90 in the MS sample and 0.93 in the general practice sample, indicative of high reliability in both samples. From these results, we conclude that the CES-D can be used to screen for depression in epidemiological studies of this psychiatric disorder among MS patients.
Association of the Apolipoprotein E ε4 Allele with Late-Onset Depression
Authors: Rigaud Anne-Sophie , Traykov Latchezar , Caputo Ludovica , Coste Joël , Latour Florence , Couderc Rémy , Moulin Florence , Boller François , Forette Françoise
Published: April 2003

Apolipoprotein E (ApoE) phenotyping was determined in 42 subjects with Alzheimer’s disease (AD), 49 with depression, including 26 with early-onset depression (EOD) and 23 with late-onset depression (LOD), and 49 controls. In the EOD group, the frequency of the ApoE Ε4 allele was not different from the control frequency (p = 0.532) but was significantly lower than in AD (p < 0.001). In the LOD group, the ApoE Ε4 frequency was significantly higher than in the controls (p = 0.034) but was not different from that in the AD group (p = 0.229). Individuals with ApoE Ε4 were at greater risk of getting AD (odds ratio, OR = 5.5, 95% confidence interval, CI, 2.0–14.0) or LOD (OR = 6.1, 95% CI, 1.9–19.0) than of EOD (OR = 0.7, 95% CI, 0.2–2.5). These results suggest an association between the ApoE Ε4 allele frequency and LOD. Patients with LOD could be at risk of developing AD by an Ε4-dependent pathway.
Association Study of Suicidal Behavior and Affective Disorders with a Genetic Polymorphism in ABCG1, a Positional Candidate on Chromosome 21q22.3
Authors: Rujescu D. , Giegling I. , Dahmen N. , Szegedi A. , Anghelescu I. , Gietl A. , Schäfer M. , Müller-Siecheneder F. , Bondy B. , Möller H.-J.
Published: April 2003

The gene that codes for the ABC transporter ABCG1 is located in a chromosomal susceptibility region (21q22.3) for affective disorders. Genetic variations in ABCG1 have been associated with affective disorders in Japanese males. In this study, we investigated the distribution of a G2457A polymorphism in patients with affective disorders, suicide attempters with various psychiatric diagnoses and healthy subjects. We initially found a trend towards a modest association with affective disorders in males (p = 0.046 for allele frequencies and p = 0.046 for AA versus GG). We conducted a replication study with independent patients and controls. There was no association with affective disorders, either in the replication or in the combined group. Furthermore, we found no association with suicidal behavior. These findings do not support the hypothesis that ABCG1 is a susceptibility gene for affective disorders or suicidal behavior.
Association Analysis of a Functional Catechol-O-Methyltransferase Gene Polymorphism in Schizophrenic Patients in Taiwan
Authors: Liou Ying-Jay , Tsai Shih-Jen , Hong Chen-Jee , Wang Ying-Chieh , Lai I-Ching
Published: April 2003

The catechol-O-methyltransferase (COMT) gene was thought to be a candidate gene for schizophrenia because of its role in inactivating dopamine. This study examined the relationship between a functional polymorphism (val158met) of the COMT gene, schizophrenia and its associated behaviors. One hundred and ninety-eight Chinese schizophrenic patients and 188 controls were genotyped by polymerase chain reaction restriction fragment length polymorphism. Of the schizophrenic patients, 72 had a history of violence and 62 had a history of suicide attempts. The results failed to show significant association between val158met polymorphism and schizophrenia, violence or suicide. However, our results showed a significant difference in age at disease onset among different genotypes (F = 5.501, p = 0.005).
Plasma Concentrations of Interleukin-1β, Interleukin-6, Soluble Interleukin-2 Receptor and Tumor Necrosis Factor α of Depressed Patients in Japan
Authors: Kagaya Ariyuki , Kugaya Akira , Takebayashi Minoru , Fukue-Saeki Mayumi , Saeki Toshinari , Yamawaki Shigeto , Uchitomi Yosuke
Published: April 2003

There are a number of investigations which indicate the important relationship between depression and cytokines. In this study, we investigated plasma interleukin (IL)-1β, IL-6, soluble IL-2 receptor (sIL-2R) and tumor necrosis factor (TNF)-α of depressed patients whose clinical evaluation was performed by the Hamilton Rating Scale for Depression (HAM-D) and the Profile of Mood States (POMS). They were compared with those of the control subjects, and before and after treatment with antidepressants. Before the treatment, plasma IL-1β, IL-6, sIL-2R and TNF-α of the patients were not significantly different from those of the control subjects. sIL-2R was positively correlated with the POMS-tension-anxiety subscale and tended to have a positive correlation with HAM-D. After pharmacotherapy, TNF-α levels of the depressed patients increased, without any relationship between the change in the HAM-D or the POMS and the change in TNF-α. These results suggest that the plasma sIL-2R concentration is associated with mood state, and that the plasma TNF-α concentration is increased after pharmacotherapy in Japanese depressed patients.
Depressive Symptoms in Hypothyroid Disorder with some Observations on Biochemical Correlates
Authors: Gunnarsson Tove , Sjöberg Stefan , Eriksson Mats , Nordin Conny
Published: April 2003

Lumbar punctures and ratings of depressive symptoms were done in hypothyroid patients before and during L-thyroxine therapy. Before treatment, the most prominent symptoms were concentration difficulties, lassitude, and reduced sexual interest. All patients suffered from sleep disturbances. Suicidal thoughts did not occur at all. Inner tension was negatively correlated with the anxiogenic cholecystokinin tetrapeptide (CCK-4) in the cerebrospinal fluid (CSF), while reduced sexual interest was negatively correlated with CSF tryptophan. Furthermore, failing memory correlated negatively with T3 as well as T4 in serum. A positive correlation was found between failing memory and serum TSH. All patients improved significantly during treatment. No biochemical correlates were found. In conclusion, hypothyroidism is associated with major depressive symptoms. CSF CCK-4 and tryptophan, as well as serum thyroid hormones, may constitute biochemical correlates for some of these symptoms.
Association between GABA-A Receptor Alpha 5 Subunit Gene Locus and Schizophrenia of a Later Age of Onset
Authors: Papadimitriou George , Dikeos Dimitris , Daskalopoulou Eugenia , Karadima Georgia , Avramopoulos Dimitrios , Contis Costas , Stefanis Costas
Published: April 2003

Heritability is considered to be a major etiologic factor for schizophrenia. Among the genes considered as candidates for the disease, are those related to GABAergic neurotransmission. Our aim was to test for a genetic association between GABA-A receptor alpha 5 subunit gene locus (GABRA5) and schizophrenia. Genotyping of the GABRA5 locus was performed by the use of a dinucleotide (CA) repeat marker in 46 schizophrenic patients and 50 healthy individuals, all unrelated Greeks. Eight alleles were identified, 276–290 bp long. A nonsignificant excess of the 282-bp allele, which was found in a previous study in a Greek population to be associated with bipolar affective disorder, was observed in schizophrenic patients (33.8 vs. 23.9% in the controls). The frequency of this allele was 43.3% among patients with a later age of onset (over 25 years), differing at a statistically significant level from the controls (p < 0.05). These results suggest that common pathophysiological mechanisms may possibly underlie affective disorders and schizophrenia, at least in a subgroup of patients.
Posttraumatic Stress Disorder: Diagnosis and Epidemiology, Comorbidity and Social Consequences, Biology and Treatment
Authors: Brunello Nicoletta , Davidson Jonathan R.T. , Deahl Martin , Kessler Ron C. , Mendlewicz Julien , Racagni Giorgio , Shalev Arieh Y. , Zohar Joseph
Published: April 2003

Epidemiological studies clearly indicate that posttraumatic stress disorder (PTSD) is becoming a major health concern worldwide even if still poorly recognized and not well treated. PTSD commonly co-occurs with other psychiatric disorders, and several symptoms overlap with major depressive disorders, anxiety disorders and substance abuse; this may contribute to diagnostic confusion and underdiagnosis. This anxiety disorder provokes significant occupational, psychiatric, medical and psychosocial disability, and its consequences are enormously costly, not only to the survivors and their families, but also to the health care system and society. Work impairment associated with PTSD is very similar to the amount of work impairment associated with major depression. The pathophysiology of PTSD is multifactorial and involves dysregulation of the serotonergic as well as the noradrenergic system. A rational therapeutic approach should normalize the specific psychobiological alterations associated with PTSD. This can be achieved through the use of antidepressant drugs, mainly of those that potentiate serotonergic mechanisms. Recent double-blind placebo-controlled studies report the efficacy of selective serotonin reuptake inhibitors. Several cognitive-behavioral and psychosocial treatments have also been reported to be efficacious and could be considered when treating PTSD patients.
Correlation between Platelet α2-Adrenoreceptors and Symptom Severity in Major Depression
Authors: Marazziti Donatella , Baroni Stefano , Masala Irene , Di Nasso Elena , Giannaccini Gino , Betti Laura , Lucacchini Antonio , Cassano Giovanni B.
Published: April 2003

Background: Abnormalities in different parameters of the norepinephrine system have been widely described in major depression. The presence of α2-adrenoreceptors in blood platelets, similar to those in the brain, prompted us to evaluate them in depressed patients, as compared with healthy controls. Methods: Fifteen outpatients affected by major depression, according to DSM IV criteria, and 15 comparable healthy control subjects, were included in the study. The α2-adrenoreceptors were measured by means of the specific binding of [3H]rauwolscine, a highly selective antagonist for this receptor subtype. The severity of depression was assessed by means of the Hamilton Rating Scale for Depression (HRSD). Results: The results did not show any difference in [3H]rauwolscine binding parameters (Bmax and Kd) between patients and controls. However, in the patients, a significant and positive correlation between Bmax, which measures the density of the receptors, and HRSD total score was detected. Conclusions: Therefore, although no change in α2-adrenoreceptors seems to occur in major depression, the density of these receptors would seem to be related to the severity of depressive symptoms.
Effects of Carbamazepine on Dexamethasone Suppression and Sleep Electroencephalography in Borderline Personality Disorder
Authors: De la Fuente José Manuel , Bobes Julio , Vizuete Coro , Mendlewicz Julien
Published: April 2003

The pathophysiology of borderline personality disorder (BPD) remains obscure, but there is mounting evidence of brain dysfunction without focal abnormality. The dexamethasone suppression test (DST) and sleep electroencephalography (sleep EEG) have been studied in BPD, but the findings seem to be related to a concomitant axis I diagnosis of major depression (MD) rather than to BPD itself. There is no effective treatment for BPD. Carbamazepine (CBZ) has shown contradictory results and in a previous study, our results were negative. In this study, we investigated the effects of CBZ versus placebo on the DST and sleep EEG in a sample of 20 BPD patients without concomitant MD. CBZ given at doses that are therapeutic for epilepsy and affective disorders may have an effect on the DST and sleep EEG in BPD. CBZ significantly increased the postdexamethasone plasma cortisol values. This did not parallel MD or an increase in the Hamilton depression rating scores. CBZ also increased slow wave sleep (SWS). The mechanisms by which CBZ increased postdexamethasone plasma cortisol levels and SWS in BPD are discussed.
Mitogen-Activated Protein Kinase Cascade in Breast Cancer
Authors: Maemura Michio , Iino Yuichi , Koibuchi Yukio , Yokoe Takao , Morishita Yasuo
Published: April 2003

The mitogen-activated protein (MAP) kinase is considered to play a central role in diverse cellular events including carcinogenesis and tumor progression. Indeed, expression of MAP kinase, tyrosine-phosphorylated MAP kinase, and Raf-1 protein was greater in cancerous human tissues than in the surrounding noncancerous glands. In a 7,12-dimethylbenz[a]anthracene-induced rat mammary carcinoma model, estrogen promoted and ovariectomy and antiestrogen, tamoxifen (TAM) inhibited the tumor growth. Ovariectomy suppressed expression of MAP kinase, tyrosine-phosphorylated MAP kinase and Raf-1, whereas estrogen as well as TAM induced expression of MAP kinase and Raf-1 under castrated conditions. Since it was reported that MAP kinase was activated during the progression of breast carcinoma cells, such estrogenic actions of TAM toward the MAP kinase cascade might be responsible for malignant progression.
Endocrine Therapies for Patients with Recurrent Breast Cancer: Predictive Factors for Responses to First- and Second-Line Endocrine Therapies
Authors: Kurebayashi Junichi , Sonoo Hiroshi , Inaji Hideo , Nishimura Reiki , Iino Yuichi , Toi Masakazu , Kobayashi Shunzo , Saeki Toshiaki
Published: April 2003

Breast cancer patients have been treated with four different hormonal agents, antiestrogen, progestin, luteinizing hormone-releasing hormone agonist and aromatase inhibitor, during the past 7 years in Japan. To investigate the efficacy of these agents for the treatment of recurrent breast cancer patients, we conducted a retrospective multi-institute survey in Japan. The clinico-pathological data of 131 patients, who received endocrine therapy as first-line treatment between 1993 and 1998, were collected from seven institutes. The median age of the patients was 55 (range 27–92) years, 75% of their primary tumors were estrogen receptor (ER)-positive or unknown, and 95% of the dominant metastatic sites were bone, soft tissue or lungs. The objective response rate to first-line endocrine therapy was 42.7%, and that to second-line therapy 42.5% (17 of 40 patients). Multiple regression analyses of predictive factors for a response to first- and second-line endocrine therapies indicated two independent factors, ER status of the primary tumors and dominant site of metastasis, for the former, and one independent factor, a response to first-line endocrine therapy, for the latter. Analysis of relationships between sequences of use of hormonal agents and objective response rates revealed that the choice of first-line hormonal agent did not influence the overall efficacy of first- and second-line endocrine therapies. Overall survival after first recurrence in patients with tumors exhibiting an objective response or stable disease to first-line endocrine therapy was significantly better than that in patients with tumors exhibiting progressive disease (p < 0.01). These findings suggest that an adequate selection of recurrent breast cancer patients referring the ER status, dominant site of metastasis and a prior response to endocrine therapy may contribute to better clinical outcomes of the patients.