bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inducible over‐expression of wild type α‐synuclein in human neuronal cells leads to caspase‐dependent non‐apoptotic death
Authors: Vekrellis Kostas , Xilouri Maria , Emmanouilidou Evangelia , Stefanis Leonidas 
Published: March 2009

AbstractAlpha‐synuclein (ASYN) is central in Parkinson’s disease pathogenesis. Converging pieces of evidence suggest that the levels of ASYN expression play a critical role in both familial and sporadic Parkinson’s disease. To elucidate the mechanism underlying wild type (WT) ASYN‐mediated neurotoxicity, we have generated a novel Tet‐Off SHSY‐5Y cell line, conditionally expressing WT ASYN. Induction of human WT ASYN in retinoic acid‐differentiated SHSY‐5Y cells leads to accumulation of soluble ASYN oligomers, in the absence of inclusions, and to gradual cellular degeneration. Morphologically, the death observed is non‐apoptotic. Caspases other than caspase 3, including caspase 9, are activated and caspase inhibition diminishes death by acting at a point upstream of cytochrome c release. Application of Scyllo‐inositol, an oligomer‐stabilizing compound, prevents neuronal death in this model. These findings are consistent with a model in which oligomeric ASYN triggers the initial activation of the apoptotic pathway, which is however blocked downstream of the mitochondrial checkpoint, thus leading to a death combining in a unique fashion both apoptotic and non‐apoptotic features. This novel inducible cell model system may prove valuable in the deciphering of WT ASYN‐induced pathogenic effects and in the assessment and screening of potential therapeutic strategies.
Bioenergetic analysis of isolated cerebrocortical nerve terminals on a microgram scale: spare respiratory capacity and stochastic mitochondrial failure
Authors: Choi Sung W. , Gerencser Akos A. , Nicholls David G. 
Published: March 2009

AbstractPre‐synaptic nerve terminals (synaptosomes) require ATP for neurotransmitter exocytosis and recovery and for ionic homeostasis, and are consequently abundantly furnished with mitochondria. Pre‐synaptic mitochondrial dysfunction is implicated in a variety of neurodegenerative disorders, although there is no precise definition of the term ‘dysfunction’. In this study, we test the hypothesis that partial restriction of electron transport through Complexes I and II in synaptosomes to mimic possible defects associated with Parkinson’s and Huntington’s diseases respectively, sensitizes individual terminals to mitochondrial depolarization under conditions of enhanced proton current utilization, even though these stresses are within the respiratory capacity of the synaptosomes when averaged over the entire population. We combine two novel techniques, firstly using a modification of a plate‐based respiration and glycolysis assay that requires only microgram quantities of synaptosomal protein, and secondly developing an improved method for fluorescent imaging and statistical analysis of single synaptosomes. Conditions are defined for optimal substrate supply to the in situ mitochondria within mouse cerebrocortical synaptosomes, and the energetic demands of ion cycling and action‐potential firing at the plasma membrane are additionally determined.
Chronic stress elicits prolonged activation of α‐MSH secretion and subsequent degeneration of melanotroph
Authors: Ogawa Tokiko , Shishioh‐Ikejima Nobue , Konishi Hiroyuki , Makino Tetsuya , Sei Hiroyoshi , Kiryu‐Seo Sumiko , Tanaka Masaaki , Watanabe Yasuyoshi , Kiyama Hiroshi 
Published: March 2009

AbstractProlonged stress affects homeostasis in various organs and induces stress‐associated disorders. We examined the cellular changes of pituitary gland under the continuous stress condition using a rat model in which rats were kept in a cage filled with water to a height of 1.5 cm for up to 5 days. Among the pituitary hormone mRNAs, proopiomelanocortin mRNA was up‐regulated specifically in the intermediate lobe (IL) of this rat model. Additionally, the peripheral blood levels of α‐melanocyte stimulating hormone (α‐MSH), a major product of proopiomelanocortin in IL were increased. The α‐MSH secreting cells, melanotrophs, showed a markedly developed endoplasmic reticulum and Golgi apparatus in the early phase of the experiment. Subsequent continuous stress caused remarkable dilation of the endoplasmic reticulum, disruption of the Golgi structure, and the degeneration of some melanotrophs. In addition the dopaminergic nerve fibers from hypothalamus were markedly decreased in IL. A dopamine antagonist elicited the similar morphologic changes of melanotroph in normal rat. These findings suggest that prolonged stress suppressed hypothalamus‐derived dopamine release in IL, which elicited over‐secretion of α‐MSH from the melanotrophs. The present study also suggests that prolonged hyperactivation of endocrine cells could lead to disorder of secretion mechanisms and eventual degeneration.
Dynamic chromatin remodeling events in hippocampal neurons are associated with NMDA receptor‐mediated activation of Bdnf gene promoter 1
Authors: Tian Feng , Hu Xian‐Zhang , Wu Xuan , Jiang Hong , Pan Hongna , Marini Ann M. , Lipsky Robert H. 
Published: March 2009

AbstractTo determine the epigenetic events associated with NMDA receptor‐mediated activation of brain‐derived neurotrophic factor gene (Bdnf) promoter 1 by hippocampal neurons in culture, we screened 12 loci across 4.5 kb of genomic DNA 5′ of the transcription start site (TSS) of rat Bdnf for specific changes in histone modification and transcription factor binding following NMDA receptor stimulation. Chromatin immunoprecipitation (ChIP) assays showed that NMDA receptor stimulation produced a durable, time‐dependent decrease in histone H3 at lysine 9 dimethylation (H3K9me2), within 3 h after NMDA treatment across multiple loci. Concomitant increases in H3K4me2 and H3K9/14 acetylation (H3AcK9/14) were associated with transcriptional activation, but occurred at fewer sites within the promoter. The decrease in H3K9me2 was associated with release of HDAC1, MBD1, MeCP2, and REST from specific locations within promoter 1, although with different kinetics. In addition, occupancy of sites proximal to and distal to the TSS by the transcription factors NF‐κB, CREB‐binding protein (CBP), and cAMP‐response element‐binding protein were correlated with increased occupancy of RNA polymerase II at two loci proximal to the TSS following NMDA receptor stimulation. These temporal changes in promoter occupancy could occur thousands of base pairs 5′ of the TSS, suggesting a mechanism that produces waves of Bdnf transcription.
The Eocene Arctic Azolla bloom: environmental conditions, productivity and carbon drawdown
Authors: SPEELMAN E. N. , VAN KEMPEN M. M. L. , BARKE J. , BRINKHUIS H. , REICHART G. J. , SMOLDERS A. J. P. , ROELOFS J. G. M. , SANGIORGI F. , DE LEEUW J. W. , LOTTER A. F. , SINNINGHE DAMSTÉ J. S. 
Published: March 2009

ABSTRACTEnormous quantities of the free‐floating freshwater fern Azolla grew and reproduced in situ in the Arctic Ocean during the middle Eocene, as was demonstrated by microscopic analysis of microlaminated sediments recovered from the Lomonosov Ridge during Integrated Ocean Drilling Program (IODP) Expedition 302. The timing of the Azolla phase (~48.5 Ma) coincides with the earliest signs of onset of the transition from a greenhouse towards the modern icehouse Earth. The sustained growth of Azolla, currently ranking among the fastest growing plants on Earth, in a major anoxic oceanic basin may have contributed to decreasing atmospheric pCO2 levels via burial of Azolla‐derived organic matter. The consequences of these enormous Azolla blooms for regional and global nutrient and carbon cycles are still largely unknown. Cultivation experiments have been set up to investigate the influence of elevated pCO2 on Azolla growth, showing a marked increase in Azolla productivity under elevated (760 and 1910 ppm) pCO2 conditions. The combined results of organic carbon, sulphur, nitrogen content and 15N and 13C measurements of sediments from the Azolla interval illustrate the potential contribution of nitrogen fixation in a euxinic stratified Eocene Arctic. Flux calculations were used to quantitatively reconstruct the potential storage of carbon (0.9–3.5 1018 gC) in the Arctic during the Azolla interval. It is estimated that storing 0.9 1018 to 3.5 1018 g carbon would result in a 55 to 470 ppm drawdown of pCO2 under Eocene conditions, indicating that the Arctic Azolla blooms may have had a significant effect on global atmospheric pCO2 levels through enhanced burial of organic matter.
The Jews in the Medieval Polish Economy: Some Thoughts on the Historiography of the Twentieth Century
Authors: Komornicka Jolanta N. 
Published: March 2009

AbstractThis essay was runner‐up in the 2007History CompassGraduate Essay Prize, Europe Section.The historiography of medieval Jewry has often by‐passed the place of Jews in Poland, leaving that region for early modern scholars to tackle. Yet Poland had a significant Jewish population by the thirteenth century, though ascertaining its origins has been an issue of considerable debate among scholars and one heavily influenced by modern prejudices. As the scholarship has pulled itself from the anti‐Semitic morass of the early twentieth century, gradually greater weight has been given to the place of Jews in Polish communities apart from the stereotyped role of moneychanger and royal financer. Yet East and West have still to come together to provide a better nuanced understanding of both the Jews in Europe and the growth of cities and communes along the eastern border of the Latin West.
Lack of effect of norfloxacin on hyperdynamic circulation in bile duct‐ligated rats despite reduction of endothelial nitric oxide synthase function: result of unchanged vascular Rho‐kinase?
Authors: Hennenberg Martin , Trebicka Jonel , Buecher Doris , Heller Jörg , Sauerbruch Tilman 
Published: March 2009

AbstractBackground/Aims: In cirrhosis, portal hypertension is maintained by splanchnic vasodilation owing to overproduction of the vasodilator nitric oxide (NO) and defective contractile signalling by Rho‐kinase. NO overproduction is partially caused by bacterial translocation from the gut to mesenteric lymph nodes. However, the effects of intestinal bacterial decontamination on hyperdynamic circulation or vascular contractility are unknown. We investigated the haemodynamic and vascular effects of norfloxacin in rats with secondary biliary cirrhosis.Methods: Cirrhosis was induced by bile duct ligation (BDL). One group was treated with norfloxacin (20 mg/kg/day, 5 days, orally). Bacterial growth in the lymph nodes was determined on blood agar plates. Invasive haemodynamic measurements were combined with coloured microspheres. Aortic contractility was assessed myographically. Protein expression/phosphorylation was examined by Western blot analysis.Results: Norfloxacin treatment of BDL rats abolished bacterial translocation to mesenteric lymph nodes. BDL rats had hyperdynamic circulation, including portal hypertension and splanchnic vasodilation. None of these parameters was changed by norfloxacin, although norfloxacin reduced endothelial NO synthase expression and phosphorylation. The latter was associated with a diminished activity of protein kinase G (PKG), which mediates NO‐induced vasodilation. However, norfloxacin had no effect on aortic contractility to methoxamine or Ca2+, or the aortic expression of RhoA, Rho‐kinase and β‐arrestin 2, or the phosphorylation of the Rho‐kinase substrate moesin.Conclusions: Short‐term treatment of BDL rats with norfloxacin does not change hyperdynamic circulation or vascular contractility, despite reduction of PKG activity.
Partial epilepsy syndrome in a Gypsy family linked to 5q31.3‐q32
Authors: Angelicheva Dora , Tournev Ivailo , Guergueltcheva Velina , Mihaylova Violeta , Azmanov Dimitar N. , Morar Bharti , Radionova Melania , Smith Shelagh J. , Zlatareva Dora , Stevens John M. , Kaneva Radka , Bojinova Veneta , Carter Kim , Brown Matthew , Jablensky Assen , Kalaydjieva Luba , Sander Josemir W. 
Published: March 2009

SummaryPurpose:  The restricted genetic diversity and homogeneous molecular basis of Mendelian disorders in isolated founder populations have rarely been explored in epilepsy research. Our long‐term goal is to explore the genetic basis of epilepsies in one such population, the Gypsies. The aim of this report is the clinical and genetic characterization of a Gypsy family with a partial epilepsy syndrome.Methods:  Clinical information was collected using semistructured interviews with affected subjects and informants. At least one interictal electroencephalography (EEG) recording was performed for each patient and previous data obtained from records. Neuroimaging included structural magnetic resonance imaging (MRI). Linkage and haplotype analysis was performed using the Illumina IVb Linkage Panel, supplemented with highly informative microsatellites in linked regions and Affymetrix SNP 5.0 array data.Results:  We observed an early‐onset partial epilepsy syndrome with seizure semiology strongly suggestive of temporal lobe epilepsy (TLE), with mild intellectual deficit co‐occurring in a large proportion of the patients. Psychiatric morbidity was common in the extended pedigree but did not cosegregate with epilepsy. Linkage analysis definitively excluded previously reported loci, and identified a novel locus on 5q31.3‐q32 with an logarithm of the odds (LOD) score of 3 corresponding to the expected maximum in this family.Discussion:  The syndrome can be classified as familial temporal lobe epilepsy (FTLE) or possibly a new syndrome with mild intellectual deficit. The linked 5q region does not contain any ion channel–encoding genes and is thus likely to contribute new knowledge about epilepsy pathogenesis. Identification of the mutation in this family and in additional patients will define the full phenotypic spectrum.
Asymmetric seizure termination in primary and secondary generalized tonic–clonic seizures
Authors: Walser Gerald , Unterberger Iris , Dobesberger Judith , Embacher Norbert , Falkenstetter Tina , Larch Julia , Kuchukhidze Giorgi , Gotwald Thaddaeus , Ortler Martin , Bauer Gerhard , Trinka Eugen 
Published: March 2009

SummaryPurpose: In temporal lobe epilepsies an asymmetric termination (AST) of the clonic phase of secondary generalized tonic–clonic seizures (sGTCS) reliably lateralizes the side of seizure onset. The last clonic activity occurs ipsilateral to the side of the seizure onset zone. We compared the prevalence and lateralizing value of AST in sGTCS of frontal and temporal lobe origin as well as in primary generalized tonic–clonic seizures (pGTCS).Methods: We analyzed 177 seizures in 84 consecutive patients. Forty‐one patients had temporal lobe epilepsy (TLE), 24 frontal lobe epilepsy (FLE), and 19 had nonfocal (primary) generalized epilepsies (GE). All patients underwent intensive video‐EEG (electroencephalography) monitoring, high‐resolution magnetic resonance imaging (MRI), neuropsychological testing, and single photon emission computed tomography/positron emission tomography (SPECT/PET) when feasible. Two investigators blinded for diagnosis, EEG, and imaging data assessed frequency and side of the last clonic jerk.Results: AST occurred in 63% of patients with TLE (47% of seizures), in 71% with FLE (60% of seizures), and in 42% with GE (21% of seizures). These results were not significant for patients, but significant for seizures in TLE versus GE and in FLE versus GE (p < 0.001). The positive predictive value (PPV) for the side of seizure onset was 74% (p = 0.003) in TLE and 75% (p = 0.008) in FLE.Discussion: AST in sGTCS lateralizes the side of seizure onset in TLE and in FLE to the ipsilateral hemisphere with a high PPV. However, AST was also observed in GE. Therefore, asymmetric clinical signs should not inevitably lead to the assumption of focal epilepsy syndromes.
Cardiac function and antiepileptic drug treatment in the elderly: A comparison between lamotrigine and sustained‐release carbamazepine
Authors: Saetre Erik , Abdelnoor Mikael , Amlie Jan Peder , Tossebro Morten , Perucca Emilio , Taubøll Erik , Anfinsen Ole Gunnar , Isojärvi Jouko , Gjerstad Leif 
Published: March 2009

SummaryPurpose:  To investigate the comparative effects of carbamazepine (CBZ) and lamotrigine (LTG) on electrocardiography (ECG) parameters in elderly patients with newly diagnosed epilepsy.Methods:   The study was conducted in the Norwegian subcohort (n = 108) of an international randomized double‐blind 40‐week trial, which compared the efficacy and tolerability of LTG and sustained‐release CBZ in patients aged 65 and older with newly diagnosed epilepsy. Target maintenance doses were 400 mg/day for CBZ and 100 mg/day for LTG, with adjustments based on clinical response. Patients with significant unpaced atrioventricular (AV) conduction defect were excluded. Resting 12‐lead ECG recordings were made under standardized conditions at pretreatment (baseline) and at the 40‐week study visit (treatment visit). Changes in QRS interval (primary endpoint), heart rate (HR), PQ, and QTc (HR‐corrected QT) intervals were assessed and compared between groups.Results:  Of the 108 patients randomized, 33 discontinued prematurely because of adverse events (n = 24, none of which was cardiac) or other reasons (n = 9), and 15 were nonevaluable due to incomplete ECG data. None of the assessed ECG parameters differed significantly between groups at baseline. No significant ECG changes were recorded between baseline and treatment visit for QRS duration and QTc intervals, whereas HR fell and PQ intervals increased slightly on both treatments. However, there were no differences between groups in changes from baseline to treatment visit. There were no significant relationships between individual ECG changes and serum drug concentrations, except for QTc intervals, which decreased slightly with increasing CBZ concentrations. The proportion of patients with ECG parameters outside the normal range at treatment visit was similar to that recorded at baseline.Discussion:  Clinically significant ECG changes are not common during treatment with CBZ or LTG in elderly patients with no preexisting significant AV conduction defects.
Effects of Prenatal Ethanol Exposure on Hypothalamic‐Pituitary‐Adrenal Function Across the Estrous Cycle
Authors: Lan Ni , Yamashita Fiona , Halpert Alison G. , Sliwowska Joanna H. , Viau Victor , Weinberg Joanne 
Published: March 2009

Background: Rats prenatally exposed to ethanol (E) typically show increased hypothalamic‐pituitary‐adrenal (HPA) responses to stressors in adulthood. Importantly, prenatal ethanol may differentially alter stress responsiveness in male and female offspring, suggesting a role for the gonadal hormones in mediating the effects of ethanol on HPA activity. We investigated the role of ethanol‐induced changes in hypothalamic‐pituitary‐gonadal (HPG) activity in the differential HPA regulation observed in E compared to control females across the estrous cycle.Methods: Peripheral hormones and changes in central neuropeptide mRNA levels were measured across the estrous cycle in adult female offspring from E, pair‐fed (PF) and ad libitum‐fed control (C) dams.Results: Ethanol females showed normal estrous cyclicity (vaginal smears) but delayed sexual maturation (vaginal opening). Both HPG and HPA activity were differentially altered in E (and in some cases, PF) compared to control females as a function of estrous cycle stage. In relation toHPG activity,E and PF females had higher basal and stress estradiol (E2) levels in proestrus compared to other phases of the cycle, and decreased GnRH mRNA levels compared to C females in diestrus. Further, E females had greater variation in LH than PF and C females across the cycle, and in proestrus, only E females showed a significant LH increase following stress. In relation toHPA activity, both basal and stress CORT levels and overall ACTH levels were greater in E than in C females in proestrus. Furthermore, AVP mRNA levels were increased overall in E compared to PF and C females.Conclusions: These data demonstrate ethanol‐induced changes in both HPG and HPA activity that are estrous phase‐specific, and support the possibility that changes in HPA activity in E females may reflect differential sensitivity to ovarian steroids. E females appear to have an increased HPA sensitivity to E2, and a possible shift toward AVP regulation of HPA activity. That PF were similar to E females on some measures suggests that nutritional effects of diet or food restriction played a role in mediating at least some of the changes observed.
Altering the Relative Abundance of GABAAReceptor Subunits Changes GABA‐ and Ethanol‐Responses inXenopusOocytes
Authors: Hurley Joyce H. , Ballard Carrie J. , Edenberg Howard J. 
Published: March 2009

Background: Variations inGABRA2andGABRG3, genes encoding the α2 and γ3 subunits of the pentameric GABAAreceptor, are associated with the risk of developing alcoholism in adults, conduct disorder at younger ages, and with differences in electroencephalographic power in the β frequency range. The SNPs associated with alcoholism did not alter the coding of these genes, and extensive DNA sequencing ofGABRA2did not find coding changes in the high‐risk haplotypes. Therefore, we hypothesize that the associations arise from differences in gene expression.Methods: Here we report studies inXenopusoocytes to examine the functional effects of altering the relative abundance of these 2 receptor subunits on GABA current and response to ethanol, as a model of potential effects of regulatory differences.Results: When human α2β2γ3 subunits are co‐expressed, increasing the amount of the α2 subunit mRNA increased GABA current; in contrast, increasing the amount of the γ3 subunit decreased GABA currents. Acute ethanol treatment of oocytes injected with a 1:1:1 or 2:2:1 ratio of α2:β2:γ3 subunit mRNAs resulted in significant potentiation of GABA currents, whereas ethanol inhibited GABA currents in cells injected with a 6:2:1 ratio. Overnight treatment with ethanol significantly reduced GABA currents in a manner dependent on the ratio of subunits.Conclusions: These studies demonstrate that changes in relative expression of GABAAreceptor subunits alter the response of the resulting channels to GABA and to ethanol.
SIAM‐Like Phenomenon Caused by Low Doses of Alcohol
Authors: Shimamoto Akiko , Liu Jin‐Yao , Fujimiya Tatsuya 
Published: March 2009

Background: Swift increase in alcohol metabolism (SIAM) is usually evoked by a large dose of ethanol, which is often demonstrated by an abrupt increase in oxygen uptake. SIAM was induced by low doses of ethanol and evaluated by pharmacokinetic analyses of ethanol and its metabolites.Methods: Rabbits were initially administered 1.0 g/kg of ethanol solution and the same dose was given to the bolus group 6 hours after the first injection. The infusion group was administered 0.25 g/kg/h of ethanol 2 hours after the first injection. Blood concentrations of ethanol, acetaldehyde, and acetate were then determined and comparisons were made using pharmacokinetic parameters.Results: A significantly higher ethanol elimination rate was observed after re‐administration of ethanol to the bolus group. Other pharmacokinetic parameters were unaffected. The concentration at steady state (Css) for the infusion group was stable. A significantly higher level of mean residence time (MRT) in blood acetaldehyde was observed for the bolus group, whereas no MRT changes were observed for the infusion group. A significantly higher level of blood acetate Css was observed after re‐administration of ethanol to the bolus group, following the changes in area under concentration and MRT. No Css changes were observed for the infusion group. The Css of acetate at stage 2 was significantly higher for the bolus group, compared to the infusion group.Conclusion: Low doses of ethanol enhanced alcohol metabolism in rabbits, according to a pharmacokinetic analysis of circulating ethanol concentrations. Simultaneous analyses of its metabolites followed the kinetic of ethanol.