bluuebunny/crossref_metadata_2025_split huggingface dataset:
Choline is transported by vesicular acetylcholine transporter
Authors: Bravo Dawn T. , Kolmakova Natalia G. , Parsons Stanley M. 
Published: October 2004

AbstractPreviously published results appeared to show that vesicular acetylcholine transporter (VAChT) does not transport choline (Ch). Because it is uniquely suited to detect transport of weakly bound substrates, a recently developed assay that detects transmembrane reorientation of the substrate binding site was used to re‐examine transport selectivity. Rat VAChT was expressed in PC12A1237 cells, postnuclear supernatant‐containing microvesicles was prepared, and the reorientation assay was conducted with unlabeled Ch and tetramethylammonium (TMA). Also, [14C]Ch and [3H]acetylcholine (ACh) were used in an optimized accumulation assay. The results demonstrate that Ch is transported at least as well as ACh is, but with sevenfold lower affinity. Even TMA is transported, but with 26‐fold lower affinity. Ch transport by VAChT is of interest in view of the possibilities that Ch (i) occurs at higher concentration than ACh does in terminal cytoplasm under some conditions, and (ii) is an agonist for α7 nicotinic receptors.
Detecting bioactive amyloid β peptide species in Alzheimer's disease
Authors: Liu Yuanbin , Dargusch Richard , Banh Cindy , Miller Carol A. , Schubert David 
Published: October 2004

AbstractAmyloid β peptide (Aβ) is believed to play a central role in the pathogenesis of Alzheimer's disease (AD). However, the form of Aβ that induces neurodegeneration in AD, defined here as bioactive Aβ, is not clear. Preventing the formation of bioactive Aβ or inactivating previously formed bioactive Aβ should be a promising approach to treat AD. We have previously developed a cell‐based assay for the detection of bioactive Aβ species. The assay is based upon the correlation between the ability of an Aβ sample to induce a unique form of cellular MTT [3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide] formazan exocytosis, and its ability to activate glia and induce neurotoxicity. Here, we show that this cell‐based assay is not only useful for a cellular model of Aβ amyloidogenesis but is also able to detect bioactive Aβ species in a transgenic mouse model of AD, as well as in post‐mortem cortex samples from AD patients. There is a good correlation between the extent of glia activation and the level of bioactive Aβ species in the mouse brain. A promising deuteroporphyrin that can inactivate bioactive Aβ species was also identified using this assay. These novel insights and findings should have important implications for the treatment of AD.
Ca2+/calmodulin‐dependent protein kinase II is reversibly autophosphorylated, inactivated and made sedimentable by acute neuronal excitation in rats in vivo
Authors: Yamagata Yoko , Obata Kunihiko 
Published: October 2004

AbstractCa2+/calmodulin‐dependent protein kinase II (CaMKII) is highly enriched in the central nervous system, and is proposed to play important roles in activity‐dependent modifications of neuronal functions. We reported previously on the dynamic regulation of the autonomous CaMKII in homogenates from hippocampus and parietal cortex by acute neuronal excitation induced by electroconvulsive treatment (ECT) in rats in vivo. In the present study, we examined in more detail the biochemical changes in CaMKII under such conditions. We unexpectedly found a concurrent increase in autophosphorylation at Thr286(α)/287(β) and decrease in the specific activity of CaMKII in the particulate fraction in either hippocampus or parietal cortex during ECT‐induced acute, brief seizure activity. On the other hand, the soluble CaMKII showed a marked decrease in autophosphorylation with unchanged or rather increased specific activity. Increased autophosphorylation and decreased CaMKII activity were associated with the detergent‐insoluble particulate fraction. All these changes disappeared soon after the termination of seizure activity. The reversible formation of such an autophosphorylated, inactivated and sedimentable form of CaMKII during acute neuronal excitation may indicate the existence of a novel regulatory mechanism of CaMKII that may be important for normal functioning of the brain.
HaRas activates the NADPH oxidase complex in human neuroblastoma cells via extracellular signal‐regulated kinase 1/2 pathway
Authors: Serù Rosalba , Mondola Paolo , Damiano Simona , Svegliati Silvia , Agnese Savina , Avvedimento Enrico V. , Santillo Mariarosaria 
Published: October 2004

AbstractIn this study we have investigated the effects of the small GTP‐binding‐protein Ras on the redox signalling of the human neuroblastoma cell line, SK‐N‐BE stably transfected with HaRas(Val12). The levels of reactive oxygen species (ROS) and superoxide anions were significantly higher in HaRas(Val12) expressing (SK‐HaRas) cells than in control cells. The treatment of cells with 4‐(2‐aminoethyl) benzenesulfonylfluoride, a specific inhibitor of the membrane superoxide generating system NADPH oxidase, suppressed the rise in ROS and significantly reduced superoxide levels produced by SK‐HaRas cells. Moreover, HaRas(Val12) induced the translocation of the cytosolic components of the NADPH oxidase complex p67phox and Rac to the plasma membrane. These effects depended on the mitogen‐activated protein kinase kinase/extracellular signal‐regulated kinase (MEK/ERK1/2) pathway, as the specific MEK inhibitor, PD98059, prevented HaRas‐mediated increase in ROS and superoxide anions. In contrast, the specific phosphoinositide 3‐kinase (PI3K) inhibitors LY294002 and wortmannin were unable to reverse the effects of HaRas(Val12). Moreover, cholinergic stimulation of neuroblastoma cells by carbachol, which activated endogenous Ras/ERK1/2, induced a significant increase in ROS levels and elicited membrane translocation of p67phox and Rac. ROS generation induced by carbachol required the activation of ERK1/2 and PI3K. Hence, these data indicate that HaRas‐induced ERK1/2 signalling selectively activates NADPH oxidase system in neuroblastoma cells.
Evaluation of 5‐(2‐(4‐pyridinyl)vinyl)‐6‐chloro‐3‐(1‐methyl‐2‐(S)‐pyrrolidinylmethoxy)pyridine and its analogues as PET radioligands for imaging nicotinic acetylcholine receptors
Authors: Brown LaVerne , Chefer Svetlana , Pavlova Olga , Vaupel D. Bruce , Koren Andrei O. , Kimes Alane S. , Horti Andrew G. , Mukhin Alexey G. 
Published: October 2004

AbstractA novel series of compounds derived from the high‐affinity nicotinic acetylcholine receptor (nAChR) ligand, 5‐(2‐(4‐pyridinyl)vinyl)‐6‐chloro‐3‐((1‐methyl‐2‐(S)‐pyrrolidinyl)methoxy)pyridine (Me‐p‐PVC), originally developed by Abbott Laboratories, was characterized in vitro in nAChR binding assays at 37°C to show Ki values in the range of 9–611 pm. Several compounds of this series were radiolabeled with 11C and evaluated in vivo in mice and monkeys as potential candidates for PET imaging of nAChRs. [11C]Me‐p‐PVC (Ki =56 pm at 37°C; logD = 1.6) was identified as a radioligand suitable for the in vivo imaging of the α4β2* nAChR subtype. Compared with 2‐[18F]FA, a PET radioligand that has been successfully used in humans and is characterized by a slow kinetic of brain distribution, [11C]Me‐p‐PVC is more lipophilic. As a result, [11C]Me‐p‐PVC accumulated in the brain more rapidly than 2‐[18F]FA. Pharmacological evaluation of Me‐p‐PVC in mice demonstrated that the toxicity of this compound was comparable with or lower than that of 2‐FA. Taken together, these results suggest that [11C]Me‐p‐PVC is a promising PET radioligand for studying nAChR occupancy by endogenous and exogenous ligands in the brain in vivo.
Macrophage colony stimulatory factor and interferon‐γ trigger distinct mechanisms for augmentation of β‐amyloid‐induced microglia‐mediated neurotoxicity
Authors: Li M. , Pisalyaput K. , Galvan M. , Tenner A. J. 
Published: October 2004

AbstractDysregulated stimulation of microglia, the resident macrophages in the brain, can lead to excessive induction of inflammatory agents and subsequently damage to neurons. Fibrillar β‐amyloid peptide (fAβ), a major component of senile plaques in Alzheimer's disease (AD) brain, is known to induce microglial‐mediated neurotoxicity under certain conditions. Microglial ‘priming’ by macrophage colony stimulatory factor (MCSF) or interferon‐gamma (IFNγ) appears to be required for this fAβ‐induced microglia mediated neurotoxicity in vitro. We report here that while both MCSF and IFNγ induce microglial‐mediated fAβ neurotoxicity, their mechanisms of toxicity differ. The enhancement of neurotoxicity by IFNγ or MCSF is not due to enhanced Aβ ingestion by microglia or to the direct effect of proinflammatory cytokine production. The neurotoxicity resulting from IFNγ/fAβ treatment was blocked by pretreatment with nitric oxide synthase inhibitor l‐N‐5‐(1‐iminoethyl) ornithine hydrochloride (l‐NIO), consistent with a role for nitric oxide in the IFNγ‐mediated toxicity mechanism. In contrast, no induction of nitric oxide production was detected for microglia treated with MCSF/fAβ. Furthermore, inhibiting the generation of reactive oxygen species (ROS) using the specific NADPH oxidase inhibitor apocynin reversed fAβ/MCSF‐induced neurotoxicity while l‐NIO had little effect. As MCSF is endogenously expressed within the brain, and both its level and that of the MCSF receptor are dramatically increased in the AD brain, the neurotoxicity resulting from ROS release by fAβ/MCSF coactivated microglia may be a more appropriate model for assessing fAβ‐induced microglial‐mediated neuropathology in AD.
Induction of cyclin‐dependent kinase 5 and its activator p35 through the extracellular‐signal‐regulated kinase and protein kinase A pathways during retinoic‐acid mediated neuronal differentiation in human neuroblastoma SK‐N‐BE(2)C cells
Authors: Lee Jong‐Hee , Kim Kyong‐Tai 
Published: October 2004

AbstractCyclin‐dependent kinase 5 (Cdk5), a neuronal Cdc2‐like kinase, exhibits a variety of functions in neuronal differentiation and neurocytoskeleton dynamics, as well as neuronal degeneration. However, its role and induction mechanisms in retinoic acid (RA)‐induced neuronal differentiation have not been well understood. In this study we newly found that RA treatment of SK‐N‐BE(2)C, human neuroblastoma cells, increased the expression of Cdk5 and its neuron specific activator p35 through the extracellular‐signal‐regulated kinase1/2 (ERK1/2) and cAMP‐dependent protein kinase A (PKA) pathway. Inhibition of Cdk5 activity either by an inhibitor, roscovitine, or by transfection with a dominant negative form of Cdk5 caused a dramatic decrease in RA‐induced differentiation, suggesting the requirement of Cdk5 kinase activity for the RA‐induced neurite outgrowth. Furthermore, Cdk5 and p35 expression was decreased by ERK1/2 inhibition with PD98059 and increased by overexpression of a constitutive active mitogen‐activated protein kinase kinase 1 (MEK1) mutant, suggesting the critical role of ERK1/2 in the induction of Cdk5 and p35. In addition, a transcription factor early growth response 1 (Egr‐1) was induced by RA through the ERK1/2 pathway, suggesting its possible involvement in the p35 induction. RA treatment also induced c‐fos mediated AP‐1 binding, and cAMP‐responsive element binding protein (CREB) mediated CRE binding via ERK1/2 and PKA pathway, respectively, in the Cdk5 promoter region, resulting in the induction of Cdk5. Our results suggest that ERK1/2 and PKA‐induced regulation of Cdk5 activity possibly through Egr‐1, c‐fos, and CREB plays a critical role in the RA‐induced neuronal differentiation.
ShcA regulates neurite outgrowth stimulated by neural cell adhesion molecule but not by fibroblast growth factor 2: evidence for a distinct fibroblast growth factor receptor response to neural cell adhesion molecule activation
Authors: Hinsby Anders M. , Lundfald Line , Ditlevsen Dorte K. , Korshunova Irina , Juhl Lone , Meakin Susan O. , Berezin Vladimir , Bock Elisabeth 
Published: October 2004

AbstractHomophilic binding in trans of the neural cell adhesion molecule (NCAM) mediates adhesion between cells and leads, via activation of intracellular signaling cascades, to neurite outgrowth in primary neurons as well as in the neuronal cell line PC12. NCAM mediates neurite extension in PC12 cells by two principal routes of signaling: NCAM/Fyn and NCAM/fibroblast growth factor receptor (FGFR), respectively. Previous studies have shown that activation of mitogen‐activated protein kinases is a pivotal point of convergence in NCAM signaling, but the mechanisms behind this activation are not clear. Here, we investigated the involvement of adaptor proteins in NCAM and fibroblast growth factor 2 (FGF2)‐mediated neurite outgrowth in the PC12‐E2 cell line. We found that both FGFR substrate‐2 and Grb2 play important roles in NCAM as well as in FGF2‐stimulated events. In contrast, the docking protein ShcA was pivotal to neurite outgrowth induced by NCAM, but not by FGF2, in PC12 cells. Moreover, in rat cerebellar granule neurons, phosphorylation of ShcA was stimulated by an NCAM mimicking peptide, but not by FGF2. This activation was blocked by inhibitors of both FGFR and Fyn, indicating that NCAM activates FGFR signaling in a manner distinct from FGF2 stimulation, and regulates ShcA phosphorylation by the concerted efforts of the NCAM/FGFR as well as the NCAM/Fyn signaling pathway.
Distribution and localization of pro‐brain‐derived neurotrophic factor‐like immunoreactivity in the peripheral and central nervous system of the adult rat
Authors: Zhou Xin‐Fu , Song Xing‐Yun , Zhong Jin‐Hua , Barati Shahram , Zhou Fiona H.‐H. , Johnson Stephen M. 
Published: October 2004

AbstractThe precursors for neurotrophins are proteolytically cleaved to form biologically active mature molecules which activate their receptors p75NTR and trks. A recent study showed that the precursor for nerve growth factor (NGF) can bind to p75NTR with a high affinity and induces apoptosis of neurons in vitro. Mutation in Val66Met of brain‐derived neurotrophic factor (BDNF) results in reduction in hippocampal function in learning and in the dysfunction of intracellular BDNF sorting and secretion. To examine the functions of pro‐neurotrophins in vivo, it is essential to know where they are expressed in the nervous system. In the present study, we have raised and characterized rabbit polyclonal antibodies against a peptide coding for the precursor region of the BDNF gene. The antibody specifically recognizes the precursor for BDNF by western blot. With the affinity purified precursor antibody, we have mapped the distribution and localization of the precursor for BDNF. The results showed that, like mature BDNF, pro‐BDNF is localized to nerve terminals in the superficial layers of dorsal horn, trigeminal nuclei, nuclei tractus solitarius, amygdaloid complex, hippocampus, hypothalamus and some peripheral tissues. These results suggest that pro‐BDNF, like mature BDNF, is anterogradely transported to nerve terminals and may have important functions in synaptic transmission in the spinal cord and brain.
Preparing for Portfolio Assessment in Art and Design: A Study of the Opinions and Experiences of Exiting Secondary School Students in Canada, England and The Netherlands
Authors: Blaikie Fiona , Schönau Diederik , Steers John 
Published: October 2004

AbstractThis study utilises survey questionnaires to compare 107 Canadian, English and Dutch students' opinions and experiences of portfolio preparation for final assessment in the terminal year of secondary school. The aim is to reveal what students value about portfolio assessment and if they see portfolio assessment as a valid preparation for their futures, particularly for those who plan to continue on studying art and design at college or university. Common approaches to assessment are examined, followed by a more focused discussion of curriculum and assessment practices in all three countries at the time of writing (March 2004). This is followed by a description of methodology; tentative findings are presented and the article concludes with a short discussion of some implications for art and design education.
Beat‐to‐Beat Heart Rate and QT Variability in Patients with Congestive Cardiac Failure: Blunted Response to Orthostatic Challenge
Authors: Desai Nagaraj , D.S. Raghunandan , Mallavarapu Mallika , Berger Ronald D. , Yeragani Vikram K. 
Published: October 2004

Background: Congestive cardiac failure is associated with increased sympathetic activity and impaired baroreflex function. We sought to test the hypothesis that these patients also have blunted response of beat‐to‐beat QT interval variability during orthostatic challenge. Methods: We compared beat‐to‐beat heart rate and QT interval data in 17 patients with congestive cardiac failure and 17 age‐matched normal controls in supine normal breathing, supine controlled breathing, and standing controlled breathing conditions. The ECG data were acquired in lead II configuration at a sampling rate of 1000 Hz. Results: Supine controlled breathing was associated with an increase in spectral HF power (0.15–0.5 Hz) of HR and QT interval time series compared to spontaneous breathing condition only in controls. While there were significant changes in HR, HR LF power, HR LF/HF ratios, and QT variability measures in standing posture in controls, there were no such changes in patients. Conclusions: This impairment of postural changes of HR variability is most likely due to an impaired baroreceptor function in patients with congestive heart failure. The etiology of this is likely due to an increased cardiac sympathetic and a decreased vagal function. However, the relationship of postural changes in beat‐to‐beat QT interval variability and baroreflex need further investigation.
Wavelet‐Based Analysis of Heart‐Rate‐Dependent ECG Features
Authors: Stiles Martin K. , Clifton David , Grubb Neil R. , Watson James N. , Addison Paul S. 
Published: October 2004

Background: Wavelet‐based methods of analyzing ECG signals have been used to identify specific features in cardiac arrhythmias. Since some of these features are rate dependent, it is a requirement that they are examined across a range of physiological heart rates. The wavelet transform is a signal analysis tool that can elucidate spectral and temporal information simultaneously from complex signals, including the ECG. The aim of this study was to identify the local frequency characteristics of the ECG using a real‐time wavelet scalogram and to study the rate dependence of these features. Methods: We examined the spectral temporal behavior of the local characteristics of the electrocardiogram (ECG) of 10 patients, in whom precise control of heart rate was achieved using right atrial pacing. Temporary reprogramming was used to adjust the paced atrial rate to predetermined values so that a rate‐controlled rhythm was produced that closely resembled sinus rhythm. Results: Rate‐dependent features are seen on time–frequency scalograms. As the rate increases, the temporal spacing of features decrease and the frequency bands shift upward on the plot. Two patients with abnormal atrioventricular conduction demonstrate features of Wenckebach conduction and fusion. Conclusions: Characterization of the rate‐dependent features of the ECG in a paced atrial rhythm by wavelet transform techniques has revealed some additional information not readily seen on single lead ECG analysis. This model provides a surrogate for changes that might be expected during rate changes in physiological sinus rhythm. It is envisaged that this method will offer advantages in detecting features of clinical significance that may not be readily seen by existing methods.
Association of Stage of Left Ventricular Diastolic Dysfunction with P Wave Dispersion and Occurrence of Atrial Fibrillation after First Acute Anterior Myocardial Infarction
Authors: Yilmaz Remzi , Demirbag Recep , Durmus Ismet , Kasap Hasan , Baykan Merih , Kucukosmanoglu Mehmet , Celik Sukru , Erdol Cevdet 
Published: October 2004

Objectives: The aim of this study was to investigate the association of stage of left ventricular diastolic dysfunction after acute myocardial infarction (AMI) with P maximum, P dispersion, and atrial fibrillation (AF) occurrence rate. Background: The occurrence of AF following AMI is frequently associated with a left ventricle restrictive filling pattern. Increased P dispersion is also associated with the occurrence of AF after AMI. But, the relation between the stage of left ventricular diastolic dysfunction and the P wave measurements after AMI has not yet been investigated. Methods: Electrocardiograms of 90 patients with first anterior AMI were recorded on admission, and P wave measurements were performed. The left ventricular diastolic functions were evaluated by transthoracic echocardiography. On the basis of mitral inflow, subjects were stratified into three left ventricular diastolic filling patterns. All patients were monitored continuously for the detection of AF in the Coronary Care Unit. Results: Thirty patients had a normal filling pattern (33.3%) (NF group), 37 had impaired relaxation (41.1%) (IR group), and 23 had pseudonormal/restrictive filling pattern (25.6%) (PN/R group). P maximum was longer in the PN/R group (103 ± 12 ms) compared with the NF group (94 ± 9 ms, P = 0.019), but no significant difference was found between PN/R and IR (96 ± 13 ms, P > 0.05) groups, and between NF and IR groups (P > 0.05). There was no significant difference for P minimum among the groups (P > 0.05). P dispersion was longer in the PN/R group (35 ± 6 ms) than in the NF (26 ± 7 ms, P < 0.001) and IR groups (26 ± 6 ms, P < 0.001), but not different between the NF and IR groups (P > 0.05). Occurrence of AF was significantly more frequent in the PN/R group (52.2%) than in the NF (16.7%, P = 0.007) and IR groups (10.8%, P = 0.001). Frequency of AF was not different between the NF and IR groups (P > 0.05). In multivariate analyses, the stage of diastolic dysfunction was independently associated with P maximum, P minimum, P dispersion, and the occurrence of AF (P < 0.001, P = 0.035, P < 0.001, and P = 0.002, respectively). Conclusions: P maximum and P dispersion are increased, and AF occurrence risk is higher in patients with pseudonormal/restrictive filling pattern after first anterior AMI. The stage of diastolic dysfunction is an independent predictor of P wave measurements and AF occurrence.
The Significance of P Wave Duration and P Wave Dispersion for Risk Assessment of Atrial Tachyarrhythmias in Patients with Corrected Tetralogy of Fallot
Authors: Hallioglu Olgu , Aytemir Kudret , Celiker Alpay 
Published: October 2004

Background: The aim of the present study was to determine the potential role of P wave duration and P wave dispersion for risk assessment of atrial tachyarrhythmias in patients with corrected tetralogy of Fallot (ToF). Methods: The maximum P wave duration, minimum P wave duration, and the P wave dispersion from the 12‐lead surface electrocardiogram of the patients and controls were measured. Electrophysiological study was performed only in the patient group. Results: The study group consisted of 25 patients with corrected ToF with a mean age of 16.4 ± 4.25 years and 25 age‐matched healthy control subjects. Patients underwent repair at a mean age of 4.6 ± 3.41 years (range: 1–19), and the mean duration of follow‐up of 11.8 ± 1.7 years (range: 9–15) after surgery. On electrophysiological study sinus node dysfunction was detected in 3 patients (12%), atrial tachyarrythmias—atrial flutter or fibrillation—in 5 patients (20%), both sinus node dysfunction and atrial flutter in 1 patient (4%), and AV conduction delay in 1 patient (4%). P wave dispersion is significantly higher in patients with atrial tachyarrhythmia inducible by electrophysiological study than in other patients (P < 0.05). A P wave dispersion value of >35 ms has a high predictive accuracy (sensitivity = 83% and specificity = 89%) for inducible atrial tachyarrhythmia in patients with corrected tetralogy of Fallot. Conclusion: P wave dispersion is an easily measured electrocardiographic marker with a good sensitivity and specificity for predicting atrial arrhythmias in patients after correction of ToF.