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991.
992.
993.
Lanzendörfer C 《Deutsche medizinische Wochenschrift (1946)》2003,128(4):162; discussion 162
994.
Regulation of HERG potassium channel activation by protein kinase C independent of direct phosphorylation of the channel protein 总被引:10,自引:0,他引:10
Thomas D Zhang W Wu K Wimmer AB Gut B Wendt-Nordahl G Kathöfer S Kreye VA Katus HA Schoels W Kiehn J Karle CA 《Cardiovascular research》2003,59(1):14-26
OBJECTIVE: Patients with HERG-associated long QT syndrome typically develop tachyarrhythmias during physical or emotional stress. Previous studies have revealed that activation of the beta-adrenergic system and consecutive elevation of the intracellular cAMP concentration regulate HERG channels via protein kinase A-mediated phosphorylation of the channel protein and via direct interaction with the cAMP binding site of HERG. In contrast, the influence of the alpha-adrenergic signal transduction cascade on HERG currents as suggested by recent reports is less well understood. The aim of the present study was to elucidate the biochemical pathways of the protein kinase C (PKC)-dependent regulation of HERG currents. METHODS: HERG channels were heterologously expressed in Xenopus laevis oocytes, and currents were measured using the two-microelectrode voltage clamp technique. RESULTS: Application of the phorbol ester PMA, an unspecific protein kinase activator, shifted the voltage dependence of HERG activation towards more positive potentials. This effect could be mimicked by activation of conventional PKC isoforms with thymeleatoxin. Coexpression of HERG with the beta-subunits minK or hMiRP1 did not alter the effect of PMA. Specific inhibition of PKC abolished the PMA-induced activation shift, suggesting that PKC is required within the regulatory mechanism. The PMA-induced effect could still be observed when the PKC-dependent phosphorylation sites in HERG were deleted by mutagenesis. Cytoskeletal proteins such as actin filaments or microtubules did not affect the HERG activation shift. CONCLUSION: In addition to the known effects of PKA and cAMP, HERG channels are also modulated by PKC. The molecular mechanisms of this PKC-dependent process are not completely understood but do not depend on direct PKC-dependent phosphorylation of the channel. 相似文献
995.
Eisen C 《Deutsche medizinische Wochenschrift (1946)》2003,128(11):571; author reply 571-571; author reply 572
996.
Gianinazzi C Grandgirard D Imboden H Egger L Meli DN Bifrare YD Joss PC Täuber MG Borner C Leib SL 《Acta neuropathologica》2003,105(5):499-507
Bacterial meningitis causes neuronal apoptosis in the hippocampal dentate gyrus, which is associated with learning and memory impairments after cured disease. The execution of the apoptotic program involves pathways that converge on activation of caspase-3, which is required for morphological changes associated with apoptosis. Here, the time course and the role of caspase-3 in neuronal apoptosis was assessed in an infant rat model of pneumococcal meningitis. During clinically asymptotic meningitis (0-12 h after infection), only minor apoptotic damage to the dentate gyrus was observed, while the acute phase (18-24 h) was characterized by a massive increase of apoptotic cells, which peaked at 36 h. In the subacute phase of the disease (36-72 h), the number of apoptotic cells decreased to control levels. Enzymatic caspase-3 activity was significantly increased in hippocampal tissue of infected animals compared to controls at 22 h. The activated enzyme was localized to immature cells of the dentate gyrus, and in vivo activity was evidenced by cleavage of the amyloid-beta precursor protein. Intracisternal administration of the caspase-3-specific inhibitor Ac-DEVD-CHO significantly reduced apoptosis in the hippocampal dentate gyrus. In contrast to a study where the decrease of hippocampal apoptosis after administration of a pan-caspase inhibitor was due to downmodulation of the inflammatory response, our data demonstrate that specific inhibition of caspase-3 did not affect inflammation assessed by TNF-alpha and IL-1beta concentrations in the cerebrospinal fluid space. Taken together, the present results identify caspase-3 as a key effector of neuronal apoptosis in pneumococcal meningitis. 相似文献
997.
Fliessbach K Urbach H Helmstaedter C Pels H Glasmacher A Kraus JA Klockgether T Schmidt-Wolf I Schlegel U 《Archives of neurology》2003,60(4):563-568
BACKGROUND: Long-term neurotoxicity is a frequent complication of combined radiotherapy and chemotherapy in patients with primary central nervous system lymphoma. Treatment protocols without radiotherapy have been implemented to avoid this; however, little detailed neuropsychologic and neuroradiologic data exist to assess the frequency of long-term treatment sequelae in this patient group. OBJECTIVE: To determine whether a polychemotherapy regimen based on high-dose methotrexate results in cognitive impairment and/or changes detectable by magnetic resonance imaging of the brain during long-term follow-up. PATIENTS AND METHODS: Twenty patients with histologically proven primary central nervous system lymphoma were treated with a novel chemotherapy protocol that included systemic and intraventricular administration of methotrexate and cytarabine (ara-C). Standardized neuropsychologic testing and magnetic resonance imaging investigations were performed prior to therapy and prospectively during a median follow-up period of 36 months (range, 21-69 months). RESULTS: Ten patients achieved durable remissions without relapse for more than 1 year after completion of chemotherapy. There was no gross cognitive decline in any of these patients during the follow-up period. In contrast, magnetic resonance imaging revealed therapy-induced white matter changes in 5 of these patients. CONCLUSIONS: We conclude that chemotherapy alone is associated with a low risk of long-term neurotoxicity in primary central nervous system lymphoma. Methotrexate-induced white matter lesions detectable on magnetic resonance imaging are not inevitably associated with significant cognitive decline. 相似文献
998.
Neurological aspects of taste disorders 总被引:2,自引:0,他引:2
999.
Biochemical diagnosis of Alzheimer disease by measuring the cerebrospinal fluid ratio of phosphorylated tau protein to beta-amyloid peptide42 总被引:3,自引:0,他引:3
Maddalena A Papassotiropoulos A Müller-Tillmanns B Jung HH Hegi T Nitsch RM Hock C 《Archives of neurology》2003,60(9):1202-1206
BACKGROUND: The antemortem diagnosis of Alzheimer disease (AD) requires time-consuming and costly procedures. Therefore, biochemical tests that can direct the physician rapidly to the correct diagnosis are highly desirable. Measurement of single biochemical markers in cerebrospinal fluid (CSF), such as total tau protein and beta-amyloid peptide42 (Abeta42), shows robust alterations that highly correlate with the clinical diagnosis of AD but generally lack sufficient diagnostic accuracy. OBJECTIVE: To study the combination of CSF phosphorylated tau protein (phospho-tau) and Abeta42 as biochemical markers for AD. METHODS: We combined CSF measurements of phospho-tau and Abeta42 in 100 consecutive patients who under-went diagnostic workup for dementia and in 31 healthy control subjects. RESULTS: We found that the calculated ratio of phospho-tau to Abeta42 was significantly increased in patients with AD and provided high diagnostic accuracy in distinguishing patients with AD from healthy control subjects (sensitivity, 86%; specificity, 97%), subjects with non-AD dementias (sensitivity, 80%; specificity, 73%), and subjects with other neurological disorders (sensitivity, 80%; specificity, 89%). CONCLUSION: The diagnostic usefulness of the CSF ratio of phospho-tau to Abeta42 is superior to either measure alone and can be recommended as an aid to evaluating individuals suspected of having dementia. 相似文献
1000.
Greiner C Wölfer J Hülsmann S Vanhatalo S Köhling R Pannek HW Speckmann EJ Wassmann H 《Brain research》2003,968(2):199-205
Nimodipine and dimethyl sulfoxide (DMSO) have been shown to affect electrophysiological responses in rodent brain tissue in an vitro model of hypoxia. In the present study, the same agents were now examined for their effects on human neocortical brain slices under repeated hypoxic conditions. DMSO (0.4%), with and without addition of nimodipine (40 micromol/l), did not increase the latency of anoxic depolarization (AD). This finding is not in line with our previous observations of DMSO effects, with and without nimodipine, on brain slices of guinea pigs. AD latency was significantly longer in human neocortical brain slices compared with hippocampal slices of rodents even without any pharmacological influence. A possible acute effect of DMSO-nimodipine may therefore be masked by an interspecies difference of hypoxia resistance. 相似文献