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  • 1
    Keywords: DISTINCT ; GENE ; BREAST-CANCER ; COPY-NUMBER ; SONIC HEDGEHOG ; GERMLINE ; LI-FRAUMENI-SYNDROME ; ACUTE MYELOID-LEUKEMIA ; telomere length ; FAMILIAL SYNDROME
    Abstract: Genomic rearrangements are thought to occur progressively during tumor development. Recent findings, however, suggest an alternative mechanism, involving massive chromosome rearrangements in a one-step catastrophic event termed chromothripsis. We report the whole-genome sequencing-based analysis of a Sonic-Hedgehog medulloblastoma (SHH-MB) brain tumor from a patient with a germline TP53 mutation (Li-Fraumeni syndrome), uncovering massive, complex chromosome rearrangements. Integrating TP53 status with microarray and deep sequencing-based DNA rearrangement data in additional patients reveals a striking association between TP53 mutation and chromothripsis in SHH-MBs. Analysis of additional tumor entities substantiates a link between TP53 mutation and chromothripsis, and indicates a context-specific role for p53 in catastrophic DNA rearrangements. Among these, we observed a strong association between somatic TP53 mutations and chromothripsis in acutemyeloid leukemia. These findings connect p53 status and chr
    Type of Publication: Journal article published
    PubMed ID: 22265402
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  • 2
    ISSN: 1435-1463
    Keywords: L-dopa ; dopamine ; Parkinson's disease ; cerebral dialysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary We have used cerebral dialysis to monitor striatal metabolism of exogenously administered L-dopa (L-dihydroxyphenylalanine) in rats with unilateral lesions of the substantia nigra. The concentration of extracellular dopamine (DA) increased in both striata following L-dopa administration but the increase was markedly attenuated in the lesioned striatum. The formation of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), the major DA metabolites, was also reduced in the lesioned striata following L-dopa administration; however, the reduction was not as great as was that of DA formation. A significant metabolism of exogenous L-dopa to 3-O-methyldopa occurred in both striata. L-dopa administration transiently increased extracellular levels of 5-hydroxyindoleacetic acid (5 HIAA) in both the lesioned and intract striata. These results suggest that the striatum with a reduction in DA nerve terminals is deficient both in the capacity to synthesize DA and in the storage mechanisms necessary to protect the newly synthesized DA from oxidative metabolism.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1435-1463
    Keywords: Yohimbine ; norepinephrine ; dopamine ; cerebral microdialysis ; lateral ventricle ; striatum
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Following the administration of yohimbine, an α2-adrenoreceptor antagonist, the levels of norepinephrine (NE), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5HIAA) increased significantly in the lateral ventricular fluid of rats. These increases were abolished when animals were pretreated with α-methyl-para-tyrosine or reserpine. Dopamine (DA) was not detected in ventricular fluid either before or after yohimbine administration. Yohimbine administration did, however, increase intracellular DA levels in the corpus striatum. These findings indicate that yohimbine promotes NE and DA release in the brain and suggest that it also modifies the activity of the serotonin system.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1435-1463
    Keywords: Dopamine ; L-DOPA ; monoamine oxidase ; deprenyl ; pargyline ; clorgyline ; Ro 41-1049 ; MAO-A ; MAO-B Parkinson's disease ; cerebral microdialysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Utilizing the cerebral microdialysis technique, we have compared in vivo the effects of selective MAO-A, MAO-B, and nonselective MAO inhibitors on striatal extracellular levels of dopamine (DA) and DA metabolites (DOPAC and HVA). The measurements were made in rats both under basal conditions and following L-DOPA administration. Extracellular levels of dopamine were enhanced and DA metabolite levels strongly inhibited both under basal conditions and following L-DOPA administration by pretreatment with the nonselective MAO inhibitor pargyline and the MAO-A selective inhibitors clorgyline and Ro 41-1049. The MAO-B inhibitor deprenyl had no effect on basal DA, HVA, or DOPAC levels. Nervertheless, deprenyl significantly increased DA and decreased DOPAC levels following exogenous L-DOPA administration, a finding compatible with a significant glial metabolism of DA formed from exogenous L-DOPA. We conclude that DA metabolism underbasal conditions is primarily mediated by MAO-A. In contrast, both MAO-A and MAO-B mediate DA formation when L-DOPA is administered exogenously. The efficacy of newer, reversible agents which lack the “cheese effect” such as Ro 41-1049 are comparable to the irreversible MAO-A inhibitor clorgyline. The possible relevance of these findings for the treatment of Parkinson's disease is discussed.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1435-1463
    Keywords: Stroke ; dopamine ; norepinephrine ; cerebral dialysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The cerebral dialysis technique was employed to monitor extracellular concentrations of dopamine (DA), norepinephrine (NE), dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) in the dorsal hippocampus of gerbils before and after cerebral ischemia induced by carotid artery occlusion. Extracellular concentrations of DA and NE in the dorsal hippocampus increased from baseline levels of 〈35 fmol/collection interval to 180 and 200 fmol/collection, respectively, within 36 minutes following carotid artery ligation (n=8 animals). Extracellular concentrations of the DA metabolites, DOPAC and HVA, did not change significantly following carotid artery ligation. These data demonstrate that ischemia in the dorsal hippocampus is associated with a mared release of DA and NE. This release may contribute to the selective vulnerability of the dorsal hippocampus to neuronal damage during ischemia.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1435-1463
    Keywords: Bromocriptine ; dopamine ; Parkinson's disease ; cerebral microdialysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary We wished to determine if low and high doses of bromocriptine produce distinct patterns of dopamine release and metabolism. Accordingly, we administered bromocriptine (0, 2.5, 5, and 10 mg/kg, IP) to rats and monitored extracellular concentrations of dopamine and dopamine metabolites in the corpus striatum with the technique of cerebral microdialysis. Extracellular dopamine levelsincreased following administration of 2.5 and 5 mg/kg bromocriptine. In contrast, dopamine levelsdecreased following 10 mg/kg bromocriptine. Dopamine metabolite levels decreased 45 minutes following all doses of bromocriptine. Bromocriptine administration had no effect on the levels of 5HIAA, the major serotonin metabolite. These findings with high dose bromocriptine fit the predicted profile of a dopamine D2 receptor agonist. The delayed decrease in dopamine metabolites at all bromocriptine doses is consistent with the known dopamine synthesis inhibiting action of bromocriptine. In contrast, the increased dopamine release observed following low and medium doses of bromocriptine is not readily explainable by current theories of bromocriptine action which predict decreased dopamine release and therefore decreased striatal extracellular dopamine levels with both high and low-doses of bromocriptine. Our findings indicate that bromocriptine has a complex pharmacological action that extends beyond simple agonism at dopamine D2 receptors.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1435-1463
    Keywords: L-dopa ; dopamine ; electroconvulsive therapy ; Parkinson's disease ; cerebral microdialysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A course of treatments with electroconvulsive shock (ECS) has been reported to reestablish L-dopa efficacy in patients with advanced Parkinson's disease. We wished to determine if ECS could modify L-dopa and dopamine metabolism in an animal model of Parkinson's disease. Therefore, we administered repeated ECS (8 ECS at 48 hr intervals) to rats with partial destruction of the nigrostriatal dopamine pathway and used the cerebral microdialysis technique to monitor extracellular concentrations of dopamine and dopamine metabolites (DOPAC and HVA) in the corpus striatum. The control group of animals received sham-ECS treatments. Basal dopamine levels were decreased by 20% in animals receiving repeated-ECS versus sham-ECS. DOPAC levels, on the other hand, were increased by 84% in animals receiving repeated-ECS. HVA levels were equal in the two groups. Following L-dopa administration, dopamine and HVA levels increased equally in control animals and animals which had previously received repeated-ECS. DOPAC concentrations were uniformly greater in rats receiving repeated-ECS. When ECS was administered acutely, dopamine levels increased 390% and returned to baseline values in 75 minutes, DOPAC and HVA were unchanged, and 5HIAA levels decreased 30%. We conclude that 1) acute ECS administration produces a transient, marked release of striatal dopamine and 2) repeated ECS can reset the level of basal dopamine release, a finding compatible with ECS-induced dopamine receptor supersensitivity, and 3) neither single nor repeated administration of ECS has a major effect on the formation of dopamine or HVA from exogenously administered L-dopa although there was a strong tendency for increased DOPAC formation. ECS may exert its putative antiparkinsonian effect by enhancing dopamine receptor sensitivity.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1435-1463
    Keywords: Dopamine ; body temperature ; Parkinson's disease ; cerebral microdialysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Dopamine release and metabolism in the corpus striatum increased markedly when the core body temperature of anesthetized rats was increased from 35 ° to 41 °C while temperatures below 34 ° were associated with a marked attenuation of dopamine release. These observations may have clinical relevance in cases where alterations in body temperature are associated with extrapyramidal dysfunction.
    Type of Medium: Electronic Resource
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