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J Dichgans

Publications and source records attributed to J Dichgans.

At least 73 records · Page 4Linked to original sources
PubMed2000

Treosulfan chemotherapy for recurrent malignant glioma.

Treosulfan is a bifunctional alkylating prodrug with activity against various solid tumors. To improve the outcome for patients with recurrent malignant glioma, we assessed the efficacy of intravenous treosulfan (6-10 g/m2 4-weekly) as salvage therapy for patients with recurrent or progressive glioblastoma (GB, n = 14) or anaplastic astrocytoma (AA, n = 2). All patients had prior involved-field radiotherapy and adjuvant nitrosourea-based chemotherapy. A total of 56 cycles were administered. Tumor responses were assessed radiologically and clinically prior to each cycle. All patients were assessable for toxicity, response and survival. There were no complete or partial responses (CR, PR). Two patients progressed after the first cycle, 14 patients had initially stable disease (SD). Median progression-free survival was 3.25 months for the GB patients. Five patients were progression-free at 6 months (30%), including the 2 AA patients. The 2 AA patients are stable at 22 months. Myelosuppression was the dose-limiting toxicity in this cohort of nitrosourea-pretreated patients. Treosulfan has modest activity in patients with recurrent malignant glioma. Further evaluation of treosulfan in chemonaive malignant glioma patients is warranted.

Adult↗
PubMed2000

Evoked potentials in multiple system atrophy (MSA).

OBJECTIVES: To study the involvement of pyramidal tracts and sensory pathways in multiple system atrophy (MSA). MATERIALS AND METHODS: Evoked potential studies were performed in 45 MSA patients suffering from either MSA of cerebellar type (MSA-C) or MSA of parkinsonian type (MSA-P). RESULTS: Motor evoked potentials were normal in all MSA patients, whereas visual and somatosensory evoked potential abnormalities were found in about 40% of the MSA patients with no significant difference between the cerebellar (MSA-C) and parkinsonian (MSA-P) subgroup. Abnormal latencies of wave III in brainstem auditory evoked potentials were significantly more frequent in MSA-C. CONCLUSIONS: Abnormalities of somatosensory, visual and auditory evoked potentials are frequent findings in MSA, whereas abnormal motor evoked potentials are not a characteristic feature of the disease.

Adult↗
PubMed2000

Glutathione, oxidative stress and neurodegeneration.

There is significant evidence that the pathogenesis of several neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Friedreich's ataxia and amyotrophic lateral sclerosis, may involve the generation of reactive oxygen species and mitochondrial dysfunction. Here, we review the evidence for a disturbance of glutathione homeostasis that may either lead to or result from oxidative stress in neurodegenerative disorders. Glutathione is an important intracellular antioxidant that protects against a variety of different antioxidant species. An important role for glutathione was proposed for the pathogenesis of Parkinson's disease, because a decrease in total glutathione concentrations in the substantia nigra has been observed in preclinical stages, at a time at which other biochemical changes are not yet detectable. Because glutathione does not cross the blood-brain barrier other treatment options to increase brain concentrations of glutathione including glutathione analogs, mimetics or precursors are discussed.

Alzheimer Disease↗
PubMed2000

Deficiency of inducible nitric oxide synthase protects against MPTP toxicity in vivo.

MPTP produces clinical, biochemical, and neuropathologic changes reminiscent of those that occur in idiopathic Parkinson's disease (PD). In the present study we show that MPTP treatment led to activation of microglia in the substantia nigra pars compacta (SNpc), which was associated and colocalized with an increase in inducible nitric oxide synthase (iNOS) expression. In iNOS-deficient mice the increase of iNOS expression but not the activation of microglia was blocked. Dopaminergic SNpc neurons of iNOS-deficient mice were almost completely protected from MPTP toxicity in a chronic paradigm of MPTP toxicity. Because the MPTP-induced decrease in striatal concentrations of dopamine and its metabolites did not differ between iNOS-deficient mice and their wild-type littermates, this protection was not associated with a preservation of nigrostriatal terminals. Our results suggest that iNOS-derived nitric oxide produced in microglia plays an important role in the death of dopaminergic neurons but that other mechanisms contribute to the loss of dopaminergic terminals in MPTP neurotoxicity. We conclude that inhibition of iNOS may be a promising target for the treatment of PD.

Animals↗
PubMed2000

Bag-1 and Bcl-2 gene transfer in malignant glioma: modulation of cell cycle regulation and apoptosis.

Bag-1 is a heat shock 70 kDa (Hsp70)-binding protein that can collaborate with Bcl-2 in suppressing apoptosis under some conditions. Here, we report that 11 of 12 human glioma cell lines express Bag-1 protein in vitro. Moreover, 15 of 19 human glioblastomas expressed Bag-1 as assessed by immunohistochemistry in primary tumor specimens. To examine the biological effects of Bag-1 in glioma cells, we expressed Bag-1 or Bcl-2 transgenes in 2 human malignant glioma cell lines, LN-18 and LN-229. Bag-1 significantly slowed glioma cell growth and reduced clonogenicity of both cell lines in vitro. Coexpressed Bcl-2 abrogated these effects of Bag-1. Intracranial LN-229 glioma xenografts implanted into nude mice revealed a substantial growth advantage afforded by Bcl-2. Bag-1 had no such effect, either in the absence or presence of Bcl-2. Upon serum starvation in vitro, Bcl-2 prevented cell death whereas Bag-1 did not. Both Bcl-2 and Bag-1 slowed proliferation of serum-starved cells when expressed alone. Importantly, coexpression of Bcl-2 and Bag-1 provided a distinct growth advantage under conditions of serum starvation that is probably the result of (i) the death-preventing activity of Bcl-2 and (ii) the property of Bag-1 to overcome a Bcl-2-mediated enhancement of exit from the cell cycle. In contrast to these Bcl-2/Bag-1 interactions observed under serum starvation conditions, Bag-1 did not further enhance the strong protection from staurosporine-, CD95 (Fas/Apo1) ligand-, Apo2 ligand (TRAIL)- or chemotherapeutic drug-induced apoptosis afforded by Bcl-2. Taken together, these results indicate a role for Bag-1/Bcl-2 interactions in providing a survival advantage to cancer cells in a deprived microenvironment that may be characteristic of ischemic/hypoxic tumors such as human glioblastoma multiforme, and suggest that Bcl-2/Bag-1 interactions also modulate cell proliferation.

Animals↗
PubMed2000

Effect of prolonged neck muscle vibration on lateral head tilt in severe spasmodic torticollis.

UNLABELLED: Short term vibration of the dorsal neck muscles (10-35 s) is known to induce involuntary movements of the head in patients with spasmodic torticollis. To investigate whether neck muscle vibration might serve as a therapeutic tool when applied for a longer time interval, we compared a vibration interval of 5 seconds with a 15 minute interval in a patient with spasmodic torticollis with an extreme head tilt to the right shoulder. Head position was recorded with a two camera optoelectronic motion analyzer in six different test conditions. Vibration regularly induced a rapid change of head position that was markedly closer to a normal, upright posture. After 5 seconds of vibration, head position very quickly returned to the initial position within seconds. During the 15 minute interval, head position remained elevated. After terminating vibration in this condition, the corrected head position remained stable at first and then decreased slowly within minutes to the initial tilted position. CONCLUSIONS: (1) In this patient, muscle vibration was the specific sensory input that induced lengthening of the dystonic neck muscles. Neither haptic stimulation nor transcutaneous electrical stimulation had more than a marginal effect. (2) The marked difference in the change of head position after short and prolonged stimulation supports the hypothesis that spasmodic torticollis might result from a disturbance of the central processing of the afferent input conveying head position information-at least in those patients who are sensitive to sensory stimulation in the neck region. (3) Long term neck muscle vibration may provide a convenient non-invasive method for treating spasmodic torticollis at the central level by influencing the neural control of head on trunk position.

Female↗
PubMed2000

Nerve conduction studies in multiple system atrophy.

To study the frequency and severity of peripheral neuropathy in multiple system atrophy (MSA), we performed nerve conduction studies in 42 MSA patients suffering from either cerebellar MSA (MSA-C) or parkinsonian MSA (MSA-P). Abnormal nerve conduction was present in 24% of the patients. Abnormalities were significantly more frequent in MSA-P (43%) compared to MSA-C (14%). Motor nerve conduction velocities were reduced in 4% of the MSA-C and in 7% of the MSA-P patients. Abnormal compound muscle action potentials were more frequent in MSA-P (29% versus 7% in MSA-C) pointing to a more pronounced loss of motor axons in this subgroup. Sensory nerve conduction velocities were abnormal in 4% of the MSA-C and 14% of the MSA-P patients, and mean sensory nerve action potentials were normal in all MSA-C and reduced in 7% of the MSA-P patients. The data provide evidence that the peripheral nervous system is differentially affected in MSA-C and MSA-P.

Action Potentials↗
PubMed2000

Human malignant glioma cell lines are refractory to retinoic acid-mediated differentiation and sensitization to apoptosis.

BACKGROUND: Retinoids are candidate differentiation-inducing agents for glial tumors. Differentiation therapy is an attractive approach to cancers that resist surgery, irradiation and chemotherapy. METHODS: We examined the effects of retinoids on proliferation, morphology and sensitivity to apoptosis in human malignant glioma and neuroblastoma cell lines. RESULTS: In contrast to neuroblastoma cells, retinoids are devoid of acute cytotoxic effects and have only moderate antiproliferative effects on human glioma cell lines upon long-term exposure at high concentrations. Electron microscopy fails to reveal features of differentiation or apoptosis in retinoid-treated glioma cells and untransformed rat astrocytes. Retinoids do not modulate CD95 or CD95L expression or susceptibility to CD95-mediated apoptosis and fail to act in synergy with interferon (IFN)-alpha or IFN-gamma or cancer chemotherapy drugs to promote growth inhibition or apoptosis. CONCLUSION: Glioma cell lines are refractory to the induction of differentiation or apoptosis by retinoids.

Animals↗
PubMed1999

Locoregional Apo2L/TRAIL eradicates intracranial human malignant glioma xenografts in athymic mice in the absence of neurotoxicity.

Glioblastoma multiforme is a lethal neoplasm refractory to radiochemotherapy. Although glioma cells undergo apoptosis when exposed to the death ligand, CD95 (Fas/APO-1) ligand, the therapeutic use of CD95L is considered impossible because of lethal side effects. Here, we report that the locoregional application of Apo2 ligand (Apo2L) exerts strong antitumor activity on preestablished intracranially growing human U87MG glioma xenografts in athymic mice. Two repetitive intratumoral injections of 2 microg Apo2L resulted in long-term survival of mice (>100 days), whereas the median survival of mock-treated mice was 36 days. The assessment of tumor volumes at 21 and 35 days after inoculation showed complete eradication of glioma xenografts in Apo2L-treated mice. Histology and TUNEL assay confirmed the induction of apoptosis by Apo2L in glioma cells in vivo. Importantly, the intracerebral injection of Apo2L does not result in acute or delayed neurotoxicity. We propose that a phase 1 trial of intralesional Apo2L therapy for human glioblastoma multiforme is warranted.

Animals↗
PubMed1999

MPP+ inhibits proliferation of PC12 cells by a p21(WAF1/Cip1)-dependent pathway and induces cell death in cells lacking p21(WAF1/Cip1).

The molecular and biochemical mode of cell death of dopaminergic neurons in Parkinson's disease (PD) is uncertain. In an attempt at further clarification we studied the effects of 1-methyl-4-phenylpyridinium (MPP+), the active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), on dopaminergic PC12 cells. In humans and nonhuman primates MPTP/MPP+ causes a syndrome closely resembling PD. MPP+ toxicity is thought to be mediated by the block of complex I of the mitochondrial electron transport chain. Treatment of undifferentiated PC12 cells with MPP+ primarily inhibited proliferation of PC12 cells and secondarily led to cell death after the depletion of all energy substrates by glycolysis. This cell death showed no morphological characteristics of apoptosis and was not blocked by treatment with caspase inhibitors. The inhibition of cell growth was not dependent on an inhibition of complex I activity since MPP+ also inhibited cell proliferation in SH-SY5Y cells lacking mitochondrial DNA and complex I activity (p0 cells). As shown by flow cytometric analysis, MPP+ induced a block in the G0/G1 to S phase transition that correlated with increased expression of the cyclin-dependent kinase inhibitor p21(WAF1/Cip1) and growth arrest. Since treatment with 1 microM MPP+ caused apoptotic cell death in p21(WAF1/Cip1)-deficient (p21(-/-)) but not in parental (p21(+/+)) mouse embryo fibroblasts, our data suggest that in an early phase MPP+-induced p21(WAF1/Cip1) expression leads to growth arrest and prevents apoptosis until energy depletion finally leads to a nonapoptotic cell death.

1-Methyl-4-phenylpyridinium↗
PubMed1999

Cerebellar ataxia with glutamic acid decarboxylase autoantibodies.

Degenerative cerebellar ataxia with autoantibodies against glutamic acid decarboxylase (GAD) is a rare disorder and may represent a subset of ataxias previously classified as idiopathic. The authors report a patient with progressive cerebellar ataxia, insulin-dependent diabetes mellitus, and GAD antibodies who responded to i.v. immunoglobulins.

Aged↗
PubMed1999

Deficits in phasic muscle force generation explain insufficient compensation for interaction torque in cerebellar patients.

A simple paradigm was used to investigate how patients with cerebellar lesions cope with the need to correct for joint interactions during a multi-joint movement. Normal subjects and patients with cerebellar degeneration performed fast unconstrained elbow flexions with the instruction to voluntarily fixate the shoulder joint. Angular kinematics and inverse dynamics analyses were performed. A susceptibility index quantified how strong-concomitant shoulder-motion depended on interactions from the elbow. Amplitudes of involuntary shoulder movements increased with elbow movement speed and were generally larger in patients. Susceptibility indices were smaller in patients, indicating a more variable compensatory response, however, increased with elbow movement speed. We conclude that patients were significantly less able to 'tune' their postural stabilizing response to match interaction torques. However, the velocity dependence of this effect points to a deficit in generating normal levels of phasic torque.

Adult↗
PubMed1999

Gemcitabine cytotoxicity of human malignant glioma cells: modulation by antioxidants, BCL-2 and dexamethasone.

Gemcitabine is a novel antimetabolite drug that acts by multiple mechanisms, including inhibition of ribonucleoside diphosphate reductase, of dCMP deaminase and of dCTP incorporation into DNA and RNA. Here, we report that gemcitabine induces cytotoxic and clonogenic death of 12 human malignant glioma cell lines at clinically relevant concentrations around 1 microM. Gemcitabine is thus approximately 100-fold more active than the congener drug, cytarabine. Gemcitabine cytotoxicity of glioma cells does not require wild-type p53 activity: (i) there was no difference in the susceptibility to gemcitabine between cell lines with wild-type p53 and cell lines with mutant or deleted p53; (ii) ectopic expression of a temperature-sensitive p53 protein either at wild-type (32.5 degrees C) or at mutant (38.5 degrees C) conformation had no significant influence on gemcitabine-induced cell death. Gemcitabine cytotoxicity was unaffected by the antioxidants, N-acetylcysteine and phenyl-N-tert-butyl-alpha-phenylnitrone. There was no correlation between the susceptibility to gemcitabine and the endogenous expression of the B cell lymphoma-2 (BCL-2)-family proteins BCL-2, BCL-XL, myeloid cell leukemia-1 (MCL-1), BCL-2-associated X protein (BAX), BCL-2 homologous antagonist/killer (BAK) and BCL-XS. Ectopic expression of BCL-2 moderately attenuated gemcitabine-induced cell death. Similarly, preexposure to the synthetic steroid, dexamethasone, which is commonly used to control cerebral edema in brain tumor patients, reduced gemcitabine cytotoxicity. We conclude that the clinical evaluation of gemcitabine for the adjuvant chemotherapy of malignant glioma is warranted.

Antimetabolites, Antineoplastic↗
PubMed1999

New insights into positional alcohol nystagmus using three-dimensional eye-movement analysis.

The semicircular canals selectively transduce angular velocity and are normally insensitive to gravity and linear acceleration. In acute alcohol intoxication, however, the cupula becomes lighter than the endolymph, rendering it sensitive to gravity (buoyancy hypothesis). This results in positional alcohol nystagmus (PAN) and rotatory vertigo. We evaluated PAN in 8 normal subjects by means of three-dimensional eye-movement analysis in an attempt to clarify if the buoyancy mechanism is sufficient to explain PAN. Forty minutes after intake of 0.8 g of alcohol/kg of body weight, the subjects were positioned such that the lateral canals were earth vertical. They were then rotated in the plane of the lateral canals about an earth-horizontal axis to either 45 degrees or 90 degrees , right or left ear down, and eye movements were recorded for 40 seconds in each position. The spatial analysis of the responses showed that in addition to the nystagmus induced by the buoyancy of all six cupulae, alcohol intoxication also causes a vertical velocity offset (in all subjects, slow phase down) that is independent of the orientation of the subject in space. The offset may represent a toxic effect on central vestibular pathways, producing a tone imbalance of the vertical vestibulo-ocular reflex.

Adult↗
PubMed1999

Tremorlytic activity of budipine in Parkinson's disease.

In order to objectively quantify the tremorlytic activity of budipine in Parkinson's disease (PD) we performed longterm tremor recordings in a subset of patients enrolled in two clinical trials. Eleven PD patients with marked tremor participating in an open-label study underwent longterm recording before and during medication. Nine patients completed the study. Tremor occurrence was reduced from 52 +/- 18.6% to 34.7 +/- 19.3% (p < 0.05); tremor intensity decreased from 15.3 +/- 4.8 (SNR) to 11.3 +/- 4.8 (p < 0.01). UPDRS tremor subscores were also significantly improved. Fourteen patients who enrolled in a multicenter, double-blind, placebo-controlled study underwent longterm tremor analysis in addition to the Columbia University Rating Scale (CURS). Tremor occurrence was improved in the budipine group (n = 7) from 24.7 +/- 15.5% to 14.8 +/- 14.5% (p < 0.05). Tremor intensity decreased from 9.1 +/- 2.5 (SNR) to 7.2 +/- 1.6. However, the latter result was statistically not significant, probably due to the small patient number. In the placebo-group (n = 7) there was no reduction of tremor occurrence or of tremor intensity. The CURS sum score was improved from 5.7 to 3.0 in the budipine group, whereas there was only a smaller improvement in the placebo group (from 7.1 to 5.5). These data suggest that budipine is an effective tremorlytic agent in PD, which may be used as an alternative to anticholinergics.

Aged↗
PubMed1999

[New insights in the molecular genetics and pathophysiology of hereditary ataxias].

The hereditary ataxias are a heterogeneous group of inherited neurodegenerative disorders characterised by progressive ataxia that results from degeneration of the cerebellum and its afferent and efferent connections. With respect to the pathogenic mechanisms, the hereditary ataxias may be tentatively divided into three groups: (1) The recessive ataxias are induced by the functional impairment of a protein that is essential for the survival of specific neurons while the autosomal dominant ataxias are either caused by (2) mutations of genes coding for ion channels thus resulting in a channelopathy or by (3) a novel deleterious function of a extended polyglutamine sequence within the proteins encoded by the respective genes.

Adolescent↗