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J Dichgans

Publications and source records attributed to J Dichgans.

At least 127 records · Page 7Linked to original sources
PubMed1998

Exteroceptive suppression of temporalis muscle activity in patients with fibromyalgia, tension-type headache, and normal controls.

Changes of the second suppressive period (ES2) of the exteroceptive suppression of the temporalis muscle activity are found in patients with chronic tension-type headache (TTH) and are suggested to reflect an abnormal endogenous pain control system. We investigated whether similar changes are found in patients with the fibromyalgia syndrome (FMS) that is also believed to result from disturbed central pain processing. The ES2 values of 27 patients with FMS were compared with those of 18 patients with TTH and 40 healthy volunteers. The duration of ES2 (+/-SD) in FMS patients was 30.6+/-7.5 ms and was not significantly different from the control group (33.1+/-7.8 ms), whereas it was significantly shortened in TTH patients (22.9+/-11.5 ms). Our results indicate that, despite similar concepts on the pathophysiology of the two chronic pain disorders, there are no comparable changes of this brain stem reflex activity in FMS.

Adult↗
PubMed1998

CD95 expression and CD95-mediated apoptosis of T cells in multiple sclerosis. No differences from normal individuals and no relation to HLA-DR2.

CD95-mediated apoptosis is a potent endogenous pathway of T cell elimination that has been suggested to be altered in multiple sclerosis (MS). MS is associated with the HLA-DR2, Dw2, DQ6 HLA class II haplotype. We have previously reported that T cell lines from HLA-DR2-positive individuals show enhanced production of tumor necrosis factor (TNF), a cytokine homologous to CD95 ligand, in response to specific antigen. Here we have studied CD95 expression and susceptibility to CD95-mediated apoptosis in peripheral blood mononuclear cells (PBMC) and activated T cells of 20 healthy individuals and 20 MS patients, half of whom were HLA-DR2-positive. MS patients did not differ from healthy individuals in either parameter. There was also no difference in CD95 expression or CD95-mediated apoptosis when MS patients and healthy individuals were grouped and compared according to HLA-DR status. These data reveal no differential regulation of PBMC/T cell apoptosis induced by CD95 receptor ligation in MS and show no impact of HLA-DR2 status on PBMC/T cell susceptibility to the same apoptotic stimulus. However, to assess the contribution of T cell apoptosis to the pathogenesis of MS further studies on other details of the complex system leading to T cell apoptosis are required.

Apoptosis↗
PubMed1998

Anticonvulsant drugs fail to modulate chemotherapy-induced cytotoxicity and growth inhibition of human malignant glioma cells.

Adjuvant chemotherapy after cytoreductive surgery and irradiation plays an increasingly important role in the management of human malignant glioma. Here we have examined the effect of three anticonvulsants most commonly administered to glioma patients, carbamazepine, phenytoin and valproic acid, on the cytotoxic and antiproliferative actions in vitro of several cancer chemotherapy drugs currently evaluated for human gliomas. We find that none of the anticonvulsants reduces glioma cell viability or proliferation or modulates glioma cell clonogenicity at clinically relevant concentrations when administered alone. Therapeutic concentrations of either drug fail to alter the effect of cancer chemotherapy drugs in acute cytotoxicity assays or modified clonogenicity assays. A lack of interactions of anticonvulsants and cytotoxic drugs is also observed when the glioma cells are preexposed to the anticonvulsants for prolonged times, suggesting that chronic exposure to anticonvulsants in vivo may not change intrinsic glioma cell sensitivity to cancer chemotherapy. Thus, changes in hepatic enzyme activity or immunological parameters, but not modulation of intrinsic chemotherapeutic drug sensitivity, may influence the choice of an anticonvulsant for seizure control in glioma patients receiving adjuvant chemotherapy.

Anticonvulsants↗
PubMed1998

Chemosensitivity of human malignant glioma: modulation by p53 gene transfer.

Loss of wild-type p53 activity is one of the most common molecular abnormalities in human cancers including malignant gliomas. The p53 status is also thought to modulate sensitivity to irradiation and chemotherapy. Here, we studied the effect of a p53 gene transfer on the chemosensitivity of three human glioma cell lines with different endogenous p53 status (LN-229, wild-type; LN-18, mutant; LN-308, deleted), using the murine temperature-sensitive p53 val135 mutant. Expression of mutant p53 enhanced proliferation of LN-308 cells but reduced proliferation in the other cell lines. Expression of wild-type p53 caused reversible growth arrest of all cell lines but failed to induce apoptosis. Growth arrest induced by wild-type p53 was associated with strong induction of p21 expression. Strong induction of BAX expression and loss of BCL-2 expression, which are associated with p53-dependent apoptosis rather than growth arrest, were not observed. Wild-type p53 failed to sensitize glioma cells to cytotoxic drugs including BCNU, cytarabine, doxorubicin, teniposide and vincristine. The combined effects of wild-type p53 gene transfer and drug treatment were less than additive rather than synergistic, suggesting that the intracellular cascades activated by p53 and chemotherapy are redundant. Unexpectedly, forced expression of mutant p53 modulated drug sensitivity in that it enhanced the toxicity of some drugs but attenuated the effects of others. These effects may represent a dominant negative effect of mutant p53 in LN-229 cells which have wild-type p53 activity but must be considered a gain of function-type effect in the other two cell lines which have no wild-type p53 activity. Importantly, no clear-cut pattern emerged among the three cell lines studied. We conclude that somatic gene therapy based on the reintroduction of p53 will limit the proliferation of human malignant glioma cells but is unlikely to induce clinically relevant sensitization to chemotherapy in these tumors.

Amino Acid Substitution↗
PubMed1998

Taxol-mediated augmentation of CD95 ligand-induced apoptosis of human malignant glioma cells: association with bcl-2 phosphorylation but neither activation of p53 nor G2/M cell cycle arrest.

The anti-tumour alkaloid taxol shows strong cytotoxic and antiproliferative activity in two human malignant glioma cell lines, T98G and LN-229. CD95 (Fas/APO-1) ligand is a novel cytotoxic cytokine of the tumour necrosis factor (TNF) family that exerts prominent antiglioma activity. At clinically relevant taxol concentrations of 5-100 nM, taxol and CD95 ligand showed significant synergistic cytotoxicity and growth inhibition. High concentrations of taxol induced G/M cell cycle arrest in both cell lines. The synergy of taxol and CD95 ligand was independent of cell cycle effects of taxol as synergy was achieved at much lower taxol concentrations than G2/M arrest and as cell cycle effects of taxol were unaffected by co-exposure to CD95 ligand. Similarly, high concentrations of taxol were required to induce p53 activity in the p53 wild-type cell line LN-229. This effect was not modulated by CD95 ligand, suggesting that synergy is also independent of p53 activation. However, taxol induced a mobility shift of the bcl-2 protein on immunoblot analysis, indicative of bcl-2 phosphorylation. Bcl-2 phosphorylation on serine was confirmed by immunoprecipitation and phosphoserine immunoblot analysis. Considering (1) that phosphorylation of bcl-2 interferes with its heterodimerization with bax and (2) the inhibition of CD95-mediated apoptosis by bcl-2, we propose that taxol sensitizes malignant glioma cells to CD95 ligand by increasing the functional bax/bcl-2 rheostat in favour of bax and thus cell death.

Antineoplastic Agents, Phytogenic↗
PubMed1998

Fas/CD95/Apo-I activates the acidic sphingomyelinase via caspases.

Fas/CD95/Apo-I has been shown to stimulate a variety of molecules including several members of the caspase family and the acidic sphingomyelinase (Martin and Green 1995; Gulbins et al, 1995). Here, we demonstrate that Fas receptor-triggered activation of the acidic sphingomyelinase, consumption of sphingomyelin, release of ceramide, and subsequent activation of JNK and p38-K are regulated by caspases. Inhibition of caspases by Ac-YVAD-chloromethylketone or transient CrmA transfection prevented stimulation of acidic sphingomyelinase, release of ceramide and activation of JNK and p38-K upon Fas-receptor crosslinking. Likewise, Fas triggered apoptosis was almost completely blocked by Ac-YVAD-chloromethylketone or CrmA mediated inhibition of caspases. The results suggest a new signalling cascade from the Fas receptor via caspases to acidic sphingomyelinase, ceramide and JNK/p38-K.

Acids↗
PubMed1998

Extended therapeutic window for caspase inhibition and synergy with MK-801 in the treatment of cerebral histotoxic hypoxia.

In rats, striatal histotoxic hypoxic lesions produced by the mitochondrial toxin malonate resemble those of focal cerebral ischemia. Intrastriatal injections of malonate induced cleavage of caspase-2 beginning at 6 h, and caspase-3-like activity as identified by DEVD biotin affinity-labeling within 12 h. DEVD affinity-labeling was prevented and lesion volume reduced in transgenic mice overexpressing BCL-2 in neuronal cells. Intrastriatal injection of the tripeptide, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD-fmk), a caspase inhibitor, at 3 h, 6 h, or 9 h after malonate injections reduced the lesion volume produced by malonate. A combination of pretreatment with the NMDA antagonist, dizocilpine (MK-801), and delayed treatment with zVAD-fmk provided synergistic protection compared with either treatment alone and extended the therapeutic window for caspase inhibition to 12 h. Treatment with cycloheximide and zVAD-fmk, but not with MK-801, blocked the malonate-induced cleavage of caspase-2. NMDA injections alone resulted in a weak caspase-2 cleavage. These results suggest that malonate toxicity induces neuronal death by more than one pathway. They strongly implicate early excitotoxicity and delayed caspase activation in neuronal loss after focal ischemic lesions and offer a new strategy for the treatment of stroke.

Amino Acid Chloromethyl Ketones↗
PubMed1998

Decorin gene transfer-mediated suppression of TGF-beta synthesis abrogates experimental malignant glioma growth in vivo.

Cytokines such as transforming growth factor-beta (TGF-beta) are thought to mediate escape from immune surveillance in human malignant glioma. Here, we report that ectopic expression of the small TGF-beta-binding proteoglycan, decorin, inhibits not only TGF-beta bioactivity but also TGF-beta 1 and TGF-beta 2 mRNA transcription and TGF-beta protein synthesis by human LN-18, LN-229, T98G and rat C6 glioma cells in vitro. Ectopic expression of decorin in C6 rat glioma cells results in strong inhibition of tumor formation in vivo. Decorin-expressing C6 gliomas grow initially but regress to very small residual tumors at 12 weeks after implantation whereas all control animals die or have to be killed within 4 weeks. Decorin-expressing tumors show a four-fold increase of infiltration by activated T cells and a 1.6-fold increase in total B and T cells. Chronic steroid-mediated immunosuppression abrogates the inhibitory effects of decorin gene transfer. We conclude that decorin-induced inhibition of TGF-beta release by glioma cells significantly enhances antiglioma immune responses in vivo. Clinical evaluation of decorin gene therapy for human malignant gliomas may be warranted.

Animals↗
PubMed1998

Space exploration in neglect.

The present study investigated the gaze as well as the head and the eye-in-head movements of neglect patients while they were exploring their surroundings. A random configuration of letters was presented on the inner surface of a sphere that surrounded the subject, requiring free exploratory eye and head movements. The subjects were requested to search for a single (non-existent) target letter. The co-ordination of eye and head movements in patients with neglect resembled the pattern usually observed in healthy subjects orienting to eccentric visual targets. They performed hypometric head movements with additional shifts of eye-in-head position. Moreover, like healthy subjects, the patients with neglect explored space with gaze, with head and eye-in-head movements that were symmetrically distributed around preferred orientations in space. However, in contrast to controls, these centres of exploration were shifted towards the right. The average horizontal position of gaze and of head movements lay right of the body's mid-sagittal plane, the average eye-in-head position right of the head midline. The preferred orientations were located far away from the anatomical limits of horizontal gaze, head and eye-in-head movements. The decrease of exploration towards more eccentric locations left and right of these orientations thus could not be explained by anatomical restrictions. The results argue against a model of neglect that proposes a lateral gradient of attentional orienting towards the ipsilesional side. Exploring the surroundings, the patients did not orient gaze, the head or the eyes in the head towards the extreme ipsilesional side, nor even close to it. The results favour a deviation model suggesting a shift of the whole frame for exploratory behaviour towards the ipsilesional side. In addition to this shift, we found a second component of altered visual exploration in neglect. The patients' head and gaze movements exhibited a reduced variability around the deviated centre of exploration. The variability was not generally reduced but rather concerned specifically the horizontal dimension. The latter was found even when the area of exploration was paralleled between the groups, requiring the control subjects to search only in that part of the letter array that the neglect patients had explored spontaneously. Possible mechanisms, such as a disturbed ability to update the spatial representation of visual targets or an altered neural representation of space in the horizontal dimension, are discussed.

Aged↗
PubMed1998

The natural history of degenerative ataxia: a retrospective study in 466 patients.

The aim of the present study was (i) to compare disease progression and survival in different types of degenerative ataxia, and (ii) to identify variables that may modify the rate of disease progression. We included patients suffering from Friedreich's ataxia (FRDA, n = 83), early onset cerebellar ataxia (EOCA, n = 30), autosomal dominant cerebellar ataxia (ADCA) type I (ADCA-I, n = 273), ADCA-III (n = 13) and multiple system atrophy (MSA, n = 67). Molecular genetic testing allowed us to assign 202 ADCA-I patients to one of the following subgroups: spinocerebellar ataxia type I (SCAI, n = 36), SCA2 (n = 56) and SCA3 (n = 110). To assess disease progression we defined the following disease stages: stage 0 = no gait difficulties; stage 1 = disease onset, as defined by onset of gait difficulties; stage 2 = loss of independent gait; stage 3 = confinement to wheelchair; stage 4 = death. Disease progression was most rapid in MSA, intermediate in FRDA, ADCA-I and ADCA-III and slowest in EOCA. The rate of progression was similar in SCA1, SCA2 and SCA3. The CAG repeat length was a significant risk factor for faster progression in SCA2 and SCA3, but not in SCA1. In FRDA, the time until confinement to wheelchair was shorter in patients with earlier disease onset, suggesting that patients with long GAA repeats and early disease onset have a poor prognosis. Female gender increased the risk of becoming dependent on walking aids or a wheelchair, but it did not influence survival in FRDA, SCA3 and MSA. In SCA2, female gender was associated with shortened survival. In MSA, later age of onset increased the risk of rapid progression and death.

Adolescent↗
PubMed1998

Smooth pursuit eye movements and otolith-ocular responses are differently impaired in cerebellar ataxia.

Horizontal and vertical smooth pursuit was compared with otolith-ocular responses in 11 patients with cerebellar ataxia and 21 normal subjects using three-dimensional magnetic search coil eye movement recordings. Otolith-ocular responses were investigated during off-vertical axis rotation. This stimulus induces nystagmus consisting of the exponentially decaying canalicular response, and an eye-velocity modulation and offset which arise from the excitation of the otoliths by the gravity vector, which lasts as long as the rotation continues. Otolith-ocular reflexes are intimately interrelated with visual tracking when real targets are viewed during linear motion. The responses of both the translational vestibulo-ocular reflex and the pursuit system have been shown to be linearly dependent on the inverse of the viewing distance, so that a common central pathway for the two systems has been suggested, probably travelling through the cerebellum. Thus, the aim of the study was to evaluate to what extent these reflexes are disturbed in cerebellar disease. The results confirm the earlier notion that in normal subjects pursuit performance is better for horizontal than for vertical tracking, and that it is better for upward than for downward tracking. This pattern is also found in patients. In addition, smooth pursuit performance is clearly degraded in patients, but the modulation of eye-velocity during off-vertical axis rotation is enhanced. Since the amount of this enhancement does not correlate with the amount of pursuit impairment, degradation of smooth pursuit and pathological enhancement of otolith-ocular responses seem to be independent effects of cerebellar degeneration. Thus, the increase in the otolith-ocular response in patients cannot be attributed to adaptational mechanisms trying to overcome the smooth pursuit deficiency; it is more likely to represent pathological disinhibition of otolith derived responses. The absence of compensatory eye-velocity offset during off-vertical axis rotation may reflect the fact that in patients the otolith signals are not utilized in computations thought to be important for spatial orientation mechanisms arising from the interaction of vestibular, visual and somatosensory signals.

Adult↗
PubMed1998

Autosomal dominant cerebellar ataxia type I. MRI-based volumetry of posterior fossa structures and basal ganglia in spinocerebellar ataxia types 1, 2 and 3.

Twenty-six patients suffering from autosomal dominant cerebellar ataxia type I were subjected to a genotype-phenotype correlation analysis using molecular genetic assignment to the genetic loci for spinocerebellar ataxia type 1, 2 or 3 (SCA1, SCA2, SCA3) and MRI-based volumetry of posterior fossa structures and basal ganglia nuclei. There was significant atrophy of the cerebellum and brainstem in all three SCA mutations compared with a group of 31 age- and sex-matched controls. Comparison between the SCA groups showed that cerebellar and brainstem atrophy was more severe in SCA2 than in SCA1 and SCA3. Putaminal and caudate volume was reduced only in SCA3, but not in SCA1 and SCA2. A set of three morphological criteria was defined that enabled us to assign all SCA2 and SCA3 patients correctly to the underlying genotype. In contrast, these criteria did not distinguish SCA1 from SCA2 and SCA3. Regression analysis failed to reveal a significant association between CAG repeat length and the volumes of the respective brain structures in any of the SCA mutant types. The present data provide in vivo evidence that SCA2 and SCA3 lead to distinct patterns of brain atrophy, while the atrophy changes in SCA1 overlap with both SCA2 and SCA3.

Adult↗
PubMed1998

Clinical presentation and therapeutic outcome in 26 patients with primary CNS lymphoma.

This retrospective study analyzes clinical features and therapeutic outcome in 26 immunocompetent patients with primary central nervous system lymphoma (PCNSL). Most patients presented with personality changes. PCNSL lesions were mainly iso- or hyperdense, enhancing lesions on CT scan, hypointensive on T1-, and hyperintensive on T2-weighted MRI. Multiple lesions were found in about 60% of patients. Nine of 11 patients receiving radiotherapy alone showed complete remission (CR). Median survival time after diagnosis (MST) was 13 months. Seven patients received intravenous and intrathecal methotrexate, radiotherapy, and postirradiation intravenous cytarabine. Six of these patients had CR and 5 patients are alive in CR after a median follow-up of 12 months. Five patients received various other radiochemotherapy regimens (MST 6 months), and 3 patients died before receiving any radio- or chemotherapy. Our preliminary treatment results show a tendency to improved survival with radiochemotherapy. This is consistent with pertinent data from the literature which favors radiochemotherapy for patients with PCNSL.

Adrenal Cortex Hormones↗
PubMed1998

Anticipation in familial cavernous angioma: ascertainment bias or genetic cause.

OBJECTIVES: Anticipation has been linked to unstable trinucleotide repeats in many neurological disorders. We examined the hypothesis of genetic anticipation in familial cavernous angioma (FCA) of the central nervous system. MATERIAL AND METHODS: The mean ASO of affected individuals was compared between successive generations in 55 families. Intergenerational pair-wise comparisons were employed to avoid several ascertainment biases. Regarding severity of disease both type of manifestation and number of cavernous angiomas were compared between generations. RESULTS: The mean ASO decreased significantly both from the first to the second generation (31.6 vs 17.8 years; P = 0.000) and from the second to the third generation (17.8 vs 6.7 years; P = 0.002). The pair-wise comparisons also showed significantly earlier ASO. No clear evidence for anticipation with regard to severity of disease was found. CONCLUSIONS: Molecular genetic studies will determine whether trinucleotide repeats are the underlying mechanism for our observation of anticipation in FCA.

Adolescent↗
PubMed1998

CD95 ligand: lethal weapon against malignant glioma?

CD95 (Fas/APO-1) and its ligand (CD95L) belong to a growing cytokine and cytokine receptor family that includes nerve growth factor (NGF) and tumor necrosis factor (TNF) and their corresponding receptors. CD95 expression increases during malignant progression from low-grade to anaplastic astrocytoma and is most prominent in perinecrotic areas of glioblastoma. There is, however, no evidence that CD95 expression in malignant gliomas is triggered by hypoxia or ischemia. Agonistic antibodies to CD95, or the natural ligand, CD95L, induce apoptosis in human malignant glioma cells in vitro. Glioma cell sensitivity to CD95-mediated apoptosis is regulated by CD95 expression at the cell surface and by the levels of intracellular apoptosis-regulatory proteins, including bcl-2 family members. Several cytotoxic drugs synergize with CD95L to kill glioma cells. For as yet unknown reasons, glioma cells may co-express CD95 and CD95L in vitro without undergoing suicide or fratricide. Yet, they kill T cells via CD95/CD95L interactions and are sensitive to exogenously added CD95L. Since CD95L is expressed in gliomas in vivo, too, forced induction of CD95 expression might promote therapeutic apoptosis in these tumors. That glioma cells differ from nontransformed T cells in their sensitivity to CD95 antibodies or recombinant ligand, may allow the development of selective CD95 agonists with high antitumor activity that spare normal brain tissue. A family of death ligand/receptor pairs related to CD95L/CD95, including APO2L (TRAIL) and its multiple receptors is beginning to emerge. Although several issues regarding glioma cell sensitivity to CD95L/CD95-mediated apoptosis await elucidation, CD95 is a promising target for the treatment of malignant glioma.

Animals↗
PubMed1998

Acute disseminated encephalomyelitis following Pontiac fever.

We report the case of a 35-year-old woman who developed headache and psychosis and gradually became comatose within 3 weeks after a flu-like infection. MRI revealed bifrontal demyelination consistent with acute disseminating encephalomyelitis (ADEM). Two different cerebrospinal fluid samples were positively tested for Legionella cincinnatiensis by direct sequencing of a PCR-amplified Legionella-specific fragment. This result made it possible to interpret the initial symptoms as Pontiac fever. We think it most likely that this is a case of ADEM following the very rare situation of a systemic infection with L. cincinnatiensis. A review of the literature on Legionella-associated encephalopathy suggests that some of these cases may also have had ADEM.

Adult↗
PubMed1998

Changes of cerebrovascular CO2 reactivity during normal aging.

BACKGROUND AND PURPOSE: During the past decade, transcranial Doppler sonography has widely been used to assess blood flow velocities in the basal intracranial arteries and cerebrovascular reactivity (CR) to various stimuli. Although numerous studies have shown a decline of cerebral blood flow velocity with age, the age dependency of CR, including cerebrovascular CO2 reactivity, however, is controversial. Recently, we have reported a significant sex-related difference in CR, stressing the need to study the relation between normal aging and CR in both sexes separately. METHODS: By means of transcranial Doppler sonography, CR was determined in 100 healthy, nonsmoking volunteers (age 20 to 70 years, 10 men and 10 women per decade). RESULTS: In men, no change of CR with increasing age could be observed (P=0.98). In contrast, CR in women declined significantly, with a step decrease from the 4th to the 5th decades (F=4.413; P<0.01) and was significantly higher in the 3rd and 4th compared with the 5th, 6th, and 7th decades (P<0.05). Information on hormone replacement therapy (HRT) in women of the 6th and 7th decades was obtained retrospectively. HRT was associated with enhanced CR (HRT, n = 7 versus non-HRT, n = 13; P<0.001), with values similar to those found in premenopausal women. CONCLUSIONS: There are no changes of CR during normal aging in men, whereas CR declines significantly from the 4th to the 5th decades in women. HRT in postmenopausal women appears to enhance CR.

Adult↗