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J Dichgans

Publications and source records attributed to J Dichgans.

At least 145 records · Page 8Linked to original sources
PubMed1998

Three-dimensional eye movement analysis during caloric stimulation used to test vertical semicircular canal function.

HYPOTHESIS AND BACKGROUND: Quantitative caloric testing is considered to be one of the most sensitive parameters in the diagnosis of peripheral vestibular disorders. In the past, because of limitations in the methods, the evaluation of the caloric response was restricted to mainly lateral semicircular canal functions. In this study, the authors tried to extend caloric testing to the function of all semicircular canals by using three-dimensional (3-D) analysis techniques. METHODS: The authors studied in seven normal subjects 3-D eye movement responses to air caloric of the right ear with the subjects positioned in standard caloric position (lateral semicircular canal vertical) or such that one of the three semicircular canals of the right side was horizontal. Movement of the left eye was measured in 3-D with a dual-magnetic search coil. During stimulation, 10 seconds of maximum response were selected and desaccaded to yield the slow-phase velocity profile. From this profile, the average magnitude and direction of the eye rotation axis (velocity vector) were calculated in head coordinates. RESULTS: In all subjects, in standard caloric position, warm caloric produced eye velocity vectors that clustered closely along the direction expected from an excitation of the right lateral semicircular canal. When the subjects were positioned with one of the vertical semicircular canals horizontal, the orientation of the velocity vectors shifted toward a direction expected from the combined excitation of the lateral and the other vertical semicircular canal and vice versa. CONCLUSIONS: The 3-D eye movement recordings during caloric stimulation in different head positions allow the evaluation of the function of all semicircular canals.

Adult↗
PubMed1997

Topoisomerase-I inhibitors for human malignant glioma: differential modulation of p53, p21, bax and bcl-2 expression and of CD95-mediated apoptosis by camptothecin and beta-lapachone.

Beta-lapachone and camptothecin are structurally unrelated agents thought to inhibit topoisomerase-I activity through distinct mechanisms. We find that beta-lapachone is much more potent than camptothecin in inducing acute cytotoxic effects on human malignant glioma cells. Acute cytotoxicity induced by both drugs is apoptotic by electron microscopy, but not blocked by inhibitors of RNA or protein synthesis and not associated with changes in the expression of bcl-2, bax, p53, p21 or GADD45 proteins. In contrast, prolonged exposure of glioma cells to both drugs for 72 hr results in growth inhibition and apoptosis, with EC50 values around 1 microM. None of 7 glioma cell lines tested were resistant to either drug. LN-229 cells which have partial p53-wild-type activity show enhanced expression of p53, p21 and bax protein, whereas bcl-2 levels decrease, after exposure to camptothecin. In contrast, beta-lapachone increases bax protein expression in the absence of p53 activation. T98G cells are mutant for p53. In these cells, p53 levels do not change and p21 is not induced. bax accumulation in T98G cells is induced by both drugs, with bcl-2 levels unaltered. Surprisingly, ectopic expression of murine bcl-2 fails to abrogate the toxicity of either drug. Camptothecin, but not beta-lapachone, sensitizes human malignant glioma cells to apoptosis induced by the cytotoxic cytokines, tumor necrosis factor-alpha and CD95 ligand. Thus, both drugs have potent anti-glioma activity that may be mediated by enhanced bax expression but is not inhibited by ectopic bcl-2 expression. Camptothecin-like agents are particularly promising for immunochemotherapy of malignant glioma using cytotoxic drugs and CD95 ligand.

Apoptosis↗
PubMed1997

Dissociation between the perception of body verticality and the visual vertical in acute peripheral vestibular disorder in humans.

Estimates of the subjective visual and postural vertical were obtained from five patients with acute peripheral vestibular lesions and 20 normal subjects. The visual vertical was assessed by asking the subjects to align a target line to earth vertical by means of remote control. Postural vertical judgments were obtained by exposing them to rotational displacements in the roll plane while sitting on a motor-driven chair and requiring them to align their body to vertical using a joystick control. While the patients showed strong deviations of the visual vertical towards the lesion side, their postural vertical judgments remained veridical. We conclude that the above perceptions are not processed identically and that the participating sensory systems are differently weighted during these tasks.

Adult↗
PubMed1997

Human autoreactive and foreign antigen-specific T cells resist apoptosis induced by soluble recombinant CD95 ligand.

Mature T cells are susceptible to activation-induced cell death in the periphery. Activation-induced cell death is thought to involve CD95/CD95 ligand interactions in vivo. Here we report that stimulated, CD45RO+ human T cell lines specific for myelin basic protein or tetanus toxoid from multiple sclerosis patients and healthy individuals resist apoptosis induced by soluble recombinant CD95 ligand in vitro. In contrast, the same CD95 ligand effectively kills Jurkat T lymphoma and human malignant glioma cells. The resistance of the T cell lines is not due to a lack of CD95 expression at the cell surface and is not overcome by coexposure to CD95 ligand and inhibitors of RNA or protein synthesis. The expression level of BCL-2 is lower in Jurkat than in Ag-specific T cells. After exposure to soluble CD95 ligand, Jurkat T cells, but not Ag-specific T cells, exhibit loss of BCL-2 and BCL-X expression whereas BAX expression is not affected. Surprisingly, Ag-specific T cells are rather sensitive to CD95 ligand expressed at the cell surface of N2A neuroblastoma cells. Accessory molecules expressed by the CD95 ligand-expressing effector cell are dispensable for apoptosis since the T cells are equally sensitive to agonistic APO-1 Ab. Further studies are required to determine whether resistance to soluble CD95 ligand-mediated apoptosis is a possible escape mechanism for T cells from peripheral deletion that may have relevance for autoimmune disorders.

Antibodies, Monoclonal↗
PubMed1997

Lipoxygenase inhibitors block CD95 ligand-mediated apoptosis of human malignant glioma cells.

CD95 ligand is a cytotoxic cytokine that induces apoptosis. Here we report that CD95-mediated apoptosis of human malignant glioma cells is associated with arachidonic acid (AA) release. Inhibitors of phospholipase A2, phospholipase C or diacylglycerol lipase have minor effects on AA release and fail to modulate apoptosis. Formation of two AA metabolites generated during CD95-dependent apoptosis is attenuated by the lipoxygenase inhibitor, nordihydroguaretic acid (NDGA). NDGA also blocks CD95 ligand-induced apoptosis. This effect is independent of antioxidant properties of NDGA. Lipoxygenase may thus play a critical role in CD95 ligand-induced apoptosis of human malignant glioma cells.

Animals↗
PubMed1997

Control of repetitive lip and finger movements in Parkinson's disease: influence of external timing signals and simultaneous execution on motor performance.

This study addresses the question of whether external timing signals and/or simultaneous rhythmic movements of other limbs can alleviate sequencing motor deficits associated with Parkinson's disease (PD). Subjects performed rhythmic lip and finger movements simultaneously or in isolation. In addition, they had to self-pace their movements or match them to an external signal. Our results are summarized as follows: (1) Seven of 12 patients had adequate mean repetition rates; that is, they fulfilled the task requirements on a global scale. The remaining five patients had various degrees of hastened responses and were not fully able to synchronize their movements to an external pacing signal. (b) PD patients exhibited hypometria in their finger tapping, but not in their lip movements. Their movements were not abnormally slowed, but peak velocity was appropriately scaled, even to reduced movement amplitudes. (c) Mean repetition rates, stability of frequency response, and kinematics did not differ between conditions of external and internal stimulation within the PD group, but were different form the control group performance. (d) Kinematic measures were not improved during dual-task execution. PD patients were not able to maintain a 1:1 rhythm between effectors. The incidence of hastening increased during simultaneous motor execution. We conclude that the use of external pacing signals might aid movement initiation of PD patients, but does not improve their temporal or spatial coordination when generating repetitive movements. Simultaneous execution does not necessarily enhance motor performance, but might actually have detrimental effects in patients prone to hastening.

Aged↗
PubMed1997

Gait initiation in Parkinson's disease.

We studied the kinematic patterns of gait initiation in 31 patients with Parkinson's disease and in 20 age- and sex-matched normals by using an optoelectronic tracking system (ELITE). Position markers were attached to the skin overlying the ankle, knee, hip, elbow, shoulder, and zygomatic bone. Subjects were instructed to start walking immediately after an acoustic go signal. Gait initiation was defined as the phase between standing motionless and steady-state locomotion. This phase was subdivided into a movement preparation period (the time between go signal and movement onset) and a movement execution period (the time between movement onset and the end of the first stride). Onset and duration of ankle, knee, hip, trunk, and arm motion within the first stride were analyzed. Movement preparation time was significantly increased in Parkinson's disease (p = 0.01), whereas movement execution times were similar in both groups (p = 0.23). Initiation of ankle, knee, hip, arm, and trunk movements was delayed in patients as compared with healthy subjects, but the relative timing and the sequence of submovements was comparable in both groups, indicating that the overall pattern of submovements was preserved in the patients. Our data suggest that gait initiation deficits in Parkinson's disease cannot be explained by a disordered sequence of limb and trunk submovements. More likely, gait initiation problems originate from the basal ganglia's internal cueing deficit for movement sequences, delaying onset and slowing the execution of all subcomponents.

Adult↗
PubMed1997

Validity of long-term electromyography in the quantification of tremor.

We previously developed a method of tremor quantification using long-term electromyography registration of antagonistic forearm muscles that is reliable, sensitive, and specific for pathologic tremors. The present study demonstrates that tremor occurrence as measured by this method correlates well with clinical parameters of tremor in idiopathic Parkinson's disease (PD) and essential tremor (ET) (subscores of the Unified Parkinson's Disease Rating Scale for PD, tremor rating according to Bain et al. for ET). We conclude that the method is a valid and objective means of tremor quantification in PD and ET.

Activities of Daily Living↗
PubMed1997

Developmental and genetic regulation of programmed neuronal death.

Apoptotic neuronal death is a key mechanism that regulates the elimination of neuronal precursor cells during the development of the mammalian brain. The principal action of neurotrophins such as nerve growth factor is probably the suppression of the preexistent machinery of programmed cell death that is readily activated in neurons deprived of neurotrophins. Potassium-mediated neuronal depolarization prolongs neuronal survival in vitro and has become a major model of examining neuronal apoptosis. Apoptosis induced by potassium deprivation triggers a lethal cascade of events that includes specific RNA and protein synthesis, induction of interleukin 1-converting enzyme-like protease activity, and generation of free radicals. Neuronal susceptibility to apoptosis is also regulated by the expression of bcl-2 family proteins. Current research focuses on the significance of these findings for the premature death of adult neurons in human neurodegenerative diseases.

Adult↗
PubMed1997

The development of goal-directed reaching in infants. II. Learning to produce task-adequate patterns of joint torque.

Nine young infants were followed longitudinally from 4 to 15 months of age. They performed multi-joint reaching movements to a stationary target presented at shoulder height. Time-position data of the hand, shoulder, and elbow were collected using an optoelectronic measurement system. In addition, we recorded electromyographic activity (EMG) from arm extensors and flexors. This paper documents how control problems of proximal torque generation may account for the segmented hand paths seen during early reaching. Our analysis revealed the following results: first, muscular impulse (integral of torque) increased significantly between the ages of 20 (reaching onset) and 64 weeks. That is, as infants got older they produced higher levels of mean muscular flexor torque during reaching. Data were normalized by body weight and movement time, so differences are not explained by anthropometric changes or systematic variations in movement time. Second, while adults produced solely flexor muscle torque to accomplish the task, infants generated flexor and extensor muscle torque at shoulder and elbow throughout a reach. At reaching onset more than half of the trials revealed this latter kinetic profile. Its frequency declined systematically as infants got older. Third, we examined the pattern of muscle coordination in those trials that exhibited elbow extensor muscle torque. We found that during elbow extension coactivation of flexor and extensor muscles was the predominant pattern in 67% of the trials. This pattern was notably absent in comparable adult reaching movements. Fourth, fluctuations in force generation, as measured by the rate of change of total torque (NET) and muscular torque (MUS), were more frequent in early reaching (20-28 weeks) than in the older cohort (52-64 weeks), indicating that muscular torque production became increasingly smoother and task-efficient. Our data demonstrate that young infants have problems in generating smooth profiles of proximal joint torques. One possible reason for this imprecision in infant force control is their inexperience in predicting the magnitude and direction of external forces. That infants learned to consider external forces is documented by their increasing reliance on these forces when performing voluntary elbow extensions. The patterns of muscle coordination underlying active elbow extensions were basically the same as during the prereaching phase, indicating that the formation of functional synergies is based on a basal repertoire of innervation patterns already observable in very early, spontaneous movements.

Child Development↗
PubMed1997

[Multiple sclerosis. New therapeutic strategies in the experimental stage].

Extensive research in the field of multiple sclerosis (MS) has lead to a preliminary pathogenetic concept without solving the etiopathogenesis. According to animal experiments and human in vitro studies MS is a T cell-mediated autoimmune disease. Experimental therapeutical strategies are aiming at the inhibition of T cell activation, transmigration through the blood brain barrier and local inflammation and demyelination. Several substances are already being tested in clinical studies with magnetic resonance imaging as a tool to quantify inflammatory lesions and to shorten the study course. This review will give a summary about actual experimental therapies resulting from the current pathogenetic concept.

Animals↗
PubMed1997

[New developments in diagnosis and therapy of primary non-Hodgkin's lymphoma of the central nervous system].

Primary central nervous system lymphomas (PCNSLs) are increasing in frequency both in immunocompetent and immunodeficient individuals. The majority of PCNSLs are high grade B cell lymphomas. In AIDS patients most tumors contain EBV genome. PCNSLs usually present as intracerebral, often deep-seated lesions half of which are multilocular. Less frequent are diffuse periventricular, exclusively leptomeningeal, ocular or spinal spread. On imaging PCNSLs show as contrast-enhancing lesions with relatively little perifocal edema. CSF protein is usually elevated. Malignant cells are present in 20-30% of cases. Demonstration of a monoclonal B cell population by immunocytology or FACS analysis may also be diagnostic. Once PCNSL is suspected extensive systemic evaluation is not useful. Instead, (stereotactic) biopsy of brain lesion(s) should be performed. Prior to biopsy, corticosteroids should be withheld as they may obscure diagnosis. Symptomatic edema or increased intracranial pressure should therefore initially be treated with osmotherapeutics. All immunodeficient patients should receive empiric anti-toxoplasmosis therapy for about 14 days prior to biopsy. AIDS patients with PCNSL survive 3 to 5 months (median) after whole brain irradiation and usually do not benefit from chemotherapy. Immunocompetent patients have a median survival of 12 to 18 months after whole brain irradiation alone, but a median survival of 33 to 43 months after combined radiochemotherapy using cytostatic drugs which penetrate the blood-brain barrier. Based on these encouraging results current concepts aim to intensify chemotherapy and to reduce or delay radiotherapy in the treatment of immunocompetent patients.

Central Nervous System Neoplasms↗
PubMed1997

The development toward stereotypic arm kinematics during reaching in the first 3 years of life.

We recorded reaching movements from nine infants longitudinally from the onset of reaching (5th postnatal month) up to the age of 3 years. Here we analyze hand and proximal joint trajectories and examine the emerging temporal coordination between arm segments. The present investigation seeks (a) to determine when infants acquire consistent, adult-like patterns of multijoint coordination within that 3-year period, and (b) to relate their hand trajectory formation to underlying patterns of proximal joint motion (shoulder, elbow). Our results show: First, most kinematic parameters do not assume adult-like levels before the age of 2 years. At this time, 75% of the trials reveal a single peaked velocity profile of the hand. Between the 2nd and 3rd year of life, "improvements" of hand- or joint-related movement units are only marginal. Second, infant motor systems strive to obtain velocity patterns with as few force reversals as possible (uni- or bimodal) at all three limb segments. Third, the formation of a consistent interjoint synergy between shoulder and elbow motion is not achieved within the 1st year of life. Stable patterns of temporal coordination across arm segments begin to emerge at 12-15 months of age and continue to develop up to the 3rd year. In summary, the development toward adult forms of multijoint coordination in goal-directed reaching requires more time than previously assumed. Although infants reliably grasp for objects within their workspace 3-4 months after the onset of reaching, stereotypic kinematic motor patterns are not expressed before the 2nd year of life.

Aging↗
PubMed1997

Immunochemotherapy of malignant glioma: synergistic activity of CD95 ligand and chemotherapeutics.

Malignant glioma cells are susceptible to CD95(Fas/APO-)-mediated apoptosis triggered by agonistic antibody. Here we examined the proapoptotic effects of the natural CD95 ligand, a cytotoxic cytokine homologous to tumor necrosis factor, on malignant glioma cell lines LN-229, LN-308 and T98G. We assessed whether glioma cell killing is synergistically enhanced by cotreatment with CD95 ligand and chemotherapeutic agents, including doxorubicin, carmustine, vincristine, etoposide, teniposide, 5-fluorouracil and cytarabine. Synergy was examined at low concentrations of cytotoxic drugs and CD95 ligand with a defined effect level (IC15). Short-term-cytotoxicity assays showed prominent killing of the glioma cells by CD95 ligand but not by the drugs at relevant concentrations. CD95 ligand induced apoptosis in the acute toxicity paradigm was augmented by doxorubicin and vincristine. Growth-inhibition assays revealed prominent synergy between CD95 ligand and all drugs examined. The best synergy was obtained with CD95 ligand and doxorubicin, vincristine or teniposide. The strong synergistic antiproliferative effects were observed at much lower concentrations of CD95 ligand and cytotoxic drugs than the moderate synergistic acute cytotoxic effects. All cell lines examined express the Bcl-2 protein. LN-229 has partial wild-type p53 activity. T98G has mutant p53, LN-308 has a deleted p53 gene and lacks p53 protein expression. Thus, synergistic effects of CD95 ligand and cytotoxic drugs were observed in cell lines exhibiting two features thought to play a role in the chemoresistance of human malignant glioma cells: loss of wild-type p53 activity and acquisition of bcl-2 expression. Ectopic expression of murine bcl-2 conferred partial protection from CD95 ligand and drugs when administered alone but did not interfere with the mechanisms underlying the synergistic effects of CD95 ligand and chemotherapeutic drugs.

Antineoplastic Agents↗
PubMed1997

Clinical and genetic analysis of three German kindreds with autosomal dominant cerebellar ataxia type I linked to the SCA2 locus.

The detailed clinical, electrophysiological and imaging data of three German autosomal dominant cerebellar ataxia (ADCA) families are reported. Linkage to SCA2 was established using microsatellite markers D12S105, D12S1339(1328), D12S1304(1329) yielding a lod score exceeding +3.0 for the combined data. Analysis of the pedigree data provided evidence of anticipation as observed in other neurodegenerative disorders due to polyglutamine expansion encoded by a CAG repeat. This hypothesis was confirmed by the detection of the SCA2-specific pathological protein using the 1C2 monoclonal antibody which selectively recognizes large polyglutamine expansions and the characterization of a CAG expansion in the patients. Clinically, the families were characterized by progressive ataxia of stance, gait and limbs. Saccade velocity was markedly reduced in SCA2. Further oculomotor findings were gaze palsy, impaired smooth pursuit and reduced optokinetic reflex. Dementia and pyramidal tract signs were rather rare, while peripheral involvement (reduced or absent ankle reflexes, fasciculation-like movements, amyotrophy) was a prominent feature. Electrophysiological investigations provided evidence of sensory neuropathy of the axonal type and degeneration of the posterior columns. Imaging studies demonstrated severe shrinkage of brain-stem structures even in early stages of the disease.

Adult↗
PubMed1997

Comparison of psychophysical and evoked potential methods in the detection of visual deficits in multiple sclerosis.

We compared the diagnostic sensitivity of traditional visual tests such as the Snellen-test and pattern reversal VEPs with psychophysical and electrophysiological tests involving motion processing and psychophysical tests of contrast processing in detecting visual deficits in a group of MS patients. A total of 30 patients with a definite diagnosis of MS and 22 age-matched controls selected from a pool of healthy volunteers participated in this study. Visual evoked potentials elicited by reversing checkerboards and moving random dot patterns (motion-onset VEPs) were recorded. The recognition of motion-defined forms (motion-defined letter test, MDL-test) and of contrast reduced optotypes was measured psychophysically. Of 30 patients, 29 showed deficits in at least one of the tests applied. The highest detection rate was obtained for a simple psychophysical test, the MDL-test, which revealed abnormalities in 80% of the patients. This is about 12% more than pattern VEPs could detect. Conversely, abnormalities in motion-onset VEPs were found in only 16% of the patients. Our results show that by adding a simple psychophysical test of form-from-motion analysis our capability to demonstrate an involvement of the visual system in MS patients may be promoted considerably.

Adult↗
PubMed1997

Language processing in aphasia: changes in lateralization patterns during recovery reflect cerebral plasticity in adults.

During single word processing the negative cortical DC-potential reveals a left frontal preponderance in normal right-handers as well as in patients with a history of transient aphasia. Lateralization of DC-negativity therefore provides a reliable and robust method for the assessment of language dominance. In 11 stroke patients with permanent aphasia this physiological pattern changed to bilateral activation reflecting an additional right-hemispheric involvement in compensatory mechanisms in aphasia. Along with complete clinical recovery the classical aphasic syndromes revealed specific differences in changes of their lateralization patterns. In Broca's aphasia the initial right-hemispheric preponderance changed to a left frontal lateralization while in Wernicke's aphasia a presumably permanent shift towards the right hemisphere occurred. Differences in lateralization patterns might reflect different mechanisms of recovery such as the initial disinhibition of homologous areas contralaterally and subsequent collateral sprouting and synaptic modulation. The assessment of changes in lateralization of the cortical DC-potential during language tasks in a non-invasive, safe method with excellent time resolution that might provide further insights in the neural basis of recovery from aphasia.

Action Potentials↗