Trinucleotide repeats and hereditary ataxias.
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Ataxia↗
Biomedical subjects
J Dichgans
Publications and source records attributed to J Dichgans.
A new look at the role of p53 in leukemia cell sensitivity to chemotherapy.
A gene encoding the p53 val135 mutant, which assumes mutant conformation at 38.5 degrees C and wild-type conformation at 32.5 degrees C, was introduced into p53-deficient K562 myeloid leukemia cells. Forced expression of wild-type, but not mutant, p53 resulted in growth arrest, accumulation of p21 and Bax proteins, and delayed cell death. Wild-type p53 enhanced the cytotoxic effects of some drugs and attenuated those of others. Compared with wild-type p53, mutant p53 induced much stronger sensitization to drug cytotoxicity. This occurred in the absence of effects on cell cycle progression or activation of several p53 target genes. Although both mutant and wild-type p53 induced changes of immunophenotype, no specific pattern of differentiation was associated with enhanced chemosensitivity. Thus, (1) induction of growth arrest and activation of p53 target genes such as p21 and bax are linked to the wild-type conformation of p53; (2) p53 induces immunophenotypic changes of myeloid leukemia cells suggestive of multidirectional differentiation in a conformation-dependent manner; and (3) (so-called) mutant p53 induces chemosensitization in the absence of effects on cell cycle progression, activation of bax, p21, gadd45 and mdm-2, or a specific pattern of differentiation; and (4) chemosensitization mediated by wild-type p53 may be masked by transcription-dependent induction of growth arrest.
Animals↗
Autosomal dominant cerebellar ataxia type I. Nerve conduction and evoked potential studies in families with SCA1, SCA2 and SCA3.
Forty-one patients suffering from autosomal dominant cerebellar ataxia type I (ADCA-I) were subjected to a genotype-phenotype correlation analysis using molecular genetic assignment to the spinocerebellar ataxia type 1, 2 or 3 (SCA1, -2 or -3) genetic locus, clinical examination and nerve conduction as well as evoked potential studies. Pyramidal tract signs, pale discs, and dysphagia were more frequent in SCA1 compared with SCA2 and SCA3 patients, while double vision occurred less frequently. Visual evoked potentials and motor evoked potentials following transcranial magnetic stimulation were abnormal in almost all SCA1 patients, but only in a minority of SCA2 and SCA3 patients. In contrast, somatosensory evoked potentials were delayed or absent in the majority of patients with no significant differences between the mutations. Abnormalities of brainstem auditory evoked potentials were found in about half of the patients irrespective of the underlying mutation. In addition, reduced sensory nerve action potentials, suggesting sensory axonal neuropathy were found in all three mutations. These findings provide electrophysiological evidence that pyramidal and visual pathways are differentially affected in SCA1, SCA2 and SCA3 patients.
Action Potentials↗
Ocular myasthenia gravis: response to long-term immunosuppressive treatment.
OBJECTIVE: Ocular myasthenia gravis is a subtype of myasthenia gravis that causes relatively mild disability, but may convert into severe generalised muscle weakness. A universal management plan for ocular myasthenia gravis has not been established. This study was performed to determine the outcome of ocular myasthenia gravis with the currently available therapeutic options. METHODS: Retrospective analysis of 78 patients with ocular myasthenia gravis with a mean disease duration of 8.3 (range 0.5-58.3) years. RESULTS: In 54 patients (69%) symptoms and signs remained confined to the extraocular muscles during the observation period. The remaining 24 patients (31%) developed symptoms of generalised myasthenia gravis; 50% of them within two years, 75% within four years after onset. A somewhat reduced risk of generalisation was found in those with mild symptoms, normal repetitive nerve stimulation test, and low or absent antiacetylcholine receptor (AChR) antibodies at the time of diagnosis. Patients receiving immunosuppressive treatment (corticosteroids and/or azathioprine) rarely developed generalised myasthenia gravis (six of 50, 12%). Those without such treatment, usually due to uncertain diagnosis and late referral, converted into generalised myasthenia gravis significantly more often (18 of 28, 64%). CONCLUSIONS: The prognosis of ocular myasthenia gravis is good. A conventional scheme with short-term corticosteroids and long-term azathioprine seems adequate to achieve remission in most patients. The proportion of patients developing generalised myasthenia gravis was smaller in this population compared with previously published groups (usually 50%-70%). Early immunosuppressive treatment is at least partially responsible for this finding. Thymectomy (performed here in 12 patients with an abnormal chest CT) also correlated with a good outcome, but had no apparent advantage over medical treatment alone.
Adolescent↗
Saccade velocity in idiopathic and autosomal dominant cerebellar ataxia.
Slow saccades are often found in degenerative ataxia. Experimental studies have shown that horizontal saccades are generated in the paramedian pontine reticular formation and that lesions in this area produce slow saccades. Based on these findings, saccade slowing should be a frequent feature of olivopontocerebellar atrophy, a type of cerebellar degeneration with prominent involvement of the pons. To test this hypothesis, saccade velocity was measured in 31 patients with autosomal dominant cerebellar ataxia (ADCA) and 17 patients with idiopathic cerebellar ataxia (IDCA). Saccade velocity was reduced in most patients with ADCA whereas it was normal in IDCA although olivopontocerebellar atrophy occurred in both groups. Saccade velocities correlated with pontine size in ADCA but not in IDCA. The data disprove the hypothesis that saccadic slowing is a clinical hallmark of olivopontocerebellar atrophy. Instead, only patients with ADCA and morphological features of olivopontocerebellar atrophy have slow saccades.
Adult↗
Gluteal compartment syndrome due to rhabdomyolysis after heroin abuse.
We report a 30-year-old man who developed painful swelling of his right leg and complete sciatic nerve palsy after an i.v. injection of heroin. Excessive elevation of serum creatine phosphokinase indicated the presence of rhabdomyolysis. Fasciotomy of the gluteus maximus led to rapid and complete recovery from sciatic nerve palsy. Nontraumatic rhabdomyolysis may cause a gluteal compartment syndrome that requires immediate fasciotomy.
Adult↗
Color vision tests for early detection of antiepileptic drug toxicity.
A previous suggestion that antiepileptic drugs may induce color vision deficiencies prompted us to examine whether color vision deficiencies may occur at lower drug serum concentrations than those associated with symptoms of neurotoxicity. Eighty patients presenting with epilepsy received monotherapies of valproic acid, phenytoin, or carbamazepine; 18 patients did not receive antiepileptic drug therapy. Color vision was tested by the Farnsworth-Munsell 100-hue test, spectral sensitivity, and the newly developed tritan screening plates. Patients treated with phenytoin or carbamazepine developed blue-yellow color vision deficiencies. In contrast, patients exposed to valproic acid or receiving no drug treatment showed normal color vision. There was a significant correlation (p < 0.0001) between signs of neurotoxicity induced by phenytoin or carbamazepine and blue-yellow color vision deficiencies. In contrast, we found no correlation between these signs of neurotoxicity and the drug serum concentrations (p = 0.0637). Color vision testing in epileptic patients treated with phenytoin or carbamazepine appears to be a sensitive method for early detection and monitoring of clinical neurotoxicity.
Adolescent↗
Chemotherapy of human malignant glioma: prevention of efficacy by dexamethasone?
Steroids are commonly administered for the control of edema, mass effect, and side effects from therapy to patients with malignant glioma who are receiving radiotherapy and chemotherapy. Here, we report that therapeutic concentrations of dexamethasone (DEX) attenuate cytotoxicity and growth inhibition of human malignant glioma cells induced by exposure to several chemotherapeutics, including ACNU, VM-26, vincristine, cytarabine, methotrexate, and adriamycin. DEX-mediated cytoprotection is not linked to DEX effects on glioma cell proliferation. However, the cytoprotective effects of DEX appeared to be more prominent in cell lines with wild-type p53 status (n = 2) than in p53 mutant cell lines (n = 3). Further, DEX-mediated rescue from chemotherapy does not directly involve Bcl-2 family proteins since DEX failed to change the expression of Bcl-2 or Bax proteins and since bcl-2 gene transfer-mediated cytoprotection was not redundant with the effects of DEX. DEX thus appears to control a common, bcl-2-independent death pathway in glioma cells that is not limited to specific drug actions. Chemotherapy is usually given as an elective, adjuvant treatment to glioma patients in stable condition who can tolerate steroid withdrawal. To maximize therapeutic efficacy, steroids should be withdrawn from glioma patients prior to chemotherapy.
Antibiotics, Antineoplastic↗
The role of mitochondrial dysfunction and neuronal nitric oxide in animal models of neurodegenerative diseases.
Excitotoxicity, mitochondrial dysfunction and free radical induced oxidative damage have been implicated in the pathogenesis of several different neurodegenerative diseases, such as amyotrophic lateral sclerosis, Parkinson's disease (PD), Alzheimer's disease (AD), and Huntington's disease. Much of the interest in the association of neurodegeneration with mitochondrial dysfunction and oxidative damage emerged from animal studies using mitochondrial toxins. Within mitochondria 1-methyl-4-phenylpyridinium (MPP+), the active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), acts to inhibit NADH-coenzyme Q reductase (complex I) of the electron transport chain. MPTP produces Parkinsonism in humans, primates, and mice. Similarly, lesions produced by the reversible inhibitor of succinate dehydrogenase (complex II), malonate, and the irreversible inhibitor, 3-nitropropionic acid (3-NP), closely resemble the histologic, neurochemical and clinical features of HD in both rats and non-human primates. The interruption of oxidative phosphorylation results in decreased levels of ATP. A consequence is partial neuronal depolarization and secondary activation of voltage-dependent NMDA receptors, which may result in excitotoxic neuronal cell death (secondary excitotoxicity). The increase in intracellular Ca2+ concentration leads to an activation of Ca2+ dependent enzymes, including the constitutive neuronal nitric oxide synthase (cnNOS) which produces NO.. NO. may react with the superoxide anion to from peroxynitrite. We show that systemic administration of 7-nitroindazole (7-NI), a relatively specific inhibitor of cnNOS in vivo. attenuates lesions produced by striatal malonate injections or systemic treatment with 3-NP or MPTP. Furthermore 7-NI attenuated increases in lactate production and hydroxyl radical and 3-nitrotyrosine generation in vivo, which may be a consequence of peroxynitrite formation. Our results suggest that neuronal nitric oxide synthase inhibitors may be useful in the treatment of neurologic diseases in which excitotoxic mechanisms play a role.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
Three-dimensional human VOR in acute vestibular lesions.
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Adult↗
Acceleration deficit in patients with cerebellar lesions. A study of kinematic and EMG-parameters in fast wrist movements.
Slowness of goal-directed movements is a frequent symptom following cerebellar lesions. So far it has not been demonstrated whether this slowness represents compensation for impaired braking which is a feature of cerebellar dysfunction with the consequence of hypermetria, or whether it is an independent part of cerebellar movement disorder. To resolve this question we tested 18 cerebellar patients in a paradigm where they not only had to perform fast goal-directed wrist flexion movements (amplitudes 5 degrees and 30 degrees) but also wrist flexion movements as fast and large as possible without particular target. In normals antagonist activity is minimal in large movements without target. Although subjects were clinically only mildly affected they regularly showed a 'slowness of movement' resulting from a reduction of peak acceleration. This in turn was due to the reduced generation of agonist activity. Peak velocity was not significantly decreased because the acceleration phase was adequately prolonged. Since these changes were most pronounced in the 'fast' movements without target the compensation hypothesis should be discarded. The reduction of acceleration must at least partially be due to a genuine cerebellar deficiency in the fast generation of agonist activity.
Adolescent↗
Otolith-semicircular canal interaction during postrotatory nystagmus in humans.
The otolith-semicircular canal interaction during postrotatory nystagmus was studied in ten normal human subjects by applying fast, short-lasting, passive head and body tilts (15, 30, 45, or 90 degrees in the roll or pitch plane) 2 s after sudden stop from a constant-velocity rotation (100 degrees/s) about the earth-vertical axis in yaw. Eye movements were measured with three-dimensional magnetic search coils. Following the head tilt, activity in the semicircular canal primary afferents continues to reflect the postrotatory angular velocity vector in head-centered coordinates, whereas otolith primary afferents signal a different orientation of the head relative to gravity. Despite the change in head orientation relative to gravity, postrotatory eye velocity decayed closely along the axis of semicircular canal stimulation (horizontal in head coordinates) for large head tilts (90 degrees) and also for small head tilts (15-45 degrees) for reorientations in the pitch plane. Only for small head tilts (15-45 degrees) in the roll plane was there a reorientation of the eye rotation axis toward the gravitational vector. This reorientation was approximately compensatory for 15 degrees head tilts. For 30 degrees and 45 degrees head tilts the eye rotation axis tilted toward the gravitational vector by about the same amount as for 15 degrees head tilts. These results suggest that, with the exception of small head tilts in the roll plane, there was no compelling data showing a relationship between the eye rotation axis and head tilt and that postrotatory nystagmus is largely organized in head-centered rather than gravity-centered coordinates in humans. This indicates a rudimentary, nonlinear, and direction-specific interaction of semicircular canal and otolith signals in the central vestibular system in humans.
Adult↗
Ocular exploration of space as a function of neck proprioceptive and vestibular input--observations in normal subjects and patients with spatial neglect after parietal lesions.
We recently argued that the specific compensation of spatial neglect by manipulating neck proprioceptive and vestibular input is due to a central "correction" of the disturbed neural transformation process converting the afferent input coordinates from the peripheral sensory organs into a central representation of egocentric space. Both types of stimulation were proposed to induce a reorientation of the deviated or distorted egocentric spatial reference frame. The aim of the present study was to observe this process of reorientation under a condition in which no visual stimulus can attract the subject's attention and thus influence exploration behaviour from outside. We recorded eye movements of normal subjects and of three patients with spatial neglect after right parietal lesions while searching for a non-existent target in complete darkness. It was assumed that the area of the outer space that subjects spontaneously explore under this condition is a direct function of the subject's representation of egocentric space. Ocular space exploration was biased and confined almost entirely to the right side of the midsagittal plane in patients with neglect. This spatial distribution of exploratory eye movements changed remarkably with left-sided neck muscle vibration as well as with left-sided vestibular stimulation using ice water calorics. The spatial area of exploration was significantly enlarged to the contralesional side and the exploration maximum shifted in the same direction. Whereas with both types of stimulation space exploration of patients with neglect was similar to that of normal subjects when not being stimulated, neck proprioceptive and vestibular stimulation in normal subjects induced a quasi neglect-like exploration pattern, i.e. a bias to one side of the objective midsagittal plane. If ocular space exploration was, however, related to the subjectively perceived position of the midsagittal plane in space, eye movements were symmetrically distributed and carried out to both sides of subjective "straight ahead" in all experimental conditions, in normal subjects as well as in patients with neglect. The present results support the above hypothesis and indicate that neck proprioceptive as well as vestibular input directly contribute to the computation of the subject's central representation of egocentric space used for localizing body orientation and for guiding motor behaviour in space.
Adult↗
[Neurologic side-effects of pharmacologic corticoid therapy].
Many side effects of steroid treatment have been reported. Even experienced neurologists may not know all important side effects to the nervous system. Autonomic nervous system dysfunction, psychosis and myopathy are more frequently encountered than dependency, reversible dementia, brain atrophy and benign intracranial hypertension. This review describes symptomatology, pathogenesis and treatment of these steroid-induced side effects.
Adrenal Cortex Hormones↗
Disintegration and reorganization of cortical motor processing in two patients with cerebellar stroke.
Cerebello-cerebral interaction plays a fundamental role in movement processing. Extensively studied in monkeys, cerebello-thalamo-cerebral information processing is less clear in humans. Taking advantage of the tight linkage between cerebellum and cerebral motor cortex, the objective of this experiment was to gain information on cerebellar function, dysfunction and recovery by analyzing movement-related cortical potentials (MRCPs). MRCPs were recorded prior to voluntary repetitive finger movements from two cerebellar stroke patients, in the acute phase of cerebellar stroke and after clinical recovery. Ten normal subjects served as controls. The main result was a significant depression of late MRCP components over the contralateral motor cortex when patients performed index finger movements of the affected side in the acute phase, and improvement of depressed components after clinical recovery, 8-10 months later. Topographic maps of late MRCP components showed diffusely enlarged potential fields with ataxic movements in the acute phase, and re-focused fields on follow-up. We conclude that (1) late MRCP components are particularly sensitive to cerebellar input in humans and can reflect different functional states of the cerebellum, (2) disturbance of motor cortex function after cerebellar stroke (diaschisis) can occur as a temporary phenomenon that reverses with good clinical recovery.
Adult↗
P3 and contingent negative variation in Parkinson's disease.
Patients with idiopathic Parkinson's syndrome, most of them in early stages of the disease, and matched healthy controls participated in a continuous performance task while their EEGs were recorded from 15 electrodes. During preparation of movements, a contingent negative variation (CNV) maximal at central and posterior sites was visible. This CNV was reduced in the patient population. A large P3-like positive deflection occurred after go and no-go stimuli that called for execution (go) or suppression (no-go) of a button press. Compared to healthy controls, the positive wave in Parkinson patients was significantly reduced after go stimuli and maximally attenuated when no-go stimuli had indicated to suppress the motor response. In contrast, P3 amplitudes after irrelevant "ignore' stimuli was not significantly reduced in the patients. These results are interpreted in the framework of a model of striatal function postulating (i) that populations of cortical and striatal neurons form distributed functional units (Hebbian cell assemblies), and (ii) that mutual inhibition between such cortico-striatal cell assemblies is mediated by the neostriatum, the forebrain structure primarily affected in Parkinson's disease.
Behavior↗
Wrist tremor: investigation of agonist-antagonist interaction by means of long-term EMG recording and cross-spectral analysis.
We have developed a method to observe and quantify the phasic relationship between the burst patterns of antagonistic muscles in any roughly periodic movement, such as tremor, for up to 24 h. This paper describes our approach, in which long-term EMG recordings are evaluated by a procedure based on cross-spectral analysis. The method is then illustrated by data from 6 patients with essential tremor. Our data confirm earlier observations that a particular patient may show different burst patterns at different times. However, as opposed to tremor analysis based on short-term recording, our method allows quantitative statements on the relative frequency of the burst patterns, as they occur under everyday conditions. In addition, our data suggest that in ET (a) alternating tremor activity in one hand may occur simultaneously with synchronous activity in the other hand; (b) along with the classical alternating and co-contracting patterns there may be significant 'non-classical' activity, that cannot be called alternating or synchronous.
Aged↗
Vestibular neuritis spares the inferior division of the vestibular nerve.
Acute unilateral vestibulopathy, or vestibular neuritis, is the second most common cause of vertigo. To quantify the involvement of the different semicircular canal (SCC) afferents in this disease, we studied the three-dimensional (3D) properties of the vestibuloocular reflex (VOR) in 16 patients 3-10 days after onset of symptoms. Using 3D magnetic search coil eye movement recordings, we measured the speed and axis of eye rotation during spontaneous nystagmus and during rotation in the planes of the different SCCs. In all patients, spontaneous nystagmus axes clustered between the direction expected with involvement of just one horizontal SCC and the direction expected with combined involvement of the horizontal and anterior SCC on one side. Likewise, dynamic asymmetries were found only during rotations about axes which stimulated the ipsilesional horizontal or ipsilesional anterior SCCs. No asymmetry was found when the ipsilesional posterior SCC was stimulated. Thus, both measurements suggest that vestibular neuritis is a partial and not a complete unilateral vestibular lesion and that this partial lesion affects the superior division of the vestibular nerve which includes the afferents from the horizontal and anterior SCCs.
Adult↗