Biomedical subjects

R Dengler

Publications and source records attributed to R Dengler.

At least 19 recordsLinked to original sources

PubMed2006

Temporospatial coupling of networked synaptic activation of AMPA-type glutamate receptor channels and calcium transients in cultured motoneurons.

AMPA-type glutamate receptor (GluR) channels provide fast excitatory synaptic transmission in the CNS, but mediate also cytotoxic insults. It could be shown that AMPA-type GluR channel-mediated chronic excitotoxicity leads to an increased intracellular calcium concentration and plays an important role in neurodegenerative diseases like for example amyotrophic lateral sclerosis (ALS). As calcium is an important mediator of various processes in the cell and calcium signals have to be very precise in the temporospatial resolution, excessive intracellular calcium increases can seriously impair cell function. It is still unclear if AMPA-type receptors can directly interact with the intracellular calcium homeostasis or if other mechanisms are involved in this process. The objective of this study was therefore to investigate the calcium homeostasis in rat motoneurons under physiological stimulation of AMPA-type GluR channels using calcium imaging techniques and patch-clamp recordings simultaneously. It was found that spontaneous excitatory postsynaptic currents of cultured motoneurons did not elicit significant intracellular calcium transients. Large intracellular calcium transients occurred only when preceding fast sodium currents were observed. Pharmacological experiments showed that activation of AMPA-type GluR channels during synaptic transmission has a great functional impact on the calcium homeostasis in motoneurons as all kinds of activity was completely blocked by application of the selective kainate- and AMPA-type GluR channel blocker 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). Furthermore we suggest from our experiments that calcium transients of several hundred milliseconds' duration result from release of calcium from the endoplasmic reticulum via activation of ryanodine receptors (calcium-induced calcium release, CICR). Our results help to understand the regulatory function of AMPA-type GluR channels in the intracellular calcium homeostasis which is known to be disturbed in neurodegenerative diseases.

Amyotrophic Lateral Sclerosis↗

PubMed2006

High-affinity blockade of voltage-operated skeletal muscle sodium channels by 2,6-dimethyl-4-chlorophenol.

BACKGROUND AND OBJECTIVE: The aromatic alcohol most closely resembling the aromatic tail of lidocaine is 2,6-dimethylphenol. This agent is as potent as lidocaine in blocking voltage-operated sodium channels. The aim of this study was to show the effect of halogenation in the para-position on the potency of this compound to block voltage-operated sodium channels. METHODS: Insertion of the halogen chloride into the para-position of the molecule 2,6-dimethylphenol yielded 2,6-dimethyl-4-chlorophenol. Block of sodium currents by this compound was studied using heterologously expressed voltage-operated rat neuronal (rat IIa) sodium channels. RESULTS: 2,6-dimethyl-4-chlorophenol reversibly suppressed depolarization-induced whole-cell sodium inward currents. The ECR50 for block of resting channels at a hyperpolarized holding potential (-150 mV) was 127 micromol, the Hill coefficient nH 1.7. Membrane depolarization inducing either fast or slow-inactivation strongly increased the blocking potency. This is an important feature of a local-anaesthetic-like action. The estimated half-maximum effect concentration for the fast-inactivated channel state ECI50 was 28 micromol, the Hill coefficient nH 3.8. When 20-30% of channels were slow-inactivated using long (2.5 s) prepulses, followed by a 10 ms repolarization period to allow recovery from fast inactivation, the IC50 at -100 mV holding potential was reduced to 53 micromol. CONCLUSION: These results, which show that 2,6-dimethyl-4-chlorophenol blocks voltage-operated sodium channels in a lidocaine-like manner while having a several fold higher potency than the non-halogenated parent compound, highlight a potentially meaningful principle of increasing the sodium channel blocking potency of phenol derivatives.

Algorithms↗

PubMed2006

[Sacral nerve root cysts--a rare cause of bladder dysfunction. Case report and review of the literature].

INTRODUCTION: Asymptomatic cysts of the sacral nerve roots display a prevalence of 5 % and are occasionally demonstrated by MRI of the spine. Depending on their size and localization, arachnoid cysts may cause sacral or perineal pain, radicular sensomotory symptoms and neurogenic bladder and bowel dysfunction by compression of the nerve roots. CASE REPORT: We report on a case of a recently developed neurogenic bladder dysfunction. MRI of the spine demonstrated two large, liquor-filled cysts of 2.5 and 3 cm diameter, bilaterally localized at the nerve roots S2/3. Neurological and urological examinations confirmed the diagnosis of symptomatic nerve root cysts at the level S2/3, resulting in detrusor areflexia. A microsurgical excision of the cysts ameliorated the patient's pain symptoms. However, the detrusor areflexia did not improve. CONCLUSIONS: Tarlov cysts are predominantly regarded an asymptomatic incidental feature of CT and MRI scans of the spine. The case of our patient, as well as the so far published reports indicate, however, that a Tarlov cyst may cause a variety of neurological and urological symptoms. Nerve root cysts should be seriously considered and not excluded at an early stage, especially when coincident with persistent neurological and urological symptoms.

Arachnoid Cysts↗

PubMed2005

Motor cortex excitability during unilateral muscle activity.

The effect of unilateral tonic muscle activity with and without co-activation of the antagonists on motor cortex excitability has been studied. Motor evoked potentials (MEPs) were recorded from the first dorsal interosseus muscles of both hands in response to transcranial magnetic stimulation (TMS) during relax, isometric index finger abduction and antagonistic co-activation. The intracortical inhibition (ICI) and intracortical facilitation (ICF) were investigated by paired-pulse TMS with interstimulus intervals of 3 and 13 ms. The unilateral tonic activation of the right hand facilitated contralateral and ipsilateral responses (cMEP and iMEP) recorded from both hands with an exception of iMEPs recorded from the left hand. During paired-pulse TMS ICI for cMEPs was not influenced by the unilateral tonic activity in both hands, while ICF was suppressed when MEPs were recorded from the active right hand. The effect of unilateral tonic activity on iMEP in response to paired-pulse TMS was essentially different: generally, ICI was greater for iMEPs and ICF was completely abolished with an exception of iMEPs recorded from the left hand during right finger isometric abduction when a strong ICF was evident. The decreased ICF and/or increased ICI are assumed to reflect mechanisms underlying the co-activation of antagonists.

Action Potentials↗

PubMed2005

The cellular mRNA expression of GABA and glutamate receptors in spinal motor neurons of SOD1 mice.

ALS is a fatal neurodegenerative disorder characterized by a selective loss of upper motor neurons in the motor cortex and lower motor neurons in the brain stem and spinal cord. About 10% of ALS cases are familial, in 10-20% of these, mutations in the gene coding for superoxide dismutase 1 (SOD1) can be detected. Overexpression of mutated SOD1 in mice created animal models which clinically resemble ALS. Abnormalities in glutamatergic and GABAergic neurotransmission presumably contribute to the selective motor neuron damage in ALS. By in situ hybridization histochemistry (ISH), we investigated the spinal mRNA expression of the GABAA and AMPA type glutamate receptor subunits at different disease stages on spinal cord sections of mutant SOD1 mice and control animals overexpressing wild-type SOD1 aged 40, 80, 120 days and at disease end-stage, i.e. around 140 days) (n=5, respectively). We detected a slight but statistically significant decrease of the AMPA receptor subunits GluR3 and GluR4 only in end stage disease animals.

Aging↗

PubMed2005

EFNS task force on management of amyotrophic lateral sclerosis: guidelines for diagnosing and clinical care of patients and relatives.

Despite being one of the most devastating diseases known, there is little evidence for diagnosing and managing patients with amyotrophic lateral sclerosis (ALS). Although specific therapy is lacking, correct early diagnosis and introduction of symptomatic and specific therapy can have a profound influence on the care and quality of life of the patient and may increase survival time. This document addresses the optimal clinical approach to ALS. The final literature search was performed in the spring of 2005. Consensus recommendations are given graded according to the EFNS guidance regulations. Where there was lack of evidence but consensus was clear we have stated our opinion as good practice points. People affected with possible ALS should be examined as soon as possible by an experienced neurologist. Early diagnosis should be pursued and a number of investigations should be performed with high priority. The patient should be informed of the diagnosis by a consultant with a good knowledge of the patient and the disease. Following diagnosis, the patient and relatives should receive regular support from a multidisciplinary care team. Medication with riluzole should be initiated as early as possible. PEG is associated with improved nutrition and should be inserted early. The operation is hazardous in patients with vital capacity < 50%. Non-invasive positive pressure ventilation improves survival and quality of life but is underused. Maintaining the patients ability to communicate is essential. During the entire course of the disease, every effort should be made to maintain patient autonomy. Advance directives for palliative end of life care are important and should be fully discussed early with the patient and relatives respecting the patients social and cultural background.

Amyotrophic Lateral Sclerosis↗

PubMed2004

High dose vitamin E therapy in amyotrophic lateral sclerosis as add-on therapy to riluzole: results of a placebo-controlled double-blind study.

UNLABELLED: Increasing evidence has suggested that oxidative stress may be involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). The antioxidant vitamin E (alpha-tocopherol) has been shown to slow down the onset and progression of the paralysis in transgenic mice expressing a mutation in the superoxide dismutase gene found in certain forms of familial ALS. The current study, a double blind, placebo-controlled, randomised, stratified, parallel-group clinical trial, was designed to determine whether vitamin E (5000 mg per day) may be efficacious in slowing down disease progression when added to riluzole. METHODS: 160 patients in 6 German centres with either probable or definite ALS (according to the El Escorial Criteria) and a disease duration of less than 5 years, treated with riluzole, were included in this study and were randomly assigned to receive either alpha-tocopherol (5000 mg per day) or placebo for 18 months. The Primary outcome measure was survival, calculating time to death, tracheostomy or permanent assisted ventilation, according to the WFN-Criteria of clinical trials. Secondary outcome measures were the rate of deterioration of function assessed by the modified Norris limb and bulbar scales, manual muscle testing (BMRC), spasticity scale, ventilatory function and the Sickness Impact Profile (SIP ALS/19). Patients were assessed at entry and every 4 months thereafter during the study period until month 16 and at a final visit at month 18. Vitamin E samples were taken for compliance check and Quality Control of the trial. For Safety, a physical examination was performed at baseline and then every visit until the treatment discontinuation at month 18. Height and weight were recorded at baseline and weight alone at the follow-up visits. A neurological examination as well as vital signs (heart rate and blood pressure), an ECG and VEP's were recorded at each visit. Furthermore, spontaneously reported adverse experiences and serious adverse events were documented and standard laboratory tests including liver function tests performed. For Statistical Analysis, the population to be considered for the primary outcome measure was an "intent-to-treat" (ITT) population which included all randomised patients who had received at least one treatment dose (n = 160 patients). For the secondary outcome measures, a two way analysis of variance was performed on a patient population that included all randomised patients who had at least one assessment after inclusion. RESULTS: Concerning the primary endpoint, no significant difference between placebo and treatment group could be detected either with the stratified Logrank or the Wilcoxon test. The functional assessments showed a marginal trend in favour of vitamin E, without reaching significance. CONCLUSION: Neither the primary nor the secondary outcome measures could determine whether a megadose of vitamin E is efficacious in slowing disease progression in ALS as an add-on therapy to riluzol. Larger or longer studies might be needed. However, administration of this megadose does not seem to have any significant side effects in this patient population.

Amyotrophic Lateral Sclerosis↗

PubMed2004

Linewidth and tuning characteristics of terahertz quantum cascade lasers.

We have measured the spectral linewidths of three continuous-wave quantum cascade lasers operating at terahertz frequencies by heterodyning the free-running quantum cascade laser with two far-infrared gas lasers. Beat notes are detected with a GaAs diode mixer and a microwave spectrum analyzer, permitting very precise frequency measurements and giving instantaneous linewidths of less than -30 kHz. Characteristics are also reported for frequency tuning as the injection current is varied.

Journal Article↗

PubMed2004

Familial ALS in Germany: origin of the R115G SOD1 mutation by a founder effect.

Mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1) account for approximately 20% of patients with familial amyotrophic lateral sclerosis (FALS). In this study, sequence analysis of exons 1-5 of SOD1 in a large German cohort with FALS was performed. Among 75 affected patients, who were not obviously related probands with a positive family history, nine had missense mutations in SOD1. Four of the nine probands carry the same R115G mutation in exon 4 of the SOD1 gene. Genotyping with markers from the SOD1 locus revealed a common haplotype and shared allelic characteristics in these patients. These findings suggest that the R115G mutation in the German population originates from a common founder.

Adult↗

PubMed2003

Kinetic analysis of recombinant mammalian alpha(1) and alpha(1)beta glycine receptor channels.

To analyze the influence of the beta-subunit on the kinetic properties of GlyR channel currents, alpha(1)-subunits and alpha(1)beta-subunits were transiently expressed in HEK 293 cells. A piezo dimorph was used for fast application of glycine to outside-out patches. The rise time of activation was dose dependent for both receptors and decreased with increasing glycine concentrations. Subunit composition had no effect on the time course of activation. Coexpression of alpha(1)- and beta-subunits resulted in a significantly lower EC(50) and a reduced slope of the dose-response curve of glycine compared with expression of alpha(1)-subunits alone. For both receptor subtypes, the time course of desensitization was concentration dependent. Desensitization was best fitted with a single time constant at 10-30 micro M, with two at 0.1 mM, and at saturating concentrations (0.3-3 mM) with three time constants. Desensitization of homomeric alpha(1)-receptor channels was significantly slower than that of alpha(1)beta-receptor channels. The time course of current decay after the end of glycine pulses was tested at different pulse durations of 1 mM glycine. It was best fitted with two time constants for both alpha(1) and alpha(1)beta GlyR channels, and increased significantly with increasing pulse duration.

Animals↗

PubMed2003

IgG from patients with Guillain-Barré syndrome interact with nicotinic acetylcholine receptor channels.

In Guillain-Barré syndrome (GBS), immunoglobulin G (IgG) antibodies block neuromuscular transmission pre- and postsynaptically and thus are of potential pathogenic relevance. We investigated whether IgG from GBS patients has a direct interaction with nicotinic acetylcholine receptor (nAChR) channels. Purified IgG fractions from six GBS patients that blocked neuromuscular transmission in a previous study were analyzed by the patch-clamp technique in combination with an ultrafast system for solution exchange. Sera from three patients with other inflammatory neurological disorders were used as controls. Mouse myotubes expressing native embryonic-type nAChR channels and human embryonic kidney (HEK) 293 cells transiently transfected with recombinant adult-type nAChR channels were used. Repeated 20-ms pulses of acetylcholine (ACh) were applied to outside-out patches in the presence of GBS-IgG. IgG of the patients had a significant reversible blocking action on embryonic- and adult-type nAChR channels with some variability in the magnitude of the block. Activation and desensitization kinetics were not affected when GBS-IgG was applied. None of the control sera blocked the AChR channels. The observed postsynaptic block effect fulfills the criteria of a channel-blocking IgG antibody similar to those seen in autoimmune myasthenia and may contribute to muscle weakness during the acute phase of GBS.

Animals↗

PubMed2003

Intrathecal synthesis of monocyte chemoattractant protein-1 (MCP-1) in amyotrophic lateral sclerosis: further evidence for microglial activation in neurodegeneration.

Autopsy studies and animal experiments suggest that microglial inflammation contributes to the pathogenesis of amyotrophic lateral sclerosis (ALS). Monocyte-chemoattractant protein (MCP-1) might play an important role in microglial recruitment. We studied MCP-1 levels in sera and cerebrospinal fluid of 29 ALS patients and compared the results with 11 control patients with tension headache. The MCP-1 level was determined using enzyme-linked immunosorbent assays (ELISA). A significant increase in cerebrospinal fluid MCP-1 level but not serum level was seen in the patients with ALS compared to the control subjects. These results suggest that cerebrospinal fluid MCP-1 activity may be a sensitive marker for neuroinflammation in ALS useful for monitoring treatment trials in ALS.

Age of Onset↗

PubMed2003

Three-dimensional computerized analysis of diadochokinetic movements of Parkinsonian patients.

OBJECTIVES: Considering the rapid appearance of new pharmaceutical and surgical treatments for Parkinson's disease, a development of quantitative and objective methods for measuring treatment effects is highly warranted. The purpose of this study was to investigate the usability of a computerized movement analysis system in Parkinson's disease patients. MATERIAL AND METHODS: We analysed the effect of L-dopa in a group of 14 patients with idiopathic Parkinson's disease and compared the results to those of 14 control persons. The results were compared to those achieved with the UPDRS, Hoehn & Yahr and Schwab & England Scales, as well as, to time-measured manual testing according to the CAPIT and CAPSIT-PD protocols. RESULTS: We found that the computerized analysis results correlated well with the findings obtained with traditional scales and manual techniques, and that the computer-analysis had the advantage of delivering more exact and quantitative information not only concerning movement speed but also aspects of movement quality. CONCLUSION: We conclude that this form of computerized movement analysis can have an important role in evaluating the effect of treatments, individualizing the therapy, as well as, for diagnostic procedures in patients with Parkinson symptomatology.

Adult↗

PubMed2003

[[123I]beta-CIT SPECT imaging of dopamine and serotonin transporters in Parkinson's disease and multiple system atrophy.

AIMS: Definition of the regional pattern of dopamine transporter (DAT) dysfunction in advanced Parkinson's disease (PD) and evaluation of a potential correlation between DAT binding and symptoms; elucidation of the role of DAT imaging in the differential diagnosis of PD and multiple system atrophy (MSA); assessment and comparison of serotonin transporter (SERT) binding in PD and MSA. METHODS: [(123)I]beta-CIT SPECT was performed in 14 patients with advanced PD, 10 with moderate MSA and 20 healthy persons. Specific to nonspecific tracer binding ratios (V(3)") were calculated via ROI analysis of uptake images at 4 h (SERT binding) and 24 h (DAT binding) p. i. RESULTS: In PD bilateral reduction of striatal DAT binding (63-70%) was seen. The caudate ipsilateral to the clinically predominantly affected side showed relatively the least impairment. Significant correlations (r = -0.54 to -0.64) between DAT binding and Hoehn and Yahr stage, UPDRS-scores and duration of disease were found. In MSA DAT binding was less reduced (40-48%) targeting the putamen contralateral to the side of clinical predominance. Significantly lower SERT binding was observed in PD midbrain and MSA hypothalamus compared to controls -- and in MSA relative to PD mesial frontal cortex. CONCLUSIONS: In advanced PD striatal DAT binding is markedly reduced with the least reduction in caudate ipsilateral to the clinically predominantly affected side. In moderate MSA with asymmetrical symptoms DAT dysfunction is predominant in the contralateral putamen, a pattern seen in early PD. The reduction of SERT in the midbrain area of PD patients suggests additional tegmental degeneration while in MSA the serotonergic system seems to be more generally affected.

Brain↗

PubMed2002

Effects of subthalamic nucleus (STN) stimulation on motor cortex excitability.

BACKGROUND: Deep brain stimulation of the internal global pallidus (GPi) and the subthalamic nucleus (STN) has become a treatment alternative in advanced PD. Although the effects of GPi stimulation have been examined recently, little is known about STN stimulation effects on motor cortex excitability. METHODS: The effects of STN stimulation were studied in eight patients with advanced PD using paired-pulse transcranial magnetic stimulation (TMS) in comparison with healthy control subjects. Motor evoked potentials following paired-pulse TMS (interstimulus interval 3 ms to test for corticocortical inhibition vs 13 ms for facilitation) have been recorded from the extensor carpi radialis and its functional antagonist, the flexor carpi radialis muscle. Silent period (SP) was also determined. Patients were examined under four conditions: medication "off"/stimulator "off" vs medication "on"/stimulator "off" vs medication "off"/stimulator "on" vs medication "on"/stimulator "on." RESULTS: Although the mean values for intracortical inhibition (ICI) were not significantly different, data variation was smaller and levels of significance higher with the STN stimulator switched "on," suggesting that ICI was more consistent. SP during stimulator "on"/medication "on" was longer than during stimulator "off"/medication "off." Motor performance as indicated by a finger-tapping test and Unified PD Rating Scale III was significantly better with dopaminergic medication and further improved with stimulator "on." CONCLUSIONS: Results suggest an effect of subthalamic nucleus stimulation on intracortical inhibitory mechanisms. This hypothesis could at least partially explain a more consistent depression of motor evoked potentials following inhibiting paired-pulse transcranial magnetic stimulation, a longer silent period (under stimulator "on"/medication "on"), and a reduction of akinesia and rigidity leading to a better motor performance in subthalamic nucleus-stimulated patients.

Aged↗

PubMed2002

Electrical stimulation of the sural nerve partially compensates effects of central fatigue.

OBJECTIVES: Depression of motor evoked potentials (MEPs) following transcranial magnetic stimulation (TMS) may be a sign of central motor fatigue. Abnormal fatigue can be observed in MS patients. We have examined whether post-exercise MEP depression can be compensated by application of sensory stimuli prior to TMS. METHODS: We studied 15 healthy volunteers (aged 21 to 28 years) who were required to perform an exercise protocol of ankle dorsiflexion until force fell below 66% of maximum force. MEPs were recorded from the right tibialis anterior muscle. Prior to TMS, electrical stimuli were applied to the ipsilateral sural nerve with an individual interstimulus interval between 50 to 80 ms. RESULTS: MEP areas decreased after exercise. When a sensory stimulus was administered MEPs did not change. DISCUSSION: We conclude that the effects of central fatigue may be--at least partially compensated--by application of sensory stimuli. Sensory stimulation (e.g. by implantation of a neurostimulator) might be a useful therapy for abnormal central fatigue.

Adult↗

PubMed2002

Botulinum toxin (DYSPORT) in tension-type headaches.

OBJECTIVES: Botulinum toxin type A is effective in the reduction of muscle tenderness and pain in many diseases associated with myofascial pain. Since increased muscle tension may contribute to tension-type headaches, injections of botulinum toxin could be of therapeutic value. METHODS/PATIENTS: Results of own investigations are presented, in particular a double-blind, placebo-controlled study with 21 patients fulfilling the International Headache Society criteria for tension-type hedaches. Participants were randomly assigned to verum (pericranial injection of 10 x 20 MU DYSPORT) or placebo condition (injection of isotonic saline in the same manner). RESULTS: After 4, 8, and 12 weeks no significant differences between placebo and verum could be observed. Nevertheless, both groups significantly improved. DISCUSSION: The findings strongly suggest that higher doses or other injection sites might be necessary to achieve therapeutic effects of botulinum toxin in tension-type headaches. Actually, we are participating in a multi-center study using 500 MU of DYSPORT. Besides dose-finding problems, another explanation could be that peripheral mechanisms--such as increased pericranial muscle tension--only play a minor role in the pathogenesis of tension-type headaches.

Adult↗

PubMed2002

[Cerebellar symptoms in motor neuron diseases. Special form of amyotrophic lateral sclerosis plus syndrome].

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive and selective loss of motor neurons in the cerebral cortex, brainstem, and spinal cord. The upper motor neuron syndrome is characterized by symptoms of spastic paresis. Muscle weakness and atrophy, fasciculations, and cramps are typical signs for the degeneration of the lower motor neurons. In 1994, the El Escorial criteria were proposed for the diagnosis of ALS. These criteria include ALS-plus syndromes, which are defined by an association of ALS with extrapyramidal features or dementia. In this paper, we present two cases of ALS associated with signs of cerebellar degeneration. According to the revised El Escorial criteria, the described unusual combination of upper and lower motor neuron signs in association with cerebellar ataxia can be classified as a specific form of ALS-plus syndromes.

Aged↗