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Biomedical subjects

R Dengler

Publications and source records attributed to R Dengler.

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

Different effects of mexiletine on two mutant sodium channels causing paramyotonia congenita and hyperkalemic periodic paralysis.

Effects of the antiarrhythmic and antimyotonic drug mexiletine were studied on two sodium channel mutants causing paramyotonia congenita (R1448H) and an overlap paramyotonic and hyperkalemic paralytic syndrome (M1360V). Channels were expressed in human embryonic kidney cells and studied electrophysiologically, using the whole-cell patch-clamp technique. Compared to the wild-type, channel, both mutants showed alterations of inactivation, i.e. slower inactivation, left shift of steady-state inactivation and faster recovery from inactivation. Mexiletine caused a significantly larger use-dependent block of the R1448H mutant when compared to M1360V and wild-type channels. This can be explained by a prolonged recovery from mexiletine block as observed for R1448H channels, since the affinity of mexiletine for the inactivated state was similar for all three clones. The use-dependent block of sodium channels by mexiletine reduces repetitive series of action potentials and therefore improves muscle stiffness in myotonic patients. The enhanced use-dependent block as seen with R1448H may explain the extraordinary therapeutic efficacy of mexiletine in most patients with paramyotonia congenita.

Cell Line↗
PubMed2000

Effects of somatosensory input on central fatigue: a pilot study.

OBJECTIVE: Depression of motor evoked potentials (MEPs) following transcranial magnetic stimulation (TMS) may be a sign of central motor fatigue. As a pilot study, 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 21-28 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 and 80 ms. RESULTS: MEP areas decreased after exercise. When a sensory stimulus was administered MEPs did not change. CONCLUSION: We conclude that the effects of central fatigue may be influenced by application of sensory stimuli.

Adult↗
PubMed2000

Alteration of sensorimotor integration in musician's cramp: impaired focusing of proprioception.

OBJECTIVE: The influence of muscle vibration (MV) as a strong proprioceptive input on motorcortical excitability was studied in 5 patients with musician's cramp, 5 musician controls and 5 non-musician controls. METHODS: The relaxed flexor carpi radialis (FCR), involved in the dystonic movement in all patients, was vibrated using low frequency (80 Hz) and low amplitude (0.5 mm). Transcranial magnetic stimulation (TMS; intensity, 120% of motor threshold) was applied without MV, 3 and 9 s after the onset of MV. Motor-evoked potentials (MEPs) in the FCR and in the antagonistic extensor carpi radialis (ECR) were recorded. RESULTS: With MV, musician and non-musician controls showed a facilitation of MEPs in the FCR and a decrease of MEPs in the ECR. In musician's cramp, both phenomena were significantly less pronounced. CONCLUSIONS: The reduced facilitation of MEPs in musician's cramp indicates a reduced MV-induced activation of motorcortical areas representing the FCR. The less pronounced inhibition by MV reflects a reduced inhibitory control of the antagonistic ECR. As there were no differences between musician and non-musician controls, the observed changes in musician's cramp refer to this special form of focal dystonia. An impairment of focused motorcortical activation by proprioceptive input from a muscle involved in the dystonic movement is suggested.

Brain↗
PubMed2000

Dopamine D2 receptor imaging in Gilles de la Tourette syndrome.

OBJECTIVES: To examine postsynaptic dopamine D2 receptors in Tourette syndrome (TS). MATERIAL AND METHODS: Seventeen patients and a control group were investigated using single photon emission computed tomography (SPECT) and iodobenzamide (123I-IBZM). RESULTS: In neuroleptic treated patients (n = 7) 123I-IBZM-binding was significantly reduced compared to both normal controls (P < 0.0001) and unmedicated patients (P < 0.001). In unmedicated patients (n = 10) mean binding ratio did not differ from that of control group. Patients in advanced stages of the disease, however, revealed significantly reduced relative striatal binding compared to patients in the early stages (P<0.005) and normal controls (P<0.0001). CONCLUSION: The results lend further support to the hypothesis that the dopamine receptor is involved in TS pathology. During the natural course of the disease tics often improve in early adulthood. It is suggested that this spontaneous recovery from tics may be associated with reduced receptor binding capacity.

Adolescent↗
PubMed2000

Voltage-dependent blockade of normal and mutant muscle sodium channels by benzylalcohol.

1. We studied the effects of benzylalcohol on heterologously expressed wild type (WT), paramyotonia congenita (R1448H) and hyperkalaemic periodic paralysis (M1360V) mutant alpha-subunits of human skeletal muscle sodium channels. 2. Benzylalcohol blocked rested channels at -150 mV membrane potential, with an ECR(50) of 5.3 mM in wild type, 5.1 mM in R1448H, and 6.2 mM in M1360V. When blockade was assessed at -100 mV, the ECR(50) was reduced in R1448H (2 mM) compared with both wild type (4.3 mM; P<0.01) and M1360V (4.3 mM). 3. Membrane depolarization before the test depolarization significantly promoted benzylalcohol-induced sodium channel blockade. The values of K(D) for the fast-inactivated state derived from benzylalcohol-induced shifts in steady-state availability curves were 0.66 mM in wild type and 0.58 mM in R1448H. In the presence of slow inactivation induced by 2.5 s depolarizing prepulses, the ECI(50) for benzylalcohol-induced current inhibition was 0.59 mM in wild type and 0.53 mM in R1448H. 4. Recovery from fast inactivation was prolonged in the presence of drug in all clones. 5. Benzylalcohol induced significant frequency-dependent block at stimulating frequencies of 10, 50, and 100 Hz in all clones. 6. Our results clearly show that benzylalcohol is an effective blocker of muscle sodium channels in conditions that are associated with membrane depolarization. Mutants that enter voltage-dependent inactivation at more hyperpolarized membrane potentials compared with wild type are more sensitive to inhibitory effects at the normal resting potential.

Amino Acid Substitution↗
PubMed2000

Treatment of tension-type headache with botulinum toxin type A: a double-blind, placebo-controlled study.

OBJECTIVE: To determine whether injections of botulinum toxin could be of therapeutic value in the treatment of tension-type headache. BACKGROUND: Botulinum toxin A is very effective at reducing muscle tenderness and pain in many diseases. Increased muscle tension may contribute to tension-type headache. METHODS: We performed a double-blind, placebo-controlled study with 21 patients fulfilling the International Headache Society criteria for tension-type headache. Participants were randomly assigned to treatment (pericranial injection of 10 x 20 mouse units botulinum toxin A) or placebo (injection of isotonic saline in the same manner). RESULTS: After 4, 8, and 12 weeks, no significant differences between placebo and treatment could be observed (with respect to visual analog scale, frequency and duration of headache attacks, consumption of analgesics, pressure pain threshold, total tenderness score, and quality-of-life parameters). CONCLUSIONS: The findings of our study strongly support the hypothesis that peripheral mechanisms, such as increased muscle tenderness, only play a minor role in the pathogenesis of tension-type headache.

Adult↗
PubMed2000

The role of electromyography (EMG) in the diagnosis of ALS.

Electromyography (EMG) plays a key role in the diagnostic evaluation of ALS. This paper deals with the contribution of conventional needle EMG and electroneurography to the neurophysiological assessment of ALS. In addition, special EMG techniques such as single fibre EMG and macro EMG are discussed as they mirror the decline of the number of motor units during the disease process and the remodelling capacity of the surviving motor units.

Amyotrophic Lateral Sclerosis↗
PubMed2000

Succinylcholine metabolite succinic acid alters steady state activation in muscle sodium channels.

BACKGROUND: Animal experiments revealed that succinylcholine produced masseter muscle rigidity and activated myotonic discharges despite neuromuscular blockade with a nondepolarizing blocker. These results suggest that either succinylcholine or its metabolites might interfere directly with voltage-operated ion channels of the sarcolemma. The aim of this study was to examine effects of one product of succinylcholine hydrolysis, succinic acid, on voltage-gated muscle sodium (Na+) channels. METHODS: Alpha subunits of human muscle sodium channels were heterologously expressed in HEK293 cells. Activation of Na+ currents was examined applying standard whole-cell voltage-clamp protocols in the absence (control and washout) and presence of succinic acid in different concentrations (0.05-10 mm). RESULTS: Succinic acid shifted the midpoints of steady state activation plots in the direction of more negative test potentials, indicating that channels open during smaller depolarizations in the presence of the drug. The maximum amount of the negative shift in 10 mm succinic acid was -6.3 +/- 1.7 mV; the EC50 for this effect was 0.39 mm. In addition, succinic acid (10 mm) significantly enhanced maximum currents after depolarizations with respect to a series of control experiments. CONCLUSION: Succinic acid facilitates voltage-dependent activation in muscle sodium channels in vitro. This might lead to muscle hyperexcitability in vivo.

Anti-Ulcer Agents↗
PubMed2000

Low-dose treatment of cervical dystonia, blepharospasm and facial hemispasm with albumin-diluted botulinum toxin type A under EMG guidance. An open label study.

Several studies support the hypothesis that low-dose botulinum toxin treatment may be as beneficial as high-dose regimen. Therefore, we studied 115 patients (aged 27-84; mean 58.0, SD = 12.9 years; 68% females, 32% males) suffering from cervical dystonia (n = 66), blepharospasm (n = 28), and facial hemispasm (n = 21) over a period of 2 years in an open label, non-controlled pilot study. Patients received low-dose treatment with botulinum toxin type A (Dysport((R))). The toxin was diluted in 20 ml of 0.1% albumin solution to arrive at a concentration of 25 MU/ml and injected under EMG control. Patients responded to the treatment about 1 week after injection (mean 7.3 days, SD = 4.6). The mean duration of beneficial effects was 11.7 weeks (SD = 5.6). Patients evaluated the clinical global improvement on a scale ranging from 0 to 4. For the whole population, the mean was 2.7 points (SD = 1.1). In none of the subjects could antibodies to botulinum toxin type A be detected, and only a few side effects were observed. In conclusion, low-dose therapy with botulinum toxin A merits further controlled studies.

Adult↗
PubMed2000

Acamprosate reduces motor cortex excitability determined by transcranial magnetic stimulation.

Acamprosate is effective in reducing alcohol intake in weaned alcoholics. We were interested if acamprosate had an effect on the excitability of cortical motoneurons determined by transcranial magnetic stimulation (TMS). We studied 12 male healthy volunteers (mean age 29.5 years, SD = 4.8) who were either treated with 6 tablets of acamprosate (each containing 333 mg verum) per day or placebo (randomized cross-over design) for 1 week. TMS was performed after each treatment session including a paired stimulation paradigm. Motor evoked potentials (MEPs) of the placebo and verum group did not differ with respect to paired stimulation. However, motor threshold increased in the acamprosate group (verum: 61.5% (SD = 7.9) vs. placebo: 58.9% (SD = 8.8), p = 0.036). We conclude that acamprosate leads to a hypoexcitability of the motor cortex. This might be due to subcortical mechanisms, e.g. thalamocortical pathways since intracortical inhibition and facilitation was not affected.

Acamprosate↗
PubMed2000

Pentobarbital has curare-like effects on adult-type nicotinic acetylcholine receptor channel currents.

UNLABELLED: Pentobarbital (PB) is widely used as a short-term sedative and anticonvulsive drug with a side-effect of relaxing muscle tone. We investigated block of nicotinic acetylcholine receptor (nAChR) channel currents by PB using the patch-clamp technique in combination with an ultrafast system for solution exchange. As a preparation, recombinant rat adult-type nAChR channels transiently expressed in HEK293 cells were used. Appli-cation of 1 mM acetylcholine to small cells or outside-out patches showed a transient current with fast activation and desensitization kinetics. Adding PB to the acetylcholine-containing solution resulted in a decrease of the time constant of current decay and of the peak current amplitude starting at concentrations >0.01 mM PB. Preincubation of nAChR channels with PB led to a decrease of the peak current amplitude without alteration of activation and desensitization kinetics caused by competitive block of nAChR channels. In conclusion, similar to the effect of d-Tubocurarine, block of nAChR channel currents by PB can be explained by a combination of open-channel and competitive block. IMPLICATIONS: The interaction between adult-type nicotinic acetylcholine receptors, acetylcholine, and pentobarbital was biophysically investigated by using the patch-clamp technique in combination with tools for ultrafast solution exchange. PB elicited open-channel block and competitive block of nicotinic acetylcholine receptor channel currents, whereas the latter seems to be effective in clinically relevant concentrations.

Acetylcholine↗
PubMed1999

Muscle vibration: different effects on transcranial magnetic and electrical stimulation.

Transcranial magnetic stimulation (TMS) and transcranial electrical stimulation (TES) were applied before and 3 s after onset of vibration (0.5 mm, 80 Hz) of the right extensor carpi radialis muscle in 5 healthy subjects. Vibration induced significant augmentation and latency shortening of motor evoked potentials elicited by TMS, but not TES. This provides evidence for an involvement of cortical mechanisms by muscle vibration in the augmentation of MEPs following TMS.

Adult↗
PubMed1999

Modulation of motor evoked potentials by muscle vibration: the role of vibration frequency.

Augmentation of motor evoked potentials (MEPs) by muscle vibration (MV) was studied in 10 healthy subjects with regard to the vibration frequency (VF). The extensor carpi radialis muscle (ECR) was vibrated using VFs of 80, 120, and 160 Hz. Motor evoked potentials following transcranial magnetic stimulation were recorded simultaneously from the vibrated ECR and the antagonist flexor carpi radialis muscle (FCR) without MV, 0.5 s and 3 s after onset of MV and 1 s after offset. Only the VFs of 80 Hz and 120 Hz caused MEP augmentation and latency shortening in ECR, whereas depression of MEPs in FCR was induced by all VFs used. It appears that MEP augmentation and latency shortening in ECR are mediated by the primary muscle spindle endings which respond with optimal discharge rates to VFs of up to 100 Hz. Motor evoked potential depression in FCR, being well expressed also with VF 160 Hz, seems to involve other dynamic mechanoreceptors.

Adult↗
PubMed1999

Demyelinating sensorimotor neuropathy with congenital cataract, mental retardation, and unique, dysplastic perineurial cells within the endoneurium.

We report on a 27-year-old Caucasian female with congenital cataract and mental retardation complaining of progressive paresis and atrophy of the lower legs beginning at the age of 16 years followed by atrophy of the thighs and small hand muscles. Motor and sensory conduction velocities (CV) of the upper and lower limbs were reduced (distal peroneal nerve: 21 m/s; median nerve: motor CV: 28 m/s, sensory CV 30 m/s). In the sural nerve biopsy specimens there were unique endoneurial cells immunoreactive for antibodies against the epithelial membrane antigen with multiple surface indentations and projections considered to be dysplastic perineurial cells. To the best of our knowledge these cells have not been reported in any other type of human peripheral neuropathy. The present case with the above clinical and structural findings appears to represent a new, complex, demyelinating type of a sporadic or possibly recessively inherited motor and sensory neuropathy.

Adult↗
PubMed1999

Voltage-dependent block of normal and mutant muscle sodium channels by 4-Chloro-m-Cresol.

1 The effects of 4-Chloro-m-Cresol (4-CmC) were examined on heterologously expressed wild type (WT), Paramyotonia Congenita (R1448H) and Hyperkalemic Periodic Paralysis (M1360V) mutant alpha-subunits of human muscle sodium channels. 2 Block of rested sodium channels caused by 4-CmC was concentration-dependent with an ECR50 of 0.40 mM in WT, 0.45 mM in R1448H and 0.49 mM in M1360V. 3 Inactivation significantly promoted 4-CmC-induced sodium channel block in all clones indicated by 4-CmC-induced shifts of steady-state availability curves, reflecting a higher proportion of channel block at depolarized membrane potentials. Channel block was almost complete (>90%) at concentrations close to the ECR50 (0.5 mM) on application of an inactivating prepulse before the test pulse. 4 4-CmC accelerated the current decay following depolarization and prolonged recovery from inactivation in all clones. Of these, R1448H, the mutant which displayed severely impaired inactivation in the controls, responded to 4-CmC with the most pronounced acceleration of inactivation. Control experiments revealed enhanced recovery from inactivation in the mutants, which was restored to normal in 0.1 mM 4-CmC. 5 4-CmC induced no additional frequency-dependent block. 6 Our results clearly demonstrate that 4-CmC is as effective as lidocaine (Fan et al., 1996) in blocking muscle sodium channels. Low concentrations of the compound (</=ECR50) were able to restore pathologically accelerated recovery from inactivation and impaired inactivation in the mutants to the WT value.

Amino Acid Substitution↗