Simulating focal demyelinating neuropathies: membrane property abnormalities.

Membrane properties such as potentials (intracellular, extracellular, electrotonic) and axonal excitability indices (strength-duration and charge-duration curves, strength-duration time constants, rheobasic currents, recovery cycles) can now be measured in healthy subjects and patients with demyelinating neuropathies. They are regarded here in two cases of simultaneously reduced paranodal seal resistance and myelin lamellae in one to three consecutive internodes of human motor nerve fiber. The investigations are performed for 70 and 96% myelin reduction values. The first value is not sufficient to develop a conduction block, but the second leads to a block and the corresponding demyelinations are regarded as mild and severe. For both the mild and severe demyelinations, the paranodally internodally focally demyelinated cases (termed as PIFD1, PIFD2, and PIFD3, respectively, with one, two, and three demyelinated internodes) are simulated using our previous double-cable model of the fiber. The axon model consists of 30 nodes and 29 internodes. The membrane property abnormalities obtained can be observed in vivo in patients with demyelinating forms of Guillain-Barré syndrome (GBS) and multifocal motor neuropathy (MMN). The study confirms that focal demyelinations are specific indicators for acquired demyelinating neuropathies. Moreover, the following changes have been calculated in our previous papers: (1) uniform reduction of myelin thickness in all internodes (Stephanova et al. in Clin Neurophysiol 116: 1153-1158, 2005); (2) demyelination of all paranodal regions (Stephanova and Daskalova in Clin Neurophysiol 116: 1159-1166, 2005a); (3) simultaneous reduction of myelin thickness and paranodal demyelination in all internodes (Stephanova and Daskalova in Clin Neurophysiol 116: 2334-2341, 2005b); and (4) reduction of myelin thickness of up to three internodes (Stephanova et al., in J Biol Phys, 2006a,b, DOI: 10.1007/s10867-005-9001-9; DOI: 10.1007/s10867-006-9008-x). The membrane property abnormalities obtained in the homogeneously demyelinated cases are quite different and abnormally greater than those in the case investigated here of simultaneous reduction in myelin thickness and paranodal demyelination of up to three internodes. Our previous and present results show that unless focal demyelination is severe enough to cause outright conduction block, changes are so slight as to be essentially indistinguishable from normal values. Consequently, the excitability-based approaches that have shown strong potential as diagnostic tools in systematically demyelinated conditions may not be useful in detecting mild focal demyelinations, independently of whether they are internodal, paranodal, or paranodal internodal.

Motor cortex excitability changes preceding voluntary muscle activity in simple reaction time task.

The effect of transcranial magnetic stimulation (TMS) on reaction time (RT) and motor cortex excitability in the premovement period was investigated. Single and paired-pulse TMS with 3 and 13 ms interstimulus intervals (ISI) were applied to the left motor cortex at different delays after a visual command for isometric right hand index finger abduction. Motor evoked potentials (MEPs) recorded from the right first dorsal interosseous (FDI) were analysed to assess cortex excitability. The MEPs in response to single pulse TMS were gradually increased in the premovement period in general, but strongly augmented in a period of 90-100 ms before the voluntary myoelectrical activity (EMG) onset. In paired-pulse TMS (13 ms ISI), the MEP augmentation was smaller but started earlier before the EMG burst, and a gradual increase of MEP amplitudes was not evident. In case of 3 ms ISI, the expected intracortical inhibition (ICI) was evident only when TMS preceded the voluntary EMG by an interval of more than 60 ms, but at shorter intervals, rather some MEP augmentation was observed. Generally, the augmentation of MEPs in the premovement period was more pronounced in single pulse TMS. Most strikingly, a dead band period without MEP occurrences was observed within an interval of 30-50 ms before the voluntary EMG. In conclusion, parallel action of intracortical facilitation (ICF) and ICI as well as different dynamic behaviour of ICF and pre movement facilitation may explain the earlier mentioned effects. Moreover, this leads to an extended description of the rather subtle TMS influence on RT.

Maintenance antipsychotic medication patterns in outpatient schizophrenia patients: a naturalistic cohort study.

OBJECTIVE: Newer antipsychotics are increasingly used in schizophrenia maintenance. The UK change has been slow with little known on switching patterns. We aimed to investigate antipsychotic prescribing patterns in schizophrenia patients. METHOD: A naturalistic six-site cohort sample of 600 patients were interviewed by researchers at 6-monthly intervals for 2 years to record their clinical and social functioning; use of services and medication for the preceding 6 months was obtained by structured extraction from clinical case notes. RESULTS: Alterations in antipsychotic medication were frequent in this group, mainly during periods of inpatient care. Atypical prescribing increased steadily, though slowly, across the period. Polypharmacy was less than anticipated. CONCLUSION: Inpatient care remains the main forum for switching of antipsychotics. The UK maintains a slow shift to atypical antipsychotics.

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.

The electrophysiological profile of hereditary motor and sensory neuropathy-Lom.

OBJECTIVE: To make electrophysiological observations on a large kindred with hereditary motor and sensory neuropathy-Lom (HMSN-L) containing 27 affected individuals. CLINICAL FINDINGS: Onset was in early childhood with gait difficulty related to progressive lower limb weakness. Upper limb weakness developed later. Bulbar involvement was present in one third of the patients, and deafness appeared during the second or third decades. ELECTROPHYSIOLOGICAL FINDINGS: Electromyographic evidence of denervation was progressive, more severe distally, and greater in the legs, being total in distal lower limb muscles in most patients. Sensory action potentials were absent and motor nerve conduction was severely slowed. This included proximal upper limb (musculocutaneous and axillary), hypoglossal, and facial nerves. The severity of slowing increased during childhood. M waves, often multiple, were recorded in all affected individuals. The blink reflex showed an unusual three component response. The latencies of all three components were prolonged. CONCLUSIONS: HMSN-L is shown to be a demyelinating neuropathy involving severe and early axonal loss. The progressive slowing of nerve conduction during childhood differs from the static reduction seen in type I HMSN.

The efficacy of a bivalent vaccine against pasteurellosis and rabbit haemorrhagic disease virus.

Rabbit haemorrhagic disease virus (RHDV) and Pasteurella multocida bacteria cause severe losses among rabbit populations. The efficacy of a recently developed bivalent vaccine against pasteurellosis and RHDV was investigated. Doses exceeding 2 haemagglutinating units (HU) of viral antigen were sufficient to protect rabbits against infection with RHDV. The bivalent vaccine appeared to be safe for use in all age groups of rabbits, including pregnant females, even after treatment with 20 times the normal vaccine dose. Rabbits injected with 8 or 4 HU of bivalent vaccine showed high antibody titres against both organisms for 9 months after inoculation. The antibody levels against RHDV in young rabbits at 30 days of age were elevated when they originated from mothers with high antibody titres. The most suitable period for vaccination of offspring appeared to be around 50 days of age. The bivalent vaccine against pasteurellosis and RHDV combined speed and longevity of the immune response. Immune protection against pasteurellosis and RHDV can thus be achieved with only one manipulation.

A-waves in patients with novel hereditary motor and sensory neuropathy Lom.

OBJECTIVES: To determine A-waves of a family with autosomal recessive form of demyelinatig hereditary motor and sensory neuropathy Lom (HMSNL). METHODS: A-waves were investigated during conventional F-wave study of family members with HMSNL which had genetic testing. RESULTS: During routine F-wave studies A-waves were observed in all tested nerves. They appeared between M-responses and F-wave. The A-waves were with low amplitude, shorter duration and constant shape and latency than F-waves. They appeared independently of F-waves. A-waves were more often recorded as multiple waves in lower and upper extremities. More than three A-waves per nerve were found mostly in ulnar and facial nerves. In 16 cases A-waves were found in the absence of F-waves. CONCLUSION: It is assumed that the A-waves could be seen as additional signs of pathology because they were not observed in unaffected members of the family and in healthy subjects.

Comparative analyse of single motor unit pattern in healthy subjects and patients with neuromuscular disorders.

OBJECTIVE: The motor unit (MU) spike trains in human muscle contractions are an object to new mathematical processing. The aim is to identify the interspike interval relations characterizing normal and changed physiological states (neuro-muscular disorders). METHODS: MU activities in healthy subjects and patients with Schwartz-Jampel syndrome, neuromiotonia and Parkinson disease were investigated. Motor unit action potentials (MUAPs) were recorded by surface multielectrode with small leading-off area without provoking a burst of activity, as usually was observed during the needle electromyography study in patients with Schwartz-Jampel syndrome and neuromiotonia. RESULTS: Different single motor unit activity in healthy subjects and patients was observed. Discharge pattern of patients was basically changed. Disturbance of different parts of the motor system leads to the changes of temporal order of interspike interval. This permit us to suppose that the pattern of repetative neuronal discharges suggests an influence at a higher level than the muscle in all investigated patients but the reason of multiple discharges with an interimpulse interval of 2 to 10 ms probably originated in the muscle membrane. CONCLUSIONS: The comparative analysis of MU patterns in healthy subjects and patients with neuro-muscular disorders can help us to disclose inapparent connections between cortical and spinal level of motor control.

Serum ganglioside patterns in multiple sclerosis.

The relative distribution of gangliosides was determined in the serum of 37 patients with multiple sclerosis (MS) and of 30 healthy subjects. There was a significant increase of GM1 and GD1a, and a decrease of GM3 proportion in the serum of relapsing-remitting MS patients (RRMS) during their first MS attack. The RRMS patients in relapse with a long duration of the disease had a significant decrease of GM1 and an increase of GD1a portion in the serum. An increase of GD1a, one of the major brain neuron ganglioside fraction, suggested the neuron injury in the early and with a long duration RRMS. The finding of an increase of GM1, the main human myelin ganglioside, during the first MS attack in RRMS patients confirms previous evidence for the possible involvement of gangliosides in the early pathological course of demyelination in MS.

Peripheral late waves in patients with hereditary motor sensory neuropathy.

Patents with different forms of hereditary motor sensory neuropathy (HMSN) were investigated. Peripheral late waves (PLWs) were recorded when determining F wave at supramaximal stimulation. We registered them most frequently in patients with demyelinating neuropathies (HMSN1--58% and HMSN3--100%) and in patients with HMSN2--24% and HMN--13%. In patients with HMSN1 and HMSN3 the peripheral late waves sometimes were more than one--two or three. They had a consistent appearance above a maximal threshold of stimulation, an invariable latency, amplitude and wave-form. Their latency times were in parallel with the M-response latency. These PLWs can be explained by collateral regeneration in case of axonal neuropathy. The ephaptic transmission might be taken in consideration when interpreting data from patients with demyelinating processes.

Comparative analysis between Duchenne and Becker types muscular dystrophy.

Duchenne and Becker types of muscular dystrophy are usually differentiated according to age of onset and rate of progression criteria which are not sufficient. The aim of this paper was to re-establish the clues for distinguishing Duchenne from Becker types of muscular dystrophy. According to the onset and progression of the disease, one hundred and eleven patients were subdivided into two groups. First group--Becker muscular dystrophy--consisted of 40 patients and second one of 71 patients with Duchenne type of muscular dystrophy. Clinical data confirm some well known differences between Duchenne and Becker muscular dystrophy concerning the age of onset, severity of disease and rate of progression. Electromyographic signs of myopathic changes and spontaneous activity were found in both diseases. Spontaneous activity--bizarre and fibrillation potentials, as well as sharp waves are more common for Duchenne type. The differences between the Becker from Duchenne type of muscular dystrophy can be described on the basis of complex investigations (clinical, electromyographical, histological and biochemical).

Comparison between normal and parkinsonian pattern of motor unit firing.

There are many approaches to the study of the activity of separate motor units (MU) in man. In humans alpha motoneuron activity consists in generating spike trains that innervate groups of muscle fibers thus building MU. In the present study we used a new evolution of the joint interval density analysis in patients with Parkinson disease.

Comparative molecular epidemiological investigation on different bovine herpes viruses.

Eight Bulgarian bovine herpes viruses, two Hungarian herpes viruses 1A, 3A, calves isolate named Mramor, buffalo isolate 723 and two referents BHV 1 strains were investigated by restrictase fragment pattern analysis. Migration profile of viral DNA by using different restrictase enzymes Hpa I, BamH I and Hind III were compared. Clearly differences among two Hungarian strains, calves isolate Mramor, buffalo isolate 723 and 8 Bulgarian and two referents BHV 1 strain was observed. The strain Sartze was determined as a genital type BHV 1, whereas Ozet, Tch.voda, Slivnitza, B. Budinov, Ptcelarovo, Vrana and Podgumer as a respiratory type. Hungarian strains 1A, 3A, calves isolate Mramor and buffalo isolate 723 had similar migration profile as swine herpes viruses. Hybridisation between the K 22 fragment and 8 bovine herpes viruses after Southern blotting were observed. That is evidence for genetic relation of these strains. Such hybridisation with Hungarian 1A, 3A, Mramor and buffaloes 723 strains were not observed. This fact allowed us to conclude that these strains are genetically different from BHV 1.

Dominant-lethal mutations and micronucleus induction in male BALB/c, BDF1 and H mice by tobacco smoke.

The mutagenicity of whole tobacco smoke (TS) was examined in male BALB/c, BDF1 and H mice using the dominant lethal and micronucleus tests in bone marrow polychromatic erythrocytes. Male mice (about 80 days old) from the three strains were treated with TS on 5 days/week for 8 weeks. The animals were divided into three groups for every strain: control and two experimental groups. Two doses--low (1h treatment/day) and high (2 h treatment/day)--were used. In the first case 8 exposures of 7.5 min each with 1-min intervals were given and to realize the high dose this was repeated 4 h later. It was found that TS induces significant dominant-lethal mutations in both experimental groups of BALB/c, BDF1 and H mice (p < 0.001), but some strain differences existed. The data obtained suggest that in BALB/c and BDF1 mice TS induces dominant-lethal mutations mainly in spermatocytes, spermatogonia and gonial stem cells, while in H mice only spermatids and spermatocytes are affected. The bone marrow from each strain and each dose group was investigated for the presence of micronucleated polychromatic erythrocytes (PCE) at 5, 19, 38, 54, and 63 days after beginning of the treatment with TS, using the same exposure regimen. Exposure of male mice to TS caused an up to 2-3-fold increase in the number of PCE in the bone marrow of BALB/c and BDF1 mice in both dose groups. In H mice this effect is observed only on days 19 and 38 of sampling. No cumulative or dose-dependent effects were detected. Increased formation of micronuclei within PCE of femoral bone marrow after passive smoking was regarded as being due to the effect of TS.