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Biomedical subjects

J Borg

Publications and source records attributed to J Borg.

At least 19 recordsLinked to original sources
PubMed2000

Muscle biopsy, macro EMG, and clinical characteristics in patients with schizophrenia.

BACKGROUND: In a previous study of motor unit properties in patients with schizophrenia, muscle fiber histologic and electrophysiologic abnormalities were observed. The present study was designed to compare patients with schizophrenia with healthy control subjects with regard to muscle fiber histology and motor unit function. A second objective was to relate these variables to clinical characteristics. METHODS: Twelve patients with first-episode schizophrenia and fifteen patients with chronic schizophrenia (DSM-III-R) and 27 matched control subjects were included in the study. Muscle biopsies were performed either in m. tibialis anterior or m. vastus lateralis. Electromyographic recordings (macro EMG) were made from the m. tibialis anterior motor units. Psychiatric ratings included the PANSS and extrapyramidal side effects. RESULTS: Seven of the muscle biopsy specimens from the patients and one from the control subjects were classified as abnormal (p =.049). The most frequent abnormality was atrophic muscle fibers. Eight patients and no control subjects exhibited pathological macro EMG (p =.032). The findings were present in chronic as well as in first-episode patients with schizophrenia. CONCLUSIONS: In approximately 50% of the patients, neuromuscular abnormalities were found either in the muscle biopsy or the macro EMG investigations. The results indicate that either a common pathologic process or different pathological processes are at hand in the neuromuscular system in patients with schizophrenia. The findings are compatible with a disturbed cell membrane function.

Acute Disease↗
PubMed2000

Early and selective loss of neuromuscular synapse subtypes with low sprouting competence in motoneuron diseases.

The addition or loss of synapses in response to changes in activity, disease, or aging is a major aspect of nervous system plasticity in the adult. The mechanisms that affect the turnover and maintenance of synapses in the adult are poorly understood and are difficult to investigate in the brain. Here, we exploited a unique anatomical arrangement in the neuromuscular system to determine whether subtypes of synapses can differ in anatomical plasticity and vulnerability. In three genetic mouse models of motoneuron disease of diverse origin and severity, we observed a gradual and selective loss of synaptic connections that begun long before the onset of clinical deficits and correlated with the timing of disease progression. A subgroup of fast-type (fast-fatiguable) neuromuscular synapses was highly vulnerable and was lost very early on. In contrast, slow-type synapses resisted up to the terminal phase of the disease. Muscle-specific differences were also evident. Similar selective losses were detected in aged mice. These selective vulnerability properties of synapses coincided with hitherto unrecognized major differences in stimulus-induced anatomical plasticity that could also be revealed in healthy mice. Using paralysis and/or growth-associated protein 43 overexpression to induce synaptic sprouting, we found that slow-type, disease-resistant synapses were particularly plastic. In contrast, fast-type synapses with the highest vulnerability failed to exhibit any stimulus-induced change. The results reveal pronounced subtype specificity in the anatomical plasticity and susceptibility to loss of neuromuscular synapses and suggest that degenerative motoneuron diseases involve a common early pathway of selective and progressive synaptic weakening also associated with aging.

Aging↗
PubMed2000

Macro-EMG and muscle biopsy of paretic foot dorsiflexors in Charcot-Marie-Tooth disease.

Twelve patients with Charcot-Marie-Tooth disease type 1 (CMT1) and 11 with type 2 (CMT2), with a clinically similar range of muscle weakness of foot dorsiflexion, were subjected to macroelectromyographic (macro-EMG) examination and muscle biopsy of the tibialis anterior (TA) muscle in order to elucidate the denervation-reinnervation process in the two CMT forms. The macro-EMG examination showed higher median amplitude values and median area values for the CMT1 patients, with a mean value of 1,515 +/- 1,222 microV and 3,953 +/- 2,613 microV. ms, respectively, than for the CMT2 patients, with a mean value of 865 +/- 971 microV and 2,525 +/- 2,575 microV. ms, respectively. When corrected for muscle fiber area, the difference was statistically significant for amplitude (P < 0.01) and area (P < 0.05). For CMT1 patients, the increase of macro-EMG potentials varied from 2 to 14 times and for CMT2 patients from less than 1 to 8 times larger than corresponding age-matched values. Muscle biopsies of TA showed that the type I fiber percentage was significantly higher (P < 0.05) in the CMT1 patients (99 +/- 2.2%) than in the CMT2 patients (86 +/- 12.3%). Morphometric data showed a significantly higher (P < 0.05) mean type I fiber area in the CMT2 patients (8,130 +/- 4,721 microm(2)) when compared with the CMT1 patients (5,066 +/- 3,431 microm(2)). The present data indicate that denervation in CMT1 is associated with prominent collateral reinnervation but only minor muscle fiber changes, whereas in CMT2 there is only minor collateral reinnervation but prominent muscle fiber changes including significant muscle fiber hypertrophy.

Adult↗
PubMed2000

Prevention of mutant SOD1 motoneuron degeneration by copper chelators in vitro.

An animal model of familial amyotrophic lateral sclerosis (FALS) has been generated by overexpression of human CuZn superoxide dismutase (SOD1) containing a substitution of glycine to alanine at position 93 in transgenic G93A mice. The loss of motoneurons shown in this model has been attributed to a dominant gain of function of this mutated enzyme, which might be due to copper toxicity. This hypothesis was tested in purified spinal motoneurons cultures originating from G93A transgenic embryos. Spinal motoneurons were isolated from E13 embryos by several steps including density gradient centrifugation. The effect of copper chelators on survival and neurite growth of motoneurons was investigated. Survival of G93A motoneurons was decreased by 46% as compared to wild-type motoneurons. Moreover, G93A motoneurons showed reduced neurite outgrowth. Copper chelators strikingly increased viability of G93A motoneurons (by over 200%) but had no effect on wild-type cells. Presence of DDC in the medium increases the length of neurites from G93A motoneurons. The present results suggest the capacity of copper chelators to reduce the effect of reverse function of mutated SOD1 on motoneurons.

Amyotrophic Lateral Sclerosis↗
PubMed2000

Tissue mitochondrial DNA changes. A stochastic system.

Several lines of evidence support the view that the bioenergetic function of the mitochondria in postmitotic tissue deteriorates during normal aging. Skeletal muscle is one such tissue that undergoes age-related fiber loss and atrophy and an age-associated rise in the number of cytochrome c oxidase (COX) deficient fibers. With such metabolic pressure placed on skeletal muscle it would be an obvious advantage to supplement the cellular requirement for energy by up-regulating glycolysis, and alternative pathway for energy synthesis. Analysis of rat skeletal muscle utilizing antibodies directed against key enzymes involved in glycolysis has provided evidence of an age-associated increase in the enzymes involved in glycolysis. Fructose-6-phosphate kinase, aldolase, glyceraldehyde-3-phosphate dehydrogenase, and pyruvate kinase protein levels appeared to increase in the soleus, gracilis, and quadriceps muscle from aged rats. The increase in the level of these proteins appeared to correlate to a corresponding decrease in the amount of cytochrome c oxidase protein measured in the same tissue. Together these results are interpreted to represent a general upregulation of glycolysis that occurs in response to the age-associated decrease in mitochondrial energy capacity. Mitochondrial DNA (mtDNA) damage and mutations may accumulate with advancing age until they reach a threshold level were they impinge on the bioenergy capacity of the cell or tissue. Evidence indicates that mtDNA from the skeletal muscle of both aged rats and humans not only undergoes changes at the nucleotide sequence level (mutations and DNA damage), but also undergoes modifications at the tertiary level to generate unique age-related conformational mtDNA species. One particular age-related conformational form was only detected in aged rat tissues with high demands on respiration, specifically in heart, kidney, soleus muscle, and, to a lesser extent, the quadriceps muscle. The age-related form was not detected in gracilis muscle which is predominantly dependent upon glycolysis with regard to its energy requirements. Finally, a comprehensive hypothesis is presented that features the stochastic nature of the mitochondrial system. The basis of the hypothesis is that a dynamic relationship exists between endogenous mutagen production, DNA repair, mtDNA turnover, and nuclear control of mtDNA copy number and that age-associated changes in the dynamics of this relationship lead to a loss of functional full-length mtDNA that eventually leads to bioenergy decline.

Aging↗
PubMed2000

Monte Carlo study of correction factors for Spencer-Attix cavity theory at photon energies at or above 100 keV.

To develop a primary standard for 192Ir sources, the basic science on which this standard is based, i.e., Spencer-Attix cavity theory, must be established. In the present study Monte Carlo techniques are used to investigate the accuracy of this cavity theory for photons in the energy range from 20 to 1300 keV, since it is usually not applied at energies below that of 137Cs. Ma and Nahum [Phys. Med. Biol. 36, 413-428 (1991)] found that in low-energy photon beams the contribution from electrons caused by photons interacting in the cavity is substantial. For the average energy of the 192Ir spectrum they found a departure from Bragg-Gray conditions of up to 3% caused by photon interactions in the cavity. When Monte Carlo is used to calculate the response of a graphite ion chamber to an encapsulated 192Ir source it is found that it differs by less than 0.3% from the value predicted by Spencer-Attix cavity theory. Based on these Monte Carlo calculations, for cavities in graphite it is concluded that the Spencer-Attix cavity theory with delta = 10 keV is applicable within 0.5% for photon energies at 300 keV or above despite the breakdown of the assumption that there is no interaction of photons within the cavity. This means that it is possible to use a graphite ion chamber and Spencer-Attix cavity theory to calibrate an 192Ir source. It is also found that the use of delta related to the mean chord length instead of delta = 10 keV improves the agreement with Spencer-Attix cavity theory at 60Co from 0.2% to within 0.1% of unity. This is at the level of accuracy of which the Monte Carlo code EGSnrc calculates ion chamber responses. In addition, it is shown that the effects of other materials, e.g., insulators and holders, have a substantial effect on the ion chamber response and should be included in the correction factors for a primary standard of air kerma.

Air↗
PubMed1999

Compensatory mechanism of motor defect in SOD1 transgenic mice by overactivation of striatal cholinergic neurons.

Expression of a mutant superoxide dismutase 1 (SOD1) gene in transgenic mice induces a gradual degeneration of cholinergic motor neurons in the spinal cord, causing progressive muscle weakness and hindlimb paralysis. Transgenic mice over-expressing the human SOD1 gene containing a Gly-->Ala substitution at position 93 (G93A) were employed to explore the effects of the SOD1 mutation on choline acetyltransferase (ChAT) expression in the striatum, and in the lumbar and cervical spinal cord. These mice showed a progressive loss of their spinal cord motor neurons, and at 130 days of age showed an up-regulation of ChAT mRNA expression in the striatum. On the other hand, ChAT mRNA decreased in cervical and lumbar motor neurons. These findings suggest that cholinergic interneurons in striatum in SOD1 transgenic mice are over-activated in an attempt to compensate for the death of spinal motor neurons.

Adaptation, Physiological↗
PubMed1999

Respiratory response to exercise in postpolio patients with severe inspiratory muscle dysfunction.

OBJECTIVES: To evaluate the limiting factors of exercise performance and to analyze the respiratory strategies adopted during exercise in postpolio patients with severe inspiratory muscle dysfunction. PATIENTS: Five patients with prior poliomyelitis associated with scoliosis and with respiratory muscle dysfunction (mean vital capacity, 1.74L [range, 1.1 to 2.4]) were studied at rest and during leg or arm cycle exercise. METHODS: Gas exchange was examined by arterial blood gases and mass spectrometry of expired air. Ventilatory mechanics were studied by measurement of esophageal and gastric pressures. RESULTS: Blood gases at rest were normal, except for subnormal PO2 levels in three patients. In all but one patient, ventilatory insufficiency was the limiting factor for exercise. A compensatory breathing pattern with abdominal muscle recruitment during expiration was present already at rest in three of the patients. The pressures generated by the diaphragm were below fatiguing margins, ie, levels that in healthy subjects can be sustained for at least 45 minutes. CONCLUSIONS: The extent of ventilatory dysfunction was not evident in blood gas values at rest; however, it was revealed by blood gas values during the exercise test. Diaphragm fatigue seems to be avoided at the cost of impaired blood gases.

Adult↗
PubMed1999

Spectra and air-kerma strength for encapsulated 192Ir sources.

The photon spectra in vacuum around four types of 192Ir HDR brachytherapy sources are calculated using the Monte Carlo code EGS4 and the most recent spectral information on 192Ir decay. The air-kerma strengths per unit activity are calculated based on the photon fluence around a bare 192Ir source and around each of four types of encapsulated sources using recent mass energy-absorption coefficients. For the full spectrum the bare vs encapsulated difference is up to 23% due to the large air-kerma contribution from the unfiltered low-energy photons. For the penetrating part of the photon spectrum (> 11.3 keV), the air-kerma strength per unit source activity on the transverse axis for a bare source is 2-15% higher than for the encapsulated sources due to the attenuation and absorption in the core and the encapsulating material. The contribution to the air-kerma strength from photons scattered in the capsule and from bremsstrahlung are calculated to increase the air-kerma strength by 2-4% and 0.2-0.3%, respectively. Air-kerma strengths for a variety of sources agree well with previously reported results for sources from Nucletron International, Best Industries, Inc., and Alpha-Omega Services, Inc. In addition we present air-kerma strengths for the present model of the HDR source from Nucletron International and the source from Varian Associates, Inc.

Brachytherapy↗
PubMed1999

Motor neuropathy in porphobilinogen deaminase-deficient mice imitates the peripheral neuropathy of human acute porphyria.

Acute porphyrias are inherited disorders caused by partial deficiency of specific heme biosynthesis enzymes. Clinically, porphyrias are manifested by a neuropsychiatric syndrome that includes peripheral neuropathy. Although much is known about the porphyrias' enzyme defects and their biochemical consequences, the cause of the neurological manifestations remains unresolved. We have studied porphyric neuropathy in mice with a partial deficiency of porphobilinogen deaminase (PBGD). PBGD-deficient mice (PBGD-/-) imitate acute porphyria through massive induction of hepatic delta-aminolevulinic acid synthase by drugs such as phenobarbital. Here we show that PBGD-/- mice develop impairment of motor coordination and muscle weakness. Histologically femoral nerves of PBGD-/- mice exhibit a marked decrease in large-caliber (>8 microm) axons and ultrastructural changes consistent with primary motor axon degeneration, secondary Schwann cell reactions, and axonal regeneration. These findings resemble those found in studies of affected nerves of patients with acute porphyria and thus provide strong evidence that PBGD deficiency causes degeneration of motor axons without signs of primary demyelination, thereby resolving a long-standing controversy. Interestingly, the neuropathy in PBGD-/- mice developed chronically and progressively and in the presence of normal or only slightly (twofold) increased plasma and urinary levels of the putative neurotoxic heme precursor delta-aminolevulinic acid. These data suggest that heme deficiency and consequent dysfunction of hemeproteins can cause porphyric neuropathy.

Acute Disease↗
PubMed1998

The effect of the nonpeptide neurotrophic compound SR 57746A on the progression of the disease state of the pmn mouse.

1. The progressive motor neuronopathy (pmn) mouse is an autosomal recessive mutant, in which the homozygotes suffer caudio-cranial degeneration of motor axons and die several weeks after birth. This strain provides the opportunity of testing potential therapeutic strategies for the treatment of motor neurone diseases such as amyotrophic lateral sclerosis. We have performed a study of the effects on the pmn mouse of SR 57746A, an orally-active, non-peptide compound which has been found to exhibit neurotrophic effects in vitro and in vivo. In order to treat the affected mice from birth, the mothers were administered 2.5 mg kg(-1). p.o., SR 57746A every two days until the weaning of the offspring (at day 20); then the offspring were given every two days a dose of 30 microg kg(-1), p.o., until their death. 2. Affected mice treated with SR 57746A had a lifespan 50% longer than that of the vehicle-treated mice (P=0.01). Compared to vehicle-treated pmn mice, SR 57746A improved the performance of the pmn mice in three different behavioural tasks. SR 57746A also maintained the amplitude of the motor evoked response of the gastrocnemius muscle, reduced the distal motor latency, and delayed the occurrence of the spontaneous denervation activity in this muscle. Histological studies indicated that at 20 days of age the mean surface areas of the fibres of the sciatic nerve were higher in SR 57746A-treated than in vehicle-treated mice. 3. At present, SR 57746A is the only orally active, nonpeptide compound known to be capable of delaying the progression of the motor neurone degeneration in pmn mice.

Animals↗
PubMed1998

Obstructive sleep apneas in relation to severity of cervical spinal cord injury.

Thirty-three subjects (28 men, five women) with complete or incomplete cervical cord injury representing a wide range of neurological impairment were investigated with regard to the prevalence of Obstructive Sleep Apnea (OSA). The relation between OSA and neurological function, respiratory capacity, body mass index and symptoms associated with OSA were studied. Overnight sleep recordings employed combined oximetry and respiratory movement monitoring. Pulmonary function tests included static and dynamic spirometry, maximal static inspiratory and expiratory pressures at the mouth. The subjects answered a questionnaire concerning sleep quality and tiredness. The prevalence of OSA was 15% (5/33) in this nonobese cervical cord injury study population. Nine percent of the subjects (3/33) fulfilled the criteria for obstructive sleep apnea syndrome, but daytime sleepiness or fatigue were also common in subjects without OSA. There was an inverse correlation between oxygen desaturation index and American Spinal Injury Association (ASIA) motor score in the subjects with complete injury, while there was no such correlation in the whole study group. There were significant correlations between maximal inspiratory and expiratory pressures and vital capacity and between ASIA motor score and vital capacity.

Adult↗
PubMed1997

MLP-deficient mice exhibit a disruption of cardiac cytoarchitectural organization, dilated cardiomyopathy, and heart failure.

MLP is a LIM-only protein of terminally differentiated striated muscle cells, where it accumulates at actin-based structures involved in cytoarchitecture organization. To assess its role in muscle differentiation, we disrupted the MLP gene in mice. MLP (-/-) mice developed dilated cardiomyopathy with hypertrophy and heart failure after birth. Ultrastructural analysis revealed dramatic disruption of cardiomyocyte cytoarchitecture. At birth, these hearts were not hypertrophic, but already abnormally soft, with cell-autonomous and MLP-sensitive alterations in cytoarchitecture. Thus, MLP promotes proper cardiomyocyte cytoarchitecture, whose perturbation can lead to dilated cardiomyopathy. In vivo analysis revealed that MLP-deficient mice reproduce the morphological and clinical picture of dilated cardiomyopathy and heart failure in humans, providing the first model for this condition in a genetically manipulatable organism.

Animals↗
PubMed1997

Progressive motor neuron impairment in an animal model of familial amyotrophic lateral sclerosis.

Mutations of Cu,Zn superoxide dismutase cause an autosomal dominant form of familial amyotrophic lateral sclerosis. An animal model of the disease has been produced by expressing mutant human SOD1 in transgenic mice (G93A). In order to quantify the dysfunction of the motor unit in transgenic mice, electromyographic recordings were performed during the course of the disease. The first alterations in neuromuscular function appeared between P63 and P90. The deficits became even more striking after P100; compound muscle action potentials in the hindlimb decreased by 80% of initial value. Spontaneous fibrillation potentials were measured in more than 50% of transgenic mice. The number of motor units in the gastrocnemius muscle was progressively reduced over time, down to 18% of the control value at P130. Moreover, distal motor latencies increased after P120. These data suggest that the initial dysfunctions of motor unit are related to a severe motor axonal degeneration, which is followed at later periods by myelin alteration.

Amyotrophic Lateral Sclerosis↗
PubMed1997

Sternocleidomastoid muscle responses to transcranial magnetic stimulation in patients with cervical dystonia.

Ten cervical dystonia (CD) patients, with involuntary head rotation to one side and contralateral sternocleidomastoid muscle (SCM) hypertrophy, were investigated with transcranial magnetic stimulation, and the results were compared to those of 10 healthy subjects. Monopolar needle electrodes with isolated shafts were used for bilateral electromyographic recordings in the SCMs of the motor evoked potentials (MEPs) elicited by the magnetic stimulator. The latencies of ipsilateral SCM MEPs were shorter in the CD patients than in the control subjects (P < 0.001). The latencies of SCM activity suppression by TMS were longer in the CD patients than in the control group when stimuli were given on the contralateral side (P < 0.05). Both the clinically dystonic and the contralateral SCM of the CD patients exhibited significantly abnormal latencies of the ipsilateral SCM MEPs (P < 0.01) and of the SCM suppression (P < 0.05). Three CD patients also had consistent activity in the SCM counteracting the direction of head rotation during the suppression experiments. The latencies of the suppression of this abnormal activation were shorter (P < 0.05), than the latencies of the suppression in the SCM during normal voluntary activation by these CD patients (i.e. rotation of the head in the contrary direction). The results suggest bilaterally enhanced motoneuronal excitability and disturbed inhibitory regulation in patients with CD.

Adult↗
PubMed1996

Enhancement of mouse sciatic nerve regeneration by the long chain fatty alcohol, N-Hexacosanol.

The purpose of the present study was to determine the effects of n-hexacosanol (hexa) on nerve regeneration. Hexa, a long chain fatty alcohol has been shown to possess neurotrophic properties on cultured neurons and to attenuate the degeneration of cholinergic neurons after injury. The effects of daily intraperitoneal injections of hexa (1 mg/kg) on regeneration of nerve fibers were studied in mice following a sciatic nerve crush. Measurement of axonal regeneration using the pinch test 7 days postlesion showed a 40% increase of the regeneration rate of sensory fibers in hexa-treated mice compared to controls (1.67 +/- 0.15 mm/day and 1.09 +/- 0.03 mm/day, respectively). The recovery of neuromuscular function was significantly improved, as shown by quantitative electromyography and and sensorimotor tests. Clinical signs of recovery evaluation with toe spreading reflex appeared earlier in hexa group than in control animals. Electrophysiological recordings were performed each 3 days during 34 days following nerve injury. Higher values of the compound muscle action potential (CMAP) were obtained in hexa-treated animals that correspond to an improved regeneration. Moreover, hexa induced a significantly faster regeneration rate (hexa: 2.87 +/- 0.15 mV/day; control: 2.00 +/- 0.06 mV/day), as measured by the slope of CMAP increase (44% enhancement). A morphometric analysis performed 7 days following crush showed an increased number of regenerating fibers, as well as increased diameter and thickness of the myelin in hexa-treated mice. Thus, hexa increased the regeneration of both sensory and motor axons in lesioned nerve, leading to an improved functional recovery.

Animals↗