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Biomedical subjects

A J Hudson

Publications and source records attributed to A J Hudson.

At least 37 records · Page 2Linked to original sources
PubMed1994

Frontal lobe atrophy in motor neuron diseases.

Neuronal degeneration in the precentral gyrus alone cannot account for the occurrence of spastic paresis in motor neuron diseases. To look for more extensive cortical atrophy we measured MRIs of the upper parts of the frontal and parietal lobes in 11 sporadic cases of classical amyotrophic lateral sclerosis (ALS), eight patients with primary lateral sclerosis (PLS) and an age- and sex-matched group of 49 neurologically normal people. None of the patients had overt dementia or other mental diseases. In PLS there is progressive spastic paresis but in contrast to ALS there is no lower motor neuron degeneration. The surface area of the precentral gyri and the amount of underlying white matter in PLS were consistently approximately 75% of the normal size. By contrast, there was some shrinkage of the precentral gyri in some of the ALS patients but the mean measurements for the group did not differ significantly from the controls. Anterior to the precentral sulci, the cortical surface area in PLS was approximately 85% of that of the controls, with correspondingly reduced white matter. In ALS the cortical surface areas of the anterior frontal lobes did not differ from those of the controls, but the amount of underlying white matter was reduced almost as much in ALS as it was in PLS. The measured changes in the frontal lobes suggest that in PLS there is simultaneous atrophy of the primary, premotor and supplementary motor areas of the cortex, with consequent degeneration of corticospinal and corticoreticular axons descending through the underlying white matter. These changes could account for the progressive upper motor neuron syndrome. In ALS, with no significant frontal cortical atrophy, the shrinkage of the white matter may be due to degeneration of axons projecting to the frontal cortex from elsewhere. Deprivation of afferents could explain the diminution of motor functions of the frontal lobes in ALS and also the changes in word fluency, judgement and attention that can be detected by appropriate testing in some patients with the disease. Incidental observations include slightly larger parietal lobes but no difference in the frontal lobes in men as compared with women. There was also a small but significant decrease in size of the normal frontal lobes with age. The latter change was much smaller than the atrophy seen in patients with ALS and PLS.

Adult↗
PubMed1993

Overproduction, purification and characterization of the Escherichia coli ferritin.

Recent studies have indicated that Escherichia coli possesses at least two iron-storage proteins, the haem-containing bacterioferritin and ferritin. The ferritin protein has been amplified 600-fold to 11-14% of total cell protein in a bfr mutant and purified to homogeneity with an overall yield of 13%. The cellular ferritin content remained relatively constant throughout the growth cycle and amplification was accompanied by a 2.5-fold increase in cellular iron content. The isolated ferritin contained 5-20 non-haem iron atoms/holomer and resembled the eukaryotic ferritins rather than the prokaryotic bacterioferritins in containing no haem. The 24 subunits of this ferritin (M(r) 19,400) assemble into a spherical protein shell (12 +/- 1 nm diameter, M(r) 465,000) which sequesters at least 2000 iron atoms in vitro to form an electron-dense iron core of 7.9 +/- 1 nm diameter. Electron-microscopic and Mössbauer spectroscopic studies with iron-loaded ferritin showed that the core can be either crystalline (ferrihydrite) or amorphous, depending on the absence or presence of phosphate, respectively. Mössbauer spectroscopy with intact E. coli revealed a novel-high spin Fe(II) component which is enhanced in bacteria amplified for ferritin but not in the parental strain. Western blotting showed that ferritin and bacterioferritin are immunologically distinct proteins. E. coli is thus an organism containing both a ferritin and a bacterioferritin and the relative roles of the two iron-storage proteins are discussed in this study.

Amino Acid Sequence↗
PubMed1993

Clinicopathological features of primary lateral sclerosis are different from amyotrophic lateral sclerosis.

Primary lateral sclerosis (PLS) bears close resemblance to cases of amyotrophic lateral sclerosis (ALS) presenting with spasticity, but histopathological studies have shown significant difference between the two conditions. When the lower motor neurons in cases of ALS and PLS are compared with the equivalent cells of control subjects, morphometric studies indicate significantly decreased size and increased convexity (rounding) of the cell bodies only in ALS. In both disorders there is loss or shrinkage of the largest cortical motor neurons (Betz cells) in the primary motor cortex, though this change is not conspicuous in all cases of ALS. Morphometry reveals in both diseases a general reduction in the sizes of pyramidal cells in the precentral gyrus, indicating that smaller neurons are involved. The cortical motor neurons shrink more in PLS than in ALS. It is concluded that there is clear difference between ALS and PLS. In PLS, quantitative histopathological data show that the neuronal degeneration is confined to long descending pathways, notably the corticospinal system, with no concomitant involvement of lower motor neurons. In ALS, lower motor neuron degeneration occurs in all cases, whereas involvement of the motor cortex is variable.

Aged↗
PubMed1993

Molecular basis of Thomsen's disease (autosomal dominant myotonia congenita).

Thomsen's disease (autosomal dominant myotonia congenita) has recently been linked to chromosome 7q35 in the region of the human skeletal muscle chloride channel gene (HUMCLC). Single strand conformation polymorphism analysis (SSCP) was used to screen DNA from members of four unrelated pedigrees with this disorder for mutations in HUMCLC. Abnormal bands were detected in all affected, but no unaffected individuals in three of the families. Direct sequencing revealed a G to A transition that results in the substitution of a glutamic acid for a glycine residue located between the third and fourth predicted membrane spanning segments. This glycine residue is conserved in all known members of this class of chloride channel proteins. These findings establish HUMCLC as the Thomsen's disease gene.

Amino Acid Sequence↗
PubMed1993

Changes in shapes of surviving motor neurons in amyotrophic lateral sclerosis.

In amyotrophic lateral sclerosis, motor neurons in the spinal cord and brainstem shrink before they die. In 12 cases of sporadic amyotrophic lateral sclerosis, and in 11 control subjects, we have measured the neurons in the second sacral segment and the hypoglossal nucleus, and have calculated a 'shape index' that shows the convexity or concavity of the cell body. (The shape index, SI = 100 x C/P, where C is the circumference of the largest circle that can be inscribed in the neuron and P is the perimeter of the perikaryon, including the bases of the dendrites as seen in a Nissl preparation. The shape index increases with increasing convexity of the cell.) In the ventral horn of segment S2 and in the hypoglossal nucleus, the surviving motor neurons in amyotrophic lateral sclerosis showed significantly decreased size and increased shape index (convexity) of the cell bodies. By contrast, the nucleus of Onuf in segment S2, consisting of neurons that supply the pelvic floor muscles, was preserved in amyotrophic lateral sclerosis. Its cells did not differ significantly in size or convexity between the amyotrophic lateral sclerosis and control groups. In both the hypoglossal and S2 neuronal populations in amyotrophic lateral sclerosis, the sizes of the cells were positively correlated with the numbers of surviving motor neurons. However, there was no correlation of the shape index with numbers of cells. This is interpreted as due to shrinkage of neurons still taking place at the time of death, when the changes in shape were probably largely completed. These observations indicate that the mechanism of neuronal atrophy in amyotrophic lateral sclerosis may involve both reduced protein synthesis and enzymatic degradation of the cytoskeleton within the larger dendrites.

Aged↗
PubMed1993

Anti-neurone antibodies are not characteristic of amyotrophic lateral sclerosis.

Autoantibodies, a suggested cause of motor neurone degeneration in amyotrophic lateral sclerosis (ALS), were sought immunohistochemically after applying diluted sera to sections of normal human spinal cord. Serum from a case of paraneoplastic motor neurone disease provided a positive control, giving strong staining of motor neurones for IgG but not IgM. The sera of 11 of 21 ALS patients contained IgG that could bind to motor neurones, but similar antibodies occurred also in 5 of 8 subjects with other nervous system disorders and in 3 of 9 neurologically normal controls. Bound IgM was more weakly stained than IgG, and was seen as often with control as with ALS sera. These findings do not support the notion that humoral autoantibodies mediate neuronal destruction in ALS.

Adult↗
PubMed1992

Motor-evoked responses in primary lateral sclerosis.

Primary lateral sclerosis (PLS) may be distinguished on the basis of clinical and pathological features from amyotrophic lateral sclerosis (ALS). The former is featured by a much longer clinical course, exclusively upper motor neuron findings, losses of precentral pyramidal neurons, and preservation of anterior horn cells. Electrophysiological studies of 7 PLS cases have shown normal peripheral motor conduction, absent or very delayed motor-evoked potentials, the occasional late development of denervation activity in distal muscles, and normal somatosensory-evoked potentials.

Aged↗
PubMed1992

Exclusion of linkage between hypokalemic periodic paralysis (HOKPP) and three candidate loci.

Hypokalemic periodic paralysis (HOKPP) is an autosomal dominant neuromuscular disorder characterized by flaccid paralysis accompanied by lowered serum potassium levels. We have tested polymorphic markers linked to the adult skeletal muscle sodium channel (SCN4A) locus at 17q23-q25, the T-cell receptor beta (TCRB) locus at 7q35, and the H-Ras cellular proton-cogene locus (HRAS) at 11p15.5 for linkage with the affected phenotype in a single multigenerational pedigree. No evidence for genetic linkage to HOKPP was found at any of the candidate loci.

Chromosome Mapping↗
PubMed1992

Primary lateral sclerosis. Clinical features, neuropathology and diagnostic criteria.

Eight patients with a homogeneous syndrome of progressive symmetric spinobulbar spasticity were studied. Clinical features were limited to those associated with dysfunction of the descending motor tracts and included spastic quadriparesis, pseudobulbar affect, spastic dysarthria, hyper-reflexia and bilateral Babinski signs. Lower motor neuron findings were absent and higher cognitive function preserved. Median age of onset was 50.5 yrs and median disease duration was 19 yrs. Neuropathologic features (including morphometric analysis) in the single autopsied case confirmed the selective involvement of the motor cortex. There was complete absence of Betz cells from layer 5 of the precentral cortex and the remaining pyramidal cells were significantly smaller than those seen in normal controls. Magnetic resonance imaging (MRI) revealed atrophy of the precentral gyrus and positron emission tomography (PET) scans showed diminished glucose [18F]fluorodeoxyglucose uptake in the pericentral cortex. Magnetic motor cortex stimulation revealed markedly prolonged central motor conduction times. The literature is reviewed and diagnostic criteria for primary lateral sclerosis based on clinical, laboratory and imaging features are proposed.

Aged↗
PubMed1992

Linkage analysis of candidate loci in autosomal dominant myotonia congenita.

Electrophysiologic studies in patients with autosomal dominant myotonia congenita (ADMC) have implicated defects of both muscle membrane sodium and chloride channels. An adult skeletal muscle sodium channel (ASkM1) gene maps to chromosome 17q23-25, and defects in this gene are almost certainly responsible for at least three variants of hyperkalemic periodic paralysis (HPP)--myotonic HPP, nonmyotonic HPP, and paramyotonia congenita. A gene for a muscle chloride channel has not yet been mapped in humans, but has been identified in the mouse. The gene for the cystic fibrosis transmembrane regulator (CFTR), which has chloride channel properties, is located on chromosome 7q31. This region is syntenic with the area of mouse chromosome 6 that contains the muscle chloride channel gene, a defect in which is responsible for the ADR phenotype, a murine model of myotonia. We performed linkage analysis using chromosome 17q polymorphisms at D17S74, SCN4A, and GH1, two chromosome 7q31 restriction fragment length polymorphisms, and a dinucleotide repeat polymorphism within the CFTR gene (CFTR-DNR), in three pedigrees with ADMC. The lod scores obtained show that the locus for ADMC is not at ASkM1 and is excluded from a region of at least 24 cM on either side of the CFTR gene.

Chromosome Mapping↗
PubMed1992

Linkage of Thomsen disease to the T-cell-receptor beta (TCRB) locus on chromosome 7q35.

The chromosomal localization of the gene for Thomsen disease, an autosomal dominant form of myotonia congenita, is unknown. Electrophysiologic data in Thomsen disease point to defects in muscle-membrane ion-channel function. A mouse model of myotonia congenita appears to result from transposon inactivation of a muscle chloride-channel gene which maps to a region of mouse chromosome 6. The linkage group containing this gene includes several loci which have human homologues on human chromosome 7q31-35 (synteny), and this is a candidate region for the Thomsen disease locus. Linkage analysis of Thomsen disease to the T-cell-receptor beta (TCRB) locus at 7q35 was carried out in four pedigrees (25 affected and 23 unaffected individuals) by using a PCR-based dinucleotide repeat polymorphism in the TCRB gene. Two-point linkage analysis between Thomsen disease and TCRB showed a maximum cumulative lod score of 3.963 at a recombination fraction of .10 (1-lod support interval .048-.275). We conclude that the Thomsen disease locus is linked to the TCRB locus in these families.

Base Sequence↗
PubMed1992

Absence of HTLV-I and HTLV-II proviral genome in the brains of patients with multiple sclerosis and amyotrophic lateral sclerosis.

Previous studies have failed to provide serological evidence to incriminate a retroviral infection in the cause of multiple sclerosis. Gene amplification techniques have also failed to identify retroviral footprints in DNA from peripheral blood leukocytes. Here we provide evidence that proviral DNA of HTLV-I and HTLV-II is not found in the central nervous system tissues of patients with multiple sclerosis, patients with amyotrophic lateral sclerosis and controls.

Amyotrophic Lateral Sclerosis↗
PubMed1991

Familial amyotrophic lateral sclerosis, 1850-1989: a statistical analysis of the world literature.

We present clinical and pathologic data on four previously unreported familial ALS pedigrees and review and analyze by descriptive and exploratory statistical techniques all published cases of familial ALS (1850-1989). In contrast to the age-dependent incidence of sporadic ALS, the age of onset of familial ALS is normally distributed about a mean of 45.7 years (std. dev. 11.3 years). Survival curves for the familial ALS data also demonstrate a skewed distribution with a median survival time of 24 months with 74% surviving at 12 months, 48% at 24 months and 23% surviving at 60 months. The patient characteristics of age at onset of disease, sex and focus of disease onset are unrelated variables and age at onset of disease is the only predictor of survival (Cox's proportional hazard model, chi-square 14.74, p = 0.0001). By applying accelerated failure time models with a log-normal baseline distribution, estimated probabilities for survival adjusted by age at onset were calculated. It was found that the older the age at disease onset, the shorter the survival.

Adult↗
PubMed1991

Amyotrophic lateral sclerosis/parkinsonism/dementia: clinico-pathological correlations relevant to Guamanian ALS/PD.

In a recent report on the clinical and pathological features of Guamanian ALS/PD and post-encephalitic parkinsonism/ALS a number of similarities were described, notably in the distribution of neurofibrillary tangles throughout the nervous system. In this account additional pathological features which these disorders share (and which differ from classical ALS, Parkinson's and Alzheimer's diseases) are described. These include atrophy of the globus pallidus and the entire substantia nigra, viz. pars compacta and pars reticulata. Moreover, neither Lewy bodies nor senile plaques are features of the Guamanian and post-encephalitic disorders. The significance of these observations and their relationship, more generally, to parkinsonism, ALS and dementia are discussed.

Alzheimer Disease↗
PubMed1991

Changes in sizes of cortical and lower motor neurons in amyotrophic lateral sclerosis.

It has been suggested that the degeneration of lower motor neurons in amyotrophic lateral sclerosis (ALS) is a transneuronal event, secondary to the loss of corticospinal and corticobulbar neurons. In an attempt to test this hypothesis, the cross-sectional areas of pyramidal cells in layer 5 of the foot and tongue areas of the precentral gyri were measured in 12 cases of the classical sporadic form of ALS, and in 10 control subjects. The areas of motor neurons in the hypoglossal nuclei and in the ventral horns of segment L4 of the spinal cord were also measured. The number of neurons per 20 microns section of ventral horn or hypoglossal nucleus provided a more reliable index of severity of lower motor neuron loss at the time of death than did a semiquantitative score derived from clinical observations. Cortical neurons and lower motor neurons were significantly smaller in the cases of ALS than in the controls. In the cortex this change included, but was not confined to, the largest neurons. These observations indicate that shrinkage precedes neuronal death. There was no correlation, positive or negative, between the numbers of surviving lower motor neurons and the mean sizes of pyramidal cells in layer 5 of the corresponding areas of the precentral gyri. The absence of such a correlation indicates that functionally related cortical and lower motor neurons probably degenerate independently, and not from a transsynaptic effect. Neuronal shrinkage has been observed in other diseases in which interconnected systems of neurons degenerate. The possible association of shrinkage with cytoskeletal degradation is discussed.

Adult↗