Biomedical subjects
Publications and source records attributed to A J Hudson.
Contrary to the accepted feedback control mechanism of glycogen biosynthesis in skeletal muscle, evidence is presented here leading to the conclusion that glycogen does not control the activity of glycogen synthase phosphatase in intact human skeletal muscle tissue.
Guamanian amyotrophic lateral sclerosis with parkinsonism-dementia (ALS/PD) has been the subject of intensive study since its discovery in 1947 because of its extraordinarily high incidence in a small ethnic group (Chamorros) whose dietary lack and customs have suggested possible causes. As yet, these and other suspected causes have eluded proof. Because of marked similarities between Guamanian ALS/PD and late onset post-encephalitic (encephalitis lethargica) parkinsonism and ALS it is suggested that they have a common cause. The parkinsonism and ALS in the two disorders are clinically very similar and neuropathological studies have shown a very similar distribution of neurofibrillary tangles in neurons. Some clinical differences, such as ocular features in the post-encephalitic cases and dementia in Guamanian ALS/PD, can be explained by differences in the severity of infection and the interval between the encephalitis and onset of sequelae. Although unproven, influenza A (HswilN1 strain) has long been suspected as the cause of encephalitis lethargica because of simultaneous pandemics of the two diseases in the 1920s. Because influenza A can persistently infect cells and has a marked propensity to mutate it is an optimal candidate among other RNA viruses for delayed nervous system infection as a possible cause of ALS/PD.
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A newly developed technique for estimating the number of motor units in the biceps-brachialis muscles and for studying the innervation patterns of motor units in the same muscles has been applied to the study of 17 patients with amyotrophic lateral sclerosis (ALS). Although severe motor unit losses were seen in many ALS cases, in most there were clear indications of increases in innervation densities, linked potentials, and blocking. This technique provides a powerful new tool for quantitatively assessing the extent of motor unit losses and the accompanying changes in innervation patterns in ALS.
Six screening methods for the successful detection of significant bacteriuria--electrical impedance (Malthus), automated acridine-orange staining (Autotrak), particle counting (Ramus), bioluminescence, nitrite and leucocyte test strip (BM Nephur), and microscopy--were evaluated. All had excellent predictive values for a negative result (97%-100%) but were less accurate in predicting a positive result (31%-83%). All methods had high sensitivities (83%-100%) but lower levels of specificity (68%-79%). Bioluminescence was the method with the highest specificity (79%) and the lowest rate of false positive results (15%). It would be inappropriate to decide on treatment and management on the basis of the positive results achieved with any of the methods evaluated, but all methods tested could be used for screening out negative results.
Otolaryngological manifestations were examined in a series of 250 patients diagnosed as having ALS between 1976 and 1986. Surgical intervention was only required in 10 cases due to excessive drooling and aspiration. Five patients had submandibular gland excisions with only limited improvement in respect to drooling. One case having a unilateral tympanic neurectomy had significantly better drooling control. Cricopharyngeal myotomy is helpful when dysphagia is predominantly due to cricopharyngeal spasm. In our series, tympanic neurectomy and chorda tympanectomy provide the better control of drooling for these patients and has the added advantage of being performed under local anesthesia.
The patient with ALS can be managed almost entirely as an outpatient by a team consisting of a nurse, physiotherapist, occupational therapist, speech pathologist, nutritionist, respirologist, social worker, and certain other consultants from time to time. The team's goal is to maintain physical function and extend the useful life of the patient through the skills that the team members are trained to provide. Pulmonary function tests, especially spirometry, should be done at regular intervals and a modified barium swallow should also be done at least once in cases with dysphagia. It is possible with these tests to anticipate and even correct a number of hazards, such as upper airway obstruction and aspiration. Some patients are candidates for gastrostomy and tympanic and chorda tympani neurectomy, but full knowledge of their pulmonary function is essential before undertaking any operative procedure. Death in ALS is due to pulmonary failure and the choice of respirator care requires careful deliberation with the family. The neurologist and ALS team should work in close cooperation with the home care personnel in the patient's own community. Does the care of the ALS patient in any way affect survival? In the attempt to answer this question we have estimated the survival of ALS patients in southwestern Ontario, most of whom have visited our clinic over the period of 1978 to 1985, inclusive. As shown in Figure 4, there was an apparent decline in the annual mortality rate over this period, although there was no significant change in the incidence of ALS in this region.(ABSTRACT TRUNCATED AT 250 WORDS)
A study of glucose, insulin, lipids and lipoproteins in myotonic dystrophy (MyD) has shown elevation of fasting plasma insulin, triglycerides and very low density lipoproteins (VLDL) but no significant difference from normal in the fasting plasma glucose, total cholesterol or low and high density lipoproteins. Elevation of the total triglyceride and VLDL levels showed a direct relationship to hyperinsulinaemia. Insulin binding to cultured MyD fibroblasts under optimal conditions was significantly reduced but there was no difference in receptor affinity between MyD and control cells. In contrast to insulin binding, LDL binding to MyD fibroblasts was normal although there was a tendency to reduced LDL binding at 37 degrees C that may reflect mildly reduced lipid metabolism. The alterations in lipids and insulin in MyD are compatible with insulin resistance. Laboratory and clinical findings in MyD were compared with other inherited insulin-resistant diseases. MyD showed marked similarity to a group of disorders that have mild insulin resistance and mildly elevated plasma insulin in contrast to others with severe hyperinsulinaemia and insulin resistance. It is suggested that at least some clinical features of MyD may be due to diminished overall effect of insulin or other trophic factors on cell metabolism.
The ALS symposium in Vancouver was the first of its kind in Canada and was a contribution from both American and Canadian investigators. The main points presented were (1) a definition of what is truly ALS, in the clinical and pathological sense, based on what is called "classical" ALS: (2) how neurons may be cultured to provide a valuable experimental tool; (3) the significance of lipid abnormalities in ALS and the characterization of the ALS-like syndromes produced by hexosaminidase A deficiency; (4) the possible role of autoimmune disease as it may accompany classical ALS and nerve growth factor derived from skeletal muscle; (5) the western Pacific form of ALS as it has been intensely studied and has given rise to two hypotheses on pathogenesis: mineral toxicity caused by secondary hyperparathyroidism and poisoning through ingestion of the cycad seed, and (6) the possible abiotropic interaction of one or many environmental toxins over a lifetime with the aging nervous system, depleting it of its frail reserve of neurons.
Postmortem neuropathological findings in a patient with biopsy-proved familial Gerstmann-Sträussler-Scheinker disease of eight years' duration included severe spongy change in the neocortex, extensive and often large amyloid deposits throughout the cerebral hemispheres and cerebellum, and severe astrocytic gliosis throughout all areas of gray and white matter within the brain. The degree of cortical spongy change was much greater than that in relatives who died with a similar clinical history, indicating the phenotypic heterogeneity in this familial disorder.
A case of motor neuron disease with clinical and pathological resemblance to amyotrophic lateral sclerosis (ALS) in a woman who was severely bitten on the ankle by a cat is described. Weakness first appeared at the ankles and relentlessly advanced proximally, terminating in death from pulmonary failure in a year. A number of unusual features that are uncharacteristic of ALS were found that included a markedly elevated antinuclear antibody titre in the serum and the presence of prominent oligoclonal bands in the cerebrospinal fluid. The spinal cord showed loss of anterior horn cells and pyramidal degeneration that are characteristic of ALS, but an extraordinary finding was the presence of transmural granulomatous inflammation of numerous small and medium sized vessels, especially veins, in the subarachnoid space around the cord. There were also inflammatory changes in the brainstem and spinal cord consisting of microglial and astrocytic nodules and perivenous cuffing by mononuclear cells. Ill-defined hyaline eosinophilic cytoplasmic inclusions were seen in some remaining anterior horn cells. No viral particles were found by electron microscopy despite an extensive search. Virological studies were inconclusive but there is reason to believe that this patient's illness was caused by an as yet unidentified virus.
The incidence, prevalence, and mortality rates of amyotrophic lateral sclerosis in southwestern Ontario, Canada, were determined for the years 1978 through 1982. The average annual incidence rate was 1.63 per 100,000 population. The prevalence rate was 4.9 per 100,000 on January 1, 1983. The average annual mortality rate was 1.52 per 100,000 population and increased with age, reaching a peak in the 70 to 79-year decade in both sexes. The male:female ratio was 1.2:1. The average age at diagnosis was 62.5 years, and the average duration from date of diagnosis was 2.5 years. The distribution of the disease was uneven in 12 counties, with the highest incidence in Perth (3.33) and Essex (2.43) counties. The city of Windsor, in an industrial region, had a high average annual incidence rate of 2.81.
An environmental factor acting on the fetus is thought to cause a neonatal syndrome characterized by marked muscular hypotonia, lack of respiratory drive and feeding difficulties, in some infants born to mothers with myotonic dystrophy. Mortality is high, especially amongst those babies born prematurely, but muscle strength and tone improve rapidly in survivors. Nevertheless, most survivors have physical deformities and mental retardation and are thought to develop myotonic dystrophy later. We propose that alterations in maternal insulin secretion (usual in myotonic dystrophy subjects) alter fetal blood glucose and amino acid levels and retard growth and maturation of fetal skeletal muscle. This leads to severe muscular hypotonia in affected infants. Also, we suggest that infants who die during the perinatal period may not have inherited the defective autosomal dominant gene that causes myotonic dystrophy.
An isozyme of S-adenosylmethionine synthetase has been purified to homogeneity by ammonium sulfate fractionation, DEAE-cellulose column chromatography, and gel filtration on a Sephadex G-200 column. The purified enzyme is very unstable and has a molecular weight of 120 000 consisting of two identical subunits. Amino acid analysis on the purified enzyme showed glycine, glutamate, and aspartate to be the most abundant and the aromatic amino acids to be the least abundant. It possesses tripolyphosphatase activity which can be stimulated five to six times by S-adenosylmethionine (20-40 microM). The findings support the conclusion that an enzyme-bound tripolyphosphate is an obligatory intermediate in the enzymatic synthesis of S-adenosyl-methionine from ATP and methionine.
A family with Gerstmann-Sträussler-Scheinker disease had coincidental clinical onset in three members of two generations, a phenomenon suggesting a common source of a transmissible agent. A regular dietary supplement in this family was home-bred rabbit. The clinical picture, although generally similar to that in previous accounts, included the unusual findings of visual loss (one patient) and sensory loss (one patient), and dementia was not apparent until late in the illness in two patients. Pathological examination of a cerebellar cortical biopsy specimen from one patient and postmortem tissue from two patients revealed multicentric amyloid plaques located in cerebral and cerebellar cortex, basal ganglia, and white matter with degeneration of corticospinal, dorsal spinocerebellar, dentatorubral, and geniculocalcarine tracts and dorsal columns. Spongiform change was focal and confined to the superficial cerebral cortical layers.
Insulin receptor binding was examined in cultured skin fibroblasts from 10 myotonic dystrophy patients and 10 age- and sex-matched control subjects. The conditions for insulin binding to fibroblasts were optimal and employed HEPES binding buffer, pH 8.0 at 15 degrees C for 5 h. These conditions correspond to those previously employed with monocytes from MyD subjects. The normalized initial insulin binding capacity showed a decrease of 62% from 5.04 +/- 0.28% of the total labeled insulin added/mg protein in the control to 1.93 +/- 0.13% in the myotonic dystrophy group (P less than 0.01) due mainly to a marked reduction in high affinity receptors or in receptor affinity. The addition of 1.0 ng/ml of unlabeled insulin produced significant decreases to 3.80 +/- 0.25% in the control group and 1.24 +/- 0.09% in the MyD group. The results are similar to previously reported findings with monocytes from myotonic dystrophy patients and suggest that a surface membrane defect exists in this disease. However, the conditions that have been employed in the binding procedures in all of the studies, while optimal, are performed at a high pH and low temperature and could have an important bearing on the interpretation of a membrane disorder.
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Because serum immunoglobulin G levels are low in patients with myotonic dystrophy, it was hypothesized that it might be catabolized within abnormal muscle fibers. Accordingly, immunohistochemical stains for immunoglobulins were performed on muscle sections derived at biopsy or autopsy from patients with myotonic dystrophy, other forms of muscular dystrophy, nondystrophic muscle disease, or normal muscle. Positive staining for immunoglobulins was found only in necrotic segments of myofibers (in 7 of 19 dystrophic and 6 of 27 nondystrophic subjects), and it is believed that the staining was due to nonspecific diffusion. However, staining reactions distinguished between incipient necrosis and artifactual contraction bands and allowed us to study segmental myofiber necrosis, comparing its frequency in the various muscle diseases. Segmental myofiber necrosis was present in 4 of 16 cases of myotonic dystrophy. The relevance of this finding to the clinical and morphologic features of myotonic dystrophy is discussed.