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Biomedical subjects

S U Walkley

Publications and source records attributed to S U Walkley.

54 records · Page 3Linked to original sources
PubMed1987

Sphingomyelin lipidosis in a cat.

A 7-month-old Balinese cat with progressive neurological dysfunction had histopathological lesions of brain, liver, kidney, spleen, and lung consistent with a lysosomal storage disease. Ultrastructural examination revealed lysosomal hypertrophy with membranous inclusions. Hepatic sphingomyelin and cholesterol were elevated 10 times normal, and total phospholipids were increased 3.6 fold. Sphingomyelinase activity measured with 14C labeled sphingomyelin at pH 5.0 was virtually absent in brain and liver. Other lysosomal hydrolase activities were normal or elevated. Clinical, morphological, and biochemical findings suggest that this cat had sphingomyelin lipidosis similar to human Niemann-Pick disease type A, and that feline sphingomyelin lipidosis provides another model of human lysosomal storage disease.

Animals↗
PubMed1986

Ferric ion-ferrocyanide staining in ganglioside storage disease establishes that meganeurites are of axon hillock origin and distinct from axonal spheroids.

Ferric ion-ferrocyanide staining and safranin-0-counterstaining of neocortical tissue from cats with GM1 gangliosidosis have established that pyramidal neuron meganeurites occur proximal to axonal initial segments and that they are distinct from axonal spheroids. The latter, which were found to be widely distributed throughout cerebral cortex, were located distal to axonal initial segments and could be differentiated from meganeurites at both light and electron microscopic levels. This report confirms an earlier electron microscopic study which suggested that meganeurites are of axon hillock origin, and illustrates the striking distinction between abnormalities in the soma-dendritic and axonal domains of neurons in a lysosomal storage disease.

Animals↗
PubMed1985

Altered patterns of evoked synaptic activity in cortical pyramidal neurons in feline ganglioside storage disease.

Postsynaptic potentials evoked by ventrolateral thalamic stimulation were recorded intracellularly from neurons in the precruciate cortex of GM1 mutants with HRP- or LY-loaded microelectrodes. Ganglioside-laden pyramidal neurons exhibiting somal distention and/or meganeurite formation were found to respond to thalamic stimulation with short duration IPSPs. Evoked EPSPs were recorded from two morphologically characterized large basket intrinsic neurons which deployed extensive intracortical axonal arborizations. These findings point to the preservation of intracortical inhibitory networks in the feline model of GM1 gangliosidosis, and to the possibility of abnormal integration of somadendritic inputs in ganglioside-laden pyramidal neurons.

Animals↗
PubMed1985

GM2 gangliosidosis in a Japanese spaniel.

A storage disease in a 2-year-old Japanese Spaniel resembled a GM2 gangliosidosis previously identified in a now extinct line of German Shorthaired Pointers. Despite a later appearance of signs in the Japanese Spaniel, the distribution, staining, and ultrastructure of the stored material were similar in the two breeds. Golgi studies of cerebral cortical neurons revealed the formation of spiny and aspiny enlargements at the axon hillock region (meganeurites) and the growth of secondary neurites from this region. As in the German Shorthaired Pointer model, there was massive storage of GM2 ganglioside as well as a seemingly paradoxical increase in total beta-hexosaminidase activity measured in vitro.

Animals↗
PubMed1985

Ectopic dendritogenesis occurs on cortical pyramidal neurons in swainsonine-induced feline alpha-mannosidosis.

Golgi staining has revealed that ectopic neurites sprout from the axon-hillock region of cortical pyramidal neurons in kittens with swainsonine-induced alpha-mannosidosis. These new growth processes appeared qualitatively identical to those reported in a variety of inherited neuronal storage diseases including the gangliosidoses. In the latter, such processes have been shown to be dendritic-like and postsynaptic to afferents of unknown origin. We believe this to be the first demonstration of induced dendritogenesis in the mammalian CNS and a model system which should prove useful in exploring this remarkable phenomenon occurring in neuronal storage disorders.

Alkaloids↗
PubMed1984

Locoweed-induced neuronal storage disease characterized by meganeurite formation.

Golgi staining was performed on cerebral cortex and thalamus of adult animals chronically intoxicated with an alpha-mannosidase inhibitor found in locoweed (Astragalus lentiginosus). The widespread occurrence of large, aspiny meganeurites was discovered on cortical pyramidal and thalamic principal neurons but aberrant spines and neurite growth were not observed. Ectopic neurite growth is known to be characteristic of alpha-mannosidosis of early onset in inherited and induced feline models. The absence of neuritogenesis in a storage disease known to be so characterized when induced in younger animals suggests that this unusual phenomenon is in some way linked to normal developmental processes associated with brain maturation.

Animals↗
PubMed1984

Decreased catalepsy response to haloperidol in the genetically dystonic (dt) rat.

The rat mutant dystonic displays an autosomal recessive neurological disease characterized by slow, twisting movements of the limbs and trunk. Rats displaying clinical signs also show a decreased behavioral response to the dopaminergic blocker, haloperidol. Investigation of the development of the cataleptic response to haloperidol in the dystonic (dt) rat indicated that the response of the dt rat in the bar test is similar to that of normal littermates until after the appearance of clinical symptoms in the mutants on postnatal day 10. Mutant rats did not differ from their normal littermates in response to another cataleptic agent, morphine. Assessment of the integrity of the nigrostriatal dopamine (DA) system did not indicate the presence of any degenerative process or of any alterations in DA metabolism. No reliable differences were found between normal and dt rats in striatal DA levels or turnover rates; in DA levels in response to gamma-hydroxybutyrolactone; or in the number and affinity of striatal DA muscarinic acetylcholine receptors. Nor did qualitative light microscopic examination of Golgi-impregnated tissue from dt rats indicate the presence of any morphological abnormalities in the striatum. These findings suggest that dystonic symptoms can occur in the absence of an alteration in striatal DA metabolism and that the dt rat may have a defect in a pathway efferent to the striatum.

4-Butyrolactone↗
PubMed1984

Sphingomyelin lipidosis in a cat: Golgi studies.

Alterations in neuronal geometry in a feline model of sphingomyelin lipidosis were evaluated using Golgi staining. Neurons in cerebral cortex, basal ganglia, amygdala, thalamus, and cerebellum were impregnated and many were found to possess conspicuous enlargements at the axon hillock-initial segment region (meganeurites) and/or to sprout secondary neuritic processes from this same area. The latter were sometimes well developed and resembled small dendrites. These changes were cell type specific with distribution limited to certain types of neurons in select brain regions, while others remained normal, or underwent only simple somatic enlargement or generalized degenerative changes. Occasional cortical pyramidal neurons also displayed thinning of dendrites and extensive loss of dendritic spines. These observations add sphingomyelin lipidosis to other neuronal storage disorders in which aberrant neurite growth and meganeurite formation accompany lysosomal enzyme deficiency and the associated metabolic alterations and storage. Although meganeurite-like expansions have been reported to occur in many storage disorders, the appearance of axon hillock-associated neurite growth on morphologically mature neurons has been identified heretofore only in the gangliosidoses, and in feline models of alpha-mannosidosis and mucopolysaccharidosis type 1.

Amygdala↗
PubMed1984

Characterization of the rat mutant dystonic (dt): a new animal model of dystonia musculorum deformans.

An inherited neurological disorder characterized by sustained twisting movements during waking has been discovered in Sprague-Dawley rats. The mutation follows an autosomal recessive pattern of inheritance and has been named dystonic (dt). The rat mutants are indistinguishable from normal littermates in open field behavior and climbing activity prior to postnatal days 9 to 10. Clinical signs begin to appear on day 10 and include twisting of the axial musculature, hyperflexion of the trunk, self-clasping of forelimbs and hindlimbs, and poor placement of the limbs during locomotion. No morphological lesions of neural or non-neural tissues have been observed with routine light microscopy. Dystonic rats demonstrate significantly elevated cerebellar norepinephrine levels, although levels in other terminal fields of the locus ceruleus are similar to those of normal littermates. No differences in the pattern or density of noradrenergic innervation were apparent in cerebellar tissue from dt rats examined with histochemical fluorescence techniques. These mutants were less sensitive than unaffected littermates to the akinesic effects of the dopamine blocker haloperidol. However, striatal dopamine levels were not reliably different from normal in dt rats, and their response to the movement-stimulating effects of apomorphine appeared normal. These findings suggest the presence of biochemical disturbances in the extrapyramidal system of dt rats. The dt rat may provide a useful model for human dystonia musculorum deformans.

Aging↗
PubMed1982

Onset and regression of neuroaxonal lesions in sheep with mannosidosis induced experimentally with swainsonine.

A group of young sheep were fed a diet containing the alpha-mannosidase inhibitor swainsonine, which resulted in the induction of a neuronal lysosomal mannoside storage disease. Sheep were killed at various intervals during and following the treatment period and the nature and distribution of neuronal and axonal lesions in the brain were assessed by routine light and electron microscopy and by the rapid Golgi impregnation technique. Neuronal mannoside storage, axonal dystrophy and meganeurite formation were induced by 80 days of treatment and the lesions had regressed by 40 days after the end of treatment. The results are discussed in relation to their relevance to the current widespread interest in the pathobiology of neuronal lysosomal storage.

Alkaloids↗
PubMed1981

Ultrastructure of neurites and meganeurites of cortical pyramidal neurons in feline gangliosidosis as revealed by the combined Golgi-EM technique.

Application of the Golgi-EM technique to the study of altered cortical pyramidal neuron morphology in feline gangliosidosis has revealed the presence of aberrant synapses in relation to multiple neurites and secondary neurites of meganeurites. In addition fine neurites arising from the soma and meganeurite are found to project into and envelope elements of the surrounding neuropil. These observations provide further evidence for a disturbance in neuronal surface membrane regulation in ganglioside storage disease.

Animals↗
PubMed1981

Alterations in neuron morphology in feline mannosidosis. A Golgi study.

Studies using the Golgi method were performed on neocortical and cerebellar tissues from a 9-month-old cat with a history of progressive neurological deterioration and a subsequently demonstrated deficiency of the lysosomal enzyme alpha-D-mannosidase in both neural and non-neural tissues. Many cortical pyramidal neurons demonstrated morphological alterations involving formation of abnormal enlargements (meganeurites) at the axon hillock-initial segment area, abnormal sprouting of neurites (secondary neurites) in this same region, and various types of dendritic changes, such as formation of focal enlargements, thinning, and spine loss. Many nonpyramidal neurons also were abnormal but displaced only dendritic changes similar to those seen in pyramidal neurons. Cerebellar Purkinje cells displayed dendritic systems marked by focal swellings and often demonstrated one or more enlargements within axons (axonal spheroids) at some distance from otherwise normal-appearing cell bodies. Feline mannosidosis appears to be another of the lysosomal storage diseases in which highly specialized morphological changes accompany storage of unmetabolized substrate and contribute to the pathogenesis of the disease process.

Animals↗
PubMed1979

The gangliosidoses: comparative features and research applications.

Ganglioside storage diseases are inherited defects of lysosomal hydrolases that result in intralysosomal accumulation of gangliosides and other complex metabolites. Gangliosidoses occur in man, cats, cattle, dogs and swine. In all species, these diseases are characterized clinically by relentlessly progressive neurological deterioration. Lysosomal hypertrophy with characteristic ultrastructural inclusions occur in neurons, endothelial and other cells. Definitive diagnosis requires biochemical identification of the storage product and enzyme deficiency. Gangliosidoses in animals are important models of human lysosomal diseases and may be a significant complication in the maintenance of certain purebred stocks of domestic animals.

Animals↗
PubMed1978

Description of obesity in the PBB/Ld mouse.

A new strain of obese mouse, the PBB/Ld, has been studied in terms of fat pad cellularity, serum insulin and blood glucose levels, and response to gold thioglucose injections. Age-matched C57B1/6J mice were used as controls. Adipocyte size and number in the major fat depots were determined at various ages from weanling to maturity in the PBB/Ld and C57B1/6J strains. Results indicated that obesity in the PBB/Ld was due to hypertrophy of adipocytes in retroperitoneal and subcutaneous fat depots and to hypertrophy and hyperplasia in the epididymal fat pad. PBB/Ld mice also developed hyperinsulinemia and hyperglycemia and these findings have been discussed in terms of the developmental changes in fat pad cellularity. The injection of gold thioglucose led to increased food intake in both PBB/Ld and C57B1/6J mice. Hyperphagia was also present in the PBB/LD control group, but increased efficiency of converting calories to body weight was not observed in this group when compared to control C57B1/6J mice. The characteristics of obesity seen in the PBB/Ld mouse are discussed and comparisons are made to similar studies in other rodent models of obesity.

Animals↗
PubMed1976

Animal models of diabetes and obesity, including the PBB/Ld mouse.

Diabetes mellitus occurs in many animals species. However, only a few have been utilized in systematic studies designed to answer unsolved problems associated with the disorder in man such as molecular basis, pathogenesis of the vascular and neural lesions, and the roles of diet, exercise and obesity. Among the animal models available, rodents have been studied most thoroughly for a number of reasons: a) short generation time (sexually mature at about 3 mo of age, gestation time 21 days) and life-span is approximately 3 yr; b) hyperglycemia and/or obesity is known to be inherited in several species; c) environmental factors can be controlled easily in the laboratory because of small size; and d) economic considerations. The better-known rodent diabetes/obesity syndromes may be categorized as follows: 1) hyperglycemic with ketoacidosis, nonobese (Chinese hamster, South African hamster); 2) hyperglycemic with insulin hypersecretion, moderate obesity and may develop ketoacidosis (diabetic mouse (db/db), spiny mouse, sand rat); and 3) less pronounced hyperglycemia with hyperinsulinemia, insulin "resistance" and marked obesity (obese (ob/ob), yellow (Ay) and New Zealand obese (NZO) mice, and the Zucker "fatty" rat). The PBB/Ld mouse, described here in detail for the first time, is a new strain of mouse that also fits into the latter category. Members of this strain following maturity develop an obesity that is characterized by increasing cellularity of adipose tissue, increased serum immunoreactive insulin, reduced glucose tolerance, fatty liver, and hyperlipidemia. Therefore, this strain of mouse represents another model for study of adult onset obesity.

Adipose Tissue↗
PubMedDate not supplied

The clinical and pathologic heterogeneity of feline alpha-mannosidosis.

Three Domestic Long-haired cats from a litter of five afflicted with alpha-mannosidosis (alpha-mannosidosis) were studied clinically and pathologically. Many of these findings contrasted with those made previously in kittens with deficiency of alpha-mannosidase. In these cats, the clinical signs were generally milder, more slowly progressive, and did not include the prominent skeletal deformities, ocular abnormalities, or hepatomegaly that were reported in prior studies of Persian and Domestic Short-haired kittens. While the Domestic Long-haired cats were spared the central nervous system (CNS) myelin deficiency, which was severe in the Persian but mild in the Domestic Short-haired cats, the extensive loss of Purkinje cells in their cerebellar cortices was without precedent. Additionally, ultrastructural study of the neuronal cytosomes showed a diversity not recorded in the earlier cases. The observed phenotypic heterogeneity was sufficient enough to consider separating feline alpha-mannosidosis into severe, acute and milder, chronic forms in a manner analogous to the Type I and Type II distinctions made in infants and juveniles.

Animals↗