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Biomedical subjects

L C Cork

Publications and source records attributed to L C Cork.

120 records · Page 7Linked to original sources
PubMedDate not supplied

Developmental expression of alpha 1-antichymotrypsin in brain may be related to astrogliosis.

In the brains of individuals with Alzheimer's disease (AD) and aged monkeys, the serine protease inhibitor alpha 1-antichymotrypsin (ACT) is selectively associated with deposits of amyloid found in senile plaques and in the walls of blood vessels. The origin of ACT in the brains of these aged subjects is unclear. In this study, ribonucleic acid (RNA) blots of human brains show that ACT messenger RNA (mRNA) increases during development. Levels of mRNA were negligible in fetuses and young adults but were increased slightly in normal aged individuals and highest in individuals with AD. In situ hybridization detected ACT transcripts in astrocytes of the cortex, subependymal region, and superficial white matter. The expression of ACT mRNA was highest in subjects with AD, in an adult with Down's syndrome, in an individual with Pick's disease, and in cases of Huntington's disease. In the brains of adult monkeys, ACT expression was detected primarily in astrocytes of the subependyma and white matter. Thus the presence of ACT appears to be related to the response of astrocytes to the brain abnormalities seen in these conditions.

Adolescent↗
PubMedDate not supplied

The neural basis of memory decline in aged monkeys.

Nonhuman primates experience changes in behavior as they progress into old age. Visual recognition, spatial learning, habit formation, and visuospatial manipulation are impaired in aged rhesus monkeys relative to young controls. We have begun to study the possible neural substrate for these changes, focusing on brain areas that are known, from lesion studies, to be essential for the successful performance of specific tasks. Aged nonhuman primates develop senile plaques, most commonly in amygdala, hippocampus, and neocortex. Our preliminary data suggest that the density of plaques may be related to poor behavioral performance in some aged monkeys. However, behavioral decline begins before the appearance of significant numbers of senile plaques, suggesting that other factors may interfere with cognition. Numerous studies of several genera have shown that receptors for neurotransmitters decline in number between the adolescent years and old age. Our autoradiographic analyses of primate temporal neocortex demonstrate loss of muscarinic, nicotinic, dopaminergic and serotoninergic receptor binding sites between the ages of 2 and 22 years. Preliminary data indicate that markers for adenyl cyclase and phosphatidyl inositol second-messenger systems also are reduced in temporal cortex. Although these declines represent a potential substrate for behavioral changes, no studies have directly related a decrease in receptor number to deficits in learning and memory in aged primates. Other changes in the aging brain include loss of neurons, reduced neurochemical markers, and decreased content of neuronal ribonucleic acid (RNA). All of these decrements may be interrelated to some extent in that decreased RNA could result in changes in neurochemical markers and receptors and, eventually, in dysfunction and death of neurons. These observations underscore the importance of establishing a time course for age-associated neural abnormalities, examining regions of brain in which changes are most likely to occur, and studying their relationship to the progression of behavioral dysfunction. Detailed anatomical analyses of the distribution of in situ uptake/receptor binding sites and messenger RNA (mRNA) in aged nonhuman primates may clarify some of the factors that most likely contribute to behavioral changes in elderly humans.

Aging↗
PubMedDate not supplied

Age-related changes in multiple neurotransmitter systems in the monkey brain.

Age-associated changes in cholinergic, monoaminergic and amino acid neurotransmitter systems were analyzed in 14 brain regions of 23 rhesus monkeys that ranged in age from 2 to 37 years. In the frontal pole, the levels of choline acetyltransferase (ChAT) activity, the density of [3H]ketanserin (serotonin type-2) binding sites and endogenous levels of dopamine, homovanillic acid and serotonin, all expressed per milligram of protein, decreased significantly with aging. In precentral motor cortex, ChAT activity decreased; in parietal and occipital cortex, the number of [3H]ketanserin binding sites decreased while the number of Na+-independent [3H]glutamate binding sites increased with age. In the caudate nucleus, endogenous levels of norepinephrine decreased. This descriptive study indicates that the aging monkey may be a very useful model for future investigations of age-associated transmitter abnormalities similar to those that occur in humans.

Age Factors↗
PubMedDate not supplied

Life-long overexpression of S100beta in Down's syndrome: implications for Alzheimer pathogenesis.

Chronic overexpression of the neurite growth-promoting factor S100beta has been implicated in the pathogenesis of neuritic plaques in Alzheimer's disease. Such plaques are virtually universal in middle-aged Down's syndrome, making Down's a natural model of Alzheimer's disease. We determined numbers of astrocytes overexpressing S100beta, and of neurons overexpressing beta-amyloid precursor protein (beta-APP), and assayed for neurofibrillary tangles in neocortex of 20 Down's syndrome patients (17 weeks gestation to 68 years). Compared to controls, there were twice as many S100beta-immunoreactive (S100beta+) astrocytes in Down's patients at all ages: fetal, young, and adult (p = 0.01, or better, in each age group). These were activated (i.e., enlarged), and intensely immunoreactive, even in the fetal group. There were no neurofibrillary changes in fetal or young Down's patients. The numbers of S100beta+ astrocytes in young and adult Down's patients correlated with the numbers of neurons overexpressing beta-APP (p < 0.05). Our findings are consistent with the idea that conditions--including Down's syndrome--that promote chronic overexpression of S100beta may confer increased risk for later development of Alzheimer's disease.

Adult↗
PubMedDate not supplied

Lentiviral diseases of sheep and goats: chronic pneumonia leukoencephalomyelitis and arthritis.

This review describes the pathogenesis of a slowly progressive disease complex caused by naturally occurring nononcogenic retroviruses in sheep and goats. In nature, infections are usually clinically silent, but disease may manifest itself after prolonged incubation periods. Clinically, this is seen as dyspnea, progressive paralysis, and/or progressive arthritis. In all organs the basic lesion is inflammatory with infiltration and proliferation of lymphocytes, plasma cells, and macrophages. Other organ-specific pathologic changes such as primary demyelination in the central nervous system and degeneration of cartilaginous structures in joints accompany inflammation. The viruses infect tissue-specific macrophage populations in vivo. Viral replication in these cells is restricted to minimal levels but continues indefinitely in the animal as a result of either failure to induce specific neutralizing antibodies or antigenic drift when neutralizing antibodies develop. Consistent low-grade viral replication sets the pace for disease by providing continuous antigenic stimulation for the inflammatory cellular immune response or antibodies that localize in the target tissues. These cells and immune complexes may have adverse effects on indigenous cell populations.

Animals↗
PubMedDate not supplied

Hereditary canine spinal muscular atrophy is phenotypically similar but molecularly distinct from human spinal muscular atrophy.

Hereditary canine spinal muscular atrophy (HCSMA) is an autosomal dominant motor neuron disease that is similar in pathology and clinical presentation to various forms of human motor neuron disease. We have tested the hypothesis that the canine survival motor neuron (SMN) gene is responsible for HCSMA by genetic and molecular analysis of a colony of mixed breed dogs, all descended from a single affected individual. We cloned the canine SMN gene and determined the DNA sequence in an affected and an unaffected dog. We found no germline mutations in the SMN gene of the affected individual. Using conventional linkage analysis with canine-specific microsatellite repeat markers we screened the canine genome and identified a single linkage group likely to contain the HCSMA gene. Analysis with a panel of canine/rodent hybrid cell lines revealed that the SMN gene did not map to the same chromosome as the HCSMA linkage group. Collectively these results suggest that the molecular basis for HCSMA is distinct from that of phenotypically similar human disorders caused by inherited mutations in the SMN gene. This further suggests that additional studies on the molecular nature of HCSMA may reveal an unknown element of the molecular pathway leading to motor neuron disease.

Amino Acid Sequence↗
PubMedDate not supplied

Structure, chromosomal location, and analysis of the canine Cu/Zn superoxide dismutase (SOD1) gene.

Mutations in Cu/Zn superoxide dismutase (SOD1), a major cytosolic antioxidant enzyme in eukaryotic cells, have been reported in approximately 20% of familial amyotrophic lateral sclerosis (FALS) patients. Hereditary canine spinal muscular atrophy (HCSMA), a fatal inherited motor neuron disease in Brittany spaniels, shares many clinical and pathological features with human motor neuron disease, including FALS. The SOD1 coding region has been sequenced and cloned from several animal species, but not from the dog. We have mapped the chromosomal location, sequenced, and characterized the canine SOD1 gene. Extending this analysis, we have evaluated SOD1 as a candidate for HCSMA. The 462 bp SOD1 coding region in the dog encodes 153 amino acid residues and exhibits more than 83% and 79% sequence identity to other mammalian homologues at both the nucleotide and amino acid levels, respectively. The canine SOD1 gene maps to CFA31 close to syntenic group 13 on the radiation hybrid (RH) map in the vicinity of sodium myo/inositol transporter (SMIT) gene. The human orthologous SOD1 and SMIT genes have been localized on HSA 21q22.1 and HSA 21q21, respectively, confirming the conservation of synteny between dog syntenic group 13 and HSA 21. Direct sequencing of SOD1 cDNA from six dogs with HCSMA revealed no mutations. Northern analysis indicated no differences in steady-state levels of SOD1 mRNA.

Amino Acid Sequence↗
PubMedDate not supplied

Canine genetic linkage study using heterologous DNA probes.

We have used clones of 17 single-copy human DNA sequences to analyze their counterparts in the genome of the domestic dog by heterologous hybridization. Ten of the 17 sequences represented anchor loci proposed for comparative mammalian mapping. Eight of 17 human clones (including three of the anchor loci) gave clear hybridization signals when used with Southern blots of canine DNA. Five of these eight (including two anchor loci) showed diallelic restriction fragment length polymorphisms in a large kindred of Brittany spaniels and could be used for segregation studies. Several probes chosen from different human chromosomes also were unlinked in the dog. By contrast, linkage was found between the canine counterparts of the closely linked human serum amyloid A gene family. Three markers linked on human chromosome II appeared not to be syntenic in the dog. DNA markers linked to various human genetic neuromuscular diseases were not linked to hereditary canine spinal muscular atrophy which segregates in this kindred. However, there was evidence of possible linkage of this disorder with a canine counterpart of the tyrosinase gene. Segregation studies using heterologous single-copy DNA probes can be performed in dogs, but the level of inbreeding may reduce heterogeneity and limit the power of the analysis.

Animals↗
PubMedDate not supplied

IDPN neuropathy in the cat: coexistence of proximal and distal axonal swellings.

Administration of beta,beta'-iminodipropionitrile (IDPN) to rodents has previously been shown to produce neurofilament-filled axonal swellings in the proximal regions of motor and sensory nerve fibers. Because of the distinctive distribution of these swellings, IDPN has been classed as a proximal axonopathy and thereby distinguished from other disorders in which similar axonal swellings occur in the distal parts of the axon (distal axonopathies). This report describes the pathology in the peripheral nerves of cats which received intermittent injections of IDPN and calls attention to two previously undescribed pathological changes. First, in addition to the typical proximal swellings associated with IDPN, these animals developed numerous axonal swellings within the distal branches of the sciatic nerve. Distal swellings were present as early as 23 days after initiation of intoxication, indicating that they formed locally (rather than developing in the proximal axon and undergoing transport into the distal regions). The second finding was Wallerian-like degeneration within the affected nerve branches. These changes in the distal sciatic nerve and its branches closely resembled the pathology of the distal axonopathies produced by agents such as the neurotoxic hexacarbons and carbon disulfide. The pathological similarities suggest that IDPN may share with these agents pathogenetic mechanisms to an extent not previously suspected.

Animals↗
PubMedDate not supplied

Canine motor neuron disease: clinicopathologic features and selected indicators of oxidative stress.

Hereditary canine spinal muscular atrophy (HCSMA) is an inherited motor neuron disease affecting a kindred of Brittanies. We have examined the clinicopathologic abnormalities in 57 animals with HCSMA, including 43 affected adult dogs and 14 homozygote pups. We also measured selected biochemical indices of oxidative stress: serum vitamin E (alpha-tocopherol) and Se concentrations; serum concentrations of Cu, Zn, Mg, and Fe; and total superoxide dismutase and glutathione peroxidase activities in red blood cells. Dogs with HCSMA had the following abnormalities: regenerative anemia, hypoglobulinemia, hypochloremia, and abnormally high creatine kinase and liver alkaline phosphatase activities. Serum Cu concentration was significantly (P = .01) increased in adult dogs with HCSMA compared to control dogs. Serum vitamin E concentrations tended to be lower in adult dogs with HCSMA compared to controls, and were significantly (P = .01) lower in homozygote pups compared to control pups.

Animals↗