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Biomedical subjects

D M Mann

Publications and source records attributed to D M Mann.

At least 163 records · Page 9Linked to original sources
PubMed1986

Neurotransmitter deficits in Alzheimer's disease and in other dementing disorders.

The evidence for deficiencies in neurotransmitters in Alzheimer's disease is reviewed. Major losses occur in the subcortical afferent projection systems based on acetylcholine, noradrenaline and serotonin. Within the cortex, somatostatin containing neurones and the large pyramidal cells, presumed to use glutamate/aspartate as transmitters, are the most severely damaged cells. The anatomical distribution of cell loss is explainable if the primary site of damage lies within the cortex; nerve cells are damaged by virtue of their presence within or their connections to this region. The senile plaque may represent the site of this damage and neurofibrillary tangle formation and accumulation may lead to cell death. In patients with Down's syndrome who live past 40 years, changes in transmitters apparently identical to those in Alzheimer's disease occur. The dementia of Parkinson's disease appears related to damage to cholinergic, noradrenergic and dopaminergic systems and may reflect a failure of these subcortical regions to sufficiently "activate" an otherwise undamaged cortex.

Acetylcholine↗
PubMed1985

Correlation between senile plaque and neurofibrillary tangle counts in cerebral cortex and neuronal counts in cortex and subcortical structures in Alzheimer's disease.

The quantitative relationship between the numbers of senile plaques and neurofibrillary tangles in the temporal cortex and the degree of atrophy and loss of nerve cells from this region and from cortically projecting areas such as the nucleus basalis of Meynert, locus coeruleus and raphe nucleus was investigated in 32 patients with Alzheimer's disease. Strong correlations were noted between cortical plaque and tangle counts and nerve cell atrophy and loss in all 4 areas, suggesting that the formation of plaques and tangles may be of primary pathogenic importance to the cortical and subcortical cell loss.

Aged↗
PubMed1985

Isolation and characterization of a Mr = 38,000 protein from differentiating smooth muscle cells.

In culture, vascular smooth muscle cells grow and form a confluent monolayer of cells. Under appropriate conditions, regions of the monolayer can be induced to draw away from the substrate and form multicellular nodules. The ultrastructure of the cells in the nodules appears to be similar to that of differentiated smooth muscle cells. The process of nodulation is associated with the synthesis of a unique protein whose molecular weight is estimated from gradient gel electrophoresis to be 38,000 (38-kDa Protein). The protein is secreted into the culture medium and can be detected either by metabolic labeling or by staining with Coomassie Blue. Partial purification of 38-kDa Protein was achieved using affinity chromatography. The protein is adsorbed to heparin-agarose, but not to gelatin-agarose. The concentration of 38-kDa Protein in nodular conditioned medium is estimated at 1.9 micrograms/ml and less than 0.01 microgram/ml in conditioned medium made from monolayer cells. The presence of 5% fetal bovine serum in the labeling medium does not affect 38-kDa Protein synthesis. Cross-reactivity with fibronectin was evaluated using polyvalent antibodies to 38-kDa Protein. The 38-kDa Protein is not antigenically related to fibronectin. Furthermore, we establish that the protein is not qualitatively influenced by the presence of ascorbate (50 micrograms/ml), beta-aminoproprionitrile fumarate (50 micrograms/ml) heparin (10 ng/ml), or fibronectin (20 micrograms/ml) in the culture medium. We find that the added components neither suppress 38-kDa Protein synthesis in nodular cultures nor enhance 38-kDa Protein synthesis in monolayer cultures. The 38-kDa Protein is not detected in either monolayer or nodular cell layers and appears to be a secreted protein. Its appearance in nodular conditioned medium during nodulation suggests a relationship with that process.

Animals↗
PubMed1985

Effect of nitrosoureas on calmodulin activity in vitro and in mouse intestine in vivo.

The effects of BCNU, CCNU, methyl-CCNU, streptozotocin, and chlorozotocin on calmodulin activity were studied in vitro and in vivo. Preincubation of BCNU, CCNU, and methyl-CCNU with calmodulin produced a concentration-dependent inhibition of in vitro calmodulin activity expressed as stimulation of cyclic nucleotide phosphodiesterase. Cyclohexylisocyanate produced a similar inhibition. Streptozotocin and chlorozotocin had no effect. Calmodulin inhibition by methyl-CCNU was dependent on the concentration of calcium in the preincubation mixture. Administration of methyl-CCNU or chlorozotocin IP to CF1 mice produced a dose-dependent inhibition of calmodulin activity in the small intestine. Methyl-CCNU produced a significant decrease in intestinal calmodulin activity as early as 1 h after treatment, an effect that persisted up to 52 h. Morphologic changes in the intestinal crypt epithelial cells were evident between 27 h and 5 days after treatment, but not earlier than 27 h. Renal and testicular calmodulin activity and morphology were unaffected. Although it was not possible to correlate the extent of calmodulin inhibition with severity of the intestinal lesions, the data suggested a relationship between reduced activity of calmodulin in a tissue and the ultimate appearance of lesions. This apparent interaction between an antitumor drug and calmodulin in vivo could have multiple implications for cancer chemotherapy.

Animals↗
PubMed1985

Some morphometric observations on the cerebral cortex and hippocampus in presenile Alzheimer's disease, senile dementia of Alzheimer type and Down's syndrome in middle age.

The frequency of senile plaques and neurofibrillary tangles and the number of pyramidal neurones and the volume of their nucleolus were measured in temporal cortex (middle temporal gyrus) and hippocampus (area h1) of 32 patients with Alzheimer's disease. Plaques and tangles were greatly increased in frequency in these patients while the pyramidal cell number was reduced (due to the effects of ageing plus disease) by a total of 78% in temporal cortex and 60% in hippocampus with nucleolar volume in surviving cells being reduced in total by 56% and 63%, respectively. These total losses did not correlate with patient age. However, when corrections for the effects of ageing alone were made on these total losses, the extent of pyramidal cell loss and decrease in nucleolar volume due solely to disease as well as the frequency of plaques and tangles were all found to correlate inversely with patient age for temporal cortex; in hippocampus only cell loss so related. The extent of nerve cell loss correlated with the reduction in nucleolar volume in temporal cortex but not in hippocampus. Correlations involving nerve cell loss and decreased nucleolar volume with plaque and tangle frequency were either weak or non-significant in both regions. The number of nerve cells and the volume of their nucleolus were less (when compared with age-matched control patients) in both temporal cortex and hippocampus, in the 6 middle aged patients with Down's syndrome, and match the corresponding values seen in 8 patients of similar age with Alzheimer's disease.

Aged↗
PubMed1985

The neuropathology of Alzheimer's disease: a review with pathogenetic, aetiological and therapeutic considerations.

The neuropathology of Alzheimer's disease is reviewed in this paper emphasizing the morphological and morphometric changes that occur in the disease and their relationship to age and ageing. From this, a new hypothesis of pathogenesis is presented which accounts for the pattern of neuronal damage in Alzheimer's disease. This is that the pathogenesis of Alzheimer's disease begins with a leakage of a neurotoxin through a defective cortical blood brain barrier. This incites development of the senile plaque and later, via a retrograde transport of the same (or different) factors, intracellular neurofibrillary tangle formation and death of neurones within areas of cortex affected by plaques and in subcortical areas such as nucleus basalis of Meynert, locus caeruleus and dorsal raphe nuclei, all of which project to these same areas of cortex. Evidence consistent with this hypothesis is presented and the aetiological and therapeutic implications are discussed.

Aged↗
PubMed1985

Incorporation of cellular and plasma fibronectins into smooth muscle cell extracellular matrix in vitro.

Fibronectins isolated from the conditioned medium produced by cultures of undifferentiated (monolayer) and differentiated (nodular) swine vascular smooth muscle cells are similar but not identical. In general, the nodular-cell fibronectin has a smaller molecular mass than monolayer-cell fibronectin and appears to lack the COOH-terminal interchain disulfide linkage. We studied the incorporation of cellular and plasma fibronectins into the cell layer. Smooth muscle cells bound 2.5 times more monolayer-cell fibronectin than nodular-cell fibronectin. Polypeptide fragments of human plasma fibronectin were used as a model system to investigate fibronectin incorporation into the cell layer. Only intact molecules were incorporated into the cell layer and subsequently organized into fibers. Polypeptide fragments of molecular mass 205 kDa and 185 kDa were not incorporated even though they retained the collagen-, cell-, and heparin-binding regions. Incorporation appears to require an activity associated with either the NH2-terminal or COOH-terminal domains. We propose that fibronectin activity is lost during differentiation of smooth muscle cells.

Animals↗
PubMed1985

Pathological evidence for neurotransmitter deficits in Down's syndrome of middle age.

The number of nerve cells was counted and the volume of their nucleolus measured in the nucleus basalis of Meynert, the locus caeruleus, the dorsal motor vagus, the dorsal tegmental nucleus and the substantia nigra of seven patients with Down's syndrome, six of whom were over 50 years of age and showed within their cerebral cortex and hippocampus numerous senile plaques and neurofibrillary tangles. When compared with mentally-able age matched controls the youngest patient with Down's syndrome showed no substantial alterations in either number or nucleolar volume in any of these cell types. The six middle-aged patients showed significant loss of cells from nucleus basalis, locus caeruleus, dorsal motor vagus and dorsal tegmental nucleus but no loss from substantia nigra; nucleolar volume was, however, reduced in all five cell types. A similar pattern of change was seen in the six patients with Alzheimer's disease at that age. It is calculated that in both Down's syndrome and Alzheimer's disease of middle age there are similar degrees of damage to cholinergic, noradrenergic and serotonin neurotransmitter systems.

Adult↗
PubMed1984

Relationship between pigment accumulation and age in Alzheimer's disease and Down syndrome.

The amount of lipofuscin pigment within nerve cells of the nucleus basalis of Meynert and that of melanin pigment with nerve cells of locus ceruleus was measured in seven patients with Down syndrome, in 22 patients with Alzheimer's disease and in 18 controls ranging from 30 to 88 years of age. No significant differences in amount of either pigment in these cells at any age were noted between the patient groups and their age controls.

Adult↗
PubMed1984

A comparison of changes in the nucleus basalis and locus caeruleus in Alzheimer's disease.

In 22 patients with Alzheimer's disease loss of neurons from the nucleus basalis of Meynert and locus caeruleus averaged 58% and 71% respectively with nucleolar volume being reduced by 30% in both. These changes were greater in those patients under 80 years of age and in such patients damage to the locus was more severe than that to the nucleus basalis. In older patients (over 80 years) changes were similar in extent in both regions.

Aged↗
PubMed1983

Neurological disease and herpes simplex virus. An immunohistochemical study.

The brains of 43 patients, some with various neurological disorders, other controls, were examined for herpes simplex virus (HSV) antigen using immunoperoxidase technique. The three patients with herpes simplex encephalitis shared a pattern of staining, consistent with that reported previously. However, of the other 40 patients, only two (one a patient with Alzheimer's disease, the other a control patient) showed areas of brain positive for HSV antigen (VA). In the patient with Alzheimer's disease VA was present within nerve and glial cells of the amygdala, within oligodendrocytes of the optic and olfactory tracts and in macrophages within the temporal cortex hippocampus and cerebellum. In the control patient VA was seen only in oligodendrocytes of optic chiasma and olfactory tract. The scarcity of these findings suggests "coincidental disease" processes within these two patients and means that any hypothesis implicating HSV as an aetiological agent in degenerative disease must still remain extremely speculative.

Adult↗
PubMed1983

Possible role of neuromelanin in the pathogenesis of Parkinson's disease.

The numbers of nerve cells in the substantia nigra and locus caeruleus were counted, and the volume of their nucleolus and the amount of neuromelanin pigment they contain measured, in patients with Parkinson's disease and in age-matched and elderly individuals free from neurological illness. The number of pigmented nerve cells of both types is reduced by about 20% in the elderly when compared with age-matched controls. The melanin content of the remaining cells in the elderly is lessened (by 11% in substantia nigra and 21% in locus caeruleus) in such a way as to indicate that this age depletion in cell number results from a preferential loss of those nerve cells which contain the greatest amounts of melanin pigment. In Parkinson's disease there is a greater overall reduction in the amount of melanin within remaining cells (15% in substantia nigra, 25% in locus caeruleus) because of a more severe (80%) loss of the heavier pigmented cells. The basis for Parkinson's disease may therefore lie with an aggravation, possibly by secondary factors, of changes that occur within neurones of substantia nigra and locus caeruleus as part of their "normal" process of ageing.

Aged↗
PubMed1983

The locus coeruleus and its possible role in ageing and degenerative disease of the human central nervous system.

The central noradrenergic pathways with the mammalian brain are principally based on that group of nerve cells within the reticular substance of the upper pons known as the locus coeruleus. The physiological role of these nerve cells appears to be one of maintaining homeostasis within the central nervous system, whatever adverse conditions prevail in the rest of the body, through governing the flow of blood through, and degree of water permeability of, the capillary bed. The extensive ramifications of these noradrenergic terminals mean that the atrophy and loss of nerve cells from locus coeruleus that occurs in old age, and especially so in degenerative diseases of the central nervous system such as Alzheimer's disease and other conditions, will have widespread repercussions for brain function. The chain of physiological disturbances set up as a result of this cell loss may mean a progressive failure of homeostasis within the brain, which in the extreme may culminate in that pattern of mental breakdown which is usually termed dementia.

Adult↗
PubMed1983

The pathology of the human locus ceruleus.

The number of nerve cells of locus ceruleus and their nucleolar volume were determined in 63 normally aged individuals and in 41 cases with neurologic diseases. Pathologic alterations, such as a severe nerve cell loss and atrophy with or without extensive neurofibrillary degeneration or Lewy body formation, were generally seen in the nucleus locus ceruleus in Alzheimer's disease, Down's syndrome, dementia pugilistica, Parkinson's disease, and progressive supranuclear palsy, but such changes were only slight in normally aged individuals and minimal in motor neuron disease. Protein synthetic capacity was substantially reduced in the remaining nerve cells of the locus ceruleus, in Alzheimer's disease, Down's syndrome, and dementia pugilistica, but was unaltered in normally aged individuals (even in extreme old age), in motor neuron disease, and in the few remaining cells in Parkinson's disease and progressive supranuclear palsy. It is suggested that the pathologic alterations in the locus ceruleus found in these diseases, in conjunction with changes in the hypothalamus, lead to impairment of mental ability with eventual dementia through disturbance of the function of those pathways regulating homeostasis within the central nervous system.

Adult↗
PubMed1982

Pathogenesis of Parkinson's disease.

Nucleolar volume and melanin pigment were measured in nerve cells of the substantia nigra in cases of idiopathic Parkinson's disease and in other cases of parkinsonism associated with cerebrovascular disease. In cerebrovascular parkinsonism, nucleolar volume is reduced by 16%, whereas melanin content is unchanged, reflecting local deficiencies in circulation on function of nerve cells, otherwise normal for age. In idiopathic parkinsonism, remaining cells are atrophied, and nucleolar volume is reduced by 16%. Melanin content is decreased by 22% because of preferential loss of the highly pigmented cells. The pathogenesis of idiopathic parkinsonism may lie with a secondary aggravation of changes that occurs, as part of the "normal process of aging," in relation to the cytotoxic effects of dopamine metabolism and melanin accumulation.

Adult↗