Biomedical subjects

D G Morgan

Publications and source records attributed to D G Morgan.

At least 19 recordsLinked to original sources

PubMed1992

Aortic stenosis and bleeding gastrointestinal angiodysplasia: is acquired von Willebrand's disease the link?

An association between aortic stenosis and haemorrhage from gastrointestinal angiodysplasia has been recognised for many years, but no explanation for this link has been found. Remarkably, aortic valve replacement, rather than bowel resection, corrects the bleeding. Aortic stenosis can be complicated by acquired von Willebrand's disease type IIA (vWD-IIA), which is corrected after valve replacement, and gastrointestinal angiodysplasia is a common site of bleeding in older patients with acquired or congenital vWD. Could the stenotic aortic valve lead to an acquired, reversible deficiency of the largest multimers of plasma von Willebrand factor (equivalent to vWD-IIA) and thus explain the association with gastrointestinal haemorrhage?

Angiodysplasia↗

PubMed1992

Complement C1qB and C4 mRNAs responses to lesioning in rat brain.

These data show the presence of mRNAs for two complement components (C) in the adult rat brain and describe their responses to experimental lesions. Cortical deafferentation caused elevations in striatal C1qB and C4 mRNAs that coincided temporally and overlapped anatomically with the course of degeneration of corticostriatal afferent fibers. By in situ hybridization, C1qB mRNA in the lesioned striatum was colocalized to cells immunoreactive for CR3, a complement receptor found on microglia-macrophages. The mRNA for SGP-2, a putative C inhibitor in rat, showed parallel changes. Similarly, in hippocampus and other brain regions, kainic acid lesions increased C1qB mRNA. The data suggest that microglia-macrophages and possibly other cells in rat brain rapidly up-regulate C-mRNAs in response to deafferentation and local neuron injury. These experimental responses provide models to analyze changes in C components during Alzheimer's disease and other chronic neurodegenerative conditions.

Animals↗

PubMed1992

Slow changes of tyrosine hydroxylase gene expression in dopaminergic brain neurons after neurotoxin lesioning: a model for neuron aging.

Slow neuron regression develops during the adult phase of life in select brain systems of mammals. We describe a model in adult rats that resolves several phases in a slow atrophic process that differentially influences levels of mRNA and protein for tyrosine hydroxylase (TH). Responses of striatal dopaminergic markers to 6-hydroxydopamine (6-OHDA) lesions in rats indicated that the striatal terminals maintained TH protein, despite greater than 3-fold loss of TH mRNA in the substantia nigra pars compacta (SNC) cell bodies whose axons project to the striatum. The loss of TH mRNA/cell was progressive up to 9 months, whereas SNC cell body shrinkage stabilized by 3 months post-lesioning. Consideration of possible mechanisms in protein turnover motivated a search for PEST motifs in the TH of rats and other vertebrates that could be a point of regulation by altering the rate of TH protein turnover.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1992

Processing images of helical structures: a new twist.

Helical macromolecular assemblies are particularly difficult to study by X-ray diffraction but are quite well suited to analysis by electron microscopy. Most of our information about helical macromolecular assemblies has come from the electron microscope but has been limited to about 25 A resolution. With the use of low-dose electron cryomicroscopy, one can obtain structural data to near atomic resolution on two-dimensional crystals, but the problem is to extract the information from the noise. In this paper we present methods to extract signal from low-dose electron cryomicrographs of helically symmetric structures. We apply these methods to extract 10 A data from the bacterial flagellar filament.

Algorithms↗

PubMed1992

Myeloma-like cast nephropathy caused by human recombinant soluble CD4 (sCD4) in monkeys.

CD4 is the receptor for human immunodeficiency virus (HIV) on lymphocytes and macrophages. Soluble CD4 (sCD4), a recombinant truncated form of CD4, has been shown to inhibit HIV-1 in vitro and is being tested as a therapy for AIDS. Preclinical studies in cynomolgus monkeys revealed a protein cast nephropathy after four daily intravenous doses of 100 mg/kg/day. Renal lesions were not found in monkeys that received 10 mg/kg/day. The renal lesions consisted of proteinaceous tubular casts associated with multinucleate giant cells and neutrophils located in the tubules of the distal nephron. The affected tubules were surrounded by an interstitial mixed inflammatory cell infiltrate. By electron microscopy, the casts were composed of moderately electron dense, paracrystalline material. Immunostaining demonstrated that the casts contained sCD4-derived material and Tamm-Horsfall protein. Moreover, biochemical analysis of urine showed that a portion of sCD4 was excreted as intact protein. Because infection with HIV-1 can be associated with clinically significant nephropathy, these data suggest that renal function should be closely monitored in patients receiving soluble forms of CD4.

Animals↗

PubMed1991

Clinical and biochemical aspects of depressive disorders: II. Transmitter/receptor theories.

The present document is the second of three parts in a review that focuses on recent data from clinical and animal research concerning the biochemical bases of depressive disorders, diagnosis, and treatment. Various receptor/transmitter theories of depressive disorders are discussed in this section. Specifically, data supporting noradrenergic, serotonergic, cholinergic, dopaminergic, GABAergic, and peptidergic theories, as well as interactions between noradrenergic and serotonergic, or cholinergic and catecholaminergic systems are presented. Problems with the data and future directions for research are also discussed. A previous publication, Part I of this review, dealt with the classification of depressive disorders and research techniques for studying the biochemical mechanisms of these disorders. A future publication, Part III of this review, discusses treatments for depression and some of the controversies in this field.

Animals↗

PubMed1991

Disappearance of GAD-mRNA and tyrosine hydroxylase in substantia nigra following striatal ibotenic acid lesions: evidence for transneuronal regression.

Transneuronal regression in substantia nigra reticulata (SNR) and substantia nigra compacta (SNC) neurons was studied in Fischer 344 male rats by immunocytochemistry and by in situ hybridization. Three months after striatal lesioning by ibotenic acid, there was a shrinkage (30%) of the SNR region cross-sectional area and a 50% disappearance of neurons that contain glutamic acid decarboxylase (GAD)-mRNA, but only in the ventromedial portion of this nucleus. Loss of dopaminergic neurons, as recognized by tyrosine hydroxylase immunoreactivity, occurred only in caudal portions of the SNC and SNR. These findings suggest that lesions in reciprocally connected pathways, like the nigrostriatal and striatonigral systems, may produce a vicious cycle (feedforward cascade) of neurodegeneration due to interference with retrograde ana anterograde influences.

Animals↗

PubMed1991

Haloperidol treatment increases D2 dopamine receptor protein independently of RNA levels in mice.

Haloperidol, administered to mice in their drinking water, produced a 21% increase in striatal D2 dopamine receptor density after seven days of continuous exposure. The steady-state D2 receptor RNA prevalence was unaffected by this treatment, yet the RNA coding for preproenkephalin was elevated, as expected. These data indicate that the homologous up-regulation of dopamine receptor density by antipsychotic drugs proceeds by mechanisms other than changes in RNA abundance.

Animals↗

PubMed1991

Recombinant human soluble CD4 does not inhibit immune function in cynomolgus monkeys.

Recombinant soluble CD4 (sT4) has been shown to inhibit infectivity of HIV. Because of the role CD4 plays in the interaction of T-helper lymphocytes and cells bearing MHC Class II antigens, a potential adverse effect of therapy with sT4 is interference with lymphocyte function. To address this issue, we studied the effects of sT4 on mitogen-mediated blastogenesis, mixed lymphocyte reactions, and delayed type hypersensitivity reactions (DTH) in cynomolgus monkeys. We found no evidence of sT4-mediated suppression on the in vitro response to concanavalin A, phytohemagglutinin or pokeweed mitogen in 2-way mixed lymphocyte reactions, either when sT4 was added to the cultures or when cells were obtained 3 hr after drug administration from animals that received up to 100 mg/kg as an intravenous bolus. Furthermore, we also found no effect of sT4 on lymphocyte subsets or on the ability of monkeys to respond to dinitrochlorobenzene (DNCB)-mediated DTH. Because of the high degree of conservation of CD4 and MHC Class II antigens across the macaque-human barrier, these data suggest that soluble CD4-like molecules are unlikely to be immunosuppressive in humans.

Animals↗

PubMed1990

GFAP RNA increases during a wasting state in old mice.

A prolonged wasting condition is often associated with morbidity in older humans. The effects that such a state has on the quality/quantity of RNA are not known. In initial attempts to develop an animal model for premortem wasting, we examined whole brain RNA from mice slowly approaching death from natural causes. Glial fibrillary acidic protein (GFAP) RNA showed a three-fold increase as detected by RNA gel-blot hybridization analysis. Five other RNA sequences were stable under these circumstances. We conclude that brain RNA changes are selective during a degenerating premortem state. Moreover, RNA sequence changes in conditions such as Alzheimer's disease should be considered in the context of the wasting condition of the individual and may not be due to a direct effect of the disease process.

Animals↗

PubMed1990

Tyrosine hydroxylase mRNA concentration in midbrain dopaminergic neurons is differentially regulated by reserpine.

Tyrosine hydroxylase (TH)-mRNA, assayed by in situ hybridization combined with TH immunocytochemistry, showed a selective increase in the ventral tegmental area (A-10) but not in the substantia nigra (A-9) midbrain dopaminergic (DAergic) neurons 3 days after reserpine treatment. TH-mRNA in locus ceruleus noradrenergic (A-4) neurons was increased by reserpine, as confirmed by RNA blot hybridization. These findings show that TH-mRNA is differentially regulated in midbrain DAergic neurons in response to reserpine.

Animals↗

PubMed1990

RNA and protein metabolism in the aging brain.

Much work in the molecular neurobiology of aging is still necessarily descriptive, pending more data on the relative contributions of neuron loss vs. neuron atrophy and glial hyperactivity during normal and neuropathological aging. Major loss of neuronal cells is not the rule, even in AD. A working hypothesis holds that increased astrocytic volumes and decreased neuronal volumes are a major factor in age-related neurochemical decreases. Resolution of these questions is needed to understand how regional RNA and protein synthesis change during aging. We have presented alternative mechanisms for changes in gene expression that may be cell specific. The literature, mainly from non-neural tissues, suggests derepression of normally silent genes, possibly in association with DNA demethylation; decreased synthesis of neuronal rRNA due to deletion of rRNA genes; epigenetic changes in hnRNA splicing; reduced turnover rates and the accumulation of nonfunctional proteins. Although global qualitative changes in the inventory of mRNA and proteins are not found in neural tissues at advanced ages, the synthesis and turnover of RNA and protein may be slowed. Impaired protein turnover or catabolism could contribute to the accumulation of NFT and brain amyloid. In sum, several different types of mechanisms appear to be important in RNA and protein metabolism of the brain during aging, but selectivity for brain region and cell type seems to prevail throughout these myriad changes.

Aging↗

PubMed1990

Effects of sensitization to dinitrochlorobenzene (DNCB) on clinical pathology parameters and mitogen-mediated blastogenesis in cynomolgus monkeys (Macaca fascicularis).

Immunotoxicologic testing of drug candidates and environmental contaminants is of growing importance. Cutaneous delayed type hypersensitivity (DTH) is a convenient way of testing immune function in vivo. However, DTH testing must not interfere with interpretation of other relevant parameters. We have evaluated the effects of sensitization and challenge with dinitrochlorobenzene (DNCB) on clinical parameters routinely evaluated in toxicity testing and on lectin-mediated blastogenesis. Female cynomolgus monkeys were sensitized to DNCB with 4 daily applications of DNCB in acetone to the skin of the axilla. Fifteen days later, the monkeys were challenged for DTH by applying DNCB to the antecubital skin. Skin fold thickness was measured and the macroscopic appearance of the challenge site was scored 24 and 48 hr after challenge. All 5 monkeys were successfully sensitized to DNCB. There was a significant increase in the mean skin fold thickness (compared to pre-challenge thickness) of 2 mm at 24 hr and 1 mm at 48 hr (p less than 0.001). The clinical score of the challenge site was also increased. Histologic examination of the sensitization and challenge sites from a second group of monkeys exposed to DNCB in an identical manner showed the perivascular inflammatory cell infiltrate typical of DTH. Evaluation of hematologic parameters at days 7, 14, and 21 revealed no change in the erythron at any interval and a mild decrease in total WBC, neutrophil and lymphocyte counts on day 7 in 4/5 monkeys. The WBC parameters remained within the normal range and returned to pre-sensitization values at the later intervals.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1989

Uptake of human recombinant tissue-type plasminogen activator by rat hepatocytes in vivo: an electron microscope autoradiographic study.

The hepatic uptake of recombinant human tissue-type plasminogen activator (tPA) has been studied by electron microscope autoradiography (EMARG) of serial hepatic biopsies taken from anaesthetized, laparotomized rats following intravenous injection of 125I labeled tPA. Serial blood samples showed both radiolabel and biologic activity to be eliminated from circulation with an initial half-life of approximately two minutes. Grain half-distance distribution profiles and grain density analysis showed that the para-sinusoidal region of the hepatic parenchymal cell is the only site in the liver to concentrate radiolabeled tPA after intravenous injection. These data support the hypothesis that the parenchymal cell is the principal cell responsible for hepatic clearance of tPA from circulation and suggest that receptor mediated endocytosis may be the mechanism of cellular uptake.

Animals↗

PubMed1989

Chronic lesions differentially decrease tyrosine hydroxylase messenger RNA in dopaminergic neurons of the substantia nigra.

Long-term effects of lesions were analyzed in terms of gene expression. Nine months after unilateral 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra pars compacta (s. nigra), the remaining dopaminergic (DAergic) neurons (tyrosine hydroxylase (TH) cells determined by immunocytochemistry (ICC] on the lesioned side were atrophic with smaller nucleoli. By in situ hybridization, the DAergic neurons on the lesioned side had a 50% smaller TH-mRNA concentration than on the contralateral non-lesioned side. However, beta-tubulin mRNA concentration in DAergic neurons was unaffected by the lesion. The lesions did not alter TH-mRNA concentration in the contralateral non-lesioned side by comparison with unoperated controls. We propose that chronic lesions have long-term effects on gene expression because of damage sustained during compensatory hyperactivity after the lesion, or because of decreased trophic support from other neurons.

Animals↗

PubMed1989

Acetaminophen and p-aminophenol nephrotoxicity in aging male Sprague-Dawley and Fischer 344 rats.

Strain differences in susceptibility of rats to acetaminophen (APAP)-induced nephrotoxicity have been reported previously. Young adult male Fischer 344 (F344) rats are susceptible, whereas weight-matched Sprague-Dawley (SD) rats are not susceptible to APAP nephrotoxicity. Susceptibility to APAP nephrotoxicity is also age dependent, at least in F344 rats. Middle-aged (12-15 months old) male F344 rats are more susceptible to APAP-induced nephrotoxicity than are young adult (2-4 months old) males. APAP nephrotoxicity in aging SD rats has not been evaluated. The present studies were designed to define strain differences in the nephrotoxicity of APAP and p-aminophenol (PAP), a nephrotoxic metabolite of APAP, using 2-, 3-, and 9- to 12-month-old F344 and SD rats. At 2 months of age, F344, but not SD, rats were susceptible to APAP-induced nephrotoxicity. However, at 3 months of age, strain differences were less marked, as susceptibility to APAP nephrotoxicity appeared to increase between 2 and 3 months of age only in SD rats. By 9-12 months of age, susceptibility to APAP nephrotoxicity was comparable in F344 and SD rats. No age- or strain-related differences were observed in the excretory pattern of urinary APAP and metabolites that might explain the increased susceptibility of aging rats to APAP nephrotoxicity. Strain differences in age-matched rats were not marked for PAP-induced nephrotoxicity. Susceptibility of both 3- and 12-month-old F344 and SD rats to PAP-induced nephrotoxicity was greater compared to strain-matched 2-month-old rats. In both F344 and SD rats, PAP nephrotoxicity increased only modestly between 3 and 12 months of age, indicating that increased susceptibility to PAP probably does not play a major role in the age-dependent increase in APAP nephrotoxicity. Thus, strain differences in APAP nephrotoxicity decrease with advancing age. The mechanisms mediating the increased susceptibility to APAP nephrotoxicity in middle-aged rats are not known but may relate, at least in part, to age-dependent differences in pharmacokinetics. The present study highlights the importance of considering the age of rats when evaluating drug toxicity. Even in young adult rats, subtle maturational changes in drug metabolism and/or disposition may occur, making toxicological evaluation in weight-matched rats of different strains and ages inappropriate.

Acetaminophen↗

PubMed1989

Pathogenesis of arterial lesions induced by dopaminergic compounds in the rat.

Fenoldopam mesylate (FM), a selective post-junctional dopaminergic (DA1) vasodilator, causes lesions of large caliber splanchnic arteries (100-800 microns) in the rat characterized by necrosis of medial smooth muscle cells and hemorrhage. FM does not induce lesions in other vascular beds of the rat, or in dogs or monkeys. Dopamine, like FM, causes hemorrhagic lesions of large caliber splanchnic arteries in the rat, as well as fibrinoid necrosis of small caliber arteries (less than 100 microns) of the splanchnic, cerebral, coronary and renal vascular beds. Dopamine is an alpha- and beta-adrenoceptor and a dopaminergic receptor agonist. Because these arterial lesions are thought to result from the pharmacologic activity of these 2 compounds, we sought to ascertain the presence of DA1 receptors in mesenteric arteries of the rat and to determine the role of these or other vascular receptor subtypes in lesion induction. We also studied the process of repair after arterial injury caused by FM or dopamine. The presence of DA1 receptors was confirmed in isolated perfused mesenteric arteries by standard pharmacologic techniques; stimulation by FM resulted in vasodilation which was inhibited by the DA1 receptor antagonist SK&F 83566-C. Likewise, SK&F 83566-C prevented the induction of hemorrhagic lesions of large caliber arteries in rats upon infusion of FM or dopamine. In rats co-exposed to the alpha-adrenoreceptor antagonist phenoxybenzamine (PBZ) and either FM or dopamine, the incidence and severity of hemorrhagic lesions of large caliber arteries were increased, but PBZ prevented the formation of dopamine-induced fibrinoid lesions in arteries of small caliber. Rats exposed concurrently to dopamine, phenoxybenzamine, and SK&F 83566-C were free of all arterial lesions. Thus, the induction of splanchnic arterial lesions in the rat by dopamine and FM is caused by stimulation of, and interaction between, alpha-adrenoceptors and dopaminergic DA1 receptors. Fibrinoid lesions of small arteries (alpha-adrenoceptor-mediated) were repaired, as observed morphologically by 14 d after exposure to dopamine. Hemorrhagic lesions of large caliber arteries (DA1 receptor-mediated) had undergone significant repair by 28 d after exposure to FM but these arteries possessed a thicker media surrounded by adventitial fibrosis. Thus, morphologically distinct receptor-mediated splanchnic arterial lesions induced by dopaminergic and alpha-adrenoceptor agonists follow a markedly different course of repair. Arterial lesions induced by FM or dopamine by activation of post-junctional dopaminergic DA1 receptors may represent a model of polyarteritis nodosa.

Animals↗

PubMed1989

Ultrastructure of an arterial lesion induced in rats by fenoldopam mesylate, a dopaminergic vasodilator.

Fenoldopam mesylate (FM) is a dopaminergic vasodilator with demonstrated efficacy and a favourable safety profile in hypertensive and congestive heart failure patients. FM produced a novel arterial lesion in renal and splanchnic arteries of rats, but not dogs or monkeys. The studies reported here were undertaken to investigate the ultrastructure of the arterial lesion induced in rats by FM in an attempt to shed light on its pathogenesis. Rats were infused intravenously with FM, either 50 micrograms/kg/min for 1 or 4 h, or 5 or 100 micrograms/kg/min for 24 h. Control rats were infused for 4 or 24 h with vehicle alone. Perfusion-fixed tissue from the stomach and pancreas of control and drug-treated rats was examined by transmission electron microscopy. No arterial lesions were seen in rats infused with the drug for 1 or 4 h, or in control rats. All drug-treated rats infused with 5 or 100 micrograms/kg/min of FM for 24 h had lesions in subserosal gastric arteries and interlobular pancreatic arteries. In areas of mild arterial damage, medial smooth muscle cells contained intracytoplasmic pseudovacuoles, autophagic vacuoles, and electron-dense, myofilamentous inclusions. More severe lesions were characterized by overt medial necrosis and haemorrhage. The endothelium of affected arteries was invariably intact, except in areas of severe medial damage. The internal elastic lamina and connective tissue elements within the arterial wall were unaffected. These findings suggest that medial smooth muscle cells are the primary site of damage caused by fenoldopam mesylate in splanchnic arteries of the rat. This iatrogenic arterial lesion could provide an interesting model to study the response of medial smooth muscle to pharmacologically mediated injury.

Animals↗