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S K Durham

Publications and source records attributed to S K Durham.

108 records · Page 6Linked to original sources
PubMed1988

In vitro Sendai viral replication in pulmonary macrophages from mice treated with 4-ipomeanol.

The ability of pulmonary macrophages from female mice given 4-ipomeanol (4-IP) to support viral replication in vitro was examined. On posttreatment days 5, 7, and 9, greater numbers of macrophages were recovered in lavage fluid from lungs of mice given 4-IP, compared with those from controls. Pulmonary macrophages recovered in lavage fluid from control mice and from mice given 4-IP supported Sendai virus replication in vitro, and nearly all Sendai virus produced in pulmonary macrophages from both groups was in an infectious form. On posttreatment days 5 and 7, slightly greater absolute numbers of virions were produced in pulmonary macrophages recovered from mice given 4-IP.

Animals↗
PubMed1987

Endotoxin-induced liver injury in aged and subacutely hypervitaminotic A rats.

The plasma disappearance of endotoxin and endotoxin-induced hepatic injury were studied in two rat models: the aging rat and the subacutely hypervitaminotic A rat. The choice of these models was based on their respective association with a decreased or increased Kupffer cell endocytic activity. The half-life of endotoxin (E. coli O26: B6, phenol extracted) in plasma was significantly prolonged in aged rats as measured by both the Limulus assay (t1/2 = 2.1 +/- 0.1 h in 3-6-month-old, and 3.3 +/- 0.3 h in 24-36-month-old rats) and 51Cr-labeled endotoxin radioactivity assay (t1/2 = 5.3 +/- 0.3 h in 3-6-month old and 7.7 +/- 0.6 h in 24 36-month-old rats). In subacute hypervitaminosis A, the half-life of endotoxin was significantly decreased in the Limulus assay (t1/2 = 2.1 +/- 0.1 h in 3-6-month old and 1.4 +/- 0.2 h in subacutely hypervitaminotic A rats), but not in the radioactivity assay (t1/2 = 5.3 +/- 0.3 h in 3-6-month-old and 5.0 +/- 0.4 h in subacutely hypervitaminotic A rats). Hundred percent mortality was observed at a dose of 2 mg endotoxin/100 g body wt. in old rats, but not in young rats. Only 1 of 7 young subacutely hypervitaminotic A rats died following injection of this dose of endotoxin. The dose of endotoxin which caused only minimal parenchymal liver cell injury in young rats induced substantial parenchymal cell injury in old rats and subacutely hypervitaminotic A rats as determined by both histological and biochemical parameters. It is concluded that some basic characteristics of experimental animals, such as age and nutritional status, can dramatically influence the sensitivity to endotoxin and this is not necessarily correlated with the rate of endotoxin clearance.

Aging↗
PubMed1987

Late functional, biochemical and histological changes in the rat lung after fractionated irradiation to the whole thorax.

The influence of fractionation of the radiation dose in up to 16 fractions on late occurring effects in rat lungs was studied. Measurement of the breathing frequency (BF) was used to monitor changes in lung function during the 76-wk follow-up period. At the end of this period the lungs were examined histologically and the hydroxyproline (HP) content of the lung tissue was determined as a biochemical indicator of the amount of fibrosis. Dose-response curves for BF could only be made at 76 wk post-irradiation. No dose-response curves could be constructed for HP/mg dry tissue; dose-related increases observed in HP/total left lung were entirely attributable to increases in lung dry weight. Histopathology data indicated a dose-related increase in two histological alterations, septal fibrosis and granulomatous pneumonia. The alpha/beta ratios were calculated for each of the endpoints using both the Fe-plot and Direct Analysis method. The calculated values for alpha/beta were in the range of 1.1 to 3.6 Gy, corresponding well to published data obtained in mouse lungs. The number of tissue rescuing units (TRU's) was also calculated. It was smaller for BF than for the histopathology endpoints, suggesting different target structures. However, the difference was not significant due to large confidence intervals.

Animals↗
PubMed1987

Late effects of cyclophosphamide and total body irradiation as a conditioning regimen for bone marrow transplantation in rats (a preliminary report).

The longterm survival and occurrence of neoplastic and nonneoplastic lesions following total body irradiation (TBI), 8.5 Gy, with or without additional cyclophosphamide (Cy; 100 mg kg-1 i.p.) treatment as a conditioning regimen for bone marrow transplantation (BMT) were studied in male BN/BiRij rats. The two groups of rats that were treated with Cy (Cy and Cy + TBI) that survived beyond 100 days after treatment, had a severely decreased median (post treatment) survival time (Cy + TBI: 14.5 months and Cy: 14.1 months). Survival time in the TBI group was moderately decreased (18.5 months) as compared with the untreated controls (27.2 months). All treatment modalities were carcinogenic according to the raw data. After Cy-treatment a high incidence of, frequently multiple, malignant nerve-sheath tumours (Cy: 66 per cent, Cy + TBI: 31 per cent, controls: 2 per cent) was observed. TBI induced an increased occurrence of a great variety of tumours, especially mesenchymal tumours. This effect was more pronounced in animals receiving TBI alone as compared to animals receiving the combined treatment of Cy + TBI; an effect that most likely resulted from the longer median survival after TBI. The multi-target effect of TBI was also reflected in the occurrence of nonneoplastic effects in a variety of tissues, including high incidences of biliary cysts in the liver and severe testicular atrophy. The most important Cy-induced nonneoplastic lesion was incisor dysplasia, which resulted in feeding problems that could only be partly overcome by administering powdered food. Early mortality in the Cy-treated groups was associated with emaciation and generalized organ atrophy. A more definitive estimate of the late effects of supralethal chemoradiotherapy as part of a treatment of malignant disease has to await the results of various conditioning regimens for BMT in rats employing the acute BN myelocytic leukaemia (BNML) as a rat model for human acute myelocytic leukaemia (AML).

Animals↗
PubMed1987

4-Ipomeanol-induced effects on Sendai viral pneumonia in mice.

The effects of the pulmonary toxicant, 4-ipomeanol (4-IP), on Sendai viral pneumonia was examined in young adult female C57BL/6J mice. The histologic severity of the pneumonia was closely correlated with increasing doses of the compound. The more severe pneumonia observed in the 4-IP-treated animals was associated with higher pulmonary viral titers and a more diffuse distribution of viral antigen in bronchioles and alveolar parenchyma. There was no difference in the systemic humoral immune response against Sendai virus or pulmonary interferon production in animals that had received 4-IP or vehicle pretreatment. Classification of the antigen-positive cell types in the alveolar parenchyma resulted in a marked relative increase in the numbers of antigen-positive macrophages, as compared with other antigen-positive cell types.

Animals↗
PubMed1986

Prostatic adenocarcinoma with and without metastasis to bone in dogs.

The signalment, clinical signs, and histologic tumor pattern were compared retrospectively in 12 dogs having primary prostatic adenocarcinoma with (5 cases) and without metastasis (7 cases) to bone. Weight loss and lumbar pain were observed more frequently in dogs having prostatic adenocarcinoma with metastasis to bone. A distinctive histologic pattern was not associated with prostatic adenocarcinoma that had metastasized to bone. The alveolar papillary pattern was the predominant histologic type observed in both groups. Metastasis to extrapelvic bony sites included the scapulas, ribs, and digits. The results of this study indicate that skeletal metastasis was not uncommon in dogs having prostatic adenocarcinoma.

Adenocarcinoma↗
PubMed1985

Pulmonary endothelial and bronchiolar epithelial lesions induced by 4-ipomeanol in mice.

The morphogenesis of pulmonary edema and bronchiolar injury induced by the toxic furan, 4-ipomeanol, was studied by combined light and transmission electron microscopy. Weanling male CD-1 mice received 47 mg 4-ipomeanol/kg body weight by intraperitoneal injection and were studied at intervals from 2 to 360 hours after treatment. Interstitial edema associated with damaged endothelial cells was observed as early as 2 hours after treatment. The most severe endothelial damage was observed from 12 to 24 hours after treatment and occurred in association with alveolar edema. Capillary endothelial cell damage was characterized by marked dilation of endoplasmic reticulum and perinuclear envelopes, marked swelling of mitochondria, separation of cytoplasmic processes from other endothelial cells and their basal laminae, and occasional disruptions in the plasmalemma. Endothelial cell lesions in small caliber veins were similar but less pronounced as compared with the alterations observed in capillary endothelium. Minimal changes were present in alveolar epithelial cells. Damage to nonciliated bronchiolar epithelial cells was first observed at 4 hours after injection. The most severe changes in nonciliated cells occurred from 36 to 48 hours after treatment and included swelling of endoplasmic reticulum, necrosis, and sloughing. There was also necrosis and sloughing of ciliated bronchiolar epithelial cells. Endothelial and bronchiolar epithelial repair and resolution of the alveolar edema were complete by 240 hours after treatment. It is concluded that the endothelium lining capillaries and small veins, in addition to the nonciliated bronchiolar epithelial cell, are early targets in the development of 4-ipomeanol toxicity in the mouse and that the endothelial cell injury plays a major role in the development of pulmonary edema in this species. The results further suggest the possibility that pulmonary endothelial cells have the capability of metabolizing xenobiotic compounds such as 4-ipomeanol to form ultimate toxins.

Animals↗
PubMed1985

Pulmonary lesions induced by 3-methylindole in mice.

The morphogenesis of pulmonary lesions and associated edema induced by the pulmonary toxicant 3-methylindole (3-MI) was studied by combined light and transmission electron microscopy. Weanling male CD-1 mice received 3-MI dissolved in corn oil by intraperitoneal injection and were studied at intervals from 2 to 360 hours after treatment. Interstitial edema was observed as early as 2 hours and was associated with focal cytoplasmic swelling and membrane alterations in both capillary endothelial cells and Type I alveolar epithelial cells and with sequestration of neutrophils. Cell swelling, cytoplasmic fragmentation, and necrosis of Type I epithelial cells was most severe at 24-48 hours after treatment. Multifocal hypertrophy and hyperplasia of Type II alveolar epithelial cells was observed at 24-96 hours after treatment. Platelet aggregation and aggregates of fibrin were frequently observed in capillaries and small arteries and veins as early as 4 hours and as late as 48 hours after treatment. In airways, the nonciliated bronchiolar epithelial (Clara) cell was the predominant cell affected. Initial lesions in nonciliated cells consisted of loss of microvilli and secretory granules followed by marked swelling of the endoplasmic reticulum and mitochondria. Necrosis of cells lining airways was most pronounced at 24-48 hours after treatment. By 144 hours after administration, pulmonary repair was complete. It is concluded that the mouse is a useful model of 3-MI-induced pulmonary injury and that damage to both Type I alveolar epithelial cells and capillary endothelial cells is important in the pathogenesis of 3-MI-induced pulmonary edema.

Animals↗
PubMed1984

Characterization of spontaneous amyloidosis of Syrian hamsters using the potassium permanganate method.

Amyloid from 16 Syrian hamsters with spontaneous age-related systemic amyloidosis retained affinity for Congo red dye after treatment with potassium permanganate. Serum electrophoresis showed a slight rise in gamma globulins without a monoclonal spike. Bence-Jones proteins were not present in the urine. There was no histological evidence of plasmacytosis. Amyloidosis could not be associated with chronic inflammation. The lack of apparent etiology of this amyloid and its resistance to potassium permanganate treatment suggests that it is a primary non-AA amyloid. This finding varies with a report suggesting that the spontaneous amyloidosis of aged Syrian hamsters is associated with the AA fibril.

Amyloid↗
PubMedDate not supplied

The heparin binding domain of insulin-like growth factor binding protein (IGFBP)-3 increases susceptibility of IGFBP-3 to proteolysis.

IGFBP-3 proteolysis clears IGFBP-3 from body fluids and increases IGF bioavailability. As shown here, native human IGFBP-3 was cleaved by proteases in media conditioned by hamster and insect cells. This proteolysis was less pronounced for IGFBP-3 containing a mutated heparin binding domain, and was prevented by purifying IGFBP-3 on an IGF-I affinity column in the presence of 2 M sodium chloride, suggesting that the responsible protease(s) binds the IGFBP-3 heparin binding domain. To determine if any human proteases act this way, we first studied plasma prekallikrein since it can copurify with IGFBP-3, and found: 1) [125]IGFBP-3 binds to prekallikrein immobilized either on nitrocellulose or on immunocapture plates; 2) the IGFBP-3 heparin binding domain participates in forming the IGFBP-3/prekallikrein complex; 3) the binary IGFBP-3/prekallikrein complex can bind IGF-I to form a ternary complex; and 4) activation of prekallikrein to alpha-kallikrein by Factor XIIa resulted in proteolysis of bound IGFBP-3. This work suggests: 1) cleavage of IGFBP-3 by a protease may be aided by the ability of the protease zymogen to directly bind the IGFBP-3 heparin binding domain; and 2) direct binding of protease zymogens to IGFBP-3 may explain some instances where IGFBP-3 is preferentially proteolyzed in the presence of other IGFBPs.

Amino Acid Sequence↗
PubMedDate not supplied

Comparison of a thromboxane receptor antagonist and aspirin in experimental arterial thrombosis.

The antithrombotic activities of aspirin, the thromboxane (Tx) A2/prostaglandin endoperoxide-receptor (TP-receptor) antagonist, SQ 30,741, and heparin were determined in anesthetized rats. Heparin (3 doses of 50, 300 U/kg), aspirin (1 and 10 mg/kg), SQ 30,741 (1 mg/kg + 1 mg/kg/h), or the combination of SQ 30,741 and aspirin (10 mg/kg) was administered intravenously before inducing occlusive thrombosis with 0.1-mA stimulation of the intimal surface of the carotid artery. Light and electron microscopy revealed the thrombi to be composed predominantly of platelets enmeshed in a fibrin network. Heparin (300 U/kg), SQ 30,741 and SQ 30,741 + aspirin decreased average thrombus weight by 54, 57 and 39%, respectively. These treatments also reduced the incidence of occlusion and improved carotid blood flow during thrombosis. In contrast, aspirin alone (1 and 10 mg/kg) and the lower heparin dose (50 U/kg) did not significantly affect thrombus weight or carotid blood flow. To verify adequate drug dosage, pharmacological activities were characterized ex vivo in separate rats. Aspirin (10 mg/kg) inhibited maximum thromboxane (Tx) B2 production in whole blood by 99 +/- 1% and SQ 30,741 blocked 96% of platelet TP-receptors. Heparin increased the activated partial thromboplastin time (APTT) partially at 50 U/kg (approximately 3-fold) and maximally at 300 U/kg (> 10-fold). These experiments demonstrate the contribution of platelet and coagulation mechanisms to a thrombosis model which is sensitive to a TP-receptor antagonist, but not aspirin.

Animals↗
PubMedDate not supplied

Etoposide- and BMY-40481-induced sensory neuropathy in mice.

The effects of high toxic doses of the anticancer drugs, etoposide and its phosphate derivative, BMY-40481, on the nervous system of female CD-1 mice were examined by light microscopy (LM) and transmission electron microscopy. Mice were euthanatized 4 wk following a single iv injection of either 0, 50, 100, or 150 mg/kg of BMY-40481 or 44 or 88 mg/kg of etoposide. Mice treated with 100 or 150 mg/kg of BMY-40481 or 88 mg/kg of etoposide had clinical symptomology of progressive ataxia, impaired righting reflex, and splaying and paresis of fore- and hindlimbs at day 8. Similar, dose-related LM changes were observed with both drugs at all doses and consisted of degeneration of dorsal root ganglion cells and axonal degeneration of their distal and proximal processes in peripheral nerves, dorsal spinal roots, and dorsal funiculi of spinal cord. Axonal degeneration was characterized by LM as shrinkage, swelling, and fragmentation of axon cylinders accompanied by secondary demyelination. Degenerative changes in ganglion cell bodies included eccentric nuclei, cytoplasmic vacuolation, central chromatolysis, and peripheral clumping of Nissl's bodies. Ultrastructurally, ganglion cell bodies had focally extensive dilation of the rough endoplasmic reticulum, mitochondrial swelling, increased numbers of phagolysosomes and prominent aggregations of microfilaments (globular filamentous bodies). Ultrastructural axonal changes occurred primarily in large, myelinated fibers and consisted of axonal swelling or loss, thinning of myelin sheaths, and a decrease in the number of organelles. This is the first report of etoposide-related sensory neuropathy in laboratory rats, a model that my be useful for the study of etoposide-related peripheral neuropathy in humans.

Animals↗
PubMedDate not supplied

Comparison of acute hepatocellular proliferating cell nuclear antigen labeling indices and growth fractions, p34cdc2 kinases, and serum enzymes in carbon tetrachloride-treated rats.

We evaluated various biomarkers associated with cell proliferation immediately following insult with the classic hepatotoxicant carbon tetrachloride (CCl4). Rats were administered a single necrogenic dose of CCl4 and euthanized at either t = 4, 8, 12, 16, or 24 hr postdose. Parameters evaluated included the following: immunohistochemical detection of hepatocellular proliferating cell nuclear antigen labeling indices (PCNA-LIs; percentage of cells in S phase) and growth fractions (PCNA-GFs; percentage of cells in the cell cycle); PCNA and the cyclin-dependent kinase p34cdc2 (CDK) protein in S-9 fractions by Western blot and enzyme-linked immunosorbent assay (ELISA); and liver-related serum enzymes. An increase in PCNA-GF was observed at t = 4 hr, concomitant with elevations in CDK and PCNA protein (Western blot). PCNA-LIs were increased by t = 24 hr, as were CDK and PCNA by ELISA. Sorbitol dehydrogenase was the most sensitive enzyme, with increases observed at t = 4 hr. Our results indicate that PCNA-GF, CDK, and PCNA levels reflect hepatocellular regeneration as early as 4 hr following CCl4 insult. We conclude that these assays are early and sensitive indicators of acute hepatotoxicity that may be advantageous to evaluate in the early stages of exploratory studies.

Alanine Transaminase↗
PubMedDate not supplied

Utilization of electron probe microanalysis in gadolinium-treated mice.

Gadolinium is used as a contrast media for magnetic resonance imaging and, experimentally, to block Kupffer cell phagocytosis. In this study, we utilize electron probe microanalysis to determine the subcellular localization of gadolinium chloride (GdCl3) administered to mice in a short-term toxicology study. Male CD-1 mice were administered 0.0, 2.5, or 8.0 mg/kg GdCl3 iv for 14 consecutive weekdays. Liver-associated enzymes were significantly elevated in high-dose animals only and correlated histologically with multifocal, hepatocellular degeneration associated with a neutrophilic infiltrate. Morphological investigations were performed on high-dose animals. Hepatocytes and Kupffer cells had morphologic features of cellular injury consisting of swollen mitochondria and vesiculated profiles of endoplasmic reticulum. Hepatocytes, Kupffer cells, bile canaliculi, and neutrophils in the liver contained discrete aggregates of electron-dense granular material, as did pulmonary interstitial macrophages, splenic macrophages, and mesangial cells of the renal glomerulus. The intracellular granular material in the liver, lung, spleen, and kidney was confirmed as gadolinium by qualitative electron probe microanalysis. These results document both hepatic and extra-hepatic accumulation of gadolinium in cells of the mononuclear phagocytic system and highlight the importance of electron probe microanalysis in toxicologic assessment.

Animals↗
PubMedDate not supplied

Utilization of genetically altered animals in the pharmaceutical industry.

The study of transgenic and gene-deleted (knockout) mice provides important insights into the in vivo function and interaction of specific gene products. Within the pharmaceutical industry, genetically altered mice are used predominantly in discovery research to characterize the diverse functions of one or multiple gene products or to establish animal models of human disease for proof-of-concept studies. We recently used genetically altered animals in drug discovery to examine the NF-kappaB family of transcriptional regulatory genes and to elucidate their essential role in the early onset of immune and inflammatory responses. Transgenic and knockout mice are also useful in drug development, because questions regarding risk assessment and carcinogenesis, xenobiotic metabolism, receptor- and ligand-mediated toxicity, and immunotoxicity can be evaluated using these genetically altered mice. For example, the p53 knockout mouse is one of several genetically altered mice whose use may increase the sensitivity and decrease the time and cost of rodent carcinogenicity bioassays. As with any experimental model system, data obtained from genetically altered mice must be interpreted carefully. The complete inactivation of a gene may result in altered expression of related genes or physiologic compensation for the loss of the gene product. Consideration must also be given to the genetic background of the mouse strain and the impact of strain variability on disease or toxicity models. Despite these potential limitations, knockout mice provide a powerful tool for the advancement of drugs in the pharmaceutical industry.

Animals↗
PubMedDate not supplied

Oncostatin M: development of a pleiotropic cytokine.

Oncostatin M (OM) is a member of the interleukin-6 (IL-6) cytokine subfamily. The binding of OM to its receptor initiates signal transduction through JAK-signal transducers and activators of transcription (STAT) pathways and activates transcription activators through mitogen-activated protein (MAP) kinases. Results of in vitro assays documented that OM modulates cytokine expression and alters the production of proteases that down-regulate inflammation. Administration of OM to lipopolysaccharide (LPS)-challenged mice lowered serum tumor necrosis factor-alpha (TNF-alpha) levels and decreased the lethal effects of LPS administration. OM also reduced inflammation in animal models of human disease, including inflammatory bowel disease, antibody-induced arthritis, and experimental autoimmune encephalomyelitis. Preclinical safety studies have been conducted in the mouse and monkey. Mice were administered OM (subcutaneously) at 72, 360, or 1,560 micrograms/kg/day in a 2-wk toxicity study. Decreased body weights occurred at 1,560 micrograms/kg. Drug-related changes at 360 and 1,560 micrograms/kg consisted of dermal irritation at the injection site, leukopenia, and thymic lymphoid depletion; all changes were reversible following a 2-wk recovery period. In a 2-wk subcutaneous study in monkeys, OM was administered at 1, 5, 15, 45, or 150 micrograms/kg/day. At all doses there was reversible, transient inappetence and dermal irritation at the injection site. Drug-related changes at 5, 15, 45, and 150 micrograms/kg consisted of reversible elevations in both serum amyloid A and IL-6, and reversible thymic lymphoid depletion. Transient increases in body temperature occurred at 15, 45, and 150 micrograms/kg. The observed spectrum of immunomodulatory effects suggests that OM may have therapeutic utility in treating chronic inflammatory diseases.

Animals↗
PubMedDate not supplied

Pathophysiologic changes induced by phospholipase A2 in the isolated, perfused guinea pig lung.

Pathophysiologic changes induced by phospholipase A2 (PLA2), a lipolytic enzyme implicated in a variety of pulmonary diseases, were examined in the isolated, perfused guinea pig lung. Thirty microliters of vehicle (saline) or 30 units of PLA2 suspended in saline was given as a bolus injection into either the trachea or pulmonary artery, and the lungs were examined by combined light and transmission electron microscopy at 1, 10, and 30 min following administration. Pulmonary morphologic and physiologic changes were observed only in animals that received PLA2 via the trachea. Initially, morphologic evidence of airway constriction was accompanied by a significant increase in intratracheal pressure. No morphologic change was observed in alveolar parenchymal cell populations at this time. Later there was marked swelling of airway epithelial cells accompanied by pronounced blebbing of the apical cytoplasm with a subsequent decrease in airway lumen size. Interalveolar septa were multifocally thickened by edema and alveolar spaces contained sparse fibrogranular material 10 min after intratracheal PLA2. Significant increases in lung weight were observed at this time. Morphologic features of vasoconstriction, characterized by undulating and convoluted endothelium with prominent cytoplasmic processes resulting in decreased luminal size were observed in small caliber vessels and occurred in conjunction with significant increases in pulmonary arterial pressure. There was pronounced injury to type I alveolar epithelium, including marked cell swelling and fragmentation, accompanied by lesser injury in type II alveolar epithelium. This study demonstrates that the airway epithelium was the initial cell population having morphologic change following intratracheal PLA2, and that the airway epithelium and type I alveolar epithelium were the cell populations most severely affected following intratracheal PLA2. Results further suggest that normal circulating levels of blood-formed elements are not essential for the development of PLA2-induced morphologic change in the isolated, perfused guinea pig lung.

Animals↗