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Biomedical subjects

M R Elwell

Publications and source records attributed to M R Elwell.

88 records · Page 5Linked to original sources
PubMed1978

Virulence alterations of tacaribe virus infection in adult mice: lethal model for encephalitis.

Selection of population of Tacaribe virus strain 11573 lethal for mice was carried out by serial intracerebral passage of the virus in adult mice. Viral populations have been characterized by determination of virulence for suckling, weanling, and adult mice, and by histopathologic changes observed in brains of adult mice after intracerebral inoculation. Some of the virus preparations produced 80 to 90 per cent mortality after two or three intracerebral passages in adult mice and maintained this virulence for 1 to 3 passages, after which the virulence rapidly declined with subsequent passages. Clinical signs of infection in adult mice were manifested by a rough hair-coat, ventriflexed posture, diminished activity, increased excitability, flaccid hind-limb extension with progressive paralysis and death. Histologic examination revealed meningoencephalitis.

Age Factors↗
PubMed1977

Possible endotoxemia in rabbits after intravenous injection of Staphylococcus aureus enterotoxin B.

Staphylococcus aureus enterotoxin B (SEB) administered intravenously may exert its toxicity by damaging capillary endothelium in the large intestine and, thereby, permit absorption of endotoxin into the circulation. To investigate this possibility, we measured an index of the level of plasma endotoxin. This index was the ability of plasma to cause gelation of limulus amebocyte lysate (GLAL), before and after intravenous administration of SEB (800-1,000 microng/kg of body weight) to 13 rabbits. All samples taken before administration of SEB were negative for GLAL, but GLAL activity was detectable in the plasma of 10 of the rabbits 12 hr after SEB was injected. Only rabbits that developed GLAL activity died; the levels of GLAL in plasma were comparable to those detected by other workers after administration of an intravenous, lethal dose of endotoxin to rabbits.

Animals↗
PubMed1977

Pathogenesis of respiratory Klebsiella pneumoniae infection in rats: bacteriological and histological findings and metabolic alterations.

Gram-negative bacterial pneumonias have been increasingly important as nosocomial infections. The following model was developed to study the pathogenesis and evaluate therapy of such infections. Intranasal instillation of rats with a suspension of 5 x 10(6) Klebsiella pneumoniae caused bronchopneumonia with 24 h. Bacteria were isolated from the lungs in large numbers (greater than 10(5) colony-forming units [CFU] for at least 13 days after inoculation. Thereafter, the viable concentration decreased to about 10(3) CFU at 21 days but increased to 10(4) CFU at 25 days. Mortality rarely exceeded 25%. Plasma zinc concentration decreased, and plasma seromucoid, lysozyme, and alpha2-macrofetoprotein increased during respiratory K. pneumoniae infection in rats. There seemed to be a linear relationship between seromucoid concentration and the concentration of K. pneumoniae in the lung expressed in log10 units. Plasma zinc, alpha2-macrofetoprtoein, or lysozyme levels, however, did not change until the concentration of bacteria retrieved fron lungs exceeded 4 to 5 logs, Analysis of blood samples obtained serially from the orbital sinuses revealed that rats that succumbed to infection had significantly higher levels of seromucoid, alpha2-macrofetoprotein, and lysozyme and lower levels of plasma zinc than infected rats that survived. Progressive increases in seromucoid and particularly in lysozyme and alpha2-macrofetoprotein appeared to be predicative of death. It is postulated that the threshold effect observed for alpha2-macrofetoprotein and lysozyme reflect significant damage to lung tissue, and thus these two variables are good indexes of the severity of this infection. We propose that this model may be of value in elucidating the pathogenesis of respiratory K. pneumoniae as well as in assessing various models of therapy.

Animals↗
PubMed1977

Fibrosarcoma in a white-tailed deer.

A large, rapidly growing subcutaneous fibrosarcoma was observed on the head of an aged male white-tailed deer (Odocoileus virginianus) from Frederick County, Maryland. Although there was no evidence of distant metastasis, the large neoplastic mass had extensively invaded the osseous supraorbital process, and had several small satellite nodules nearby.

Animals↗
PubMed1976

Oral fructose tolerance, gastric emptying and absorption: a compartmental model.

Gastric emptying and intestinal absorption regulate transfer of ingested fructose from stomach to plasma. Using conscious rhesus monkeys we have developed a compartmental model which describes this system. Fructose tolerance tests were performed in groups of monkeys by intragastrically administering 2 g/kg of 10.5% D-fructose solution; fructose concentration in arterial plasma, [fructose], and intragastric volume were measured at intervals afterward. One group was pretreated with atropine; stomachs imptied with a time constant, tau, of 67 min. Another group received fructose solution with trisodium citrate added; tau was 18 min. Another group received only fructose; tau was 30 min. Using these constants, a model was developed to describe the [fructose] data. In this model k1 related amount of fructose in intestine to absorption rate and Ae represented absorption efficiency. K1 = 0.03 and Ae = 89% provided a good fit for data from the atropinized group. k1 = 0.018 and Ae = 56% provided a good fit for data from the other groups. Differences were explained by considering effects of atropine on gastrointestinal secretion. The model adequately describes our [fructose] data and may be adapted for tests utilizing other substances.

Animals↗
PubMed1975

Changes in blood pH in rats after infection with Streptococcus pneumoniae.

Acid-base alterations in Streptococcus pneumoniae infection were studied in 80 male albino rats. Hematocrit and concentrations of plasma electrolytes, glucose, and total protein were also measured. At 3-h intervals throughout a 27-h study, four control and four infected rats were anesthetized with ether, and blood samples were taken. Arterial blood pH, Po2, and hematocrit increased in the infected group, whereas arterial Pco2, HCO3-, and venous Po2 decreased. Plasma K+ concentration increased slightly and glucose levels decreased in the infected rats as the sepsis progressed. No significant changes were observed in venous blood pH, HCO3-, and Pco2. Plasma Na+, Cl-, and total protein remained unchanged. The increase in arterial blood pH and decrease in arterial Pco2 and HCO3- indicated respiratory alkalosis, which was present in rats infected with S. pneumoniae.

Acid-Base Equilibrium↗
PubMed1975

Mechanisms of oral staphylococcal enterotoxin B-induced emesis in the monkey (38553).

Vomition is the most consistent response to oral SEB challenge in the monkey. The technique of cross-circulation clearly differentiates local neural phenomenon from humoral mechanisms. Our results support the theory that SED-induced vomition follows stimulation of local neural receptors in the gut. The evidence indicates no significant amount of enterotoxin absorption or stimulation of vomition by any centrally acting humoral mechanism.

Administration, Oral↗
PubMedDate not supplied

Demonstration of a temporal relationship between ethyl acrylate-induced forestomach cell proliferation and carcinogenicity.

Ethyl acrylate (EA) is a known forestomach carcinogen in both rats and mice. Recent work in this laboratory indicated that carcinogenic doses of EA administered by gavage for 13 wk resulted in a sustained increase in forestomach epithelial hyperplasia as long as exposure to EA continued. However, hyperplasia regressed and no forestomach neoplasms were seen after a 19-mo recovery period. Current studies were designed to further investigate the time required for sustained hyperplasia to lead to neoplasia as well as the organ specificity of EA-induced cell proliferation/hyperplasia vs carcinogenicity. EA was administered at 200 mg/kg (po) to male Fischer-344 rats, 5 days/wk. Squamous cell proliferation/hyperplasia was observed in the forestomach of all rats that received EA for 6 or 12 mo. Treatment of rats with EA for 12 mo followed by 2 mo of recovery resulted in the development of forestomach papillomas in 2 of 5 treated rats. Furthermore, animals treated for 12 mo and allowed 9 mo of recovery exhibited an increase in forestomach squamous cell carcinomas and papillomas at a combined incidence of 4 in 13. In contrast, animals treated with EA for 6 mo and allowed 2 or 15 mo of recovery exhibited a time-dependent regression of cell proliferation and did not develop forestomach neoplasms. No significant elevation in liver cell proliferation or neoplasia was seen at any time in any of the rats included in the present study, further confirming the organ specificity in the relationship between EA-induced cell proliferation and carcinogenicity. In conclusion, EA resulted in increased cell proliferation in the target organ of carcinogenicity (forestomach) but not in nontarget organs such as the liver. This work indicates that cell proliferation, sustained for a sufficient period of time, results in the development of neoplasia despite cessation of chemical administration. Furthermore, a temporal relationship exists between EA-induced epithelial cell proliferation and forestomach carcinogenicity.

Acrylates↗
PubMedDate not supplied

Pathology and incidence of amelanotic melanomas of the skin in F-344/N rats.

A total of 121 spontaneous amelanotic melanomas of the skin were identified in 70 of 11,171 male and 51 of 10,927 female Fischer-344/N rats in 63 2-yr carcinogenicity studies conducted by the National Cancer Institute's Carcinogenicity Testing Program/National Toxicology Program. Amelanotic melanomas had characteristic anatomical locations and histologic features distinguishable from Schwann cell tumors. Of the 121 tumors, 84, 19, 10, and 8 cases occurred in the pinna, eyelid, scrotum, and perianal region (anus and tail), respectively. Amelanotic melanomas originated from the dermis and consisted of spindle cells arranged in an interlacing fascicular pattern often with a perivascular orientation; epithelioid cells were rarely seen. Only the tumors arising in the pinna metastasized to the lung and/or mandibular lymph nodes. The metastatic rate was 19% (16/84) of the tumors and was clearly increased with an increase in tumor size. Most metastasizing tumors had focal areas consisting of anaplastic spindle cells with an increased number of mitosis. The tumor cells stained positive for S-100 protein but negative for melanin. Ultrastructurally, the tumors were diagnosed as amelanotic melanomas based on the identification of numerous, intracytoplasmic premelanosomes without melanin formation in the tumor cells which were not enveloped by pericytoplasmic basal laminae. One localized amelanotic melanoma of the pinna was successfully transplanted to the subcutaneous tissue in the flank of 3 Fischer-344/N rats.

Anal Canal↗
PubMedDate not supplied

Incidence of nonneoplastic lesions in historical control male and female Fischer-344 rats from 90-day toxicity studies.

The incidence of all spontaneously occurring histologic lesions was determined for control Fischer-344 (F-344) rats from 90-day (13-wk) prechronic National Toxicology Program (NTP) toxicity studies. A total of 319 rats, represented by control groups of 10 males and 10 females each from dosed feed (n = 8), inhalation (n = 4), and gavage (n = 4) studies were included in the review. All protocol required tissues routinely collected for evaluation were reexamined for potential nonneoplastic and neoplastic lesions. Histopathologic findings in tissues included a spectrum of degenerative and inflammatory lesions. The most common lesions in male rats were nephropathy [145/160 (90.6%)] and cardiomyopathy [125/158 (79.1%)]. These changes were also present in the female rats, however, at much lower incidence rates [nephropathy = 30/157 (19.1%); cardiomyopathy = 36/158 (22.8%)]. Other less frequently occurring lesions included inflammation of the preputial [36/152 (23.7%)] and clitoral [34/155 (21.9%)] glands and inflammation of the liver consisting of either foci of mononuclear inflammatory cells [19/159 (11.9%) in males and 33/159 (20.8%) in females] or focal granulomatous inflammation [1/159 (0.6%) in males and 14/159 (8.8%) in females]. Pancreatic acinar cell atrophy occurred in both males [11/160 (6.9%)] and females [8/159 (5.0%)]. A variety of other less common nonneoplastic lesions were identified in both sexes of rats. Also recorded in this review are histologic changes generally considered to be components of the normal morphology of a particular tissue or organ for the F-344 rat (i.e., extramedullary hematopoiesis and hemosiderin deposition in the spleen, renal mineralization, uterine dilation, etc.). These findings were included and discussed due to potential treatment effects that may result in an increase or decrease in these changes compared to controls. Neoplasms were not observed in rats from the prechronic studies evaluated.

Animals↗
PubMedDate not supplied

Histopathology of acetaminophen-induced liver changes: role of interleukin 1 alpha and tumor necrosis factor alpha.

Administration of 500 mg/kg acetaminophen (APAP) to female B6C3F1 mice resulted in well-documented pathophysiological changes in the liver manifested as increased serum concentration of liver enzymes (aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and serum sorbitol dehydrogenase), centrilobular congestion, and hepatocellular degeneration and necrosis. The role of proinflammatory cytokines, including tumor necrosis factor alpha (TNF-alpha) and interleukin 1 alpha (IL-1 alpha), on the hepatotoxicity of APAP was examined at 4, 8, 12, and 24 hr following APAP administration. Neutralization of TNF-alpha or IL-1 alpha with specific antibodies partially prevented the hepatotoxic effects of APAP at the 4- and 8-hr time points. In addition, prior administration of anti-TNF-alpha antibodies shortened the recovery time following APAP treatment. While IL-1 receptor antagonist (IL-1ra) had only a modest protective effect against APAP-induced liver damage, as determined by serum enzyme release, IL-1ra had no effect on the degree of hepatic congestion or necrosis at any of the time points examined. On the other hand, administration of antibodies against IL-1ra exacerbated APAP-induced liver toxicity. These results suggest that TNF-alpha and IL-1 alpha play an important role in the degree of damage and recovery that the liver undergoes following APAP intoxication.

Acetaminophen↗
PubMedDate not supplied

Chemicals associated with decreases in the incidence of mononuclear cell leukemia in the Fischer rat.

A significant treatment-related decrease in the incidence of mononuclear cell leukemia (MCL) was identified in Fischer-344/N rats for 20 chemicals tested in the National Toxicology Program's 2-yr carcinogenicity bioassay. Fourteen of the 20 chemicals caused decreases of MCL in both male and female rats; 6 of the 20 caused a significant decrease only in males and a marginal or no decrease in female rats. Seventeen of the chemicals associated with a decrease in MCL had a free aromatic amine or nitro functional groups that could be metabolized to free amines. With 1 exception, all 14 chemicals causing a decrease in MCL in both sexes produced spleen toxicity in the 13-wk studies. Reduced body weight and decreased survival, related either to toxicity or to an increase in other types of lethal neoplasms, did not contribute to the decreases in MCL observed in chemical exposure groups. Thirteen of the 20 chemicals were positive in Salmonella tests, and 15 were associated with increases in neoplasms at other sites in rats and/or mice, suggesting that different metabolites could be responsible for these varied biological effects.

Animals↗
PubMedDate not supplied

Carcinogenic activity of the flame retardant, 2,2-bis(bromomethyl)-1,3-propanediol in rodents, and comparison with the carcinogenicity of other NTP brominated chemicals.

Several brominated chemicals have been shown to be multisite-multispecies carcinogens in laboratory animals, and in this paper we report that the flame retardant, 2,2-bis(bromomethyl)-1,3-propanediol (BMP) is also a multisite carcinogen in both sexes of Fischer 344 rats and B6C3F1 mice. BMP was administered continuously in the diet for up to 2 yr to rats at doses of 0, 2,500, 5,000, or 10,000 ppm and to mice at doses of 0, 312, 625, or 1,250 ppm. Interim groups of rats were examined at 15 mo. An additional recovery group of male rats received the chemical for 3 mo at 20,000 ppm in the feed, and then the control diet for the remainder of the study. Chemical exposure caused neoplasms of the skin, subcutaneous tissue, mammary gland, Zymbal's gland, oral cavity, esophagus, forestomach, small intestine, large intestine, mesothelium, kidney, urinary bladder, lung, thyroid gland, seminal vesicle, hematopoietic system, and pancreas in the male rat; mammary gland, oral cavity, esophagus, and thyroid gland in the female rat; lung, kidney, and Harderian gland in male mice; and subcutaneous tissue, lung, and Harderian gland in the female mouse. The recovery group of male rats presented with the same spectrum of treatment-related neoplasms as in the core study. In this recovery group, BMP (at 20,000 ppm) caused irreversible effects at numerous sites after 90 days of exposure that was not detectable by histologic examination, but without further exposure resulted in carcinogenic responses at 2 yr. BMP is mutagenic in the salmonella test, but it was not determined if the BMP-induced effects that eventually lead to development of neoplasms at multiple sites are the same in both species and in all organ systems affected.

Animals↗
PubMedDate not supplied

Subchronic toxicology studies of hexachloro-1,3-butadiene (HCBD) in B6C3F1 mice by dietary incorporation.

Two-week repeated-dose and 13-week subchronic studies of HCBD were conducted in B6C3F1 mice. Groups of five mice/sex received 0, 30, 100, 300, 1,000, or 3,000 ppm HCBD in feed for 15 days. Toxic responses, primarily in the higher dose groups, included abnormal clinical signs (lethargy, hunched posture, rough coat, sensitivity to light, and/or incoordination), mortality (all mice in the top two dose groups died by day 7), body and organ weight depression, and gross and histopathological changes. The most prevalent microscopic lesion, seen in all HCBD-treated mice of both sexes, was renal tubular cell necrosis and/or regeneration. Regeneration was seen only in the lower dose groups. Thirteen-week studies were conducted in which groups of 10 mice/sex received 0, 1, 3, 10, 30, or 100 ppm HCBD in feed. No treatment-related clinical signs or mortality were observed. Body weight gain was reduced in the 30- and 100-ppm males (-49 and -56, respectively), and the 100-ppm females (-47). Significant reduction in kidney weights was seen in the 30- and 100-ppm males and 100-ppm females. A treatment-related increase in tubular cell regeneration in the renal cortex occurred in both male and female mice. This lesion was characterized by an increase both in number and basophilic staining intensity of the tubular epithelial cells. Regeneration was seen in the outer stripe of the outer medulla and extended into the medullary rays (pars recta); severity increased with dose. Female mice were more susceptible to the toxicity of HCBD than male mice. Although no adverse effects were observed at the 10-ppm level for male mice in the subchronic study, the regenerative lesion was present in female mice at 1 ppm, the lowest dose administered.

Animals↗