Biomedical subjects

G E Sandusky

Publications and source records attributed to G E Sandusky.

At least 37 records · Page 2Linked to original sources

PubMed1991

Cardiovascular and adrenal proliferative lesions in Fischer 344 rats induced by long-term treatment with type III phosphodiesterase inhibitors (positive inotropic agents), isomazole and indolidan.

Male and female Fischer 344 rats were treated with the positive inotropic agents, isomazole or indolidan, in the diet for 104 weeks. The doses were 0.0, 11.5, 23.5, or 48.0 mg/kg and 0.0, 0.12, 0.40, or 1.3 mg/kg, respectively. Only 17% of the males treated with 48.0 mg/kg isomazole survived the duration of the study. The male component of the indolidan study was terminated at 22 months, with only 18% of the high-dose males surviving. Sixty-five percent of the males treated with 48.0 mg/kg isomazole and 70% of the males treated with 1.3 mg/kg indolidan were found to have severe periarteritis, often with thrombi located mainly in the mesenteric arteries. Fifty-four percent of the male rats treated with 48.0 mg/kg isomazole and 55% of the male rats treated with 1.3 mg/kg indolidan died from cardiovascular disease compared to 1-2% among the control males. Animals in the low- and middle-dose groups of both studies had a lower incidence of cardiovascular disease than did those in the high-dose group. Additional lesions associated with the long-term administration of both drugs were markedly increased incidence of adrenal medullary proliferative lesions (both hyperplasia and pheochromocytomas) and increased incidence of chronic progressive glomerulonephrosis. These lesions, like those in the cardiovascular system, occurred in a dose-dependent manner and were more frequent in males than in females. Treatment-related effects in these studies were judged to be related to the pharmacologic action of these compounds.

Adrenal Gland Neoplasms↗

PubMed1991

A retrospective survey of endocardial proliferative lesions in rats.

Sixty, proliferative, endocardial lesions were diagnosed in 19,304 rats, for an overall incidence of 0.3%. This population consisted of 10,127 Fischer 344, 8,737 Wistar, 200 Sprague-Dawley, and 240 Long Evans rats from chronic/oncogenicity studies reported at Lilly Research Laboratories from 1976 to 1988. Of the 60 proliferative lesions, 44 were classified as endocardial hyperplasia, 15 as endocardial schwannomas, and one as an endocardial sarcoma for prevalence rates of 0.2%, 0.08%, and 0.005%, respectively. Affected rats ranged in age from 42 to 110 weeks. There were no sex or treatment-related differences in the prevalence of the rat endocardial proliferative lesions. A review of endocardial lesions in 18 of 233 Wistar rats treated with carbamate derivatives revealed endocardial hyperplasia in 12 rats, schwannomas in five rats, and a sarcoma in one rat. One of the 12 rats with endocardial hyperplasia also had an intramural schwannoma. Of 200 Wistar rats given N-nitroso-N-methylurea, two had endocardial hyperplasia, and one had an endocardial schwannoma. Morphologic features were similar in either spontaneous or treatment-associated hyperplasia or neoplasia of the rat endocardium. Probable Schwann cell origin of the endocardial proliferative lesions was indicated by positive immunohistochemical staining for S-100 antigen in 10/12 spontaneous and 11/14 carcinogen-associated endocardial hyperplastic lesions. Further, 15/16 spontaneous and 6/7 carcinogen-associated neoplasms were immunoreactive to S-100. No tumor metastasis was recorded in either the spontaneously affected or carcinogen-treated rats.

Animals↗

PubMed1991

Immunocytochemical study of tissues from clinically normal dogs and of neoplasms, using keratin monoclonal antibodies.

Three commonly used keratin monoclonal antibodies (MAB)--AE1:AE3, CAM 5.2, and MAK-6--were compared with routinely used cytokeratin antibody. The expression of these antibodies was analyzed in several tissues obtained from clinically normal dogs and in a variety of neoplasms from dogs. Using appropriate enzymatic digestion, paraffin-embedded tissues processed in routine manner retained their typical keratin expression. Differentiated and poorly differentiated epithelial neoplasms, lymphomas, and melanomas were studied by use of the avidin-biotin-peroxidase technique. All 4 of the aforementioned antibodies had similar staining profiles. Of 3 anaplastic carcinomas, 2 had positive reaction to all 4 antibodies. All lymphomas, plasma cell tumors, and amelanotic melanomas had negative reaction to MAK-6, CAM 5.2, AE1:AE3, and cytokeratin MAB. Three basal cell epitheliomas had positive reaction to all 4 antibodies, whereas 1 basal cell tumor with a solid pattern had negative staining reaction. Two carcinoids had negative reaction to all markers and 1 of 2 malignant chemodectomas and 1 transitional cell carcinoma had staining reaction to only AE1:AE3 MAB. Comparing the 4 antibodies, use of AE1:AE3 MAB produced the strongest staining intensity followed by cytokeratin, MAK-6, and CAM 5.2 MAB. All 4 antibodies had low background staining. In conclusion, AE1:AE3 and MAK-6 MAB are as useful as cytokeratin MAB for identification of poorly differentiated epithelial neoplasms in dogs and cats.

Animals↗

PubMed1991

Fatal and near-fatal animal bite injuries.

Fatal and near-fatal maulings of humans by pit bulls have recently become a topic of major public concern, resulting in the passage of laws in some jurisdictions that make the owner of a pit bull criminally liable for manslaughter if his or her pet causes a human death. The authors recently investigated two cases in which children were fatally injured by pet dogs. In the first case, a 17-day-old girl suffered fatal abdominal injuries when attacked by a pregnant Siberian husky. A 2-year-old girl expired from neck wounds inflicted by a pit bull or a rottweiler or both. Because no expert would testify as to which dog caused the fatal injury, the owner of the animals was not charged under a statute which specified criminality only if a pit bull caused the fatal injury. We also examined a 12-year-old boy who attempted to pet a circus tiger; the animal grabbed his arm with its claws and bit off the arm at the shoulder. The arm could not be reattached, but the child survived. These cases and the differentiation of animal bites from other injuries will be presented.

Age Factors↗

PubMed1991

Entrapment of a cat in a new-style pet food container.

Although many regulations exist to protect human consumers from hazardous products, there are no comparable safeguards for products intended for pet use. The authors describe a case in which a new-style cat food container presented a hazard to pets.

Accidents↗

PubMed1990

Rat model of arterial thrombosis induced by ferric chloride.

The purposes of these studies were to produce a small animal model of arterial thrombosis for study of novel antithrombotic agents, to validate a simple temperature index of occlusive thrombosis, and to describe the composition of the thrombus. Small thermocouple transducers were fabricated from readily available materials. A thermocouple was inserted under a carotid artery of the anesthetized rat and vessel temperature was recorded continuously. Arterial injury was induced by FeCl3 solution applied topically to the artery above the thermocouple. To validate the relationship between thrombotic occlusion and vessel temperature, blood flow velocity, proximal to the injury, and temperature were recorded simultaneously. Temperature decreased rapidly when velocity averaged 24 +/- 12 percent of control and velocity did not differ from zero within 20 sec. In normal vessels, average flow velocity did not decrease significantly from control until a fixed stenosis decreased diameter by 78 percent. Average time to occlusion (TTO), signaled by the abrupt temperature inflection, ranged from 56 +/- 4 min to 14 +/- 1 min after 10 and 65 percent FeCl3 application respectively. Vessel segments were fixed at various times after FeCl3 exposure and examined by scanning electron microscopy. Endothelial damage was observed and was associated with thrombus composed of activated platelets, fibrin strands and entrapped erythrocytes. The results demonstrate that FeCl3 dose-dependently induced formation of an occlusive mixed thrombus that was indexed by monitoring the time between FeCl3 application and a rapid temperature decrease in the carotid artery of the rat.

Animals↗

PubMed1990

Comparative cardiovascular toxicity in dogs given inotropic agents by continuous intravenous infusion.

A comparative study of the toxicity of the inotropic amines isoproterenol hydrochloride (IP), 1-norepinephrine bitartrate (NE), dopamine hydrochloride (DP), and dobutamine hydrochloride (DB) was conducted in beagle dogs (2/sex/dose group). All drugs were administered at doses that produced maximal contractile tension in dog myocardium. Doses, continuously infused for 96 hr, were 0.625, 1.25, and 2.5 micrograms/kg/min IP, 2.5 and 5 micrograms/kg/min NE, and 25, 50, and 100 micrograms/kg/min DP and DB. Three of 4 dogs that received 5 micrograms/kg/min NE and one of 4 given 100 micrograms/kg/min DP died. Pronounced tachycardia (mean peak rate increases from baseline of 88-104 beats/min) was observed at all doses of IP. DB produced a transient moderate tachycardia (mean peak rate increases from baseline of 25-27 beats/min) at 25 and 50 micrograms/kg/min and pronounced tachycardia (mean peak rate increases from baseline of 74 beats/min) at 100 micrograms/kg/min. Moderate bradycardia occurred at both doses of NE and at 25 and 50 micrograms/kg/min DP (mean peak rate decreases from baseline of 42-46 and 22-38 beats/min, respectively). At high doses the 4 inotropes produced focal to multifocal myocardial necrosis located mainly in left ventricle and segmental medial necrosis of the coronary arteries, mainly in small intramural muscular branches. Segmental medial hemorrhage was also seen following administration of high doses of NE and DP. An additional intramural coronary arterial lesion produced by all of the inotropes consisted of a mild periadventitial cellular infiltrate and fibroplasia. The results indicated that NE and DP produced the most severe cardiovascular lesions, followed by IP which produced lesions of more moderate severity. DB produced only slight lesions in comparison to the other 3 inotropic amines.

Animals↗

PubMed1990

Catecholamine-synthesizing enzymes and chromogranin proteins in drug-induced proliferative lesions of the rat adrenal medulla.

Both epinephrine (E) and norepinephrine (NE) cells in the rat adrenal medulla are able to proliferate in response to pharmacologic stimulation. However, previous biochemical studies have suggested that drug-induced or spontaneous pheochromocytomas in rats are almost invariably NE-producing. To resolve these apparently conflicting data, immunocytochemical techniques were utilized to establish functional profiles of adrenal medullary lesions classified as pheochromocytoma or nodular hyperplasia in rats treated chronically with a phosphodiesterase inhibitor which induced pheochromocytomas. Sixteen of 17 pheochromocytomas and all hyperplastic nodules stained positively for tyrosine hydroxylase and dopamine beta-hydroxylase, consistent with an ability to produce NE. No lesion of either type stained for phenylethanolamine N-methyltransferase, consistent with an inability to produce epinephrine. Lesions of both types showed variable staining for chromogranin proteins. The findings indicate that qualitative functional differences cannot be used to discriminate hyperplastic nodules from small pheochromocytomas in rats. Some lesions currently classified as hyperplastic nodules might in fact be small pheochromocytomas. Others might represent diffuse hyperplasia within pre-existing islands of NE-cells in a background of hyperplastic epinephrine-cells.

Adrenal Gland Neoplasms↗

PubMed1990

Undiagnosed, untreated acute lymphoblastic leukemia presenting as suspected child abuse.

Natural disease being mistaken for child abuse is rare. A two-year-old child was found unresponsive at home and transported to a local hospital, where she expired in the emergency room. Several cutaneous contusions were observed. Prior to the autopsy it was learned that an anonymous report of "child abuse" had been previously filed concerning this child. At autopsy there were multiple metasynchronous cutaneous contusions, but no radiologic or gross evidence of other injuries. A pericardial effusion, massive hepatosplenomegaly and generalized lymphadenopathy were apparent. The bone marrow, liver, spleen, lymph nodes, kidneys, pancreas, heart, stomach, and dura mater showed a monotonous lymphocytic infiltrate. Immunocytochemical studies confirmed the diagnosis of acute lymphoblastic leukemia of childhood. This case reaffirms the need for an objective examination of all cases by a forensic pathologist.

Child Abuse↗

PubMed1989

Acute, subchronic, and chronic toxicity of the cardiotonic isomazole in rats.

Acute, subchronic, and chronic toxicity studies were conducted with isomazole, a new (investigational) inotropic agent with significant vasodilator properties. When given acutely to either young adult rats or mice, the oral median lethal dose was approximately 135 or 525 mg/kg, respectively. Clinical signs of toxicity were leg weakness, hypoactivity, tremors, clonic convulsions, and ataxia. Fischer 344 rats (15/sex/group) were fed diets containing isomazole in concentrations of 0, 0.03, 0.1, or 0.3% for 3 months with no resulting mortality or clinical signs of toxicity. The average daily intake of the compound was approximately 0, 20, 65, or 198 mg/kg in both sexes. Body weight gain, food consumption, and efficiency of food utilization were significantly reduced only in males in the 198 mg/kg dose group. There were no changes of toxicological significance in any of the hematology, clinical chemistry, or urine parameters. Isomazole produced significant increases in hepatic p-nitroanisole O-demethylase activity and relative liver weight primarily at the 65 and 198 mg/kg treatment levels. These effects were consistent with induction of the hepatic drug-metabolizing enzyme system. Histopathologic findings consisted of centrilobular fat deposition in the livers of 9 of 15 males in the 198 mg/kg dose group, and periarteritis in the adventitia of small and medium-sized arteries in the mesentery in 3 of 30 and 12 of 30 animals from the 65 and 198 mg/kg dose groups, respectively. The plasma levels of isomazole had a tendency to drop after 90 days compared to Day 2 in all dose groups and was more apparent in male rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1989

Toxicological evaluation of the cardiotonic isomazole in the dog.

Acute, subchronic, and chronic toxicity studies were conducted in dogs with the new vasodilator/cardiotonic drug isomazole (IMZ) to support, in part, clinical investigations of this agent in humans. Single oral doses of IMZ of 25, 50, or 100 mg/kg given to English pointer dogs (2/dose) caused a marked drop in systemic blood pressure and reflex-induced increases in heart rate to values well over 200 beats per minute. These responses were maintained for 12 to 22 hr depending on the dose given. One of the dogs receiving 100 mg/kg died at 4.5 hr postdose. Results of subchronic (3 months) and chronic (1 year) studies in beagle dogs (4/sex/dose group), in which measurable plasma levels of the drug and its metabolites were found, indicated that IMZ did not produce any discernible adverse findings when given in doses up to 16 mg/kg, other than expected cardiotoxic effects. The plasma t1/2 of IMZ at 16 mg/kg increased to between 4 and 8 hr from 2 hr noted at lower doses. In the 1-year study, at all doses and in both sexes, plasma levels of IMZ declined over the first month, stabilizing (at the 2 and 6 mg/kg doses) thereafter for the duration of the study. At the high dose of 16 mg/kg, after 1 year plasma levels of IMZ exceeded (females) or equaled (males) the 1-month values. At peak plasma levels of IMZ (2 hr postdose), plasma levels of parent drug increased linearly with the dose. The cardiotoxic effects consisted of substantial postdose increases in heart rate throughout the course of treatment (5 mg/kg and above), significant increases in heart weight (6 mg/kg and above), and multifocal myocardial fibrosis (6 mg/kg and above). There was a decline in basal heart rate at doses of 12.5 mg/kg and higher. The results of these studies demonstrated that repeated IMZ administration, as expected, was cardiotoxic to the dog, a species relatively sensitive to the pharmacological activity and hemodynamic changes induced by vasodilator/cardiotonic drugs. The no-effect dose level for cardiotoxicity in the repeated dose studies was considered to be 2 mg/kg, the lowest dose tested.

Animals↗

PubMed1988

An immunocytochemical study of pituitary adenomas and focal hyperplasia in old Sprague-Dawley and Fischer 344 rats.

Spontaneous pituitary tumors occurring in groups of 100 Sprague-Dawley (SD) and 100 Fischer 344 (F344) rats of each sex on a 2-year aging study were characterized by immunocytochemistry. The SD strain had a total of 75 tumors with 10% in males and 65% in females. Tumors immunoreactive for prolactin (PRL) alone were the most common tumor (64%) with the immunonegative tumor being the second most common (17.3%). F344 rats had a total of 62 tumors with 26% in males and 36% in females. The majority of the tumors were reactive for prolactin alone (56.5%) and tumors reactive for both growth hormone (GH) and PRL were the second most common (21%). Most tumors were immunoreactive for only 1 hormone; however, both strains had tumors that expressed multiple hormones in unusual combinations.

Adenoma↗

PubMed1987

Chronic dietary oncogenicity studies of indecainide in rats and mice.

Chronic toxicity and oncogenicity studies of indecainide, an antiarrhythmic compound, were conducted in Fischer 344 rats and B6C3F1 mice at dietary concentrations of 0.0, 0.02, 0.04, or 0.08%. Sixty animals per sex per dose of each species were tested. The duration of compound administration was 2 years for both species. The average daily dose was 9.0, 18.0, or 37.0 mg/kg for rats and approximately 27.0, 53.0, or 113.0 mg/kg for mice. In rats, no biologically significant changes were seen with respect to mortality and clinical signs. Body weight gain and daily food consumption were significantly depressed in the 0.08% dose group males and 0.04 and 0.08% females. Treatment with indecainide had no toxicologically important effects on hematologic or clinical chemistry parameters or on organ weight values. Centrilobular fat deposition was present in the livers of males in the 0.04 and 0.08% dose groups. The incidence of benign and malignant tumors in the treated groups was not increased by treatment with indecainide. Survival of B6C3F1 mice was not significantly affected by exposure to indecainide. Mean body weight gain was slightly decreased throughout the study in mice receiving 0.02 or 0.04%, while mice receiving 0.08% indecainide had moderately decreased body weight gain. Treatment with indecainide had no toxicologically important effects on the hematologic or clinical chemistry parameters measured. No biologically important effects were observed in organ weight values. The incidence of non-neoplastic and neoplastic lesions was similar to those associated with aging in this strain and these were considered to be unrelated to drug treatment. Based on the findings in these studies, indecainide was not carcinogenic to either F344 rats or B6C3F1 mice at dietary concentrations of 0.02, 0.04, or 0.08% for 2 years.

Administration, Oral↗

PubMed1987

Acute and subchronic toxicology of LY-195115 in rats and dogs.

LY-195115 is a new (investigational) inotropic agent. When given orally to either young adult rats or mice, single doses of 2500 or 5000 mg/kg were tolerated with minimal lethality. Clinical signs included muscle weakness, hypoactivity, and evidence of hemorrhage. Dogs and monkeys survived a single oral dose of 10 and 5 mg/kg, respectively; however, there was sinus tachycardia for 6-8 h post dose in both species. Rats (20/sex/group) were fed diets containing LY-195115 in concentrations of 0, 0.005, 0.025, or 0.1% for 3 months. The average daily intake of the compound was approximately 0, 3.5, 17, or 70 mg/kg in both sexes. Deaths occurred only in the high-dose group. Body weight gain, food consumption, and efficiency of food utilization were significantly reduced in males in the 0.1% dose group and animals of both sexes in this group had changes in hematology, clinical chemistry, and urinalysis parameters indicative of renal damage. Crystals containing LY-195115 were present in the urine of animals from the 0.025% and 0.1% treatment groups. Secondary hydronephrosis due to kidney stone formation was observed on gross and microscopic pathologic evaluation in the males of the 0.025% group and animals of both sexes in the 0.1% group. In addition, periarteritis was present in the adventitia and muscularis of small and medium-sized arteries in the pancreas, lymph node, kidney, and stomach of some animals in all LY-195115 treatment groups. No overt signs of toxicity were produced in beagle dogs (4/sex/group) given daily oral doses of 0.03, 0.12, or 0.5 mg/kg of LY-195115 for 3 months. The only adverse effect was the occurrence of focal subendocardial fibroplasia in the heart in 2 high-dose male dogs. Thus, subchronic exposure of rats to doses of LY-195115 as high as 70 mg/kg produced minimal mortality, renal toxicity, and mild, limited vascular changes, while dogs tolerated doses up to 0.5 mg/kg with no evidence of any effect of treatment except minimal histological changes in the heart consequent to the expected cardiotonic action of the compound.

Administration, Oral↗

PubMed1987

Diagnostic immunohistochemistry of canine round cell tumors.

Sixty-five canine skin neoplasms studied using immunocytochemistry, included 22 histiocytomas, 18 amelanotic melanomas, 14 cutaneous lymphosarcomas, six mast cell tumors, and five transmissible venereal tumors. Formalin-fixed, paraffin-embedded sections were stained using the avidin-biotin-peroxidase complex (ABC) immunoperoxidase technique for reactivity with S-100 protein, kappa and lambda immunoglobulin light chains, alpha-1-antitrypsin, alpha-1-antichymotrypsin, leukocyte common antigen (LCA), neuron-specific enolase, keratin, cytokeratin, muramidase, and vimentin. Detection of S-100, kappa and lambda light chains, neuron-specific enolase, and vimentin were most useful for screening these neoplasms. None of the markers examined was consistent in staining histiocytomas. While reactivity of S-100 (ten cases) and neuron-specific enolase (ten cases) was detected in some amelanotic melanomas, lambda light chain immunoglobulin (eight cases) was relatively consistent in cutaneous lymphomas. Mast cell neoplasms reacted with avidin and, therefore, were positive, even on negative control sections. Vimentin reacted strongly on all amelanotic melanomas and transmissible venereal tumors examined. These antibodies are helpful adjuncts in the differential diagnosis of canine skin tumors.

Animals↗

PubMed1986

Use of monoclonal antibodies to human lymphocytes to identify lymphocyte subsets in lymph nodes of the rhesus monkey and the dog.

Using commercially available monoclonal antibodies that bind to human lymphocyte subsets, we examined lymph nodes from the rhesus monkey and the dog for their binding ability to these monoclonal antibodies. The avidin biotin-peroxidase immunostaining procedure was used, and the following antibodies were reactive in the rhesus monkey: Leu 4, Leu 3a, OKT4, Leu 2a, OKT8, T8, Leu 5b, T11, Leu 14, B1, and Leu 12. No immunoreactivity was observed in the dog lymph node except for moderate reactivity of OKT8. The following antibodies failed to react in both the rhesus monkey and the dog: OKT3, T1, T2, T1B, T4, T8A, Pan B, and T29/33. Kappa and lambda immunoglobulin light chains were positive in both the dog and monkey.

Animals↗

PubMed1986

Canine atrioventricular node: scanning electron microscopy and enzyme histochemistry.

Morphologic features of the canine atrioventricular (AV) node were evaluated, using histochemical cholinesterase reactions and scanning electron microscopy. Three distinct regions of the AV node were observed: the transitional zone, superficial AV node, and deep AV node. The transitional zone lacked distinct cellular arrangement, and the cells were large and round with extensive branching on the ends. Superficial AV nodal cells were elongated, tightly packed, and smaller than were transitional cells. The superficial AV node was the densest zone of the AV node. Cell-to-cell contact was end-to-end. Deep AV nodal cells were long, formed laminated fascicles, were larger than the superficial AV nodal cells, and were continuous with the AV bundle.

Acetylcholinesterase↗

PubMed1985

Toxicology of indecainide hydrochloride in mice, rats, and dogs.

Indecainide is a new (investigational) drug for treating cardiac arrhythmias. When given orally to either young adult rats or mice, the LD50 was ca. 100 mg/kg. Leg weakness, tremors, and occasional convulsions were seen in rodents given doses in the lethal range. Dogs and monkeys survived a single oral dose of 25 mg/kg; however, there was a pronounced increase in duration of the PR and QRS intervals. In a 3-month subchronic toxicity study, rats fed dietary levels equivalent to 20 mg/kg/day indecainide were unaffected. Body weight gain was slightly depressed in both sexes of the 40-mg/kg dose group and moderately reduced in both sexes of the 85-mg/kg dose group. Alkaline phosphatase values were minimally increased in females of the 85-mg/kg dose group. In a 3-month subchronic toxicity study, dogs were given daily doses of 0, 6.25, 12.5, or 25 mg/kg indecainide. One male in the 12.5-mg/kg dose group and two females in the 25-mg/kg dose group died during the study. EKG recordings showed a prolongation of the PR and QRS intervals in all treated dogs. In addition, there was a notch in or just prior to the R wave. There were no histopathology findings related to treatment in rats and dogs in the 3-month subchronic rat and dog studies.

Administration, Oral↗