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Biomedical subjects

S J Grossman

Publications and source records attributed to S J Grossman.

At least 19 recordsLinked to original sources
PubMed1992

Indium-111 monoclonal antibody B72.3 scintigraphy in colorectal cancer. Correlation with computed tomography, surgery, histopathology, immunohistology, and human immune response.

As part of an open-labeled nonrandomized multi-institutional Phase III study, the authors compared the results of In-111 (In-111) B72.3 glycyl-tyrosyl-n-diethylenetriaminepentaacetic acid lysine (GYK-DTPA) monoclonal antibody scintigraphy with computed tomography (CT), surgery, histopathology, immunohistology, and human antibody response in 23 patients with primary colorectal carcinoma. There were no significant adverse reactions to 1 mg of In-111-labeled antibody. Planar imaging identified 16 of 23 primary colon lesions, whereas single photon emission computer tomography (SPECT) imaging identified 21. SPECT also correctly identified lymphatic involvement in four patients. (There were two false-positive results.) Liver metastases were identified with SPECT imaging. Twenty-six percent of patients developed human anti-mouse antibody (HAMA). These preliminary results demonstrate that In-111 B72.3 GYK-DTPA is a safe monoclonal antibody conjugate that has a high sensitivity for identifying primary colorectal cancer. Regional lymphatic and distant liver metastases also can be imaged, but false-positive results can occur.

Adenocarcinoma↗
PubMed1992

Studies of early hepatocellular proliferation and peroxisomal proliferation in Sprague-Dawley rats treated with tumorigenic doses of clofibrate.

Clofibrate, a peroxisome proliferator, is hepatocarcinogenic in rats in a dose-dependent fashion. While there is a relationship between peroxisome proliferation and rodent liver carcinogenesis, recent evidence also suggests an association between the tumorigenicity of peroxisome proliferators and sustained cell proliferation. To investigate the role of early cell proliferation in clofibrate-induced carcinogenesis and the predictive potential of this endpoint, in a 3-month study, rats were fed clofibrate doses equivalent to those used in the chronic bioassay, and cell proliferation was determined after 1 week and 3 months, using a 1-week continuous bromodeoxyuridine (BrdU)-labeling technique. Adult Sprague-Dawley rats were fed clofibrate at 1500, 4500, or 9000 ppm. Six rats/sex/group were killed after 1 or 13 weeks of treatment. Osmotic minipumps containing BrdU were implanted into rats 7 days prior to necropsy to determine the cumulative 7-day hepatocyte labeling index immunohistochemically. A dose-related increase in hepatocyte labeling index was seen after 1 week of treatment. However, at 13 weeks, sustained increases in hepatocyte proliferation were not seen; but a dose-related decrease in the hepatocyte labeling index was observed. Liver stereology at 13 weeks demonstrated a dose-related increase in liver weight and volume, but a decrease in hepatocyte nuclei per unit volume, a minimal increase or no change in the total number of hepatocyte nuclei per liver, and an absolute decline in the total number of BrdU-labeled hepatocyte nuclei per liver. These data suggest that in rats, clofibrate may influence hepatocarcinogenicity by decreases in normal hepatocyte proliferation over time and this effect may influence the pathogenesis of tumors at time points beyond 13 weeks of treatment.

Administration, Oral↗
PubMed1992

Dapsone-induced hemolytic anemia: effect of N-hydroxy dapsone on the sulfhydryl status and membrane proteins of rat erythrocytes.

Dapsone hydroxylamine (DDS-NOH), a known metabolite of dapsone, has recently been shown to be a direct-acting hemotoxin responsible in part for dapsone-induced hemolytic anemia in the rat. The effect of DDS-NOH on the morphology, sulfhydryl status, and membrane skeletal proteins of the rat red cell has been investigated. Exposure of rat red cells to a TC50 of DDS-NOH induced transformation of about 50% of the cells to an extreme echinocyte morphology. Reduced glutathione content of the cells was rapidly lost with concomitant increase in the formation of mixed disulfide between glutathione and the soluble protein of the cell. Oxidized glutathione content of the cells did not increase at any time during exposure to DDS-NOH. Examination of the skeletal membrane proteins by SDS-PAGE indicated that DDS-NOH caused the apparent loss of band 4.2, decrease in peaks 1, 2.1, and 3, and the appearance of new bands at about 16, 27, 40, and 54 kDa. Bands 4.1 and 7 appeared unchanged. Treatment of DDS-NOH altered proteins with dithiothreitol, reversed the protein changes, and indicated that the observed alterations were due to the formation of disulfide-linked adducts between hemoglobin and the various skeletal proteins as well as between hemoglobin monomers. The possible significance of the parallel changes in cell morphology and in membrane skeletal proteins for the premature splenic sequestration of the injured rat red cells is discussed.

Anemia, Hemolytic↗
PubMed1992

Enantioselective induction of peroxisomal proliferation in CD-1 mice by leukotriene antagonists.

The effects of a racemic leukotriene antagonist (MK-0571) and its component enantiomers (L-668,018 and L-668,019) on hepatic peroxisome proliferation were examined in mice, rats, and rhesus monkeys. Administration of racemic MK-0571 to mice resulted in increased liver weights, increased peroxisomal volume density, and a pleiotropic induction of characteristic peroxisomal and nonperoxisomal enzyme activities associated with peroxisomal proliferation. When the individual enantiomers of MK-0571 were administered to mice, a pronounced enantioselective induction of peroxisome proliferation was observed. Toxicokinetic studies showed that the levels of each enantiomer in the liver or plasma after separate administration were similar. Thus, the enantioselectivity in the induction of peroxisome proliferation could not be explained on the basis of pharmacokinetic differences between the enantiomers. The hepatic peroxisomal response of the rat to MK-0571 was greatly attenuated compared to the mouse. As has been seen with other peroxisome-proliferating agents, MK-0571 had no effect on either peroxisomal volume density or peroxisomal enzyme activity in monkeys. Due to the high degree of enantiomeric discrimination toward the induction of peroxisomal proliferation by these enantiomers, compounds of this type may prove useful as probes to examine the mechanisms by which peroxisomal proliferating agents induce their effects.

Animals↗
PubMed1992

Immunoscintigraphy performed with In-111-labeled CYT-103 in the management of colorectal cancer: comparison with CT.

Immunoscintigraphy performed after intravenous administration of indium-111-labeled CYT-103, an immunoconjugate of monoclonal antibody B72.3, was evaluated in patients with suspected primary or recurrent colorectal cancer at 25 centers in the United States. Gamma camera imaging, computed tomography (CT), and confirmatory surgical exploration were completed in 169 of 227 patients who received single infusions of In-111 CYT-103. Eight patients (3.5%) had reversible, nonserious adverse reactions, and 39% developed antimurine antibodies. Surgery revealed that 155 of 169 patients had colorectal carcinoma. In these 155 patients, immunoscintigraphy and CT demonstrated similar sensitivity (69% and 68%, respectively) and specificity (77%). However, immunoscintigraphy had greater sensitivity in detection of pelvic tumors (74% vs 57%, P = .035) and extrahepatic abdominal tumors (66% vs 34%, P less than .001); CT enabled detection of a greater proportion of liver metastases (84% vs 41%, P less than .001). These results indicate that In-111 CYT-103 can be administered safely and that immunoscintigraphy performed with this agent frequently enables identification of extrahepatic abdominal sites of disease not visualized with CT.

Adult↗
PubMed1992

Risk-taking behavior of college students and social forces.

We surveyed 1,900 first-year students at the University of Virginia 1 month after arrival. We looked at drinking and driving practices. Men drank more and they drank more often than women. Our data suggest that in defining frequent heavy drinkers, one should consider body weight. We now define frequent heavy drinking as five or more drinks in a row at least weekly for men, and for women we use three to four drinks or more in a row at least weekly. Frequent heavy drinkers and dangerous drivers appeared disproportionately among students planning to join fraternities and sororities. We believe correction of alcohol abuse and addiction by college students must focus, at least in part, on social organizations, especially fraternities and sororities. Also, we must attend to characterologic features that predispose to alcohol abuse and dependence and dangerous driving practices.

Adolescent↗
PubMed1992

Clinical impact of magnetic resonance imaging in foot osteomyelitis.

The impact of magnetic resonance imaging (MRI) on the clinical management of patients with foot inflammation and suspected osteomyelitis was evaluated in 44 patients with 47 foot MRI exams. Twenty-nine patients were diabetic. Bone biopsy or bone culture was obtained in 34 patients, and routine radiographs and bone scan studies were available in most patients for comparison. Magnetic resonance imaging showed reliable identification of bone infection with a sensitivity of 100% and specificity of 95%. Plain radiographs were inaccurate and, as expected, bone scans were highly sensitive (90%) but not specific (33%). The high accuracy of MRI allowed for better identification of patients with osteomyelitis and, therefore, improved targeting of potential operative candidates.

Adult↗
PubMed1992

Scrotal scintigraphy in testicular torsion.

Testicular torsion is a surgical emergency that requires prompt diagnosis and treatment to maximize testicular survival. When the clinical diagnosis is uncertain, testicular scintigraphy can be performed to evaluate testicular perfusion. This noninvasive imaging study is widely validated and highly accurate in predicting nontorsion, which excludes the need for exploration.

Emergencies↗
PubMed1991

Thiobenzamide-induced hepatotoxicity: effects of substituents and route of administration on the nature and extent of liver injury.

Differences in the nature and extent of hepatic injury were examined after administration of para-substituted thiobenzamides to rats. In accordance with previous studies, the extent of hepatotoxicity varied with the electron-donating ability of the substituent. There was also a good correlation between the extent of hepatic necrosis and the amount of substituted thiobenzamide sulfoxide found in the plasma after intraperitoneal dosing. The nature of the hepatic lesion, characterized as a combination of hepatic necrosis, ballooning degeneration, and biliary dysfunction, varied qualitatively with each thiobenzamide analog. When the hepatotoxicity of thiobenzamide was compared after either intraperitoneal or oral dosing, differences in the extent of hepatic necrosis, ballooning degeneration, transaminase elevation, and biliary dysfunction were observed. Intraperitoneal dosing with thiobenzamide gave less severe necrosis and more pronounced elevations in bile acids, while oral dosing led to more severe necrosis along with impaired biliary function. The route of administration was shown to dramatically affect the pharmacokinetics of thiobenzamide and thiobenzamide sulfoxide. Intraperitoneal administration of thiobenzamide gave high plasma and liver levels of both thiobenzamide and thiobenzamide sulfoxide, whereas oral administration gave slightly lower levels of the sulfoxide but much lower levels of thiobenzamide. The reason for greater hepatic necrosis after oral administration may be due to a greater ability to further metabolize the sulfoxide to a reactive metabolite in the absence of high levels of thiobenzamide.

Administration, Oral↗
PubMed1991

Alcohol and cocaine use among first-year college students.

We surveyed 1528 first-year students at the University of Virginia, 1 month after their arrival on campus, who had used alcohol at some time in their lives. Our survey was designed to identify alcohol and cocaine use, and related psychosocial patterns. Men drank more and more often than women. Our data suggest that body weight should be considered in defining those who drink heavily and often. We define 'frequent heavy drinking' as five or more drinks in a row each week for men and three to four drinks or more in a row each week for women. Frequent heavy drinkers, cocaine users, and students with psychosocial problems appeared disproportionately among students planning to join fraternities and sororities. Although first-year students used cocaine infrequently, its users followed the patterns of frequent heavy drinkers. We believe efforts to correct alcohol and cocaine misuse by college students should be directed, in part, at social organizations such as Greek-letter societies. Also, we must attend to psychosocial features that predispose to alcohol and cocaine misuse.

Adolescent↗
PubMed1991

Studies on the mechanism of simvastatin-induced thyroid hypertrophy and follicular cell adenoma in the rat.

Female Sprague-Dawley rats were treated with either simvastatin (a novel competitive inhibitor of HMG CoA reductase) or phenobarbital (positive control) to ascertain the possible relationship between the effects of simvastatin on hepatic metabolism and the thyroid hypertrophy and follicular cell adenomas which it produces in this strain of rat. The test compounds were administered orally at doses of 100 mg/kg (divided doses at 50 mg/kg, b.i.d.). (This dose of simvastatin represents approximately 250 times the human dose.) After 5 weeks of treatment, either simvastatin or phenobarbital produced significant increases (35% and 39% above control, respectively) in serum thyroid stimulating hormone (TSH), a significant increase (39% and 120% above control, respectively) in the systemic clearance of 125I-thyroxine, and slight decreases in serum thyroxine levels. Statistically significant increases in liver and thyroid weights were associated with phenobarbital treatment. With simvastatin, increased liver weights occurred. At the microscopic level, thyroid hypertrophy was observed in all phenobarbital-treated rats and to a lesser degree in most simvastatin-treated animals. Simvastatin did not markedly alter liver microsomal enzyme activities with the exception of the anticipated induction of HMG CoA reductase (which increased approximately 4.4-fold). Conversely, phenobarbital produced large increases in liver microsomal enzymes, including glucuronosyl transferase, but did not affect the activity of HMG CoA reductase. Therefore, the increased clearance of thyroxine in simvastatin-treated female rats was not associated with enzyme induction but may have been related to the increase in functional liver mass produced by this compound at this dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenoma↗
PubMed1991

HMG-CoA reductase inhibitor-induced myopathy in the rat: cyclosporine A interaction and mechanism studies.

Recent clinical evidence indicates a potential for skeletal muscle toxicity after therapy with HMG-CoA reductase inhibitors (HMGRIs) in man. Although the incidence of drug-induced skeletal muscle toxicity is very low (0.1-0.2%) with monotherapy, it may increase following concomitant drug therapy with the immunosuppressant, cyclosporine A (CsA), and possibly with certain other hypolipidemic agents. In the Sprague-Dawley rat, very high, pharmacologically comparable dosages (150-1200 mg/kg/day) of structurally similar HMGRIs (lovastatin, simvastatin, pravastatin and L-647, 318) produced dose-related increases in the incidence and severity of skeletal muscle degeneration. Physical signs included inappetence, decreased activity, loss of body weight, localized alopecia and mortality. To evaluate the interaction between HMGRIs and CsA, a rat model of CsA-induced cholestasis was developed. In this 2-week model, the skeletal muscle toxicity of the HMGRIs was clearly potentiated by CsA (10 mg/kg/day). Doses of HMGRIs which did not produce skeletal muscle toxicity when given alone caused between 75 and 100% incidence of myopathy (very slight to marked skeletal muscle degeneration) when CsA was coadministered. Typical light microscopic changes included myofiber necrosis with interstitial edema and inflammatory infiltration in areas of acute injury. Histochemical characterization of the muscle lesion indicated that type 2B fibers (primarily glycolytic white fibers) were most sensitive to this toxicity but that, with prolonged administration, all fiber types were ultimately affected. Results of pharmacokinetic studies in rats treated with various HMGRIs +/- CsA indicated that coadministration of CsA alters the disposition of these compounds, resulting in increased systemic exposure (e.g., increased area under the plasma drug concentration vs. time curve-AUC) and consequent (up to 13-fold) increases in skeletal muscle drug levels. Evaluation of the potential interaction between the HMGRI, lovastatin and CsA at the level of hepatic microsomal metabolism indicated that CsA did not inhibit the metabolism of lovastatin in isolated microsomes from female rats. In light of the above findings, it appears that HMGRI-induced myopathy is a class effect in the rat, which is potentiated by CsA as the result of altered clearance and resultant increased tissue exposure. Cholestasis associated with CsA and HMGRIs may form the basis for decreased elimination and the resultant elevated systemic exposure. Furthermore, this toxicity is muscle fiber-selective and may be associated with impaired skeletal muscle energy metabolism.

Animals↗
PubMed1991

Ventilation-perfusion scintigraphy.

Ventilation-perfusion scintigraphy remains an important diagnostic tool in the evaluation of patients suspected of having PE. It is important for the emergency physician to be able to use the information from a lung scan appropriately in the diagnostic management of this elusive and life-threatening disorder. This requires a clear knowledge of how these scans are interpreted as well as a consultative approach between the physician ordering the lung scan and the nuclear medicine physician interpreting it. Each can ultimately contribute to the development of an effective management plan. It is important for the clinician to understand that a low-probability lung scan does not rule out PE, but in fact can have up to a 40% probability of PE when clinical suspicion is high.

Adult↗
PubMed1991

Hepatobiliary imaging.

A patient's clinical presentation should prompt an imaging evaluation that is cost effective for accurate diagnosis and leads to appropriate treatment of gallbladder inflammatory disease. In the setting of recurrent biliary colic, chronic cholecystitis is the main diagnostic consideration. Imaging hallmarks include gallstones and gallbladder wall thickening for which ultrasonography is uniquely suited. When a patient appears more toxic with right upper quadrant pain, one would more strongly consider acute cholecystitis. Because the morbidity and mortality of acute cholecystitis are reduced with early cholecystectomy, it is incumbent upon the clinician to make the diagnosis promptly and accurately. Hepatobiliary imaging with an IDA derivative has proven superior sensitivity, specificity, and accuracy for this condition. The examination has validity because it detects cystic duct obstruction, the primary pathophysiologic event responsible for most acute calculous and acalculous disease. Utilizing morphine augmentation when delayed filling is present has reduced the total examination time to less than 2 hours. Use of ancillary findings including gallbladder hyperemia and the "hot rim" sign help predict complicated cholecystitis, enabling more urgent intervention. The bulk of data presented in this review supports hepatobiliary imaging as the modality of first choice in the evaluation of acute cholecystitis. In the intensive care setting, where acalculous disease and atypical presentations are common, hepatobiliary imaging also plays a major role. We recommend liberal use of Sincalide pretreatment, morphine augmentation, and delayed images to promote gallbladder filling. If the gallbladder is nonvisualizing despite these maneuvers, sonography is often added as an aid to detect secondary signs of acute cholecystitis and help confirm the diagnosis with greater certainty prior to high-risk surgery.

Acute Disease↗
PubMed1990

External genitalia abnormalities in male rats exposed in utero to finasteride, a 5 alpha-reductase inhibitor.

A series of studies was conducted to determine the developmental toxicity of the 5 alpha-reductase inhibitor finasteride (MK-0906) in rats. This compound was administered orally once daily to pregnant rats during various extended treatment periods during gestation. F1 offspring were evaluated on Day 20 of gestation as well as postnatally through mating to produce an F2 generation. MK-0906 treatment induced dosage-related incidences of hypospadias (penischisis) in male offspring with a threshold dosage level near 0.1 mg/kg/day and a 100% effect level of 100 mg/kg/day (with dosing through Day 20 of gestation). MK-0906 also caused decreased anogenital distance in male offspring. The dosage response for this effect (ranging from a 4.2% decrease at 0.003 mg/kg/day to a 38% decrease at 100 mg/kg/day) was more shallow than that for hypospadias. The decreases in anogenital distance were at least partially reversible postnatally with essentially complete recovery at dosages up to 0.1 mg/kg/day. There was also a dosage-related, temporary induction of nipples in F1 males. All of these effects were apparent following treatment on Days 6 through 17 of gestation but were more pronounced when dosing extended to Day 20 of gestation. Slight maternal toxicity consisting of minor decreases in body weight gain occurred only at dosages of 3 mg/kg/day and higher, indicating the selective nature of the developmental toxicity. The 5 alpha-reductase enzyme located in the rat fetal genital tubercle was studied in vitro and compared to that in the adult ventral prostate. The values for Km, Vmax, and IC50 for inhibition by MK-0906 were similar in the two tissues, suggesting that the enzymatic proteins in the genital tubercle and ventral prostate may be similar.

5-alpha Reductase Inhibitors↗
PubMed1990

A simple method for the separation and quantitation of radiolabeled thyroid hormones in thyroxine clearance studies.

A method was developed to facilitate the separation and quantitation of radiolabeled thyroxine in plasma for thyroxine clearance studies. Following intravenous injection of radioactive thyroxine, the radiolabeled thyroid hormones were isolated from plasma protein and polar metabolites by solid phase extraction on a C18 sorbent bed. The individual thyroid hormones were then separated by ion-pair reversed phase chromatography and sequentially eluted through a UV detector and radiochromatographic detector. The radioactivity of individual radiolabeled thyroid hormones was corrected for recovery of carrier as determined from UV absorbance. The recoveries of thyroxine and 3,5,3'-triiodothyronine (T3) were 96% and 101%, respectively.

Animals↗