In preclinical safety studies in which the administration of a test compound causes reductions in food consumption, body weights, and organ weights, it may be difficult to differentiate direct compound-induced effects on organ weights from those simply due to reduced nutrition. To address this problem in reference to the heart, hearts were obtained from rats that were known to have had reductions in body weights and absolute heart weights as a result of feed restriction. Rats (40/sex) were divided into 4 groups (10/sex) and given quantities of ad libitum diet for 2 wk as follows: Group 1, 100%; Group 2, 75%; Group 3, 50%; and Group 4, 25%. Routine histologic evaluation was performed on longitudinal sections of paraffin-embedded hearts stained with hematoxylin and eosin. Computer-assisted image analysis was conducted on left ventricular free-wall of picrosirius red-stained sections for histomorphometric evaluation of ratio of cross-sectional area occupied by myofibers versus interstitium and for quantification of myofiber width. No differences were detected histologically among groups, and no difference in the mean myofiber: interstitium ratio was detected between Groups 1 (9.1) and 4 (9.5). Mean values for myofiber width ranged from 24.6 microns for Group 1 to 17.3 microns for Group 4. Two-way ANOVA revealed a strong effect of dietary restriction on reduction of myofiber width but no consistent gender effect. The significant dietary effects occurred in Groups 3 and 4 compared to corresponding controls. The present authors speculate that, if reductions in feed intake were < 50% in short-term preclinical studies, any reductions in myofiber width could imply a primary test article effect. Conversely, if reductions in feed intake were > or = 50% in such studies, reductions in myofiber width could be caused either solely by inadequate nutrition or by combined effects of nutrition and test article.

Animals↗

PubMedDate not supplied

Lesions and identification of crystalline precipitates of glycoprotein IIb-IIIa antagonists in the rat kidney.

Two glycoprotein IIb-IIIa antagonists (xemilofiban, SC-54684A, and orbofiban, SC-57099B), which are platelet aggregation inhibitors, caused crystalline precipitates in the kidney tubules of rats at high dosages. Dogs were not affected. Depending on the degree of the precipitation, which was dosage dependent, and the location, which differed somewhat between the two compounds, the lesions varied from acute obstruction with tubule cell necrosis, nephron dilation, and sudden death with no inflammation to severe chronic pyogranulomatous inflammation. In order to understand the relevance of the lesions, it was important to identify the precipitates. This was technically challenging because the crystals were water soluble (dissolving in routine fixing and staining techniques) and were present in insufficient quantity to physically isolate. Techniques were devised to evaluate the crystals in situ in unstained frozen sections prepared without directly embedding the tissues in supporting medium, which interfered with the analyses. The crystals were analyzed in situ by infrared and Raman spectroscopy and time-of-flight secondary ion mass spectroscopy (TOF-SIMS). Uroliths found in the renal pelvis of one animal were analyzed by liquid chromatography/mass spectrometry. The resulting spectra showed that the crystals were the de-esterified acids of the parent compounds. This knowledge allowed us to predict that the crystalline precipitates would not be a hazard to humans because of the large multiples of the human dosage at which they occurred and because of differences in renal physiology between rats, dogs, and humans.

Alanine↗

PubMedDate not supplied

The nomenclature of cell death: recommendations of an ad hoc Committee of the Society of Toxicologic Pathologists.

The last several years have seen considerable confusion regarding the terms "apoptosis" and "necrosis" in pathology. This situation prompted the Society of Toxicologic Pathologists to charter the Committee on the Nomenclature of Cell Death, which was charged with making recommendations about the use of the terms "apoptosis" and "necrosis" in toxicity studies. The Committee recommends use of the term "necrosis" to describe findings comprising dead cells in histological sections, regardless of the pathway by which the cells died. The modifiers "apoptotic" and "oncotic" or "mixed apoptotic and oncotic" are recommended to specify the predominant morphological cell death pathway or pathways, when appropriate. Other standard modifiers, indicating the lesion distribution and severity, may also be used in conjunction with these. "Individual cell necrosis" (also known as "single cell necrosis") may be either of the apoptotic, oncotic, or mixed types. In many cases, more traditional terms such as "coagulation necrosis" may be used to convey a meaning similar to oncotic necrosis. It is important that pathologists use terms that accurately and concisely convey the level of information appropriate to the study's needs. Furthermore, toxicologic pathologists should actively help to disseminate these recommendations to other biologists and to regulatory authorities.

Animals↗

PubMedDate not supplied

Commentary: implementation of the STP recommendations on the nomenclature of cell death. Society of Toxicologic Pathologists.

Explore the source record for details and available documents.

Animals↗

PubMedDate not supplied

Interferon anti-viral system in Bell's palsy.

Thirty-two consecutive Bell's palsy patients were examined clinically and virologically. All the patients were assayed for serum interferon (IFN) levels at onset of the disease and most of them had repeated IFN assays during the course of the disease. In 15 patients the peripheral blood mononuclear cells (PBMC) were also evaluated for the presence of an anti-viral state (AVS). In viral infections, blood IFN levels are invariably increased, and the PBMC are usually in an AVS. Twenty-three patients (72%) had increased serum IFN values or were in an AVS. The mean serum IFN level was 95 U/ml (normal less than or equal to 16 U/ml) during the first 3 days following onset of the disease, declining later to normal values from the seventh day onwards. No patient had increased antibody titers to herpes simplex and varicella-zoster viruses. The increased blood IFN levels and the AVS of blood cells are compatible with an acute viral infection. It is concluded that the etiology of Bell's palsy is most likely an acute viral infection, possibly due to an unidentified or unusual virus, or to reactivation of a latent virus.

Facial Paralysis↗

PubMedDate not supplied

Use of regression analysis and flow cytometry for determining levels of mixed semiallogeneic immune chimerism.

It has been shown that tolerance or specific immunologic nonresponsiveness in various lymphohemopoietic transplant models can be associated with the development of mixed lymphoid chimerism. As a specific example, composite tissue (limb) allografts were studied as a model for vascularized bone marrow transplantation (VBMT) and it was demonstrated that development of stable cellular immune chimerism is associated with long-term allograft survival. Recently, studies were initiated using a new parental to hybrid VBMT model, but the detection of donor cells is complicated, due to the fact that they share one parental allotypic determinant. Therefore, regression analysis with a flow cytometric immunofluorescent staining assay was evaluated for the assessment of cellular lymphoid chimerism in donor parental to hybrid (P-->F1) lymphohemopoietic transplant models. Standard curves consisting of known mixed populations of parental donor (Lewis, LEW) and hybrid host F1 (Lew x BN, LBN) lymphocytes were established. Standard curves were analyzed by linear regression statistics and excellent coefficients of determination (r > .881) were obtained for all standard curves. A highly statistically significant (p < .016) linear relationship between level of donor cell chimerism (independent variable) and percent stained (dependent variable) was determined. The technique was then evaluated using the parental to hybrid VBMT model. Levels of donor LEW lymphoid chimerism in all VBMT LBN recipients were successfully assessed by regression analysis and inverse prediction using distinct recipient allodeterminant markers. In conclusion, this technique was proven to be reliable and accurate for the detection of of chimerism in parental to F1 lymphohemopoietic allograft models.

Animals↗

PubMedDate not supplied

Public health in North Carolina. The new deal comes to Raleigh.

Explore the source record for details and available documents.

History, 19th Century↗

PubMedDate not supplied

Behavioral and demographic correlates of diabetes, hypertension and overweight among the Catawba Indian Nation.

OBJECTIVE: In 1998, the Catawba Diabetes and Health Survey (CDHS) was conducted among adult members of the Catawba Indian Nation living in the Carolinas to determine the prevalence of diabetes and other health conditions, and to assess the population's health-related behaviors. DESIGN: A population-based sample of adult members of the Catawba Indian Nation (N = 633) were surveyed by telephone or in person regarding health status and health-related behaviors. Logistic regression was used to determine demographic and behavioral correlates of diabetes, hypertension, and overweight among the Catawba. RESULTS: Age-adjusted prevalence rates of self-reported diabetes, hypertension and overweight were 12.3%, 29.1%, and 63.8%, respectively. Older age was related to diabetes, hypertension, and overweight (P<.0001 each), and heavier weight status was related to diabetes (P = .026) and hypertension (P<.0001). Nearly 40% of the Catawba are physically inactive (29.5% men, 46.5% women). Physical inactivity was related to diabetes and hypertension among men only, and related to overweight among women only (P<.05 each). Current smoking was inversely related to overweight among men and women (P = .002). Dietary behavior was not associated with the health outcomes. CONCLUSION: Given the high rates of overweight and physical inactivity, reducing the rates of both may be very important for the health of the Catawba, considering their association with diabetes and hypertension.

Adult↗

PubMedDate not supplied