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Biomedical subjects

Z Ruben

Publications and source records attributed to Z Ruben.

At least 19 recordsLinked to original sources
PubMed1998

Diet and rat strain as factors in nervous system function and influence of confounders.

The necessity for understanding normal human cognitive processes and behavior, and the mechanisms which result in dysfunction in these processes are dependent on utilization of a suitable animal model. In order to develop pharmaceutical agents to alleviate mental disturbances and enable the individual to cope within the norms of society, it is incumbent upon investigators to choose a species in which pharmacokinetic principles are established and resemble those of humans. The choice of rats in cognition research studies has specific advantages in that these animals possess similar pharmacodynamic parameters to humans. Further advantages include availability, low cost, ease of breeding, maintenance and an extensive literature database which enable comparisons to present findings. However, there are substantial differences in the performance of various rat strains in tasks of learning, memory, attention, and responses to stress or drugs. In addition to rat strain, quantity of food also exerts profound consequences on animal behavior. The aim of this review is to demonstrate that there are differences in the central nervous system responsiveness of rat strains to chemical and these could be related to factors such as source of supplier, type and quantity of feed, or season of the year. It is also evident that the genotype differs amongst strains and this may be responsible for the observed differences in CNS sensitivity to chemicals. Strain differences must be identified and taken into consideration in interpretation of assessment of neurobehavioral functions. It is also incumbent upon the investigators to utilize healthy (diet-controlled) animal models.

Animals↗
PubMed1993

Effects of two weeks of feed restriction on some common toxicologic parameters in Sprague-Dawley rats.

This study was intended to identify changes caused by short-term reduced feed intake in rats such as may occur with unpalatable feed or other forms of anorexia. For 2 wk, groups of rats (10/sex/group) were fed ad libitum (control group) or given 75% (mildly restricted group), 50% (moderately restricted group), or 25% (severely restricted group) of the amount of feed eaten the day before by controls. The control group and mildly restricted group grew steadily, but the terminal body weights of the mildly restricted group (both males and females) were only about 80% of controls. The moderately restricted group did not grow during the first week but grew slightly during the second week (terminal body weights about 65% of control). The severely restricted group lost weight throughout the study (terminal weight about 40% of control). Restricted groups exhibited hemoconcentration directly related to the degree of feed restriction. White blood cell counts were reduced (principally due to lymphopenia) in severely restricted rats. Platelet counts were decreased in all restricted groups. Total serum protein concentration was reduced (decreased globulins) in all female restricted groups and in the severely restricted males. The severely restricted rats had increased serum bilirubin, electrolyte derangements, and (in females only) decreased cholesterol. Thymus and liver weights (absolute and relative) were decreased in the moderately and severely restricted groups. All the feed-restricted groups had an increased incidence of superficial gastric erosions. The mildly and moderately restricted groups had slightly decreased hematopoietic tissue in sternal bone marrow, while the severely restricted group had bone marrow necrosis, thymic atrophy, and mild testicular degeneration. Findings in the severely restricted group were distinct from those in the other groups on the basis of their severity and were considered adverse. Changes in the mildly and moderately restricted groups were considered adaptive and innocuous since feed restriction of this degree has historically been associated with increased longevity and decreased disease incidence in chronic studies.

Alanine Transaminase↗
PubMed1991

Changes in saccharide and phospholipid content associated with drug storage in cultured rabbit aorta muscle cells.

In the investigation of cellular changes associated with intracellular drug storage, we incubated cultured rabbit aorta muscle cells with various amphiphilic agents. Disobutamide, chloroquine, and desipramine each increased cellular content of rhamnose, arabinose, mannose, glucose, and total saccharides; these agents also elevated total and individual phospholipid of all classes. Amiodarone did not alter total saccharide content, but increased total phospholipid. Tilorone, in contrast, decreased total saccharides, but phospholipid content was unchanged. All test agents decreased xylose content. By light microscopy, disobutamide, chloroquine, and tilorone induced clear cytoplasmic vacuoles; desipramine induced dense cytoplasmic granules; and amiodarone induced both cytoplasmic changes. By electron microscopy, the content of the cellular alterations induced by disobutamide was primarily electron lucent; that of the alterations induced by desipramine was primarily concentric lamellar bodies/flocculent electron-dense structures; and that of the alterations induced by amiodarone was a mixture of both. There was no correlation, therefore, between the induced cellular chemical contents and morphologic changes. Despite the physicochemical similarity of the amphiphilic drugs (all have cationic and lipophilic moieties), the chemical responses they induced were different. The results suggest that amphiphilic drugs alter processes involving saccharides as well as those of phospholipid metabolism. The origin of the saccharide moieties associated with the induced changes in monosaccharide contents is not known. Increased content of phosphatidylinositol, mannose, and glycosyl residues is consistent with the suggestion that amphiphilic drugs may cause an increase in membrane anchor synthesis. The inhibition of lysosomal enzyme activities responsible for the degradation of phospholipid and other anchors may also account for the observed increase in monosaccharides and phosphatidylinositol content.

Amines↗
PubMed1990

Cell-mediated contraction of collagen lattices in serum-free medium: effect of serum and nonserum factors.

This study was conducted to identify a defined, serum-free culture medium that supports cell dependent contraction of a collagen lattice. Collagen lattices were found to contract in cultures containing human foreskin fibroblasts (HFF) or rabbit aortic smooth muscle (RASM) cells incubated in serum-free medium. HFF and RASM cells required different supplements to contract the collagen gels. HFF cultured in Dulbecco's modified Eagle's (DME) medium supplemented with bovine serum albumin (BSA) and either endothelial cell growth supplement (EnGS), insulin (In), or platelet derived growth factor (PDGF) supported collagen lattice contraction. Replacement of BSA with casein without the addition of other supplements improved contraction. In contrast, RASM cells supplemented with BSA, EnGS, In, and PDGF were able to contract collagen gels only minimally. Similar to HFF, RASM cells cultured in DME medium supplemented with casein, but without the addition of other supplements, contracted collagen lattices. HFF-mediated collagen contraction was inhibited by prostaglandins E1 or E2, fibronectin, or ascorbic acid. The reported serum-free model provides a useful in vitro method to investigate the role of serum and nonserum factors regulating cell mediated-contraction of insoluble collagen fibrils.

Animals↗
PubMed1990

Spontaneous bronchopneumonia in laboratory dogs infected with untyped Mycoplasma spp.

Three Mycoplasma spp. were isolated from five colony bred laboratory dogs (Canis familiaris) obtained from a single vendor. Four of these animals were Beagles and one was a mongrel. Three displayed clinical signs of respiratory disease including dyspnea, chronic coughing and moist rales, while the other two dogs were observed during thoracic surgery to have macroscopic lesions suggestive of pneumonia. All five dogs were submitted for diagnostic necropsy during which they were cultured for bacteria and mycoplasma. Mycoplasma spp. having three distinct colonial forms were isolated from the lungs of each of the animals. These three isolates were sent to the National Cancer Institute Diagnostic Microbiology Laboratory and to the National Institutes of Health, NIAID, Mycoplasmology Laboratory. Neither laboratory could serotype these isolates against antisera to 73 Mycoplasma spp., including the common canine mycoplasmas, and nine Acholeplasma spp. Histologically, the bronchopneumonia was characterized by bronchiectasis, purulent bronchiolitis, bronchial and bronchiolar epithelial hyperplasia, chronic non-suppurative peribronchiolitis and perivasculitis, bronchiolitis obliterans, and acute to subacute purulent pneumonia. The similarity between the pathologic findings in these animals and those observed in respiratory mycoplasmosis of other species, e.g. the rat, suggests a causal relationship between the isolated mycoplasmas and the pulmonary disease observed in these dogs.

Animals↗
PubMed1989

Disobutamide: a model agent for investigating intracellular drug storage.

Disobutamide, a bis tertiary amine (pKa1 = 8.6; pKa2 = 10.2) cationic amphiphilic compound, and a putative cardiac antiarrhythmic drug induced clear cytoplasmic vacuoles in dogs and rats. Ultrastructurally, the vacuoles were membrane-bound vesicles containing primarily electron-lucent material. Some concentric lamellar bodies indicative of phospholipidosis were also present. Although numerous vacuoles were seen in one-year toxicity studies in dogs and rats, there was no apparent evidence of necrosis, inflammation, atrophy, hypoplasia, hyperplasia, or metaplasia. Clinical signs or laboratory findings indicative of functional impairment were also not apparent. The picture of the vacuolation in vivo was one of storage. In cultured cells vacuoles were shown to be storage sites for disobutamide and specifically in distended vesicles of the cytoplasmic acidic compartments, such as lysosomes, endocytic, and probably transport vesicles. Storage of the drug in acidic vesicles is compatible with the dibasic nature of the cationic moiety of disobutamide. The intrinsic cell chemicals which accumulate in the vacuoles along with disobutamide remain unknown. Disobutamide may be a useful agent for defining experimentally the borderline between physiologic limits (normal function) and toxicity (functional impairment) in the condition of intracellular drug storage abnormalities and for advancing knowledge of storage mechanisms.

Animals↗
PubMed1989

Investigations in intracellular drug storage: localization of disobutamide in lysosomal and nonlysosomal vesicles.

In the investigation of the dynamic nature of intracellular drug-induced storage disorder associated with clear cytoplasmic vacuoles (CCV), rat urinary bladder carcinoma cells (RBT CC-8) were cultured with [14C]disobutamide. Cell monolayers were then harvested and analytical cell fractionation techniques were employed to examine the association of disobutamide with the various subcellular fractions. Disobutamide distributed into two modes: as a free, organelle-independent fraction and as a light membrane-associated fraction that overlapped with markers for the plasma membrane, endoplasmic reticulum, and lysosomes. The similarity in buoyant densities of these organelles derived from RBT CC-8 cells precluded resolution of these structures by isopycnic centrifugation. In additional experiments, disobutamide was incubated in vitro with a suspension of isolated rabbit renal proximal tubules. In these cells, analytic fractionation showed that the drug localized predominantly to lysosomes and to a separate light membrane fraction that was clearly resolved from the markers for the endoplasmic reticulum, brush border, mitochondria, and peroxisomes; this fraction overlapped with the most buoyant aspects of the Golgi apparatus and basolateral plasma membrane. The buoyant density of this disobutamide-associated nonlysosomal fraction was 1.11 g/ml. Electron microscopy of the disobutamide-exposed tubules showed a substantial formation of apical vesicles, especially small, smooth-surfaced vesicles, typical of the endocytic apparatus. From these findings and based on the physicochemical properties of the cationic moiety of disobutamide, we conclude that the drug localizes in lysosomal and nonlysosomal acidic vesicles.

Animals↗
PubMed1989

Spontaneous disseminated panarteritis in laboratory beagle dogs in a toxicity study: a possible genetic predilection.

Disseminated panarteritis was found in 16 (9 males and 7 females) of 49 laboratory beagle dogs (25 males and 24 females) from one breeding kennel. The dogs had been used in a 6-month oral toxicity study. Panarteritis was not associated with clinical or gross abnormalities. The incidence was similar in the control and test article-treated groups. Mainly medium-sized arteries throughout the body, particularly intercostal arteries (at their aortic origin), and coronary, epididymal and thymic vessels were affected. Chronic mononuclear-cell periarteritis was the predominant feature. Mixed cellular inflammation of the wall, proliferation or degeneration of muscle cells, focal "fibrinoid" material in the tunica media, fragmented internal elastic lamina and intimal thickening associated with myointimal cellular proliferation also occurred. These histologic changes are compatible with those of immune arteritis. Round worm intestinal infestation and granulomas of visceral larva migrans were common in several organs. Statistical analyses suggested that the pedigree of dogs is related to panarteritis, but the presence or absence of parasitization alone is not. The possible roles of genetic predilection and/or parasites in the pathogenesis are discussed. This panarteritis is spontaneous and may complicate the interpretation of lesions in toxicity studies.

Animals↗
PubMed1987

Collaborative multidisciplinary approach to investigation of chemical-induced contact dermatitis.

Immune-mediated contact dermatitis induced by chemicals is a complex biologic process, the pathogenesis of which is not completely understood. Some immuno-dermatotoxins also induce direct dermatotoxicity. This pathogenic complexity presents a serious problem if one wishes to screen chemicals for dermatotoxic effect and investigate their pathogenic mechanism. Rapid toxicologic assays such as the mouse ear swelling test are excellent for detecting chemicals that cause contact dermatitis, but are limited for pathogenic investigations. Morphologic pathology is important for determining which pathologic reactions are involved, but is a relatively crude method for investigating immunobiologic mechanisms. Immunobiologic studies are being used for mechanistic investigations, but the relevance of many measured end points to assessment of immunotoxicity is still unclear. A collaborative multidisciplinary approach involving investigators conducting rapid toxicologic screen tests, morphologic pathology and immunobiology studies is proposed as a solution. This approach is based on complementary integration of the disciplines, and considers the advantages and limitations of each specialty.

Animals↗
PubMed1987

Structural determinants of cationic amphiphilic amines which induce clear cytoplasmic vacuoles in cultured cells.

Disobutamide (D), an antiarrhythmic cationic amphiphilic amine (CAA), was withdrawn from clinical testing when clear cytoplasmic vacuoles (CCV) were found in the rat and dog during toxicity studies. To delineate the structural determinants of amines that induce CCV, we exposed cultured rat urinary bladder carcinoma and rabbit aorta muscle cells to numerous cationic drugs and chemicals and examined cells by phase light microscopy. The cationic moiety of these CAA was responsible for the induction of CCV. The very potent inducers were compounds that had two strongly basic amine (cationic) centers. The bis tertiary amines were particularly potent inducers. Aliphatic diamines of minimal lipophilicity-induced CCV, thus showing that an "amphiphilic" structural feature, though present in many CAA drugs, is not necessary for CCV induction. The distance between the two cationic centers was irrelevant to the induction of CCV. These results support the concept that CCV are a manifestation of intracellular (e.g., intralysosomal) drug storage. These structural delineations will be useful in future drug design and for further understanding of drug-cell interactions. Based on these findings, we were able to synthesize an antiarrhythmic CAA which did not induce CCV.

Amines↗
PubMed1986

Spontaneous osteogenic sarcoma in the rat.

A spontaneous osteogenic sarcoma of the spinal column (tail, sacrum and lumbar regions) with metastases to the lungs, kidneys and right ovary were found in a 15-month-old BHE rat. The literature on spontaneous osteogenic sarcoma in rats indicates that this tumour is rare (0.22 per cent), occurs in several strains and has no sex, age or site predilections; non-metastatic cases are more common than metastatic ones.

Animals↗
PubMed1986

Histology of and quantitative assays for oxazolone-induced allergic contact dermatitis in mice.

Oxazolone-induced allergic contact dermatitis in mice has been used as an in vivo model for identifying potential anti-inflammatory and immune-modulating drugs. Studies were conducted with this model to detail the histokinetics of the inflammatory response and to examine the adequacy of three assays for measuring the intensity of the inflammatory response when compared to histologic findings. CD-1 mice were sensitized with oxazolone on the flank and challenged on the dorsum of the ear pinna. The inflammatory response was quantitated by measuring the change in pinna weight and thickness and presence of 125I-2-deoxyuridine (125IUDR)-labeled cells. Cellular infiltrate was mixed with general predominance of mononuclear cells over neutrophils. Correlation with the histologic data suggests that both the ear weight and thickness assays are suitable primary screening assays, since both provided a sensitive, accurate and objective measure of the inflammatory response and its suppression by dexamethasone. The 125IUDR assay worked well in untreated mice but was unsatisfactory in mice treated topically or systemically with dexamethasone.

Administration, Topical↗
PubMed1986

Hematology reference values for peripheral blood of laboratory rats.

Reference values for peripheral red and white blood cells, platelets and coagulation parameters from 11 and 18-week-old Charles River Sprague Dawley rats [Cr1:COBS CD(SD)] were obtained using automated methods. The Coulter Model S Senior, the Clay Adams Ultra-Flo Platelet Counter and the Sherwood Lancer Coagulyzer, were used to measure these parameters on 25 rats/sex. Detailed information on instrumentation or assay methods, and the animals, their source, environment and blood collection method was given. Platelet counts were in the range of 694 X 10(9)/1 to 1412 X 10(9)/1 which was higher than previously reported. In general, the remaining ranges were similar to previously published reference ranges.

Animals↗
PubMed1985

The pH dependence of disobutamide-induced clear cytoplasmic vacuoles in cultured cells.

Cellular uptake of disobutamide (D), and clear cytoplasmic vacuoles (CCV) induction by D in cultured rat urinary bladder carcinoma cells were dependent on the culture medium pH. At pH 6.0-6.7, drug uptake was slow and no CCV formed in 24 hr. At pH 7.0-8.0, the rate of D uptake and early appearance of CCV were directly proportional to increased basicity. This was explained by the increasing fraction of un-ionized D molecules at increasing basicity of the culture medium. It is only these electrically neutral D molecules which can penetrate the lipoidal cell membrane to induce formation of CCV. Intracellular presence of D was demonstrated by mass spectrometry methods. The results indicate that D is incorporated intracellularly, that D and not its metabolite(s) is in cells, and suggest that CCV are a result of drug sequesteration.

Animals↗
PubMed1984

Disobutamide-induced cytoplasmic vacuoles in cultured dog coronary artery muscle cells.

Smooth muscle cells released by protease from the coronary artery of dogs were cultured in M199 supplemented with 10% fetal calf serum. Cells were grown on glass coverslips to semiconfluence and exposed to disobutamide at 0, 1, 2, 3, 6, 8, and 10 X 10(-4) M for 24, 48, and 72 h, examined in situ by light microscopy, then fixed in 100% methanol, stained with May-Grünwald Giemsa and examined by light microscopy. Cells were also exposed to drug for 24 h, pelleted, fixed and prepared routinely for electron microscopy. Control cells and cells exposed to 6 X 10(-4) M disobutamide were examined. Vacuole formation was dose and time dependent between 2 X 10(-4) M and 10(-3) M. By light microscopy, morphologic alterations induced by the drug were clear cytoplasmic vacuoles in live cells, vacuoles in dead cells and dead cells without vacuoles. Small round vacuoles were an early change. Dark granules were dispersed among the vacuoles. The vacuoles increased in size at higher doses or longer times. Eventually all the cytoplasm was occupied by vacuoles and the cells were enlarged. By electron microscopy, the vacuoles were round, primarily membrane-bound, contained mostly electron-lucent material and occasionally small flocculent bodies. There was vacuolar coalescence. The dose response of vacuole induction in confluent and semiconfluent cells was similar. Cytoplasmic vacuoles without cell death can be induced by disobutamide at 2 or 4 X 10(-4) M during a 3-day exposure. Cell culture is a suitable biological system for studying cytoplasmic vacuoles of the type induced by disobutamide.

Animals↗