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Biomedical subjects

S Lyubsky

Publications and source records attributed to S Lyubsky.

18 recordsLinked to original sources
PubMed2006

Clues to VIP function from knockout mice.

We have taken advantage of the availability of vasoactive intestinal polypeptide (VIP) knockout (KO) mice to examine the possible influence of deletion of the VIP gene on: (a) airway reactivity and airway inflammation, as indicators of bronchial asthma; (b) mortality from endotoxemia, a model of septic shock; and (c) the pulmonary circulation. VIP KO mice showed: (a) airway hyperresponsiveness to the cholinergic agonist methacholine, as well as peribronchial and perivascular inflammation; (b) a greater susceptibility to death from endotoxemia; and (c) evidence suggestive of pulmonary hypertension.

Animals↗
PubMed2001

Differential effects of nucleoside analogs on oxidative phosphorylation in human pancreatic cells.

Although nucleoside analogs as a group inhibit mtDNA replication, individually they target specific organs for toxicity. For example, dideoxyinosine (ddI) is most closely associated with clinical pancreatitis and dideoxycytosine (ddC) with peripheral neuropathy. Comparison of the differential effects of these analogs on mitochondrial function in relevant human cell lines could provide general clues as to the mechanisms of their differential toxicity. We compared the effects of ddI [and its intracellular metabolite dideoxyadenosine (ddA)], with other nucleoside analogs ddC, Azidothymidine (AZT) and didehydrodeoxythymidine (d4T) on mtDNA elongation, cytotoxicity, oxidative phosphorylation, and cellular ATP concentration in a human pancreatic cell line, Capan-1 cells. AZT, like all the other analogs tested, altered mtDNA elongation, but had no other effect on these cells. Both ddC and d4T, but not ddI (20 microm and 50 microM), reduced total dish protein (a measure of cell numbers) in cells grown to confluence. The effect of ddA was intermediate. All (except AZT) increased lactate concentration in the cell culture medium. Dideoxycytosine (ddC) and d4T did not significantly affect cell oxygen consumption, expressed as a fraction of total dish protein. By contrast, ddI and ddA reduced basal and/or FCCP-stimulated oxygen consumption. Dideoxycytosine (ddC) but not ddI or ddA (50 microM) was cytotoxic to cells after six days of growth. Nevertheless, the ATP content (expressed as a fraction of surviving cells) for ddC-, ddI-, and ddA-treated cells was similar to control cells. Cytotoxicity was apparent for ddI, ddA, as well as ddC after seven days. Paradoxically, cell ATP content was now significantly higher than control cells. Electron microscopy of cells treated with ddI confirmed significant ultrastructural changes affecting the inner mitochondria membrane and cristae. In conclusion, these data suggest that nucleoside analogs uniformly induce damage to mtDNA. However, the mitochondrial phenotypic damage induced by ddI and ddA appear to result in less Capan-1 cytotoxicity than ddC and d4T. The link between these differential effects and ddI pancreatitis is unclear.

Antimetabolites↗
PubMed2000

Children's well-being 11 years after the Chornobyl catastrophe.

BACKGROUND: The psychological effects of technological disasters have rarely been studied in children. This study assessed the aftermath of the 1986 Chornobyl disaster in children evacuated to Kyiv from the contaminated zone surrounding the nuclear power facility. METHODS: In 1997, we evaluated three hundred 10- to 12-year-old children in Kyiv who were in utero or infants at the time of the disaster and who had resided near Chornobyl (evacuees) and 300 sex-matched homeroom classmates who had never lived in a radiation-contaminated area. Response rates were 92% (evacuees) and 85% (classmates). Data were obtained from children, mothers, and teachers using standard measures of well-being and risk factors for childhood psychopathology. The children also received physical examinations and basic blood tests. RESULTS: The evacuees and classmates perceived their mental health similarly except for Chornobyl-related anxiety symptoms and perceived scholastic competence. No differences were found on the Iowa Conners' Teacher Rating Scale. Although the physical examination and blood test results were normal, the evacuee mothers rated their children's well-being as significantly worse, especially with respect to somatic symptoms on the Children's Somatization Inventory and Child Behavior Checklist. The most important risk factors for these ratings were maternal somatization and Chornobyl-related stress. CONCLUSIONS: Given the multiple stressful experiences to which evacuee families were exposed, the small differences in the children's self-reports suggest that there are protective factors in the lives of these children. The trauma experienced by the mothers was reflected in their perceptions of their children's well-being, particularly somatic symptoms, but was not transmitted to the children themselves.

Adolescent↗
PubMed1996

Changes in parietal cell structure and function in HIV disease.

The mechanisms underlying acid secretory failure in patients with HIV disease are unknown. We evaluated, in a series of preliminary studies, changes associated with parietal cell structure and function in early and late HIV disease, in an attempt to elucidate possible underlying mechanisms. Gastric acid and intrinsic factor secretion, vitamin B12 absorption, and light and electron microscopic evaluation of gastric mucosa were evaluated in patients with early and late HIV infection (AIDS) and compared to non-HIV-infected controls. Immunolocalization of HIV-related antigens in gastric mucosa was also examined. Fasting gastric juice pH and intrinsic factor (IF) concentration in AIDS and HIV infected subjects were significantly different from controls (P = 0.012 and P = 0.025, respectively for pH, and 0.029 and 0.035 for IF; ANOVA LSD test). By contrast, maximal acid output (MAO) was significantly lower in AIDS, but not HIV-infected subjects (P = 0.043 and P = 0.322, respectively). Similarly, Schilling test phases 1 and 2 results were significantly lower in AIDS, but not HIV-infected subjects. Varying degrees of vacuolar degeneration of parietal cells were seen on light microscopy. On electron microscopy (EM), tubulovesicles were reduced and intracellular canaliculi dilated with striking loss of microvilli. Immunofluorescent staining with antibodies to gp120, gp41, p24, and p17 demonstrated positive punctate signals in the cytoplasm of gastric glands, which includes parietal cells. Immunogold EM with anti-gp120, localized predominantly to the microvilli of intracellular canaliculi in parietal cells. Abnormal secretory function of parietal cells occurs early in HIV disease, affects acid as well as intrinsic factor secretion, and is associated with morphological changes in the acid secretory apparatus.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Transient expression of neuropeptide Y (NPY) immunoreactivity in the developing hamster paraventricular thalamic area is due to apoptosis.

1. A new population of neurons with transient expression of NPY immunoreactivity was described in the developing hamster paraventricular thalamic area. The present study was performed to discover whether this phenomenon is due to programmed cell death or apoptosis. 2. Toward this aim, immunocytochemical and electron microscopic examination of the paraventricular thalamic region, as well as DNA electrophoresis of tissue extracted from the described area, was performed on different stages of embryonic and postnatal development. 3. A sudden increase in neuropeptide Y immunoreactivity (NPY-IR) in the paraventricular thalamic area at embryonic day 14 (E14) was the first symptom of neuronal degeneration. 4. Electron microscopy revealed many neurons with large masses of condensed chromatin within nuclei and extracellular bodies. The affected cells had a convoluted shape and condensed cytoplasm. 5. DNA electrophoresis revealed a ladder of bands between 150 and 1000 bp that is specific for internucleosomal DNA fragmentation. 6. The data strongly suggest that developmental disappearance of NPY-IR neurons within the hamster dorsal thalamic area is due to apoptosis.

Animals↗
PubMed1996

Histopathology of Peromyscus leucopus naturally infected with pathogenic NY-1 hantaviruses: pathologic markers of HPS viral infection in mice.

Hantavirus research is impeded by the absence of animal models of viral pathogenesis. We have studied the histopathology of mice (P. leucopus) naturally infected with the NY-1 hantavirus on Shelter Island, New York. Five mice were determined to be seropositive in Western blotting to Four Corners Virus nucleocapsid protein and had serum antibodies to Seoul and Puumala hantavirus antigens by immunofluorescence assay. Hantavirus gene segments of the NY-1 hantavirus were identified in these mice and shown to be 99% identical to hantavirus genes isolated from the Rhode Island patient with hantavirus pulmonary syndrome. In ultrastructural examinations, we identified hantavirus particles in pulmonary endothelial cells. Morphologically, these mice demonstrate lymphohistocytic infiltrates in hepatic portal zones and slightly increased numbers of immunoblasts in splenic red pulp. Additionally, the alveolar septa in the lungs of infected mice are edematous with hyperplasia of type 1 pneumocytes. Naturally infected P. leucopus may serve as potentially useful animal models of hantavirus pulmonary syndrome disease.

Animals↗
PubMed1995

Dose-dependent effect of continuous subcutaneous verapamil infusion on experimental acute pancreatitis in mice.

Calcium antagonists may limit experimental tissue injury by membrane stabilization. We studied the effects of verapamil on pancreatic ultrastructure and zymogen extraction during diet-induced acute pancreatitis. Acute pancreatitis was induced in female Swiss-Webster mice by feeding a choline- and methionine-deficient diet (CD) supplemented with 1% ethionine (CDE). Varying doses of verapamil in normal saline were infused continuously at a rate of 0.5 microliter/hr for 96 hr through subcutaneously implanted osmotic pumps. The pancreata were examined blindly by light microscopy and by electron microscopy. Zymogen extracted from pancreatic tissue was measured and expressed per gram of protein. Mean histological scores, calculated according to a formula that incorporates the extent of necrosis, inflammation, acidophilia, and edema, were 14.1 +/- 4, 10.3 +/- 2, 9.9 +/- 4, 5.9 +/- 7, 12.5 +/- 4, and 12.7 +/- 4 for CDE-fed animals receiving 0, 0.14, 0.28, 0.56, 0.84, and 1.12 microM verapamil daily, respectively. Animals fed normal diet or CD had scores of 0 +/- 0. Histological scores were significantly lower in animals treated with 0.56 microns verapamil compared to animals who received no verapamil (p < 0.05) and was associated with reduced dissolution of the zymogen granule membrane on EM. Mean extracted trypsinogen and chymotrypsinogen content were reduced in the CD- and CDE-fed mice. The reduction in mean trypsinogen content reached statistical significance in CDE-fed mice treated with verapamil 0.56 microM daily. Mean chymotrypsinogen content was also significantly reduced CD-mice and in mice treated with 0.56 microns and 0.84 microM of verapamil daily. Increasing doses of verapamil protect against diet-induced pancreatitis in mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1994

Adult respiratory distress syndrome associated with disseminated toxoplasmosis.

Diffuse lung injury may result as a complication of disseminated toxoplasmosis in patients with AIDS. We report the case of an AIDS patient who had multiple organ failure associated with disseminated toxoplasmosis. The patient died because of ventilatory failure, and at autopsy findings in regard to the lungs were consistent with adult respiratory distress syndrome.

AIDS-Related Opportunistic Infections↗
PubMed1994

Transformation of diploid human lung fibroblasts with oncogene ras increases the frequency of abnormal mitoses.

The human oncogene ras p21 was transfected into human lung fibroblast WI-38 diploid cells. All of the clones that were isolated (n = 36), exhibited rapid growth and transformed morphology which was ascertained by both transmission and scanning electron microscopy as extensive formations of microvilli on the plasma membrane, marked distortion of the nuclear membrane and increased number of pinocytotic vesicles in the cortical cytoplasm. The frequency of abnormal metaphases rose from 15% in parental WI-38 cells to 35.5-48.4% in all ten clones examined. Lagging chromosomes in prometaphase represented 42.1-69.4% of the total abnormal mitoses followed in frequency by 3-group metaphase and C-metaphase. All transformed cells were aneuploid. These data provide evidence for the association between cellular transformation with oncogenic ras and elevated abnormal mitoses in human cells.

Aneuploidy↗
PubMed1993

Purification and characterization of a novel cytotoxic protein from transformed fibroblasts.

The mechanism by which cancer cells overwhelm normal parenchymal cells during cancer invasion remains obscure. In this article, we describe the purification of a potent cytotoxic protein from plasma membranes of ras oncogene transformed fibroblasts. Tumor cytotoxic protein was purified from detergent extracted tumor membranes by anion exchange and gel filtration chromatography. Polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate indicated that the hemolytic fractions contained a single protein with an apparent molecular weight of 62,000. A higher concentration of tumor cytotoxic protein was required to lyse fibroblasts as compared to RBC. Based on plasma membrane localization, immunological identity, and biological characteristics, tumor cytotoxic protein is a novel cytolysin which is capable of killing normal cells during cancer invasion.

3T3 Cells↗
PubMed1993

Establishment of a hydrogen peroxide resistant variant of renal tubular epithelial cells: role of calcium-independent phospholipase A2 in cell damage.

Renal epithelial cells resistant to oxidant stress mediated by hydrogen peroxide have been isolated and characterized. African green monkey kidney epithelial cell line, BSC-1 cells, chronically exposed to 50 microM hydrogen peroxide for 15 passages exhibited increased catalase (1.5-fold) and glutathione peroxidase (2.4-fold) activity, as well as increased total cellular glutathione (1.6-fold). This was associated with the acquisition of resistance to hydrogen peroxide cytotoxicity, as judged by nuclear staining with ethidium homodimer and clonogenic survival assay. H2O2-adapted and wild-type BSC-1 cells were used to examine the role of elevated cytosolic calcium concentration and the activation of phospholipase A2 in the development of lethal cell injury. Despite dramatic differences in resistance to oxidative stress, both cell types showed similar kinetics of cytosolic calcium increase in response to challenge with hydrogen peroxide. In contrast to this, oxidant-induced release of arachidonic acid correlated with the resistance of both types of BSC-1 cells to oxidative stress. A mechanism-based inhibitor of calcium-independent phospholipase A2 (Hazen et al., J. Biol. Chem. 266, 7227, 1991) reduced oxidant-induced lethal cell injury, suggesting that this class of phospholipases contributes to damage of BSC-1 cells exposed to hydrogen peroxide. H2O2-adapted BSC-1 cells may represent a valuable tool to study adaptation to oxidative stress and various mechanisms of cell injury.

Animals↗
PubMed1990

High expression of ras p21 correlates with increased rate of abnormal mitosis in NIH3T3 cells.

The modulation of responsive genes by hormonal stimulation is an attractive in vitro model system for the study of a wide variety of biological processes. Using this methodology we have investigated the effect of the human oncogene protein p21ras on mitosis using mouse mammary tumor virus long terminal repeat (MMTV-LTR)-directed gene expression. Following the induction of p21 protein, abnormal mitotic figures were scored in metaphase and anaphase. Elevated expression of p21 was associated with marked increase in the proportion of abnormal mitoses most significantly during the metaphase. Concomitant with a three fold increase in p21 levels, abnormal mitosis rose from 14.0% to 27.25%. The increase in abnormal mitosis corresponded to a 225% increase in abnormal metaphase. The p21-induced mitotic abnormalities were exhibited as lagging chromosomes in prometaphase, 3 group metaphase and C-metaphase. In addition, high expression of p21 was accompanied by significant changes in the cell morphology and fine ultrastructure, e.g. disorganization of actin, the extensive formation of microvilli on the plasma membrane and marked dilatation of the rough endoplasmic reticulum. The mitotic and structural changes were reversible upon removal of dexamethasone and decline of p21 production to its basal levels. Our results identify an important biological effect of ras p21 during mitosis and the early stages of neoplastic transformation.

Animals↗
PubMed1988

Phenotypic markers for a spectrum of colonic polyps and cancers. The malignancy potential ratio.

The purpose of this study was to determine if a panel of monoclonal antibodies could define phenotypic markers that could be used in risk assessment of a spectrum of colonic polyps and colon cancers. Using the ABC immunoperoxidase technique on formalin-fixed sections of surgical specimens, the following results were obtained: 1) Mab B72.3 demonstrated increased reactivity in villous lesions and cancers compared with hyperplastic polyps and tubular adenomas; 2) Mab anti-CAA demonstrated increased reactivity in polyps compared with colon cancers; and 3) using the two antibodies (Mab B72.3 and Mab anti-CAA), a malignancy ratio was obtained that determined malignancy risk for individual polyps. No hyperplastic polyp gave a positive ratio, but about 30 percent of villous lesions were positive. Over 50 percent of villous lesions greater than 2 cm in size had a positive ratio. The malignancy potential ratio may be a valuable marker in assessing risk of malignancy in an individual case.

Adenomatous Polyposis Coli↗
PubMed1988

A tumor-associated antigen in carcinoma of the pancreas defined by monoclonal antibody B72.3.

A retrospective analysis of 25 primary adenocarcinomas of the pancreas, 16 metastatic pancreatic tumors, 8 cases of chronic pancreatitis, and 3 adult normal pancreas was performed to ascertain the reactivity of monoclonal antibody (MAb) B72.3 to malignant and nonneoplastic pancreatic lesions. Formalin-fixed, paraffin-embedded sections of pancreas were evaluated by immunohistochemical techniques (avidin-biotin-peroxidase complex [ABC] method). Twenty-one of 25 malignant primary tumors were reactive, and all 16 metastatic sites expressed the B72.3 antigen. In contrast, all cases of pancreatitis and normal pancreas were either weakly reactive or nonreactive. Ten malignant and two benign pancreatic fine-needle aspirates provided results similar to those seen with fixed tissues. Because MAb B72.3 has selective reactivity for primary and metastatic pancreatic cancer, it may be of value as a diagnostic adjunct in cytologic examination or for radioimmunodetection of regional and/or distant metastases of adenocarcinoma of the pancreas.

Adenocarcinoma↗