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Biomedical subjects

J Kosek

Publications and source records attributed to J Kosek.

At least 19 recordsLinked to original sources
PubMed2001

Nonlinear behaviour of simple ionic systems in hydrogel in an electric field.

The stationary behavior of ionic reaction-transport systems contained in hydrogel located between two reservoirs of electrolytes is investigated. The effects of the applied voltage, the composition of the electrolytes in the reservoirs and the distribution of fixed charge in the hydrogel on the spatial patterns of charge, electric potential, temperature and concentrations of the individual components are studied systematically by mathematical modelling. Such systems, containing only several ions (for example, Cl-, K+, OH- and H+) can function as electrolyte diodes and transistors and can exhibit oscillations and hysteresis. The mathematical description of the studied systems is based on balances of species, enthalpy and charge, on Poisson's equation and on the finite rate description of the water dissociation/recombination reaction, without assuming local electroneutrality. The modeling results are compared with experiments, including the system with hydrogel connecting reservoirs of strong base and acid studied by Noszticzius and co-workers. [L.H. Hegedus, N. Kirschner, M. Wittmann and Z. Noszticzius, J. Phys. Chem. A, 1998, 102, 6491 (ref. 1); L. H. Hegedus, N. Kirschner, M. Wittmann, P. Simon and Z. Noszticzius, Chaos, 1999, 9, 283 (ref. 2).]

Journal Article↗
PubMed1999

Impaired aerobic capacity in hypercholesterolemic mice: partial reversal by exercise training.

The present study assessed whether impaired aerobic capacity previously observed in hypercholesterolemic mice is reversible by exercise training. Seventy-two 8-wk-old female C57BL/6J wild-type (+, n = 42) and apolipoprotein E-deficient (-, n = 30) mice were assigned to the following eight interventions: normal chow, sedentary (E+, n = 17; E-, n = 8) or exercised (E+ex, n = 13; E-ex, n = 7) and high-fat chow, sedentary (E+chol, n = 6; E-chol, n = 8) or exercised (E+chol-ex, n = 6; E-chol-ex, n = 7). Mice were trained on a treadmill 2 x 1 h/day, 6 days/wk, for 4 wk. Cholesterol levels correlated inversely with maximum oxygen uptake (r = -0.35; P < 0. 02), which was blunted in all hypercholesterolemic sedentary groups (all P < 0.05). Maximum oxygen uptake improved in all training groups but failed to match E+ex (all P < 0.05). Vascular reactivity and nitric oxide (NO) synthesis correlated with anaerobic threshold (r = 0.36; P < 0.025) and maximal distance run (r = 0.59; P < 0.007). We conclude that genetically induced hypercholesterolemia impairs aerobic capacity. This adverse impact of hypercholesterolemia on aerobic capacity may be related to its impairment of vascular NO synthesis and/or vascular smooth muscle sensitivity to nitrovasodilators. Aerobic capacity is improved to the same degree by exercise training in normal and genetically hypercholesterolemic mice, although there remains a persistent difference between these groups after training.

Aerobiosis↗
PubMed1998

CCR5- and CXCR4-utilizing strains of human immunodeficiency virus type 1 exhibit differential tropism and pathogenesis in vivo.

CCR5-utilizing (R5) and CXCR4-utilizing (X4) strains of human immunodeficiency virus type 1 (HIV-1) have been studied intensively in vitro, but the pathologic correlates of such differential tropism in vivo remain incompletely defined. In this study, X4 and R5 strains of HIV-1 were compared for tropism and pathogenesis in SCID-hu Thy/Liv mice, an in vivo model of human thymopoiesis. The X4 strain NL4-3 replicates quickly and extensively in thymocytes in the cortex and medulla, causing significant depletion. In contrast, the R5 strain Ba-L initially infects stromal cells including macrophages in the thymic medulla, without any obvious pathologic consequence. After a period of 3 to 4 weeks, Ba-L infection slowly spreads through the thymocyte populations, occasionally culminating in thymocyte depletion after week 6 of infection. During the entire time of infection, Ba-L did not mutate into variants capable of utilizing CXCR4. Therefore, X4 strains are highly cytopathic after infection of the human thymus. In contrast, infection with R5 strains of HIV-1 can result in a two-phase process in vivo, involving apparently nonpathogenic replication in medullary stromal cells followed by cytopathic replication in thymocytes.

Animals↗
PubMed1997

Dendritic cells that process and present nominal antigens to naive T lymphocytes are derived from CD2+ precursors.

Dendritic cells (DC) are potent APC that, in mature form, can be distinguished from other mononuclear cells on the basis of their distinct morphology, absence of lineage markers, and dense expression of MHC and costimulatory molecules. While comparing different DC preparation methods, we observed that DC derived from cultured PBMC that had been depleted of CD2+ cells before culture were functionally distinct from DC derived from PBMC that had not been depleted of CD2+ cells. Thus, both types of DC stimulated allogeneic T cells to proliferate in the MLR, but only DC derived from CD2+ precursors could sensitize naive T cells to soluble Ags such as keyhole limpet hemocyanin and HIV gp160 glycoprotein. Subsequent studies confirmed the existence of CD2+ and CD2- DC precursor populations among HLA-DRbright, lineage-negative PBMC. Immediately after their isolation, these populations were morphologically similar to one another by light and electron microscopy, and neither had substantial Ag-presenting activity. After culture for 24 to 48 h with supernatant from PHA-activated PBMC, both populations developed dendrites, formed clusters with T cells, and stimulated allogeneic T cell responses in the MLR as well as autologous T cell responses to tetanus toxoid, a recall Ag. However, CD2+ DC precursors alone gave rise to APC that presented soluble Ags to naive CD4+ T cells, a property that could be inhibited by Abs to CD4, CD11a, and CD28 on T cells or CD86 on DC. The expression of CD54 and CD86 on CD2+ DC precursors was increased markedly after their culture and differentiation, while the expression of these molecules on CD2- DC precursors was not remarkably changed. These findings reveal the existence of two functionally distinct populations of DC, each derived from a phenotypically distinct precursor present in monocyte-depleted peripheral blood.

Antigen Presentation↗
PubMed1996

Association of CD4+ T cell-dependent, interferon-gamma-mediated necrosis of the small intestine with genetic susceptibility of mice to peroral infection with Toxoplasma gondii.

Since there is a remarkable difference in susceptibility to peroral infection with Toxoplasma gondii among inbred strains of mice, we performed studies to examine the mechanism(s) of this difference in susceptibility. After peroral infection with the ME49 strain of T. gondii, C57BL/6 (B6) mice all died whereas BALB/c mice all survived. At day 7 of infection (when B6 mice began dying), massive necrosis of the villi and mucosal cells in the ilea were observed in B6 but not in BALB/c mice. To analyze the role of T cells in resistance against death and development of necrosis in the ilea after infection, studies were performed using athymic nude and euthymic control B6 and BALB/c mice. Athymic B6 mice all died after infection, but surprisingly, they survived significantly longer than control B6 mice, indicating that T cells predispose to early death in these mice. Necrosis in the ilea was observed in control B6 but not in athymic B6 mice; however, significantly less numbers of tachyzoites were observed in the ilea of the former than the latter mice. These results indicate that necrosis in the ilea of the B6 mice was not due to destruction of tissue by tachyzoites but was mediated by T cells. This deleterious effect of T cells appears to contribute to early death in these mice. In contrast, T cells conferred resistance against death in BALB/c mice but did not cause necrosis in their ilea. To analyze the T cell subset(s) that induces necrosis of the ilea in B6 mice, we examined histological changes of the small intestines after infection of mutant mice deficient in different T cell subsets (with the same H-2b haplotype as B6 mice). Mice deficient in alpha/beta or CD4+ T cells did not develop necrosis in the ilea, whereas wild-type control mice and mice deficient in gamma/delta or CD8+ T cells did, suggesting that the cells that induce necrosis in the ilea after infection are CD4+ alpha/beta T cells. Since interferon (IFN)-gamma has been shown to be critical for survival of BALB/c mice after infection with T. gondii, we examined the role of this cytokine in resistance/susceptibility of infected B6 mice. Treatment of B6 mice with anti-IFN-gamma monoclonal antibody shortly before they developed illness prolonged time to death and prevented necrosis in the ilea in these mice. These results indicate that IFN-gamma mediates necrosis in the ilea of B6 mice after infection. This CD4+ T cell-dependent, IFN-gamma-mediated necrosis of the small intestines appears to be a mechanism that underlies the genetic susceptibility of B6 mice to peroral infection with T. gondii, whereas the same cytokine plays a critical role in the resistance of genetically resistant BALB/c mice.

Administration, Oral↗
PubMed1995

Modulation of apoptosis in human myeloid leukemic cells by GM-CSF.

Apoptosis (programmed cell death) regulates cell population size. To determine the mechanisms whereby hematopoietic growth factors (HGFs) modulate apoptosis in human myeloid leukemic cells, we evaluated the roles of protein and mRNA synthesis for altering apoptosis in growth factor-stimulated vs. quiescent leukemic TF1 cells. Lysates of cells from the granulocyte-macrophage colony-stimulating factor (GM-CSF)-dependent myeloid leukemic cell line TF1 were separated into high molecular weight (HMW) pellets of intact DNA and supernatants of fragmented low MW (LMW) DNA, and the DNA purified from these fractions was quantified. In the absence of both GM-CSF and fetal bovine serum (FBS), 70% of the DNA was fragmented after 3 days in culture, with a characteristic apoptotic ladder-like pattern on agarose gel electrophoresis, whereas this proportion had initially been < 5%. In contrast, less than 5% of the DNA was fragmented in cells incubated with GM-CSF plus FBS or GM-CSF alone. Delayed addition of GM-CSF, but not FBS, permitted partial rescue of the cells, inhibiting increasing rates of accumulation of fragmented DNA. When the macro-molecular synthesis inhibitor cycloheximide (CHX) or actinomycin D (Act D) was present for 26 hours in the absence of GM-CSF and FBS, apoptosis was inhibited. In contrast, in the presence of GM-CSF or FBS, apoptosis was enhanced upon addition of CHX or Act D. The latter effect persisted even with the late addition of CHX. These findings indicate that disparate mechanisms of enhancing or inhibiting apoptosis exist in myeloid leukemic cells related to environmental conditions, including HGF-regulated cellular synthesis of distinct proteins and mRNA.

Apoptosis↗
PubMed1994

Dietary arginine prevents atherogenesis in the coronary artery of the hypercholesterolemic rabbit.

OBJECTIVES: This study was designed to test the hypothesis that long-term oral supplementation of dietary L-arginine (to provide a sustained elevation of nitric oxide activity) would inhibit atherogenesis in hypercholesterolemic rabbits, as assessed by histomorphometric measurements. BACKGROUND: Endothelium-derived nitric oxide inhibits a number of processes that are critical in atherogenesis. Hypercholesterolemia reduces endothelial nitric oxide activity, and we postulate that this may promote atherogenesis. This reduction in nitric oxide activity can be reversed acutely by intravenous infusion of L-arginine, the precursor of nitric oxide. We show that dietary supplementation of L-arginine abrogates the development of coronary atheroma in hypercholesterolemic rabbits. METHODS: Male New Zealand White rabbits were fed normal rabbit chow, 1% cholesterol chow or 1% cholesterol chow with dietary arginine or methionine supplementation to increase their intake of these amino acids sixfold. After 1 or 10 weeks of dietary intervention, the left main and left anterior descending coronary arteries were harvested for histologic study. Plasma cholesterol measurements were elevated to the same degree in all groups of rabbits receiving the 1% cholesterol diet, whereas plasma arginine levels were doubled in the arginine-treated group. High density lipoprotein (HDL) cholesterol values were not affected by arginine treatment. RESULTS: In rabbits receiving the 1% cholesterol diet, with or without methionine supplementation, light and electron microscopy revealed a marked increase from 1 to 10 weeks in the intimal accumulation of macrophages, associated with an increase in the intimal area of the left main coronary artery. By contrast, in arginine-treated hypercholesterolemic rabbits, there was a near absence of adherent monocytes and tissue macrophages and no progression of intimal thickness from 1 to 10 weeks. CONCLUSIONS: Dietary supplements of L-arginine prevent intimal thickening in the coronary arteries of hypercholesterolemic rabbits. This antiatherogenic effect is not due to an alteration in plasma total cholesterol, HDL cholesterol or caloric or nitrogen balance. The data are consistent with the hypothesis that nitric oxide has antiatherogenic properties.

Animals↗
PubMed1994

Coronary bypass grafting with biological grafts in a canine model.

BACKGROUND: Poor patency rates have limited the success of biological vascular grafts in the coronary artery position. Recently, two bovine internal mammary arterial grafts have been developed for possible use as coronary artery bypass graft (CABG) conduits: (1) Denaflex grafts (Baxter Health-care Co, 3-mm ID) treated with polyepoxy compounds and with heparin ionically bound to the luminal surface and (2) Bioflow grafts (Bio-Vascular, Inc, 3-mm ID) treated with dialdehyde starch. METHODS AND RESULTS: Thirty dogs underwent CABG with either a Denaflex (n = 20) or Bioflow (n = 10) graft to the left circumflex coronary artery (LCx). The left main coronary artery (n = 12) or proximal LCx (n = 18) was then ligated. Six-month patency (Kaplan-Meier) for Denaflex grafts was 44 +/- 13% (+/- SEM), compared with 12 +/- 11% for Bioflow grafts, but this difference did not reach statistical significance (P = .56). Among grafts open at 14 days, however, there were no occlusions among six Denaflex grafts versus five occlusions among seven Bioflow grafts. At 6 months, all six surviving Denaflex grafts appeared normal, while the only remaining patent Bioflow graft was angiographically dilated and had diffuse luminal irregularities. At 1 year, three Denaflex grafts angiographically had no dilation, stenosis, or luminal irregularities. Macroscopically, all explanted long-term (6 to 12 months) Denaflex grafts had a smooth, clean luminal surface, whereas the only patent Bioflow graft had multifocal thrombi. Microscopically, all Denaflex grafts had minimal degenerative changes, but the Bioflow graft had transmural linear cracks and medial deterioration. CONCLUSIONS: These data suggest that long-term (> 6-month) patency is possible with small-caliber, low-flow biological grafts in the canine coronary position, although both types of grafts are prone to early occlusion. If these early failures are excluded, the Denaflex graft appears to be associated with better long-term patency and an absence of degenerative changes.

Animals↗
PubMed1993

HIV induces thymus depletion in vivo.

Human immunodeficiency virus (HIV) disease is typified by declining CD4+ T lymphocyte counts in the peripheral circulation, a loss which may be secondary to accelerated destruction, to suppressed differentiation, and/or to sequestration of circulating cells into tissue spaces. As it is hard to distinguish between these possibilities in human subjects, the pathogenic mechanisms associated with HIV infection are unclear. In particular, little is known about the events that occur within infected lymphoid organs in which most CD4 T lymphocytes mature and function. To obtain a better description of HIV pathogenesis in vivo, we have implanted human haematolymphoid organs into the immunodeficient SCID mouse to create the SCID-hu mouse. We have previously shown that these organ systems promote long-term multilineage human haematopoiesis and are permissive for infection with HIV. Here we report that human thymopoiesis is suppressed by HIV infection, thereby precluding regeneration of the peripheral T-cell compartment.

Animals↗
PubMed1993

Experimental hepatic tumor necrosis. Comparison of spin-echo and pulsed magnetization transfer contrast magnetic resonance imaging.

RATIONALE AND OBJECTIVES: We compared the effectiveness of pulsed magnetization transfer contrast (MTC) magnetic resonance imaging (MRI) and spin-echo MRI in detecting tumor necrosis. METHODS: Adenocarcinoma cells were transplanted in the livers of 12 syngenic BDIX rats. To induce various degrees of tumor necrosis, the rats were randomly assigned to the following groups: 1) control; 2) localized hyperthermia; 3) intralesional cisplatin; and 4) hyperthermia plus intralesional cisplatin. At day 7 after treatment, the rats were imaged using a 1.5-T imager with 1) multiplanar gradient-recalled echo sequence (MPGR) 500/8/20 degrees with and without magnetization transfer contrast (MTC); 2) spin-echo 2500/20,80, and 3) spin-echo 300/20 pulse sequences. The rats were then sacrificed and pathologic specimens were prepared using MR images as guidance. T2 and ratios of signal intensity after saturation to signal intensity before saturation (Ms/Mo ratios) of the necrotic and granulation tissues and viable tumors were determined in 10 rats. RESULTS: Compared with standard MPGR images, MPGR images with MTC provided better contrast between the pathologic tissues and normal liver. However, T2 values were more useful than Ms/Mo ratios in distinguishing necrotic areas from viable tumor. The T2 values of coagulative necrosis and granulation tissue were significantly different from that of viable tumor. No significant difference between the Ms/Mo ratios of the different pathologic tissues and normal liver was found. CONCLUSION: Pulsed magnetization transfer contrast MRI was inferior to spin-echo MRI in distinguishing necrotic from viable tumors in rat livers using the pulse sequences described, and none of the sequences studied was thought to be reliable enough for this purpose.

Adenocarcinoma↗
PubMed1992

Human immunodeficiency virus-infected monocyte-derived macrophages express surface gp120 and fuse with CD4 lymphoid cells in vitro: a possible mechanism of T lymphocyte depletion in vivo.

Monocyte-derived macrophages (MDM) infected in vitro with a macrophage-tropic strain of human immunodeficiency virus (HIV) fused with uninfected, CD4-expressing T lymphoblastoid cells, but not with a subclone of these cells lacking surface CD4. Infected MDM also fused with uninfected autologous and heterologous MDM. Recombinant soluble CD4 protein (rsCD4) (10 micrograms/ml) and full-length recombinant glycosylated gp120 (20 micrograms/ml) each inhibited fusion by 94-99%; the inhibition was dose-dependent. The N-terminal portion of gp120 did not inhibit syncytium formation. Fusion was also inhibited by a monoclonal antibody to an epitope which binds gp120 (S3.5), but not by antibody to an epitope not involved in gp120 binding (OKT4). HIV-infected MDM specifically bound fluorescein-conjugated rsCD4, and virus could be visualized budding from the surface of these cells. HIV-infected MDM express viral gp120 on their surface and fuse with CD4-bearing cells in a fashion similar to lymphoid cells. Macrophages may contribute to CD4 lymphocyte depletion in vivo by this fusion mechanism.

Antibodies, Monoclonal↗
PubMed1991

T lymphocyte-synovial fibroblast interactions induced by mycobacterial proteins in rheumatoid arthritis.

An in vitro system was established in which single-cell suspensions of lymphocytes and synovial cells from the joints of patients with rheumatoid arthritis were cultured and produced an outgrowth of an organized inflammatory tissue with an extracellular matrix and capsule. The tissue outgrowth, which had histologic features of pannus, required the addition of mycobacterial antigen and interleukin-2 to the tissue culture medium and was dependent upon the presence of T lymphocytes and their interaction with synovial fibroblasts.

Arthritis, Rheumatoid↗
PubMed1991

Pachymeningitis associated with a pulmonary nodule.

The authors report a case of hypertrophic pachymeningitis, a rare cause of spinal cord compression. In this patient, dural inflammation was associated with a histologically identical pulmonary lesion. Such an association has not been described previously and supports the hypothesis that this disease is related to other connective tissue disorders.

Humans↗
PubMed1990

Polypoid Menetrier's disease associated with acromegaly.

There are two forms of Menetrier's disease. The common form involves thickened gastric rugae, while the rare form involves discrete gastric polyps. The clinical literature suggests an association between Menetrier's disease and acromegaly, as well as other neuroendocrine neoplasms; the radiological literature has not addressed the issue. We describe a patient with acromegaly who developed the rare polypoidal form of Menetrier's disease.

Acromegaly↗
PubMed1989

Evidence that cytotoxic lymphocytes alter and traverse allogeneic endothelial cell monolayers.

In an attempt to study the effects of allogeneic lymphocytes on endothelial cells (EC) and analyze the mechanism whereby such lymphocytes traverse an EC barrier, we have established human microvascular EC monolayers, in vitro, and analyzed the effects of lymphocyte subpopulations on such monolayers. Previous studies have shown that CD16+ (natural killer) and CD8+ (cytotoxic) lymphocytes but not CD4+ (helper) cells bind and induce the appearance of class II major histocompatibility complex antigens on allogeneic EC. The current findings indicate that these same lymphocyte subsets induce marked swirling and elongation of allogeneic EC, and traverse intact EC monolayers. In contrast, none of the functional consequences of the initial lymphocyte-EC adhesion were observed using autologous combinations, despite the presence of significant intercellular binding. Scanning and electron micrographs demonstrate extensive areas of lymphocyte-EC surface contact and EC-coated pit formation, whereas a panel of recombinant cytokines known to alter the surface phenotype of EC fail to induce the same morphologic changes whether used singly or in combination. We postulate that the cellular interactions observed here, in vitro, may represent the initial steps in the rejection of vascularized allografts in vivo.

Animals↗