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Biomedical subjects

E V Granowitz

Publications and source records attributed to E V Granowitz.

At least 19 recordsLinked to original sources
PubMed2003

Hyperbaric oxygen inhibits stimulus-induced proinflammatory cytokine synthesis by human blood-derived monocyte-macrophages.

Hyperbaric oxygen (HBO) is 100% oxygen administered at elevated atmospheric pressure to patients with inflammatory diseases. We developed an in vitro model to investigate the effects of HBO on stimulus-induced proinflammatory cytokine transcription and translation. Human blood-derived monocyte-macrophages were stimulated before being transferred to an HBO chamber where they were incubated at 97.9% O2, 2.1% CO2, 2.4 atmospheres absolute, 37 degrees C. Controls were maintained in the same warm room at normoxia at sea level, hyperoxia or increased pressure alone. A 90-min HBO exposure inhibited IL-1beta synthesized in response to lipopolysaccharide by 23%, lipid A by 45%, phytohaemagglutinin A (PHA) by 68%, and tumour necrosis factor (TNF)-alpha by 27%. HBO suppressed lipopolysaccharide-, lipid A- and PHA-induced TNF-alpha by 29%, 31% and 62%, respectively. HBO transiently reduced PHA-induced steady state IL-1beta mRNA levels. Hyperoxia alone and pressure alone did not affect cytokine production. The immunosuppressive effect of HBO was no longer evident in monocyte-macrophages exposed to HBO for more than 3 h. Interestingly, cells exposed to HBO for 12 h synthesized more IL-1beta than cells cultured under control conditions. In summary, HBO exposure transiently suppresses stimulus-induced proinflammatory cytokine production and steady state RNA levels.

Cells, Cultured↗
PubMed2002

Hyperbaric oxygen enhances apoptosis in hematopoietic cells.

Hyperbaric oxygen (HBO) is 100% oxygen administered at elevated atmospheric pressure. In this study, we examined the effect of HBO on hematopoietic cell apoptosis. Cells exposed to HBO were incubated in a chamber containing 97.9% O(2) and 2.1% CO(2) at 2.4 atmospheres absolute (ATA). HBO enhanced spontaneous HL-60 cell apoptosis in a time-dependent manner; a 12 h exposure increased apoptosis by 42%. Exposing these cells to hyperoxia at standard atmospheric pressure (95% O(2), 5% CO(2) at 1 ATA) or increased pressure alone (8.75% O(2), 2.1% CO(2) at 2.4 ATA) had minimal effect on apoptosis. HBO also enhanced stimulus-induced apoptosis. HL-60 cells stimulated to die using gamma radiation underwent 33% more apoptosis than cells exposed to radiation alone. HBO enhanced melphalan, camptothecin, and chlorambucil-induced apoptosis by 22%, 13%, and 8%, respectively. Jurkat cells stimulated to die with anti-Fas antibody underwent 44% more apoptosis when exposed to HBO. Spontaneous apoptosis was increased by 15% in HBO-exposed murine thymocytes. HBO's effect on apoptosis did not require new protein synthesis. As expected, HBO exposure increased the intracellular concentration of H(2)O(2). Incubating HL-60 cells in the presence of dehydroascorbic acid partially abrogated HBO-induced increases in intracellular H(2)O(2) and apoptosis. In summary, HBO enhances spontaneous and stimulus-induced apoptosis in hematopoietic cells, at least in part, by enhancing the intracellular accumulation of H(2)O(2).

Animals↗
PubMed2002

Exposure to increased pressure or hyperbaric oxygen suppresses interferon-gamma secretion in whole blood cultures of healthy humans.

This study examines the effects of hyperoxia, increased atmospheric pressure, and hyperbaric oxygen on cytokine synthesis. Five healthy volunteers were exposed to 90 min of room air, 100% oxygen, 10.5% oxygen at 2 atm abs, or 100% oxygen at 2 atm abs (HBO2). All subjects were blinded and randomly exposed to each of the 4 conditions. Immediately before entering the chamber, immediately after exposure, and 3 and 24 h later, blood was drawn and stimulated ex vivo with phorbol myristate acetate (PMA) and phytohemagglutinin A (PHA). Since lymphocytes are the primary source of PMA/PHA-induced interferon-gamma (IFN-gamma), these results were expressed as IFN-gamma production per 10(6) lymphocytes. Following the HBO2 exposure, PMA/PHA-stimulated lymphocytes released 51% less IFN-gamma than cells obtained before the exposure. This suppression persisted for 24 h following HBO2 (P < 0.05). Surprisingly, increased atmospheric pressure alone also inhibited IFN-gamma secretion (P < 0.05). Room air and hyperoxia alone had no significant effect upon IFN-gamma release. HBO2's anti-inflammatory effect may, in part, be due to inhibition of IFN-gamma release.

Adult↗
PubMed2000

Potentially fatal interaction between azithromycin and disopyramide.

A patient on disopyramide developed disopyramide toxicity when treated concurrently with azithromycin. Evidence of toxicity included an elevated serum disopyramide level and ventricular tachycardia requiring cardioversion. The azalide antibiotic presumably inhibited dealkylation of disopyramide to its major metabolite, mono-N-dealkyldisopyramide. Physicians should avoid using azithromycin in patients on disopyramide. If this drug combination is unavoidable, disopyramide levels must be closely monitored.

Adult↗
PubMed1998

A pseudoepidemic of Alcaligenes xylosoxidans attributable to contaminated saline.

Alcaligenes xylosoxidans is an uncommon but serious cause of nosocomial epidemics. This report describes a cluster of two patients who underwent revision of hip arthroplasties and one patient who had a lumbar puncture. Cultures obtained during all three procedures showed A. xylosoxidans with similar antibiotic sensitivity patterns. An investigation found that saline used to process these specimens was contaminated with this organism.

Aged↗
PubMed1998

Extraintestinal Clostridium difficile: 10 years' experience at a tertiary-care hospital.

OBJECTIVE: To determine the clinical characteristics of patients with extraintestinal Clostridium difficile (ECD). MATERIAL AND METHODS: All cultures obtained during a 10.5-year period (from Jan. 1, 1985, to Jun. 30, 1995) at a tertiary-care hospital were retrospectively examined. The medical records of patients from whom ECD was isolated were then reviewed. RESULTS: Fourteen patients from whom ECD was cultured were identified. Thirteen of these patients (93%) had underlying systemic disease. All but one patient had recent exposure to antibiotics, and all had major bowel pathologic conditions. Nine patients had colon perforation. Of the eight patients in whom the colonic mucosa was directly inspected at operation or endoscopy, only two had evidence of pseudomembranous colitis. Five patients (36%) had documentation of recent diarrhea. ECD was isolated from intraperitoneal sites (in nine patients), blood cultures (in three), a perianal abscess, and a prosthetic hip joint. In 13 patients (93%), the infection was polymicrobial. Seven of the 13 inpatients (54%) survived to dismissal. CONCLUSION: C. difficile is a rare isolate outside of the gastrointestinal tract. ECD is found in patients with systemic illness who have been hospitalized (usually for an extended period), have intestinal pathologic conditions, and have received antibiotics. The isolation of ECD portends a poor prognosis.

Abscess↗
PubMed1998

Aetiologies and outcomes of wounds in an outpatient programme.

This study reviewed the records of all new patients seen in an outpatient wound-care programme during a six-month period. Most of the 115 patients were referred by physicians in internal medicine or family practice (48%) or surgeons (39%); 101 had a wound (88%). Of the 92 who had their wound measured at the time of their first clinic visit, 72 (78%) had their largest wound located on a lower extremity and 40% of all lower extremity wounds were on the feet. Wounds were most frequently due to pressure (36%), venous insufficiency (16%), diabetic neuropathy (16%), or arterial insufficiency (13%). Within 12 months of their initial presentation, wound closure was documented in 35 of the 92 patients (38%). Of the four most common aetiologies, the healing rate was highest in wounds attributable to venous insufficiency (67%) (p < 0.02).

Adult↗
PubMed1997

Transforming growth factor-beta enhances and pro-inflammatory cytokines inhibit ob gene expression in 3T3-L1 adipocytes.

Leptin is a protein which is encoded by the obese (ob) gene. It is synthesized by adipocytes and binds to receptors in the hypothalamus, thereby suppressing appetite and increasing the metabolic rate. When mouse 3T3-L1 cells are induced to differentiate into adipocytes, they begin to constitutively express low levels of ob mRNA. Using reverse transcription and a semi-quantitative polymerase chain reaction, the experiments described herein demonstrate that the anti-inflammatory cytokine transforming growth factor-beta increases steady state ob mRNA. Conversely, treatment of 3T3-L1 adipocytes with the pro-inflammatory cytokines interleukin-1 beta, interleukin-6, interleukin-11, and tumor necrosis factor-alpha results in a decrease in ob transcripts. When considered in the context of animal studies showing that interleukin-1 and tumor necrosis factor-alpha induce leptin and ob mRNA, these results suggest that pro-inflammatory cytokines induce ob gene transcription in vivo via secondary mediators such as transforming growth factor-beta.

3T3 Cells↗
PubMed1996

Soluble tumor necrosis factor receptors inhibit phorbol myristate acetate and cytokine-induced HIV-1 expression chronically infected U1 cells.

Recombinant human tumor necrosis factor (TNF) binding protein-1 (r-h TBP-1) and recombinant human soluble dimeric TNF receptor (rhu TNFR:Fc) were used to determine the relative contributions of TNF to phorbol myristate acetate (PMA) and cytokine-induced human immunodeficiency virus type 1 (HIV-1) replication in chronically infected cell lines. Treatment of HIV-1-infected promonocytic U1 cells with r-h-TBP-1 or rhu TNFR:Fc reduced PMA-induced HIV-1 p24 antigen production in a concentration-dependent manner, with a maximal inhibition of approximately 90%. Maximal inhibition of p24 antigen production in T-lymphocytic ACH-2 cells was 47% with r-hTBP-1 and 42% with rhu TNFR:Fc. r-hTBP-1 and rhu TNFR:Fc also decreased p24 antigen synthesized by U1 cells in response to other stimuli, including phytohemagglutinin (PHA)-induced supernatant, granulocyte-macrophage colony-stimulating factor, interleukin-6, and TNF. Addition of r-hTBP-1 to U1 cells during the last 4 h of a 24 h incubation with PMA still inhibited p24 antigen production by 15%. U1 cells stimulated with 10(-7) M PMA released approximately 1 ng/ml endogenous TBP-1 with an initial peak observed at 1 h and a second peak at 24 h after PMA stimulation. r-hTBP-1 also partially reversed inhibition of U1 cellular proliferation caused by PMA. Both r-hTBP-1 and rhu TNFR:Fc blocked PMA induction of nuclear factor (NK)- kappa B DNA-binding activity in U1 cells in association with decreases in HIV-1 replication. We conclude that soluble TNF receptors can inhibit stimuli-induced HIV-1 expression and NK- kappa B DNA-binding activity in chronically infected U1 cells.

Base Sequence↗
PubMed1996

Clinical, hematologic, and immunologic effects of interleukin-10 in humans.

We conducted a double-blind, placebo-controlled study to investigate the safety, pharmacokinetics, and immunological properties of interleukin-10 (IL-10) administration in healthy humans. Volunteers received a single intravenous bolus injection of recombinant human IL-10 (1, 10, or 25 micrograms/kg) or placebo. Cytokine production in whole blood and peripheral blood mononuclear cells (PBMC) was assessed before and 3, 6, 24, and 48 hr after the injection. Peak serum concentrations of IL-10 (15 +/- 1.1, 208 +/- 20.1, and 505 +/- 22.3 ng/ml) occurred after 2-5 min for 1, 10, and 25 micrograms/kg IL-10, respectively. The terminal-phase half-life was 3.18 hr. A transient leukocytosis (24-63% above baseline) was observed 6 hr after injection, which coincided with a dose-dependent decrease (12-24%) in neutrophil superoxide generation. There was a marked inhibition (60-95%) of endotoxin-induced IL-6 production from whole blood in each group receiving IL-10. Production of IL-8 in endotoxin-stimulated blood was reduced in the 10 micrograms/kg group. In PBMC stimulated with phytohemagglutinin and phorbol ester, there was a decrease (72-87%) in interferon-gamma (IFN gamma) production 6 hr after IL-10 with a return to pre-IL-10 levels after 24 hr. This reduction was only partially associated with a decrease in the number of CD2-bearing cells. We conclude that IL-10 administration into humans is without significant side effects, and a single injection reduces ex vivo production of IL-6, IL-8, and IFN gamma.

Adolescent↗
PubMed1995

A randomized, controlled trial of IL-10 in humans. Inhibition of inflammatory cytokine production and immune responses.

In vitro, IL-10 inhibits T cell proliferation and LPS-induced monocyte production of IL-1, TNF-alpha, IL-6, and IL-8. We studied the safety and immunomodulatory effects of IL-10 administration in humans. Seventeen healthy volunteers received a single i.v. bolus injection of either human IL-10 (1, 10, or 25 micrograms/kg) or placebo. Routine safety parameters, lymphocyte phenotypes, T cell proliferative responses, and stimulus-induced cytokine production were assessed before and 3, 6, 24, and 48 h after injection. There were no adverse symptoms or signs after IL-10 administration. A transient neutrophilia and monocytosis that peaked at 6 h (45-160% above base line) was observed. However, lymphocyte counts fell by 25% 3 and 6 h after the injection (p < 0.01). In particular, lymphocytes expressing the T cell surface markers CD2, CD3, CD4, CD7, and CD8 were significantly decreased. Mitogen-induced T cell proliferation was suppressed by up to 50% (p < 0.01) in the two higher dose groups. Significant dose-dependent inhibition (65-95%) of TNF-alpha and IL-1 beta production from whole blood stimulated ex vivo with endotoxin occurred after each dose of IL-10. In contrast, there was no reduction in the production of their respective antagonists, TNF soluble receptor p55 or IL-1 receptor antagonist. We conclude that a single intravenous injection of IL-10 is safe in humans, has inhibitory effects on T cells, and suppresses production of the pro-inflammatory cytokines TNF-alpha and IL-1 beta.

Adolescent↗
PubMed1995

Interleukin 1 induces HIV-1 expression in chronically infected U1 cells: blockade by interleukin 1 receptor antagonist and tumor necrosis factor binding protein type 1.

BACKGROUND: Cytokines and cytokine antagonists modulate human immunodeficiency virus (HIV) replication in vitro and may be involved in HIV disease pathogenesis. An understanding of these cytokine networks may suggest novel treatment strategies for HIV-seropositive persons. MATERIALS AND METHODS: U1 cells, a chronically infected promonocytic cell line, were stimulated with interleukin 1 alpha (IL-1 alpha), IL-1 beta or tumor necrosis factor (TNF) for 24 hr. The effects of these cytokines, and of anti-IL-1 receptor type 1 and type 2 (IL-1RI and II) antibody, IL-1 receptor antagonist (IL-1Ra), and recombinant human TNF binding protein type 1 (rhTBP-1, a form of TNF receptor p55), on HIV-1 replication, as measured by ELISA for HIV-1 p24 antigen, were determined. The effects of IL-1 and IL-1Ra on nuclear factor-kappa B (NF-kappa B) DNA binding activity, as measured by electrophoretic mobility shift assays, were also determined. RESULTS: IL-1 alpha and IL-1 beta increased p24 antigen production in a concentration-dependent manner. IL-1Ra completely, and rhTBP-1 partially, suppressed IL-1-induced p24 antigen production. IL-1 increased NF-kappa B DNA binding activity and IL-1Ra blocked this effect. Since IL-1Ra blocks IL-1 from binding to both the IL-1RI and Il-1RII, monoclonal antibodies directed against each receptor were used to ascertain which IL-1R mediates IL-1-induced HIV-1 expression. Antibody to the IL-1RI reduced IL-1-induced p24 antigen production. Although anti-IL-1RII antibody blocked the binding of 125IL-1-1 alpha to U1 cells by 99%, this antibody did not affect IL-1-induced p24 antigen production. IL-1 beta enhanced TNF alpha-induced HIV expression when added before or simultaneously with TNF alpha. CONCLUSIONS: IL-1 induces HIV-1 expression (via the IL-1RI) and NF-kappa B activity in U1 cells. These effects are blocked by IL-1Ra and partially mediated by TNF. IL-1 enhances TNF alpha-induced HIV replication in U1 cells.

ATPases Associated with Diverse Cellular Activitie↗
PubMed1993

Hematologic and immunomodulatory effects of an interleukin-1 receptor antagonist coinfusion during low-dose endotoxemia in healthy humans.

Endotoxin is a component of gram-negative bacteria that causes hematologic and immunologic changes through its induction of cytokines. Interleukin-1 receptor antagonist (IL-1Ra) is a naturally occurring inhibitor of IL-1 that competes with IL-1 for occupancy of cell-surface receptors but possesses no agonist activity. We investigated the ability of human recombinant IL-1Ra to block the effects of low-dose endotoxin. Fourteen healthy male volunteers between 18 and 30 years old were injected intravenously with 3 ng/kg Escherichia coli endotoxin. Concurrent with the injections, nine volunteers received a 3-hour continuous intravenous infusion of IL-1Ra. The other five subjects were given a 3-hour infusion of saline. Volunteers injected with endotoxin experienced a threefold increase in circulating neutrophils over baseline. This neutrophilia was significantly reduced by 48% in subjects administered endotoxin plus IL-1Ra (P = .0253). Ex vivo mitogen-induced peripheral blood mononuclear cell proliferation decreased by greater than 60% at 3 and 6 hours after endotoxin injection (P = .0053). This endotoxin-induced reduction in mitogen response was reversed in subjects coinjected with IL-1Ra (P = .0253). Endotoxin-induced symptoms, fever, and tachycardia were unaffected by IL-1Ra. IL-1 appears to be an important mediator in endotoxemia because some of its hematologic and immunomodulatory effects can be blocked by IL-1Ra.

Adolescent↗
PubMed1993

Intravenous endotoxin suppresses the cytokine response of peripheral blood mononuclear cells of healthy humans.

When administered parenterally, endotoxin stimulates the synthesis of IL-1, TNF-alpha, and IL-6. However, this initial injection induces tolerance; a second injection of endotoxin results in lower levels of circulating cytokines. In our study, five healthy male volunteers between the ages of 18 and 30 were injected with Escherichia coli endotoxin. Four subjects received only saline. Immediately before the injection and 3, 6, and 24 h afterward, PBMC were isolated and stimulated in vitro with endotoxin, IL-1, or toxic shock syndrome toxin-1. Inasmuch as CD14+ monocytes are the primary source of the cytokines induced by these stimuli, results are expressed as cytokine production per 10(6) CD14+ cells. Six h after endotoxin injection, endotoxin-stimulated CD14+ cells synthesized 66% less IL-1 beta (p < 0.01), 47% less TNF-alpha (p < 0.001), 56% less IL-6 (p < 0.01), and 49% less IL-8 (p < 0.01) than cells obtained before the injection. This suppression was not specific for endotoxin; IL-1 beta-induced IL-1 alpha and TNF-alpha were reduced by 84% (p = 0.01) and 68% (p < 0.001), respectively. A decrease in cytokine synthesis was also observed using toxic shock syndrome toxin-1 as a stimulus: 57% for IL-1 beta (p = 0.06), 70% for TNF-alpha (p < 0.01), 56% for IL-6 (p < 0.05), and 71% for IL-8 (p = 0.001). When data were expressed as cytokine production per 10(6) PBMC, cells isolated 3 h after endotoxin injection synthesized significantly less stimulus-induced IL-1, TNF-alpha, IL-6, and IL-8 than did PBMC from saline-injected controls. We conclude that endotoxin tolerance is due, in part, to changes in the stimulus-induced cytokine response of circulating CD14+ cells.

Antigens, CD↗
PubMed1993

Detection of tumor necrosis factor soluble receptor p55 in blood samples from healthy and endotoxemic humans.

The tumor necrosis factor (TNF) soluble receptor derived from the cell surface p55 TNF receptor (TNFsRp55) is a naturally occurring substance generated during infection and inflammation. TNFsRp55 inhibits biologic effects of TNF. An RIA was developed to quantitate TNFsRp55 in human blood. Recovery of TNFsRp55 from blood anticoagulated with EDTA was optimal compared with recovery from serum or heparinized plasma. TNF did not interfere with the assay. With the RIA based on radiolabeled nonglycosylated Escherichia coli-derived recombinant TNFsRp55, a mean concentration of 198 +/- 15 pg/mL was found in 14 volunteers. When glycosylated CHO cell-derived TNFsRp55 was used, the mean level was 1656 +/- 95 pg/mL. Infusion of endotoxin into volunteers induced TNFsRp55, which peaked at 517 +/- 99 pg/mL for the E. coli-based RIA and 7300 +/- 1810 pg/mL for the CHO cell-based RIA. These findings demonstrate that blood collected in EDTA is optimal for measuring circulating TNFsRp55 and that this soluble receptor is present in health but elevated during endotoxemia.

Adolescent↗
PubMed1992

Effect of interleukin-1 (IL-1) blockade on cytokine synthesis: I. IL-1 receptor antagonist inhibits IL-1-induced cytokine synthesis and blocks the binding of IL-1 to its type II receptor on human monocytes.

Interleukin-1 (IL-1) induces IL-1, tumor necrosis factor alpha (TNF alpha), and IL-6 gene expression and synthesis in a variety of cells. In this study, we investigated the ability of human recombinant IL-1 receptor antagonist (IL-1ra) to inhibit IL-1-induced cytokine production in human peripheral blood mononuclear cells (PBMC) and isolated monocytes. IL-1ra alone at concentrations as high as 1 microgram/mL did not induce IL-1 alpha, IL-1 beta, TNF alpha, or IL-6 synthesis. Suppression of IL-1-induced IL-1, TNF alpha, or IL-6 synthesis was dose-dependent (P less than or equal to .0001). At a twofold molar excess, IL-1ra inhibited IL-1-induced IL-1 or TNF alpha synthesis by 50% (P less than .01); an equimolar concentration of IL-1ra inhibited synthesis of these two cytokines by over 20% (P less than .05). A 10-fold molar excess of IL-1ra over IL-1 beta reduced IL-1 beta-induced IL-1 alpha by 95% (P = .01) and IL-1 alpha-induced IL-1 beta by 73% (P less than .01). IL-1ra added to PBMC 8 hours after stimulation with IL-1 beta was still able to inhibit IL-1 alpha, TNF alpha, and IL-6 synthesis (P less than or equal to .01). A similar reduction in IL-1 beta-induced IL-1 alpha was observed when IL-1 beta was removed from the cultures after 8 hours of stimulation (P less than .05), suggesting a prolonged presence of IL-1 or restimulation of IL-1 receptors on monocytes is required for the induction of cytokines. In elutriated monocytes, a 10-fold molar excess of IL-1ra reduced IL-1 beta-induced IL-1 alpha by 82% (P less than .05), TNF alpha by 64% (P = .05), and IL-6 by 47% (P less than .05). 125I-IL-1 beta was bound to purified monocytes, cross-linked, and immunoprecipitated. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis showed a band at 85 Kd corresponding to the 68-Kd IL-1 receptor type II (IL-1RtII). Excess unlabeled IL-1 beta or IL-1ra blocked the binding of 125I-IL-1 beta to the IL-1RtII. We conclude that IL-1ra inhibits IL-1-induced cytokine synthesis and competes with IL-1 for the IL-1RtII on human monocytes.

Cytokines↗