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R Lerner

Publications and source records attributed to R Lerner.

At least 37 records · Page 2Linked to original sources
PubMed1994

Lipoxin A4 induces neutrophil-dependent cytotoxicity for human endothelial cells.

The authors have assessed the capacity of neutrophil granulocytes (PMN) to kill cultured human umbilical-vein endothelial cells (HUVEC) in vitro (as release of 51Cr) in response to the recently described double dioxygenation product of arachidonic acid, lipoxin A4 (LXA4). LXA4 conferred a marked cytotoxicity, whereas formyl-methionyl-leucyl-phenylalanine (fMLP) was less potent. The LXA4 and fMLP effects were dose dependent, with a maximum at 100 nM (which caused 2.7- and 2.3-fold increases of 51Cr release, respectively, relative to buffer-treated controls). The LXA4 and fMLP responses increased with the PMN concentration, depended on the fetal calf serum concentration, incubation temperature and duration and the presence of calcium and magnesium ions.

Cells, Cultured↗
PubMed1994

Changes of cytosolic calcium ion concentrations in human endothelial cells in response to thrombin, platelet-activating factor, and leukotriene B4.

This study concerns changes of intracellular calcium concentrations, [Ca2+]i, in human umbilical vein endothelial cells (HUVECs) in response to thrombin, platelet activating factor (PAF), and leukotriene B4 (LTB4). Thrombin (0.003 to 1 U/ml) induced a dose-dependent, pertussis toxin-insensitive rise of [Ca2+]i that was initially rapid and transient and was followed by a sustained plateau phase that required extracellular calcium to be expressed. Early during that plateau a second rise of [Ca2+]i was seen that was amplified in the presence of propranolol and abolished in calcium-free medium or by ethanol. Repeated stimulations with thrombin evoked renewed but declining responses. Pretreatment of HUVECs with PAF or lipoxin A4, but not LTB4, diminished a subsequent response to thrombin. PAF induced a small, dose-dependent increase of [Ca2+]i with kinetics similar to that of thrombin. It was blocked by previous exposure of HUVECs to PAF and thrombin but not to LTB4 or pertussis toxin. LTB4 induced a rapid but sustained increase of [Ca2+]i that resembled that of the calcium ionophore ionomycin. In contrast to responses to thrombin and PAF, it could be abolished by previous treatment with pertussis toxin and required extracellular calcium. Addition of LTB4 after previous stimulation with LTB4 or PAF gave no detectable response. Implications of these results for some specific signal transduction mechanisms for agonists studied are discussed.

Azepines↗
PubMed1993

Lipoxin A4 induces hyperadhesiveness in human endothelial cells for neutrophils.

Lipoxin A4 (LXA4), but not lipoxin B4, induced in vitro a dose-dependent, slowly emerging hyperadhesiveness in human umbilical vein endothelial cells (HUVEC), leading to a 1.9-fold increase in the binding of neutrophils (polymorphonuclear neutrophil granulocytes [PMN]). The maximal response to LXA4 occurred at 1 nmol/L and after 30 minutes of treatment of HUVEC. These response kinetics were intermediate in comparison with those of fast-acting inducers of HUVEC adhesivity (eg, thrombin, leukotriene B4 [LTB4] or platelet activating factor [PAF]), needing 5 to 15 minutes, or to the slow inducer interleukin-1 (IL-1 beta), which requires hours. The maximal LXA4 effect was slightly lower than that of LTB4 (100 nmol/L) and thrombin (1 U/mL), and less than that of PAF (100 nmol/L) or IL-1 beta (2.5 U/mL) (2.2-, 2.0-, 2.4-, or 13.6-fold increases, respectively). The LXA4 effect was inhibited by the PAF receptor antagonist WEB-2086; however, it could not be blocked by pertussis toxin. LXA4 conferred a slow, sustained increase in HUVEC cytosolic calcium ion concentrations, whereas thrombin did so rapidly and transiently. LXA4 also caused PMN to become hyperadhesive. Thus, this novel effect of LXA4 on HUVEC appears to be associated with endogenous PAF expression and slow increases of cytosolic calcium concentrations but not pertussis-sensitive G proteins.

Calcium↗
PubMed1993

Increasing the chemical potential of the germ-line antibody repertoire.

To augment the chemical potential of the immunological repertoire, a metal ion-binding light chain has been introduced into the murine genome. Mice containing the transgene were subsequently immunized with a fluorescein conjugate. The transgenic light chain was found at a high frequency in the anti-fluorescein memory B-cell compartment. This general method should be applicable to other cofactors and small molecules and should lead to generation of antibodies with unique catalytic activities.

Animals↗
PubMed1993

Oral acyclovir as prophylaxis for bacterial infections during induction therapy for acute leukaemia in adults. The Leukemia Group of Middle Sweden.

We prospectively tested the hypothesis that prevention of herpes simplex virus infection with acyclovir might also reduce the incidence of bacterial infections in adult patients with acute leukaemia. During the first induction therapy a double-blind, randomized and placebo-controlled study was undertaken. Fifty-two patients were treated with 200 mg acyclovir orally four times daily throughout the induction period, whereas 55 patients received placebo. The groups were comparable with regard to age, cytotoxic chemotherapy and duration of neutropenia. Bacteraemias were significantly fewer in the acyclovir group (20 versus 41 episodes; P = 0.007). The number of isolated microorganisms causing bacterial or fungal infections was also lower during acyclovir prophylaxis (52 isolates, versus 93 isolates; P = 0.02). There was no significant difference between the groups with regard to the number of clinically documented infections or fevers of unknown origin. Herpes simplex virus isolations occurred only in the placebo group (P = 0.001). Thus, oral acyclovir prophylaxis was associated with reductions of all microbiologically documented infections suggesting that prevention of herpes simplex virus reactivation in acute leukaemia patients may reduce the occurrence of other infections.

Acyclovir↗
PubMed1992

Leukotriene B4-induced hyperadhesiveness of endothelial cells for neutrophils: relation to CD54.

Leukotriene B4 (LTB4) induced an in vitro transient state of hyperadhesiveness in cultured human umbilical vein endothelial cells (HUVEC), leading to a 2.2-fold increase in the binding of neutrophil granulocytes (PMN), which was less than that conferred by platelet activating factor (PAF) though more than thrombin did (3.4- or 2.0-fold increases, respectively). This study concerns the role of the adhesive molecules CD18 and CD54 for the LTB4- (as well as thrombin- and PAF-) induced endothelial hyperadhesiveness. The MoAbs 60.3 (to the CD18 molecule on PMN) and 84H10 (to one epitope of CD54 on the HUVEC) blocked the adherence of PMN to LTB4-treated HUVEC, whereas MoAb LB-2 (directed at another CD54 epitope) failed to do so. MoAb 84H10 blocked 43% of the thrombin-induced hyperadhesiveness, whereas the PAF response was unaffected. Thus, LTB4-induced HUVEC hyperadhesiveness may therefore be related to a specific domain on the CD54 (or on an antigenically related molecule) as well as being dependent on CD18, whereas the involvement of CD54 was much less or non-existent for the thrombin and PAF responses, respectively.

Antibodies, Monoclonal↗
PubMed1992

Oral ketoconazole prophylaxis for Candida infections during induction therapy for acute leukaemia in adults: more bacteraemias.

We determined whether ketoconazole prophylaxis might reduce Candida colonization and infections in adult patients with acute leukaemia. During first-remission induction therapy 50 patients were treated with 200 mg ketoconazole administered orally daily, while 57 patients received placebo in a double-blind, randomized trial. The duration of severe neutropenia (granulocytes less than 0.1 x 10(9) l-1) represented 36% of the study period in the ketoconazole group and 26% in the placebo group (P = 0.043). Although fewer patients presented with positive Candida surveillance cultures and serological evidence of Candida infection in the ketoconazole group compared to the placebo group, two candidaemias and one Trichosporum fungaemia were observed in the ketoconazole group. Moreover, significantly more bacteraemias were noted in the ketoconazole group (n = 37) than in the placebo group (n = 21) (P = 0.004). Thus, although oral ketoconazole prophylaxis might be associated with less Candida colonization and fewer seroconversions, it also resulted in more bacteraemias and longer duration of severe neutropenia, suggesting that caution should be exercised when ketoconazole (or related drugs) is given to this group of immunocompromised hosts.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

Ceftazidime as initial therapy in febrile patients with acute leukemia during induction chemotherapy. Leukemia Group of Middle Sweden.

We studied the efficacy of ceftazidime as initial monotherapy in 82 adult patients with acute leukemia who developed 123 febrile episodes during induction chemotherapy. 88% of the patients survived their febrile episode(s), whereas 10% died of infection. When assessed at 72 h after initiation of treatment (early evaluation), 43/123 episodes (35%) had been successfully treated with ceftazidime. These 43 favourable responses were seen in 15/47 (32%) microbiologically documented infections, 20/46 (43%) clinically defined infections, and 8/30 (27%) fever of unknown origin (FUO). At the resolution of fever (late evaluation) 115 episodes were evaluable, and 48% had responded successfully to ceftazidime. Successful treatment was most frequently observed in FUO, 18/29 (62%). In contrast, only 19/44 (43%) microbiologically documented infections and 18/42 (43%) clinically defined infections were cured during ceftazidime treatment. In bacteremia the response rate was only 8/26 (31%). Thus, this study shows that although ceftazidime can be safely used for initial empirical monotherapy in neutropenic leukemia patients, the need for therapy modification is high and few patients with serious infections are cured with ceftazidime alone.

Adolescent↗
PubMed1992

A pilot study of piperacillin and ciprofloxacin as initial therapy for fever in severely neutropenic leukemia patients.

We studied the efficacy of piperacillin and ciprofloxacin as initial parenteral therapy in 41 adult patients with leukemia who developed 47 febrile episodes during severe neutropenia following chemotherapy. 40 patients (98%) survived their febrile episode(s), whereas 1 patient died of infection. When assessed at 72 h after initiation of treatment (early evaluation), 24/47 episodes (51%) had been successfully treated. These 24 favourable responses were seen in 15/24 (63%) microbiologically documented infections and 9/19 (47%) fever of unknown origin (FUO). At the resolution of fever (late evaluation) 46 episodes were evaluable, and 28 (61%) had responded successfully to piperacillin and ciprofloxacin. Successful treatment was most frequently observed in microbiologically defined infections, 18/23 (78%). Three of 5 (60%) Gram-positive, 11/12 (92%) Gram-negative and 1 of 2 mixed bacteremias were successfully treated. In contrast, only 10/19 (53%) FUO and none of 4 clinically defined infections had responded. Thus, this pilot study indicates that piperacillin and ciprofloxacin may be a safe and effective combination for the treatment of febrile episodes in severely neutropenic leukemia patients, which merits further investigation in randomized trials.

Adult↗
PubMed1991

Ethanol impairs certain aspects of neutrophil adhesion in vitro: comparisons with inhibition of expression of the CD18 antigen.

Since ethanol impairs polymorphonuclear leukocyte (PMNL) delivery to inflammatory sites, the effect of ethanol on PMNL adhesiveness was studied in vitro. Ethanol inhibited PMNL aggregation induced by formylmethionylleucylphenylalanine (FMLP) but not by phorbol myristate acetate (PMA), whereas responses to both stimuli were abolished by treating PMNL with monoclonal antibody 60.3 (against the adhesion protein CD18). This antibody also abrogated spontaneous and FMLP-stimulated PMNL adhesion to plastic, whereas ethanol reduced spontaneous but not FMLP-induced adherence. Chemotaxis in Boyden or agarose systems was not diminished by ethanol, but high concentrations of MAb 60.3 inhibited migration under agarose. Nonetheless, upregulation of cell surface expression of CD18 (assessed by immunofluorescence flow cytometry) induced by FMLP or PMA was similarly reduced by ethanol. Thus, ethanol inhibited only certain of PMNL adhesion, and although the stimulated up-regulation of CD18 expression was reduced it is unlikely that ethanol effects were mediated only by this inhibition.

Antigens, CD↗
PubMed1991

An alloimmunized, thrombocytopenic patient successfully transfused with acid-treated, random-donor platelets.

Alloimmunized, thrombocytopenic patients, refractory to random-donor platelet transfusion, often respond to HLA-identical single-donor platelets. HLA-compatible platelets are expensive, take time to prepare, and donors are sometimes not to be found. We have used random-donor platelets and 'peeled' the HLA-antigen off the platelets, using a modified laboratory method (incubation of platelets with citric acid solution at 0 degrees C). Platelet recovery in two healthy subjects was 72.0% for acid-treated platelets, and 73.5% for untreated control platelets, using 111In-labelled autologous platelets. Survival time (multiple hit) was 6.25 and 7.95 d, respectively. Random-donor platelets that were strongly positive in the crossmatch with serum from a patient became negative after treatment with the acid solution. Furthermore, transfusion of these platelets gave a post-transfusion, platelet-count increment comparable with transfusion of HLA-compatible single-donor platelets.

Blood Component Transfusion↗
PubMed1991

The effect of 20-trifluoromethyl leukotriene B4 on neutrophil functional responses.

20-trifluoromethyl-leukotriene B4 (20CF3-LTB4) is a stable derivative of leukotriene B4 (LTB4) that is not subjected to omega-oxidation to less active metabolites. 20CF3-LTB4 was as potent as LTB4 as a chemotactic, adhesion-promoting and aggregatory agent for human neutrophils, but had only 11 +/- 3% of the ability to induce an oxidative response. Nonetheless, both compounds were equally efficient in order to confer a rapid and monophasic increment of the concentration of cytosolic calcium. The kinetics of the calcium, aggregatory and chemiluminescent responses to 20CF3-LTB4 were similar to that of LTB4. These findings suggest that the insertion of the trifluoromethyl group into the LTB4 molecule causes a shift of the biological activity profile, suggesting that 20CF3-LTB4 binds mainly to high affinity LTB4 receptors. Moreover, the similarity of the response kinetics of LTB4 and 20CF3-LTB4 suggests that the mechanism for the rapid and transient responses of LTB4 is not due to its omega-oxidation.

Calcium↗
PubMed1990

Leukotriene B4 induced hyperadhesiveness of endothelial cells for neutrophils.

Leukotriene B4 (LTB4) induced a transient state of hyperadhesiveness in cultured human umbilical vein endothelial cells (HUVEC), leading to increased binding of neutrophil granulocytes (PMN). The effect of LTB4 was more rapidly emerging and transient than responses to platelet activating factor (PAF), thrombin and phorbol myristate acetate (PMA). At 0.1 microM of LTB4, it was comparable to hyperadhesiveness induced by 1 U/ml of thrombin, but less than that conferred by 0.1 microM of PAF and PMA. The adherence response to LTB4 was specific since the structural analogue 5S,12S-diHETE, which lacks PMN-stimulating effects, failed to promote HUVEC adhesiveness.

Cell Adhesion↗
PubMed1990

Rapid adhesive responses of endothelial cells and of neutrophils induced by leukotriene B4 are mediated by leucocytic adhesion protein CD18.

Controversy has existed as to the ability of leukotriene B4 (LTB4) to enhance adhesive properties of human neutrophils (PMN) and endothelial cells. We found that LTB4 induced a rapid but transient adhesion of PMN to an albumin-coated plastic surface and to cultured human umbilical vein endothelial cells (HUVEC). Although the adhesive response of PMN to the chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine (fMLP) was longer lasting, peak hyperadherence was of similar magnitude as to LTB4 and was less susceptible to assay conditions. Adherence induced by either LTB4 or fMLP could be abrogated by the monoclonal antibody 60.3, indicating similar dependence on the leucocyte adhesion protein CD18. Lipoxin A did not induce PMN hyperadherence. Treating HUVEC with LTB4, but not with its omega-oxidized metabolites 20-OH- and 20-COOH-LTB4, lipoxin A, or with fMLP conferred a rapid, dose-related, enhanced adhesion of PMN. This effect was dependent on CD18 and on divalent cations. It disappeared with prolonged exposure to LTB4, required a metabolically active HUVEC, and was not due to passive binding of LTB4 to HUVEC. Thus, LTB4 induces a transient expression of hyperadhesiveness in HUVEC as well as in neutrophils, and both effects are dependent on expression of CD18.

Antibodies, Monoclonal↗
PubMed1989

A synthetic peptide defines a serologic IgA response to a human papillomavirus-encoded nuclear antigen expressed in virus-carrying cervical neoplasia.

The growing awareness of the role of human papillomavirus (HPV) in cervical carcinoma has triggered a search for uncomplicated detection methods. To define a serologic response to HPV, we synthesized peptides based on sequences deduced from the genome of HPV type 16, the most common malignancy-associated type of HPV. One of these peptides reacted with IgA antibodies present in sera from 24 of 33 patients with cervical intraepithelial neoplasia or cervical carcinoma, whereas this peptide reacted with only 6 of 27 sera from individuals without cervical intraepithelial neoplasia. Immunoaffinity-purified human antipeptide IgA antibodies detected HPV-specific 58- and 48-kDa proteins in cervical carcinoma cell extracts and also detected a nuclear antigen in HPV-carrying cervical cancer cell lines and cervical intraepithelial neoplasia biopsied tissue. These antigens were also detected with mouse monoclonal and rabbit polyclonal antibodies to the same peptide. The results indicate that screening for infection with malignancy-associated types of HPV may be possible by simple synthetic peptide-based serology.

Antibodies, Neoplasm↗
PubMed1988

Platelet activating factor and leukotriene B4 induce hyperpolarization of human endothelial cells but depolarization of neutrophils.

We studied one expression of cell activation in neutrophils (PMN) and endothelial cells (EC), membrane potential changes [assessed by the fluorescent dye, di-C-O5(3)]. Human neutrophils responded with depolarization after exposure to fMLP, LTB4, A23187, PAF and PMA. In contrast, only PAF and LTB4 induced membrane potential changes in human umbilical vein EC, which responded with increased fluorescence, possibly indicating membrane hyperpolarization. These discordant responses may reflect processes of significance for interactions between EC and PMN.

Calcimycin↗