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Biomedical subjects

J Palmblad

Publications and source records attributed to J Palmblad.

At least 73 records · Page 4Linked to original sources
PubMed1995

Neutrophil membrane potential changes and homotypic aggregation kinetics are pH-dependent: studies of chronic granulomatous disease.

Activated polymorphonuclear neutrophil granulocytes (PMN) from patients with chronic granulomatous disease (CGD) show reduced electron-proton shifts and an inability to acidify the cell. We studied whether this impaired pH-regulating capacity affected PMN membrane potential changes and the kinetics of homotypic aggregation by changing the extracellular pH over a wide range. At pH 7.4 normal PMN showed a rapid, transient membrane depolarization to leukotriene B4 (LTB4) and a slower response to N-formyl-methionyl-leucyl-phenylalanine. In contrast, PMN from 13 patients with CGD exhibited no or minute depolarization to these stimuli and 77% of tested patients with CGD displayed absence or marked reductions of the disaggregation to LTB4. On acidification of pH 5.0 to 6.4, PMN membrane depolarization appeared in six of nine tested patients. Likewise, disaggregation became evident in all of three patients. On alkalinization of normal PMN to pH 8.0 to 9.0, membrane depolarization and disaggregation to LTB4 disappeared, and cells reacted as CGD PMN. This change was not due to inefficient signal transduction, because normal PMN enhanced the superoxide ion production to N-formyl-methionyl-leucyl-phenylalanine on this alkalinization. Cytosolic pH changes in resting and LTB4-activated CGD cells at pH 6.0, 7.4, and 8.5 were similar those in control cells but for absence of an initial acidification. Thus neutrophil membrane potential changes and aggregation kinetics to LTB4 are abnormal in patients with CGD and return toward normal on extracellular acidification.

Adolescent↗
PubMed1994

Signal transduction mechanisms for leukotriene B4 induced hyperadhesiveness of endothelial cells for neutrophils.

We have previously demonstrated that leukotriene B4 (LTB4) induces in vitro a transient state of hyperadhesiveness in cultured human umbilical vein endothelial cells (HUVEC) for neutrophils (PMN). The magnitude of this response is intermediate of that conferred by thrombin and by platelet-activating factor (PAF). This report shows that the LTB4 response was neither related to HUVEC expression of PAF (because it could not be blocked by the PAF receptor antagonist WEB-2086), nor to access to LTB4 receptors on neutrophils (as shown by LTB4 receptor desensitization experiments). However, it could be partly blocked by treating HUVEC with an LTB4 receptor antagonist (SC-41930). LTB4 evoked a rise of intracellular calcium concentrations, [Ca2+]i, in the HUVEC, and the hyperadhesive HUVEC response to LTB4 was abrogated by buffering of [Ca2+]i by Quin-2. The response was not inhibited by treating HUVEC with pertussis toxin before LTB4. Neutrophils showed no signs of activation when adhering to LTB4-treated HUVEC because they did not i) release lactoferrin, or ii) react with an increase of [Ca2+]i, and iii) they bound equally well to the stimulated endothelial cells after having been treated with pertussis toxin so that up-regulation of PMN adhesion to LTB4 was abolished. LTB4-treated HUVEC did not shed factors that modulated neutrophil adherence or chemotaxis. Thus, LTB4 promotes HUVEC hyperadhesiveness for PMN, and the transduction mechanism involves calcium ions, may depend on a surface receptor for LTB4, but does not involve pertussis toxin-sensitive G proteins or PMN activation.

Cations, Divalent↗
PubMed1994

Studies of neutrophil and monocyte oxidative responses in polycythaemia vera and related myeloproliferative disorders.

We have previously reported that polymorphonuclear granulocyte (PMN) chemiluminescence (CL) and superoxide anion production are abnormally low in patients with polycythaemia vera (PV) after simulation with n-formyl-methionyl-leucyl-phenylalanine (fMLP), but normal when elicited by phorbol myristate acetate (PMA). This study documents that both fMLP and PMA induced CL was normal in PMN from patients with chronic myelogenous leukaemia (CML) and essential thrombocythaemia (ET). Furthermore, we monitored intracellular hydrogen peroxide (H2O2) production in PMN and monocytes from patients with PV, CML and ET by flow cytometry. H2O2 production in resting and PMA-stimulated cells was normal in all diseases. So also was fMLP induced H2O2 generation in ET PMN and monocytes. In contrast, fMLP-induced H2O2 production was significantly lower both in PV PMN (1.8 +/- 0.7 mean fluorescence intensity units in PV compared to 8.4 +/- 3.4 in healthy controls; P < 0.02), and in PV monocytes (0.3 +/- 0.5 compared to 2.5 +/- 0.7 in controls; P < 0.02). A less pronounced reduction of fMLP stimulated H2O2 production was noted in CML PMN (3.8 +/- 3.1 compared to 8.4 +/- 3.4 in controls; P < 0.05), and monocytes (1.3 +/- 0.6 compared to 2.5 +/- 0.7 in controls; P < 0.05). The reduction of H2O2 generation in PV and CML PMN was not attributed to subpopulations of less responsive cells. However, one ET and one CML patient showed a subpopulation of less responsive PMN. Thus intracellular H2O2 (as well as extracellular release of superoxide ions) is reduced in fMLP-stimulated PV PMN and monocytes but normal after PMA stimulation, a phenomenon that is not consistently found in other myeloproliferative disorders.

Adult↗
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

Stimulus-specific defect in platelet aggregation in polycythemia vera.

We have previously reported that polymorphonuclear granulocyte (PMN) and monocyte oxidative metabolism is reduced in polycythemia vera (PV) patients compared to healthy control subjects, after stimulation with cell surface receptor-dependent stimuli such as n-formyl-methionyl-leucyl-phenylalanine, leukotriene B4 and platelet-activating factor (PAF). In contrast, the oxidative response to phorbol myristate acetate (PMA) is normal. We now show that, in PV patients exhibiting significantly reduced PMN chemiluminescence after PAF stimulation, PAF induced platelet aggregation was also reduced--40 +/- 3% compared to 50 +/- 2% in controls (p < 0.01). The defective aggregatory response to PAF in PV remained over a wide range of stimuli concentrations. Platelet aggregation induced by PMA and ADP, however, was similar in PV and controls. In contrast, platelet aggregation induced by PAF (or by ADP and PMA) was not significantly reduced in patients with chronic myeloid leukemia, essential thrombocythemia and multiple myeloma. Furthermore, the release of beta-thromboglobulin was slightly but not significantly higher after PAF stimulation in PV and this argues against an abnormal PAF receptor as the cause of the defective function. Thus, not only PV neutrophils, but also PV platelets show a discrete defect of the stimulus response coupling for PAF, indicating a disease-specific abnormality that appears to be of clonal origin.

Adenosine Diphosphate↗
PubMed1994

[The plague and iron - or why didn't everybody die?].

In the years of the Black Death, contemporary observers noted that wealthy men were more likely to die from plague than women and the poor. One hypothesis, seeking an explanation for this phenomenon, is that the iron stores of an individual are a significant virulence factor for Yersina pestis, since this microorganism is dependent on iron for its multiplication. Thus, iron deficiency might confer some protection, whereas sufficient or even overabundant body iron stores contribute to the mortality in plague as well as in some other infectious diseases.

Economics↗
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

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↗
PubMed1993

A 40-base-pair duplication in the gp91-phox gene leading to X-linked chronic granulomatous disease.

Chronic granulomatous disease (CGD) is characterized by the inability of the patients' phagocytic leukocytes to generate superoxide. Therefore, these cells fail to kill certain bacteria and fungi. As a result, patients with CGD suffer from recurrent, life-threatening infections with these micro-organisms. Superoxide is produced by NADPH oxidase, a multicomponent enzyme exclusively present in phagocytic leukocytes. The most common form of CGD is X-linked, originating from a deficiency of the high-molecular-weight subunit of cytochrome b558 (gp91-phox). Here we describe a patient suffering from X-linked CGD due to a 40-base-pair duplication in exon 7 of the CYBB gene coding for gp91-phox, predicting a frameshift, substitution of 22 amino acids and a premature stop codon at amino-acid position 253. The mother as well as the grandmother of this patient were proven to be heterozygous for this mutation; the father and sister were normal. However, the great-grandmother proved to have normal oxidative functions, suggesting that the mutation occurred three generations ago. This is the first description of a nucleotide duplication leading to CGD.

Amino Acid Sequence↗
PubMed1993

The effect of endothelin, neuropeptide Y, calcitonin gene-related peptide and substance P on neutrophil functions.

Neuropeptides are putative mediators of inflammation. At physiological concentrations substance P has been shown to prime polymorphonuclear neutrophil granulocyte (PMN) chemiluminescence (CL). In the present study we show also that both endothelin and neuropeptide Y (NPY), but not calcitonin gene-related peptide (CGRP) are able to prime PMN oxidative metabolism. At similar nanomolar concentrations SP and endothelin (but not NPY) also primed formyl-methionyl-leucyl-phenylalanine (fMLP)-induced rises of cytosolic calcium. On the other hand, NPY caused a direct and dose-related increase of cytosolic calcium concentrations. None of the mentioned neuropeptides primed PMN aggregation or directly induced CL, aggregation or chemotaxis over a wide range of concentrations (1 fM-1 microM).

Calcitonin Gene-Related Peptide↗
PubMed1993

Superoxide anion production and phospholipase D-mediated generation of diacylglycerol are subnormal after N-formyl-methionyl-leucyl-phenylalanine stimulation of polymorphonuclear granulocytes in polycythemia vera.

We have assessed aspects of the stimulus response coupling for generation of superoxide anions (O2-) in polymorphonuclear granulocytes (PMNs) from patients with polycythemia vera (PV). Those cells exhibited less than half of the O2- secretion that PMNs from healthy controls did, when that response was initiated by N-formyl-methionyl-leucyl-phenylalanine (fMLP), 0.35 +/- 0.38 nmol O2-/10(6) PMNs/min and 0.83 +/- 0.45 nmol O2-/10(6) PMNs/min, respectively (p < 0.02). In contrast, when induced by phorbol myristate acetate (PMA), O2- production in PV PMNs was normal (6.9 +/- 1.1 nmol O2-/10(6) PMNs/min vs 6.9 +/- 0.6 nmol O2-/10(6) PMNs/min for control cells). In an attempt to dissect this stimulus-specific dichotomy of the oxidative responsiveness of PV PMNs, we analyzed the number of and ligand affinity for fMLP surface receptors, fMLP-induced membrane potential changes, phospholipase C-dependent production of inositol-1,4,5-trisphosphate, and the subsequent rise of cytosolic calcium concentrations. All these variables and responses were normal in PV PMNs. However, on fMLP stimulation of PV PMNs, we observed a significantly lower diacylglycerol (DAG) generation than in control cells (1.4% +/- 0.9% and 2.2% +/- 1.2% DAG of total phospholipid, respectively; p < 0.05). Furthermore, the activation of phospholipase D, measured as the formation of phosphatidylethanol (PET) in the presence of 0.5% ethanol, was impaired in PV PMNs with a similar stimulus-specific dichotomy as observed for O2- generation. Thus PET generation was significantly lower in PV cells after fMLP stimulation in relation to control cells (1.7% +/- 0.8% and 2.7% +/- 0.8% PET of total phospholipid, respectively; p < 0.01), whereas PET formation after PMA stimulation did not differ. We suggest that the impairment of phospholipase D-mediated metabolism of phosphatidylcholine in response to fMLP stimulation of polycythemia vera granulocytes may be of significance for the reduced superoxide anion formation induced by fMLP in those cells.

Adult↗
PubMed1992

Effects of ethanol on the chemotactic peptide-induced second messenger generation and superoxide production in polymorphonuclear leukocytes.

The generation of oxygen radicals by polymorphonuclear leukocytes (PMNL) plays a pivotal role for host defense. Since ethanol reduced FMLP- but not PMA-induced superoxide ion (O2-) formation by PMNL, the effects of ethanol on second messenger systems in PMNL were studied. FMLP induced a biphasic rise in cytosolic calcium concentrations, [Ca2+]i. Ethanol treatment abolished the second phase (believed to reflect Ca2+ influx), an effect also observed in PMNL treated with La3+ or suspended in Ca(2+)-free buffer. The FMLP-induced inositol trisphosphate generation was unaffected by ethanol, whereas diacylglycerol formation was, as expected, markedly reduced. Propranolol, an inhibitor of diacylglycerol formation from phosphatidic acid, caused a prolonged transmembrane influx of Ca2+ and partially reversed the inhibitory effect of ethanol on FMLP-induced O2- production. Thus, the ability of ethanol to inhibit FMLP-induced O2- generation in neutrophils seems to be due to both impaired influx of Ca2+ across the plasma membrane and reduced phospholipase D-mediated generation of phosphatidic acid.

Calcium↗
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↗