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Biomedical subjects

R van Furth

Publications and source records attributed to R van Furth.

At least 91 records · Page 5Linked to original sources
PubMed1993

Stimulation of the intracellular killing of Staphylococcus aureus by human monocytes mediated by Fc gamma receptors I and II.

Previous studies have shown that intracellular killing of bacteria by monocytes is stimulated by interaction between IgG and Fc gamma receptors (Fc gamma R) in the membrane of these cells. In the present study anti-Fc gamma R monoclonal antibodies (mAb) were used to investigate the relative contributions of the various classes of Fc gamma R to the intracellular killing of Staphylococcus aureus by human monocytes and the biochemical pathways involved. Anti-Fc gamma RI or anti-Fc gamma RII mAb, but not anti-Fc gamma RIII mAb, efficiently stimulated the intracellular killing of bacteria by monocytes. Cross-linking Fc gamma RI or Fc gamma RII, but not Fc gamma RIII, on monocytes with mouse anti-Fc gamma R mAb followed by bridging with F(ab')2 fragments of goat anti-mouse IgG enhanced this process. Since the NADPH oxidase inhibitor diphenyleneiodonium blocked the Fc gamma R-mediated intracellular killing of S. aureus, oxygen-dependent bactericidal mechanisms are most probably involved. Cross-linking Fc gamma RI or Fc gamma RII but not binding of the mAb to the Fc gamma R on monocytes activated phospholipase C, as demonstrated by the increase in the intracellular concentration of inositol-(1,4,5)-triphosphate. The enhanced intracellular killing stimulated by cross-linking Fc gamma R on monocytes was completely blocked by U-73122, an inhibitor of phospholipase C-dependent processes. Protein kinase C activity, but not the rise in the cytosolic free Ca++ concentration or pertussis toxin-sensitive G proteins, is essential for the Fc gamma R-mediated intracellular killing of bacteria by monocytes. Together, these results demonstrate that cross-linking Fc gamma RI or Fc gamma RII is equally effective in stimulating the intracellular killing of bacteria by monocytes and that this stimulation is a phospholipase C-dependent process.

Antibodies, Monoclonal↗
PubMed1993

Strategy for antibiotic therapy in febrile neutropenic patients on selective antibiotic decontamination.

In a non-randomized prospective study the need for broad-spectrum antibiotic therapy was evaluated in selectively decontaminated neutropenic patients with fever. Fifty-two adult patients with a neutrophil count < 0.5 x 10(9)/l suffered 77 febrile episodes while receiving oral antibiotics for selective decontamination. Antibiotic treatment was only initiated if additional clinical signs or the microbiological culture results pointed to the likelihood of an infection. Treatment was either empirically based (broad-spectrum) or specific (narrow-spectrum). If a causative agent was identified, therapy was adjusted accordingly. If evidence of infection was lacking after 72-96 hours, the antibiotics were discontinued, and these patients were reexamined meticulously and repeatedly. For the 40 episodes without confirmed infection, the median duration of therapy was three days (range 0-13 days) and the survival rate 100%; for the 37 episodes with confirmed infection, the median duration of therapy was 12 days (range 1-49 days, p < 0.0001) and the survival rate 85%. After adjustment of therapy the final regimen was broad-spectrum in only 18% of treated episodes. None of the six deaths could be attributed to the withholding or stopping of broad-spectrum therapy. It is concluded that in febrile neutropenic patients on selective decontamination a standard therapy regimen with prolonged administration of broad-spectrum antibiotics is not necessary. After initial intervention antibiotic therapy can safely be tailored to the needs of the individual patient.

Adult↗
PubMed1993

Activity of erythromycin and clindamycin in an experimental Staphylococcus aureus infection in normal and granulocytopenic mice. A comparative in vivo and in vitro study.

The activity of 2 bacteriostatic antibiotics, erythromycin and clindamycin, against Staphylococcus aureus was studied in vitro and in an experimental infection in granulocytopenic as well as normal mice. In vivo, on the basis of dosage, erythromycin was 2.20 times more potent than clindamycin in normal mice and 1.95 times more potent in irradiated granulocytopenic mice. Tissue concentrations were calculated from the plasma concentrations, taking plasma protein and tissue binding into account. On the basis of the area under the curve for the free tissue concentrations, clindamycin was 1.48 times more potent than erythromycin in normal mice and 1.64 times more potent in irradiated mice, which is somewhat less than expected from the comparison in vitro. It is concluded that the relative antistaphylococcal efficacies of erythromycin and clindamycin in vivo can be predicted from the in-vitro values if the relevant pharmacokinetics are taken into account. Irradiation decreased the efficacy of both antibiotics such that an about 8-fold increase in dose led to an antibacterial effect similar to that in non-irradiated animals. This could imply that these drugs will not be sufficiently effective against staphylococcal infections in granulocytopenic patients.

Agranulocytosis↗
PubMed1993

Clinical pharmacokinetics of continuous intravenous administration of penicillins.

Theoretically, continuous intravenous administration of beta-lactam antibiotics has advantages over intermittent administration because of the close relationship between efficacy and the time the plasma concentration remains above the minimal inhibitory concentration that has been found in vitro. The aim of the present study was to establish the pharmacokinetic parameters of benzylpenicillin and cloxacillin administration in patients receiving high-dose benzylpenicillin or cloxacillin therapy by continuous infusion. A major part of the interindividual variation in the plasma concentrations at steady-state was attributable to variation in renal function, as estimated by the creatinine clearance. On the basis of these results, a nomogram was constructed that can be used to determine on an individualized basis the total daily dose of benzylpenicillin or cloxacillin necessary for each patient to obtain therapeutic plasma concentrations.

Adolescent↗
PubMed1993

Recombinant interferon-gamma enhances resistance to acute disseminated Candida albicans infection in mice.

The effect of recombinant rat interferon-gamma (rIFN-gamma) on acute disseminated Candida albicans infection in mice was investigated. Outgrowth of C. albicans in kidneys, spleen, and liver of mice treated with one intravenous (iv) dose of rIFN-gamma before iv injection of 5 x 10(5) cfu of C. albicans was significantly lower than in controls over 7 days. rIFN-gamma was protective when given 1 day before, simultaneously with, or 1-3 days after infection but not when given 3 days before. In mice pretreated with hydrocortisone acetate, rIFN-gamma significantly reduced the outgrowth only when 10(3) cfu of C. albicans was injected. Injection of rIFN-gamma did not reduce the outgrowth of C. albicans in cyclophosphamide-pretreated mice and significantly increased the capacity of peripheral blood and exudate peritoneal granulocytes to kill C. albicans in vitro. Thus, rIFN-gamma enhances host resistance against acute disseminated C. albicans infection in mice through activation of polymorphonuclear leukocytes.

Analysis of Variance↗
PubMed1993

Effects of monomethylfumarate on human granulocytes.

Monomethylfumarate (MMF) is the most active metabolite of the new antipsoriasis drug Fumaderm. Because granulocytes play an important role in the pathophysiology of psoriasis, the effects of this drug on the functional activities of these cells were investigated. MMF stimulated polarization and elastase release, and enhanced the intracellular killing of bacteria by granulocytes. This compound suppressed the formyl-Met-Nle-Phe (FMLP)-stimulated respiratory burst in these cells. MMF and dimethylfumarate but not its stereoisomer dimethylmaleate, fumaric acid, or dimethylmalate stimulated polarization of and elastase release by granulocytes, indicating that methylated fumarate derivatives interact with granulocytes in a specific fashion. MMF did not affect the binding of formyl-Nle-Leu-Phe-Nle-Tyr-Lys-fluorescein isothiocyanate to the FMLP receptor on granulocytes. This compound induced an increase in the intracellular Ca++ ([Ca++]i) and cyclic adenosine monophsphate concentration. The agonistic effects of MMF on granulocytes are thought to be mediated by the rise in the [Ca++]i and the antagonistic effects by the increase in the cyclic adenosine monophosphate concentration. These effects of MMF on granulocytes may in part explain the beneficial action of methylated fumarate derivatives on psoriatic skin lesions.

Blood Bactericidal Activity↗
PubMed1993

Interferon-gamma activates the oxidative killing of Candida albicans by human granulocytes.

Although granulocytes are essential for the resistance against infections with Candida albicans, these cells do not kill the ingested yeast optimally. Various cytokines can enhance functional activities of granulocytes, but until now only interferon-gamma (IFN-gamma) has been applied more widely, namely in patients with chronic granulomatous disease. Since it is not certain whether IFN-gamma is able to enhance the candidacidal activity of granulocytes the present study was undertaken. Human granulocytes incubated with various concentrations of recombinant human IFN-gamma (rIFN-gamma) were studied for the phagocytosis and intracellular killing of C. albicans and their oxygen metabolism after stimulation with opsonized Candida. Results showed a small increase in the rate of phagocytosis and a dose-dependent increase of the intracellular killing of C. albicans and the production of H2O2. The increased candidacidal activity and H2O2 production by rIFN-gamma-stimulated granulocytes were inhibited by diphenylene iodonium (DPI). From these results it is concluded that the increased candidacidal activity of granulocytes activated by rIFN-gamma is caused by the increased production of reactive oxygen radicals.

Candida albicans↗
PubMed1993

Increased adhesion of human monocytes to IL-4-stimulated human venous endothelial cells via CD11/CD18, and very late antigen-4 (VLA-4)/vascular cell adhesion molecule-1 (VCAM-1)-dependent mechanisms.

Expression of adhesion molecules on endothelial cells (EC) can be up-regulated or induced by cytokines. The aim of the present study was to investigate the effect of IL-4 on both the expression of adhesion molecules on EC and monocyte adhesion to EC. Flow cytometric analysis showed that VCAM-1 expression on EC was up-regulated after stimulation with IL-4 for 24 h, whereas the expression of E-selectin (formerly called endothelial leucocyte adhesion molecule-1 (ELAM-1)) was not enhanced, and that of intercellular adhesion molecule-1 (ICAM-1) only slightly. The adhesion of monocytes to EC increased to maximum values upon stimulation of EC with IL-4 for 24 h. Coating of monocytes with MoAb against the integrin beta 2-subunit (CD18) significantly inhibited their adhesion to IL-4-stimulated EC; maximal inhibition was found when monocytes were coated with anti-CD18 MoAb in combination with MoAb against CD49d (the alpha-chain of VLA-4), whereas no inhibition was found when monocytes were coated only with MoAb against CD49d. Monocyte adhesion was not significantly inhibited when IL-4-stimulated EC were coated with MoAbs against ICAM-1 or VCAM-1 alone or in combination. Adhesion of monocytes was inhibited to a greater extent when in addition to coating of monocytes with MoAb against CD18 the EC were coated with MoAb against VCAM-1. From these results we conclude that monocytes bind to IL-4-stimulated EC via interaction of CD11/CD18 molecules on the monocytes with an as yet unknown endothelial ligand, and interaction of VLA-4 on monocytes with VCAM-1 on EC.

Antigens, CD↗
PubMed1993

Differences in the rate of intracellular killing of catalase-negative and catalase-positive Listeria monocytogenes by normal and interferon-gamma-activated macrophages.

Intracellular killing of catalase-positive bacteria by murine resident macrophages requires the presence of extracellular serum, whereas killing of catalase-negative bacteria can occur in the absence of serum. To find out whether the intracellular killing of bacteria by rIFN-gamma-activated macrophages also requires serum stimulation, we investigated the handling of ingested catalase-negative and -positive Listeria monocytogenes by peritoneal macrophages of normal Swiss mice and mice injected i.p. with 1 x 10(4) U rIFN-gamma 18 h earlier. In the absence of extracellular serum, rIFN-gamma-activated macrophages killed ingested catalase-negative Listeria more efficiently (P < 0.01) than normal resident macrophages. Maximal killing of catalase-negative bacteria by rIFN-gamma-activated macrophages required an extracellular serum concentration of only 1.0 to 2.5% compared with the 10% needed by normal macrophages. No differences were observed in the rates of intracellular killing of catalase-positive Listeria by rIFN-gamma-activated and normal resident macrophages: both populations of macrophages required 10% extracellular serum for maximal killing of these bacteria, and killing was minimal in the absence of serum. The rIFN-gamma-activated macrophages displayed enhanced O2-consumption after stimulation with phorbol myristate acetate and heat-killed Listeria compared with macrophages from normal mice. These findings indicate that, under suboptimal stimulation by extracellular serum, rIFN-gamma enhances the intracellular killing of catalase-negative Listeria which lack endogenous catalase acting as a scavenger of reactive oxygen intermediates. The mechanism underlying the enhancement is probably the amplification of the respiratory burst by IFN-gamma.

Animals↗
PubMed1993

Murine peritoneal macrophages activated by the mycobacterial 65-kilodalton heat shock protein express enhanced microbicidal activity in vitro.

After an intraperitoneal (i.p.) injection of purified protein derivative, peritoneal macrophages from mice infected with Mycobacterium bovis bacillus Calmette-Guérin (BCG) show an enhanced respiratory burst, inhibit the intracellular proliferation of Toxoplasma gondii, and kill Listeria monocytogenes more efficiently than peritoneal macrophages from normal mice. One of the immunodominant antigens of Mycobacterium spp. is the 65-kDa heat shock protein (Hsp 65), and in the present study, we determined whether injection of this protein into mice leads to activation of their peritoneal macrophages. After an i.p. injection of Hsp 65, peritoneal macrophages from BCG-infected CBA/J mice also released more H2O2, inhibited the proliferation of T. gondii, and killed L. monocytogenes faster than peritoneal macrophages from normal mice, although Hsp 65 was less effective than purified protein derivative. When normal mice were injected with Hsp 65 suspended in saline after a booster injection with Hsp 65, their macrophages did not display enhanced antimicrobial activity, indicating that an adjuvant was required for a cellular immune response against Hsp 65. In the present study, the adjuvant dimethyl dioctadecylammonium bromide (DDA) was preferred because it contains no endotoxin or mycobacterial antigens and because it has been reported that DDA does not induce the production of gamma interferon. Peritoneal macrophages from C57BL/6 and CBA/J mice that had received a subcutaneous injection of Hsp 65 suspended in DDA followed by an i.p. booster injection of Hsp 65 suspended in saline were activated, as indicated by the enhanced production of H2O2, inhibition of the intracellular proliferation of T. gondii, and increased rate of intracellular killing of L. monocytogenes in vitro relative to that by resident peritoneal macrophages and peritoneal macrophages obtained from mice that had received ovalbumin instead of Hsp 65. The rate of phagocytosis of L. monocytogenes was not affected by Hsp 65 treatment. Despite the in vitro expression of enhanced microbicidal activity of peritoneal macrophages, no difference in the growth of L. monocytogenes in the liver and spleen between Hsp 65-treated and control mice was found.

Animals↗
PubMed1993

Antimicrobial proteins of murine macrophages.

Three murine microbicidal proteins (MUMPs) were purified from cells of the murine macrophage cell line RAW264.7 that had been activated by gamma interferon. Similar proteins were also present in nonactivated RAW264.7 cells, in cells of the murine macrophage cell line J774A.1, and in resident and activated murine peritoneal macrophages. MUMP-1, MUMP-2, and MUMP-3 killed Salmonella typhimurium, Escherichia coli, Staphylococcus aureus, Listeria monocytogenes, Mycobacterium fortuitum, and Cryptococcus neoformans in vitro. MUMP-1 resembled an H1 histone but was unusual because its N-terminal residue (serine) was not N acetylated. Although MUMP-2 was N terminally blocked, its high lysine/arginine ratio and its reactivity with an antibody to H1 histones suggested that it also belonged to the H1 histone family. MUMP-3 was identical to histone H2B in 30 of 30 amino-terminal residues. Although the antimicrobial properties of histones have been recognized for decades, this is the first evidence that such proteins may endow the lysosomal apparatus of macrophages with nonoxidative antimicrobial potential. Other MUMPs, including some with a more restricted antimicrobial spectrum and one that appeared to be induced in RAW264.7 cells after gamma interferon stimulation, were noted but remain to be characterized.

Amino Acid Sequence↗
PubMed1993

Monocyte adherence to human vascular endothelium.

An acute inflammatory response requires that circulating monocytes bind to and migrate across the endothelium of the vessel wall to gain access to inflamed sites. Various mediators of inflammation--cytokines and chemoattractants--have been shown to initiate and regulate the margination and extravasation of monocytes. This review summarizes evidence that the mechanism underlying the initial adhesion of monocytes to normal and cytokine-stimulated endothelial cells and their subsequent transendothelial migration are successive events in monocyte-endothelial cell interaction. Special emphasis is given to the current knowledge of the contribution of adhesion molecules belonging to the family of beta 1- and beta 2-integrins, the immunoglobulin supergene family, and the selectins to such cellular interaction. The sequence of events that allow monocytes to attach to, migrate over and finally pass the endothelium is discussed in detail.

Cell Adhesion↗
PubMed1992

[Opinions of family physicians and specialists on vaccination against influenza].

About 50 percent of the patients who because of an underlying disease should be vaccinated annually against influenza, do not receive the vaccine. One of the major reasons is that they are not informed by their physicians about the need to be vaccinated. To understand the attitude of the physicians concerning influenza vaccination and the way the vaccination of these patients is organized, questionnaires were send to 250 general practitioners, 125 cardiologists and 125 pulmonologists in the Netherlands. Eighty-four percent of the questionnaires were returned. The results show that the physicians were well informed about the indications for vaccination. A minority of the physicians had doubts about the efficacy of the vaccine. Both specialists and general practitioners agreed that vaccination should be performed by the general practitioner. Instruction of the patients and application of the vaccine were generally rather well organized. It is to be expected, however, that improvement of the organization will enhance the rate of vaccination against influenza in the Netherlands.

Attitude of Health Personnel↗