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Biomedical subjects

Bart Jan Kullberg

Publications and source records attributed to Bart Jan Kullberg.

At least 19 recordsLinked to original sources
PubMed2006

Effect of optimized antibiotic prophylaxis on the incidence of surgical site infection.

OBJECTIVE: To compare the rate of surgical site infection (SSI) before and after an intervention period in which an optimized policy for antibiotic prophylaxis was implemented. To demonstrate that a more prudent, restrictive policy would not have a detrimental effect on patient outcomes. DESIGN: Before-after trial with prospective SSI surveillance in the Dutch nosocomial surveillance network (Preventie Ziekenhuisinfecties door Surveillance [PREZIES]), using the criteria of the Centers for Disease Control, including postdischarge surveillance for up to 1 year. METHODS: During a preintervention period and a postintervention period (both 6-13 months), 12 Dutch hospitals collected data on antimicrobial prophylaxis and SSI rates. The study was limited to commonly performed surgical procedures in 4 specialties: vascular, intestinal, gynecological and orthopedic surgery. Selected risk factors for analysis were sex, age, American Society of Anesthesiologists classification, wound contamination class, duration of surgery, length of hospital stay before surgery, and urgency of surgery (elective or acute). RESULTS: A total of 3,621 procedures were included in the study, of which 1,668 were performed before the intervention and 1,953 after. The overall SSI rate decreased from 5.4% to 4.5% (P=.22). Among the procedures included in the study, the largest proportion (55%) were total hip arthroplasty, and the smallest proportion (2%) were replacement of the head of the femur. SSI rates varied from 0% for vaginal hysterectomy to 21.1% for femoropopliteal or femorotibial bypass surgery. Crude and adjusted odds ratios showed that there were no significant changes in procedure-specific SSI rates after the intervention (P>.1). CONCLUSIONS: An optimized and restrictive antibiotic prophylaxis policy had no detrimental effect on the outcome of clean and clean contaminated surgery, as measured by SSI rate.

Antibiotic Prophylaxis↗
PubMed2006

Deficiency of interleukin-18 in mice leads to hyperphagia, obesity and insulin resistance.

Here we report the presence of hyperphagia, obesity and insulin resistance in knockout mice deficient in IL-18 or IL-18 receptor, and in mice transgenic for expression of IL-18 binding protein. Obesity of Il18-/- mice resulted from accumulation of fat tissue based on increased food intake. Il18-/- mice also had hyperinsulinemia, consistent with insulin resistance and hyperglycemia. Insulin resistance was secondary to obesity induced by increased food intake and occurred at the liver level as well as at the muscle and fat-tissue level. The molecular mechanisms responsible for the hepatic insulin resistance in the Il18-/- mice involved an enhanced expression of genes associated with gluconeogenesis in the liver of Il18-/- mice, resulting from defective phosphorylation of STAT3. Recombinant IL-18 (rIL-18) administered intracerebrally inhibited food intake. In addition, rIL-18 reversed hyperglycemia in Il18-/- mice through activation of STAT3 phosphorylation. These findings indicate a new role of IL-18 in the homeostasis of energy intake and insulin sensitivity.

Animals↗
PubMed2006

Immune sensing of Candida albicans requires cooperative recognition of mannans and glucans by lectin and Toll-like receptors.

The fungal pathogen Candida albicans has a multilayered cell wall composed of an outer layer of proteins glycosylated with N- or O-linked mannosyl residues and an inner skeletal layer of beta-glucans and chitin. We demonstrate that cytokine production by human mononuclear cells or murine macrophages was markedly reduced when stimulated by C. albicans mutants defective in mannosylation. Recognition of mannosyl residues was mediated by mannose receptor binding to N-linked mannosyl residues and by TLR4 binding to O-linked mannosyl residues. Residual cytokine production was mediated by recognition of beta-glucan by the dectin-1/TLR2 receptor complex. C. albicans mutants with a cell wall defective in mannosyl residues were less virulent in experimental disseminated candidiasis and elicited reduced cytokine production in vivo. We concluded that recognition of C. albicans by monocytes/macrophages is mediated by 3 recognition systems of differing importance, each of which senses specific layers of the C. albicans cell wall.

Animals↗
PubMed2006

Endogenous interleukin (IL)-1 alpha and IL-1 beta are crucial for host defense against disseminated candidiasis.

BACKGROUND: Interleukin (IL)-1 alpha and IL-1 beta are protective proinflammatory cytokines involved in host defense against Candida albicans. It is, however, unknown whether they provide protection through similar mechanisms. We investigated the effect of endogenous IL-1 alpha and IL-1 beta on disseminated C. albicans infection. METHODS: Mice deficient in the genes encoding IL-1 alpha (IL-1 alpha-/-), IL-1 beta (IL-1 beta-/-), or both molecules (IL-1 alpha-/- beta-/-) were used. Survival and C. albicans outgrowth in the kidneys was assessed after intravenous injection of C. albicans. RESULTS: Both mortality and C. albicans outgrowth in the kidneys were significantly increased in IL-1 alpha-/- and IL-1 beta-/- mice, compared with those in control mice, with the IL-1 alpha-/- beta-/- mice being most susceptible to disseminated candidiasis. The host defense mechanisms triggered by IL-1 alpha and IL-1 beta differed from one another. IL-1 beta-/- mice showed decreased recruitment of granulocytes in response to an intraperitoneal C. albicans challenge, and generation of superoxide production was diminished in IL-1 beta-/- granulocytes. IL-1 alpha-/- mice had a reduced capacity to damage C. albicans pseudohyphae. Protective type 1 responses were deficient in both IL-1 alpha-/- and IL-1 beta-/- mice, as assessed by production of interferon-gamma by splenocytes in response to heat-killed C. albicans. CONCLUSION: Although IL-1 alpha and IL-1 beta have differential effects on the various arms of host defense, both cytokines are essential for mounting a protective host response against invasive C. albicans infection.

Animals↗
PubMed2006

Impaired dendritic cell function in Crohn's disease patients with NOD2 3020insC mutation.

The nucleotide oligomerization domain 2 (NOD2) 3020insC (NOD2fs) mutation increases susceptibility to Crohn's disease (CD), but the mechanism remains controversial. Loss-of-function and gain-of-function phenotypes have been described as a result of NOD2fs. Here, we show that dendritic cells (DC) derived from CD patients homozygous for this mutation respond normally to purified Toll-like receptor (TLR) ligands but fail to up-regulate the costimulatory molecules CD80 and CD86 in response to the NOD2 ligand muramyl dipeptide (MDP). Moreover, they lack MDP-induced enhancement of TLR-mediated tumor necrosis factor alpha, interleukin (IL)-12, and IL-10 production, which is observed in control DC with intact NOD2. These data indicate that the NOD2fs mutation results in a loss-of-function phenotype in human myeloid DC and imply decreased immune regulation by IL-10 as a possible mechanism for this mutation in CD.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed2006

Nucleotide oligomerization domain 2 (Nod2) is not involved in the pattern recognition of Candida albicans.

Nucleotide-binding oligomerization domain 2 (Nod2) pathways are known to interact with Toll-like receptor 2 (TLR2) and TLR4, which are pattern recognition receptors for Candida albicans. We observed that the prevalence of Nod2 polymorphisms was not increased in patients with Candida infections. Candida-induced cytokine production in individuals with Nod2 polymorphisms was unaffected. We conclude that Nod2 is unlikely to play an important role in the recognition of Candida albicans.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Host defence against disseminated Candida albicans infection and implications for antifungal immunotherapy.

The different manifestations of Candida albicans infection are dictated by an underlying defect in the immune response of the host. Protective immunity to disseminated candidiasis, the manifestation of C. albicans infection discussed in this review, has traditionally been ascribed to innate immunity with emphasis on the role of granulocytes. Lately, however, immunological studies have learned that host defence against disseminated candidiasis is based on a complex interplay between innate and cell-mediated immunity. Despite the availability of new antifungal agents, mortality associated with disseminated C. albicans infection remains high. Immunotherapy that augments host defence is an important strategic option in the battle against disseminated candidiasis. Here, the authors review the chronological events in the pathogenesis of disseminated candidiasis that aid in predicting the impact of existing immunotherapy and the development of future immunomodulating strategies.

Adjuvants, Immunologic↗
PubMed2006

Recognition of fungal pathogens by toll-like receptors.

Toll-like receptors (TLRs) have been identified as a major class of pattern-recognition receptors. Recognition of pathogen-associated molecular patterns (PAMPs) by TLRs, either alone or in heterodimerization with other TLR or non-TLR receptors, induces signals responsible for the activation of innate immune response. Recent studies have demonstrated a crucial involvement of TLRs in the recognition of fungal pathogens such as Candida albicans, Aspergillus fumigatus and Cryptococcus neoformans. By studying fungal infection in knock-out mice deficient in either TLRs or TLR-associated adaptor molecules, it appeared that specific TLRs such as TLR2 and TLR4 play differential roles in the activation of the various arms of the innate immune response. Recent data also suggest that TLRs offer escape mechanisms to certain pathogenic microorganisms, especially through TLR2-driven induction of antiinflamatory cytokines. These recent developments provide crucial information for understanding the mechanisms of fungal recognition by cells of the immune system, and provide hope for designing new therapeutical approaches to fungal infections.

Animals↗
PubMed2006

Toll-like receptor 4 Asp299Gly/Thr399Ile polymorphisms are a risk factor for Candida bloodstream infection.

Toll-like receptor (TLR)-4 is an important pattern recognition receptor for Candida albicans, playing a role in innate host defense. We investigated whether there is an association between the TLR4 Asp299Gly or TLR4 Thr399Ile polymorphism, and the occurrence of Candida bloodstream infection. We performed a case-control study, involving 43 patients with a Candida bloodstream infection and 166 healthy individuals. TLR4 Asp299Gly and Thr399Ile polymorphisms were assessed, as well as cytokine production after stimulation of peripheral blood mononuclear cells (PBMC) with Candida albicans. We observed that the prevalence of TLR4 Asp299Gly polymorphism was found to be higher in patients with Candida bloodstream infection than in controls (26% versus 10%; OR 3.0; 95%CI 1.3-6.9). All patients bearing the Asp299Gly polymorphism were also positive for the Thr399Ile allele, a linkage well described in literature. IL-10 production was higher in C. albicans-stimulated PBMC from volunteers bearing the TLR4 Asp299Gly polymorphism, and a similar tendency was observed in TLR4 Asp299Gly heterozygous patients who had recovered from candidemia. These findings show that the TLR4 Asp299Gly/Thr399Ile polymorphisms are associated with an increased susceptibility to Candida bloodstream infections, and an increased production of IL-10 is probably involved in this effect.

Amino Acid Substitution↗
PubMed2005

Nucleotide-binding oligomerization domain-2 modulates specific TLR pathways for the induction of cytokine release.

The recognition of peptidoglycan by cells of the innate immune system has been controversial; both TLR2 and nucleotide-binding oligomerization domain-2 (NOD2) have been implicated in this process. In the present study we demonstrate that although NOD2 is required for recognition of peptidoglycan, this leads to strong synergistic effects on TLR2-mediated production of both pro- and anti-inflammatory cytokines. Defective IL-10 production in patients with Crohn's disease bearing loss of function mutations of NOD2 may lead to overwhelming inflammation due to a subsequent Th1 bias. In addition to the potentiation of TLR2 effects, NOD2 is a modulator of signals transmitted through TLR4 and TLR3, but not through TLR5, TLR9, or TLR7. Thus, interaction between NOD2 and specific TLR pathways may represent an important modulatory mechanism of innate immune responses.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed2005

Functional consequences of the Asp299Gly Toll-like receptor-4 polymorphism.

Toll-like receptor-4 (TLR4) is a pattern-recognition receptor not only for exogenous ligands such as lipopolysaccharide (LPS) of Gram-negative bacteria, but also for endogenous ligands such as fibronectin, heat shock proteins and hyaluronan oligosaccharides. The Asp299Gly allele of the TLR4 gene has been associated with increased risk for severe infections, but reduced progression of atherosclerosis. We have investigated the consequences of the presence of Asp299Gly polymorphism after stimulation of mononuclear cells with lipopolysaccharide (LPS), the non-LPS TLR4 microbial stimuli Aspergillus fumigatus and Cryptococcus neoformans, and the endogenous TLR4 ligand heat shock protein 60. No differences in either production of the proinflammatory cytokine TNF or the antiinflammatory cytokine interleukin-10 were observed between volunteers with the wild-type allele, volunteers heterozygous for the Asp299Gly allele and one volunteer homozygous for the TLR4 variant. In conclusion, the presence of the Asp299Gly TLR4 polymorphism does not result in defective pro and antiinflammatory cytokine production after stimulation with either exogenous (LPS and non-LPS) or endogenous TLR4 ligands, and alternative explanations are likely to be responsible for the epidemiological data showing associations with inflammatory conditions. In addition, this is the first study to demonstrate that even homozygosity for the Asp299Gly mutation does not confer hyporesponsiveness to stimulation with TLR4 stimuli.

Adult↗
PubMed2005

Influence of endogenous pro-inflammatory cytokines on neutrophil-mediated damage of Candida albicans pseudohyphae, quantified in a modified tetrazolium dye assay.

For quantitative assessment of polymorphonuclear granulocyte (PMN)-mediated pseudohyphal damage, an improved tetrazolium (2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide; XTT) dye assay was developed. The modified assay proved to be a reliable indicator of viable pseudohyphal inoculum sizes. In addition, the influence of various endogenous pro-inflammatory cytokines on the capacity of PMN to damage Candida albicans pseudohyphae was investigated. PMN obtained from mice in which the genes encoding for tumor necrosis factor-alpha/lymphotoxin-alpha (TNF/LT), interferon-gamma (IFNgamma), interleukin (IL)-1alpha, or IL-1beta were disrupted, showed a significantly reduced pseudohyphal damage capacity in comparison with control PMN. The reduction amounted 25% for TNF-/- LT-/-, 11% for IFNgamma-/-, 21% for IL-1alpha-/-, and 34% for IL-1alpha-/-beta-/- PMN. In contrast, deficiency of IL-12 or IL-18 did not result in a diminished capacity to damage pseudohyphae and the capacity of PMN to damage Candida pseudohyphae was even slightly increased by 10% in IL-18-/- mice. These data suggest that endogenous pro-inflammatory cytokines are able to modulate antihyphal activity of PMN, the main effector cells against disseminated candidiasis by virtue of their capacity to kill both Candida blastoconidia and pseudohyphae.

Animals↗
PubMed2005

Effect of recombinant murine granulocyte colony-stimulating factor with or without fluoroquinolone therapy on mixed-infection abscesses in mice.

The aim of the study was to determine if immunomodulation of host defense with recombinant murine granulocyte colony-stimulating factor (G-CSF) improves the efficacy of trovafloxacin or moxifloxacin in abscesses containing Bacillus fragilis ATCC 23745 and different Escherichia coli strains varying in virulence. Treatment of mice inoculated with 10(7) CFU B. fragilis and 10(5) CFU low-virulence E. coli with either trovafloxacin (150 mg/kg/day every 24 hours, days 3 to 7) or moxifloxacin (96 mg/kg/day every 12 hours, days 3 to 7), significantly reduced the number of B. fragilis to 6.9 +/- 0.35 and 5.8 +/- 0.10 and that of E. coli to 4.9 +/- 0.09 and 4.2 +/- 0.07 log CFU/abscess for trovafloxacin and moxifloxacin, respectively, compared to controls (B. fragilis 8.7 and E. coli 7.4 log CFU/abscess) on day 8. Also, moxifloxacin was more potent than trovafloxacin. Addition of G-CSF prophylaxis (1 mug once on day -1) or therapy (1 mug/day on days 3 to 7) to fluoroquinolone treatment did not improve the efficacy of fluoroquinolone therapy alone. The effect of moxifloxacin with or without G-CSF prophylaxis on abscesses with a virulent hemolytic E. coli strain was also studied. In moxifloxacin-treated mice, 75% survived infection compared to 10% of controls. Combining moxifloxacin with G-CSF prophylaxis significantly decreased survival (30%) compared to moxifloxacin alone. In addition, G-CSF prophylaxis resulted in a threefold (E. coli) to 100-fold (B. fragilis) increased outgrowth in the abscesses of surviving mice. In conclusion, the addition of G-CSF to a fluoroquinolone is not advisable since, depending on the virulence of the E. coli strains, this might detrimentally influence the outcome of therapy.

Abscess↗
PubMed2005

Differential cytokine production and Toll-like receptor signaling pathways by Candida albicans blastoconidia and hyphae.

Toll-like receptors (TLR) are crucial for an efficient antifungal defense. We investigated the differential recognition of blastoconidia and hyphae of Candida albicans by TLRs. In contrast to Candida blastoconidia, which stimulated large amounts of gamma interferon (IFN-gamma), the tissue-invasive Candida hyphae did not stimulate any IFN-gamma by human peripheral blood mononuclear cells (PBMC) or murine splenic lymphocytes. After stimulation with blastoconidia, the production of IFN-gamma was TLR4 dependent, as shown by the significantly decreased IFN-gamma production in anti-TLR4-treated PBMC and in splenic lymphocytes from TLR4-defective ScCr mice. In addition, peritoneal macrophages from ScCr mice produced less tumor necrosis factor alpha (TNF-alpha) than macrophages of control mice did when stimulated with Candida blastoconidia, but not with hyphae, indicating that TLR4-mediated signals are lost during hyphal germination. In contrast, macrophages from TLR2 knockout mice had a decreased production of TNF-alpha in response to both Candida blastoconidia and hyphae. Candida hyphae stimulated production of interleukin-10 through TLR2-dependent mechanisms. In conclusion, TLR4 mediates proinflammatory cytokine induction after Candida stimulation, whereas Candida recognition by TLR2 leads mainly to anti-inflammatory cytokine release. TLR4-mediated proinflammatory signals are lost during germination of Candida blastoconidia into hyphae. Phenotypic switching during germination may be an important escape mechanism of C. albicans, resulting in counteracting host defense.

Animals↗
PubMed2005

Interleukin-18 does not modulate the acute-phase response.

IL-18 is a pro-inflammatory cytokine of the IL-1 family and it induces IL-1, TNF, and IL-6, all of which are endogenous pyrogens. The pyrogenic properties of recombinant IL-18 were studied in a rabbit model of fever. rIL-18 did not cause fever when injected intravenously into rabbits. Furthermore, the ability of rIL-18 to modulate other components of the acute-phase response was assessed. rIL-18 did not induce leukocytosis, or changes of circulating concentrations of lipoproteins and corticosterone in mice. In conclusion, rIL-18 is not able to induce a febrile response in rabbits and does not modulate the acute-phase response in mice.

Acute-Phase Reaction↗
PubMed2004

Design of efficacy trials of cytokines in combination with antifungal drugs.

Resolution of invasive fungal infections is often dependent on recovery from an immunocompromised state, which indicates that host defense mechanisms are extremely important in the clearance of fungal pathogens. Immunotherapy aimed at enhancement of host defense mechanisms may improve clinical outcome of invasive mycoses. The design of trials of immunotherapy against fungal pathogens requires profound knowledge of the host defense mechanisms that are involved in invasive fungal infections. Prospective phase II studies with recombinant granulocyte colony-stimulating factor and interferon-gamma have been done. Recombinant interferon-gamma is a candidate for phase III trials of adjunctive immunotherapy for cryptococcal meningitis, invasive aspergillosis, and candidemia, but the proper design of future trials will be crucial to establish whether immunotherapy is of clinical value in the treatment of invasive fungal infections.

Antifungal Agents↗
PubMed2004

Two patients with cryptococcal meningitis and idiopathic CD4 lymphopenia: defective cytokine production and reversal by recombinant interferon- gamma therapy.

BACKGROUND: Although Cryptococcus neoformans is a fungal pathogen that causes human disease predominantly in the immunocompromised host, severe cryptococcal infections are occasionally encountered in apparently immunocompetent individuals. Activation of cellular immunity by proinflammatory cytokines plays a central role in anticryptococcal defense. METHODS: We describe 2 patients with severe cryptococcal meningitis who appeared to have idiopathic CD4 lymphopenia. For these patients and for 4 healthy volunteers, ex vivo stimulation of whole blood with microbial stimuli was used to investigate putative defects in cytokine production capacity. RESULTS: Assessment of the cytokine released from the 2 patients with CD4 lymphopenia revealed a defective production of the proinflammatory cytokines interferon (IFN)- gamma and tumor necrosis factor (TNF) but not of the anti-inflammatory cytokine interleukin-10 (IL-10). One patient with disease progression despite receipt of antifungal treatment was administered immunotherapy with recombinant IFN- gamma . Administration of recombinant IFN- gamma resulted in both restoration of immunological parameters and a sustained clinical recovery. CONCLUSIONS: Refractory meningitis may be due to defective TNF and IFN- gamma production, and IFN- gamma treatment may be useful in patients with an impaired cellular immune response and refractory cryptococcal meningitis.

Adult↗