Biomedical subjects

B J Kullberg

Publications and source records attributed to B J Kullberg.

At least 37 records · Page 2Linked to original sources

PubMed2004

Toll-like receptor-4 Asp299Gly polymorphism does not influence progression of atherosclerosis in patients with familial hypercholesterolaemia.

BACKGROUND: Toll-like receptor-4 (TLR4) is a major receptor for inflammatory stimuli potentially involved in the pathogenesis of atherosclerosis, such as lipopolysaccharide (LPS) and heat-shock proteins. The Asp299Gly polymorphism of the TLR4 gene has been associated with a reduced intima-media thickness (IMT) of the common carotid artery in healthy individuals. We have investigated whether the presence of the Asp299Gly polymorphism in patients with familial hypercholesterolaemia (FH) has a similar protective effect, and whether it influences the effects of HMG-CoA reductase treatment. MATERIALS AND METHODS: A cohort of 293 FH patients and 200 healthy volunteers were genotyped for the presence of the Asp299Gly allele using polymerase chain reaction followed by restriction fragment length polymorphism analysis. Intima-media thickness measurements, inflammatory parameters and the effect of HMG-CoA reductase inhibitors were compared between the patients with and without Asp299Gly allele. RESULTS: The Asp299Gly allele was present in 10.6% of the FH patients and 11.0% of the healthy individuals. Whereas the FH patients carrying the Asp299Gly allele displayed a reduced absolute IMT value compared with the FH patients carrying the wild-type allelle, the difference did not reach statistical significance. In addition, the effect of treatment with HMG-CoA reductase inhibitors was not influenced by the presence of Asp299Gly allele. CONCLUSION: The presence of the Asp299Gly allele of the TLR4 gene does not seem to exert a major influence on the progression of atherosclerosis in patients with FH.

Adult↗

PubMed2003

Voriconazole salvage treatment of invasive candidiasis.

Data on the salvage treatment of invasive candidiasis with voriconazole in 52 patients intolerant of other antifungal agents or with infection refractory to other antifungal agents were analyzed. Patients had received a mean of two previous antifungal agents (range, 1-4 agents), and 83% had received an azole. Manifestations of invasive candidiasis included candidemia (37%), disseminated disease (25%), and infection of other sites (38%). The median duration of voriconazole therapy was 60 days (range, 1-314 days). The overall rate of response was 56% (95%CI, 41-70), with the following response rates observed for individual Candida species: Candida albicans, 44% (20-70); Candida glabrata, 38% (14-68); Candida krusei, 70% (35-93); Candida tropicalis, 67% (30-93); and other Candida spp., 100% (40-100). The response rate in patients who had failed previous azole therapy was 58% (42-73). Common adverse events (~20%) included nausea and emesis, abnormal liver enzymes, and visual disturbances. Serious adverse events occurred in four patients, and nine patients died. Voriconazole has promise as a salvage agent for the treatment of invasive candidiasis, even in the settings of previous azole therapy and infection due to Candida krusei.

Adolescent↗

PubMed2003

Adherence to local hospital guidelines for surgical antimicrobial prophylaxis: a multicentre audit in Dutch hospitals.

OBJECTIVE: To study the adherence to local hospital guidelines for antimicrobial prophylaxis in surgery, and explore reasons for non-adherence. METHODS: A prospective, multicentre audit of elective procedures, without prior suspicion of infection, was carried out in 13 Dutch hospitals. By reviewing medical, anaesthetic and nursing records, and medication charts, the prescription of antibiotics was compared with the local hospital guideline on antibiotic choice, duration of prophylaxis, dose, dosing interval and timing of the first dose. RESULTS: Between January 2000 and January 2001, 1763 procedures were studied. Antibiotic choice, duration, dose, dosing interval and timing of the first dose were concordant with the hospital guideline in 92%, 82%, 89%, 43% and 50%, respectively. Overall adherence to all aspects of the guideline, however, was achieved in only 28%. The most important barriers to local guideline adherence were lack of awareness due to ineffective distribution of the most recent version of the guidelines, lack of agreement by surgeons with the local hospital guidelines, and environmental factors, such as organizational constraints in the surgical suite and in the ward. CONCLUSION: This study shows that, although adherence to separate aspects of local hospital guidelines for surgical prophylaxis in the Netherlands is favourable, overall adherence to all parameters is hard to achieve. Adherence to guidelines on dosing interval and timing needs improvement, in particular. To increase the quality of antimicrobial prophylaxis in surgery, effort should be put into developing guidelines acceptable to surgeons, in adequately distributing the guidelines and to facilitating logistics. Audits of surgical prophylaxis may help hospitals identify barriers to guideline adherence.

Adult↗

PubMed2003

Duration of antifungal treatment and development of delayed complications in patients with candidaemia.

The optimal duration of antifungal treatment of candidaemia is unknown. Prolonged treatment has been advocated to prevent late-onset complications caused by metastatic infectious foci. To evaluate the relationship between duration of antifungal therapy and the development of delayed complications in patients with candidaemia, a retrospective descriptive study was performed in a tertiary care centre. The study included 180 consecutive patients with candidaemia identified by at least one positive blood culture. Development of late-onset complications of candidaemia during long-term follow-up was monitored. Of the patients treated with antifungal agents, 55% completed treatment without apparent complications, 33% died during therapy, 12% developed disseminated disease and one patient continues to receive ongoing treatment. Of the 81 patients who completed treatment as scheduled, 25% received treatment for less than 2 weeks, 31% for 2-4 weeks and 38% for more than 4 weeks; duration of therapy was unknown in 6%. Only three (2%) patients developed delayed complications; in these patients, the duration of antifungal treatment had been 3 weeks, 5 weeks and 22 weeks, respectively. In conclusion, despite theoretical concerns, there seems to be no correlation between the duration of antifungal treatment and the development of late complications in patients with candidaemia. This suggests that treatment of 2 weeks or less may be sufficient, provided the initial response to therapy is favourable.

Adult↗

PubMed2003

Selecting outcome parameters in studies aimed at improving rational use of antibiotics - practical considerations.

When designing studies of the optimal use of antimicrobial drugs, it is important to define at an early stage, which outcome parameters to use. It must be clear to which category a parameter to be measured belongs: the structure, the process or a clinical outcome. Attention must be paid to the measurement scales as well as the statistical tests to be used. The outcome measure must be sensitive, specific and reliable. Furthermore, the timeframe chosen for the performance of a study should be validated. Whether process parameters or clinical outcomes are to be preferred depends on the settings and the intended purpose. The essential point is the appropriate choice of outcome measure for the study. Examples drawn from the field of quality of use of antimicrobial drugs are discussed.

Anti-Bacterial Agents↗

PubMed2003

Two cases of subcutaneous Scedosporium apiospermum infection treated with voriconazole.

Scedosporium apiospermum is a mold that is increasingly being recognized as an opportunistic pathogen in immunocompromised patients, and treatment is complicated by intrinsic resistance to several antifungal agents. In our hospital, two cases of S. apiospermum infection occurring within 2 weeks were successfully treated with voriconazole. Since both patients were infected with an uncommon pathogen, a search for a common nosocomial source was performed. As environmental cultures yielded no S. apiospermum, and random amplified polymorphic DNA (RAPD) fingerprinting showed that the patients' strains were genotypically unrelated, we considered a common nosocomial source of S. apiospermum to be unlikely.

Aged↗

PubMed2003

Severe acute respiratory syndrome: lessons and uncertainties.

The outbreak of severe acute respiratory syndrome (SARS) has produced scientific and epidemiological discoveries with unprecedented speed, and this information has been spread instantaneously to the global health community through the internet. Within a few weeks, the coronavirus associated with SARS (SARS-CoV) was identified and sequenced. The source of the outbreak and the exact modes of transmission are still subjects of research. Important lessons can be learned from the SARS outbreak about both the scientific and the public health approach to emerging pathogens.

Disease Outbreaks↗

PubMed2003

Candida-specific interferon-gamma deficiency and toll-like receptor polymorphisms in patients with chronic mucocutaneous candidiasis.

Chronic mucocutaneous candidiasis (CMC) is a group of disorders, characterised by persistent mucocutaneous infections with Candida species. The underlying defect of CMC has not been elucidated, but a defective cytokine response may be involved. Therefore, we investigated whether an imbalance between IFNgamma and IL-10 may play a role in this disorder. We assessed the cytokine production in whole-blood cultures from CMC patients using Candida albicans, lipopolysaccharide and phytohaemagglutinin as stimuli. As the Toll-like receptors are important pattern recognition receptors for Candida species, we also investigated Toll-like receptor polymorphisms in these patients. Patients with CMC had a significantly decreased IFNgamma production when whole blood was stimulated with C. albicans (232 +/- 120 vs 2279 +/- 609 pg/ml, p<0.02). When stimulated with phytohaemagglutinin, the differences were not significant (3549 +/- 1320 vs 7631 +/- 1790 pg/ml). The Candida-stimulated production of IL-10 tended to be higher in CMC patients, whereas TNF and IL-1beta production were similar in patients and controls. Stimulation with LPS showed no differences in cytokine production between patients and controls. Two out of seven patients had the TLR4 Asp299Gly polymorphism and none had the TLR2 Arg677Trp polymorphism. These data support the hypothesis that deficient IFNgamma production is involved in the pathogenesis of CMC, whereas a role for genetic polymorphisms of Toll-like receptor 2 and 4 is not obvious in these patients.

Adolescent↗

PubMed2002

Epidemiology of opportunistic invasive mycoses.

Invasive aspergillosis and disseminated candidiasis are the two major manifestations of opportunistic invasive mycoses. Their incidence has risen considerably during the past decades, due to more intensive anticancer chemotherapy, organ transplantations, intensive care, and aggressive surgical interventions. Especially bone marrow transplant recipients are at risk for developing invasive aspergillosis. Whether the infection is acquired through contaminated water or through airborne spores is a matter of much debate. Candidemia and disseminated candidiasis commonly originate from the gastrointestinal tract. Abdominal surgery and mucosal damage due to anticancer chemotherapy are the majors factor through which gut colonization may lead to invasive disease. A shift in the epidemiology of disseminated candidiasis has been noted, with an increasing incidence of Candida glabrata, C. tropicalis and C. krusei strains.

AIDS-Related Opportunistic Infections↗

PubMed2002

Th1/Th2 cytokine imbalance in a family with hyper-IgE syndrome.

BACKGROUND: Hyperimmunoglobulin E (hyper-IgE) syndrome is a rare immunodeficiency characterised by recurrent skin and respiratory tract infections, skeletal and dental abnormalities, chronic eczema, and elevated serum IgE. We describe a family with four hyper-IgE syndrome patients (38, 37, 30 and 7 years old), in which we investigated the cytokine response to both specific and non-specific stimulation. METHODS: Whole blood from patients and volunteers was stimulated for either 24 or 48h at 37 degrees C with heat-killed Staphylococcus, C. albicans or a combination of IL-12 and IL-18. Cytokine concentrations in the plasma were measured by specific radioimmuno-assays or ELISA. RESULTS: Serum IgE ranged from 5,000 to 16,670 IU/ml, and neutrophil chemotaxis was normal in all four patients. Tumour necrosis factor, interleukin (IL)-1beta, IL-6 and IL-8 production after stimulation of whole-blood cultures with lipopolysaccharide or heat-killed S. aureus did not differ between the adult patients and four healthy controls. In contrast, when blood from patients and controls was stimulated with heat-killed S. aureus or C. albicans, a severe imbalance towards a Th2 phenotype was found, with 10- to 30-fold reduction in the IFNgamma/IL-10 ratios in the hyper-IgE syndrome patients. The IFNgamma production in the patients was less severely impaired when blood was non-specifically stimulated with a combination of IL-18 and IL-12. CONCLUSION: In this family with hyper-IgE syndrome, the imbalance in the Th1/Th2 cytokine production may have been involved in the pathogenesis of the recurrent infections and/or chronic eczema characteristic of this disease.

Adult↗

PubMed2001

[Anthrax due to deliberate infection].

Anthrax is a zoonosis which is particularly prevalent in cattle, goats and sheep and is caused by Bacillus anthracis, a Gram-positive spore forming aerobic microorganism. The endospores can survive outside of the body for many decades. The natural form of anthrax has a cutaneous, pulmonary and intestinal form. The pulmonary form can be rapidly fatal but is difficult to recognise due to an initially non-specific, flu-like clinical picture. As a result of spores being inhaled, a mediastinal lymphadenitis arises from which a systemic disease develops with a violent toxaemia, damage to the vascular endothelium, oedema, internal haemorrhages and circulatory collapse. Anthrax is diagnosed by demonstrating the presence of the bacteria in the cutaneous abnormality, in blood or another sterile body component such as cerebrospinal fluid, by means of a direct preparation, immunofluorescence or surface antigens, molecular diagnostics with PCR, or by means of culturing. B. anthracis is sensitive to quinolones, clindamycin and tetracyclines, and often to penicillin. Although naturally acquired cutaneous anthrax can be effectively treated with a short antibiotic cure, it is nevertheless advised in the USA to complete the full 60-day cure and to regard the cutaneous manifestation as a telltale sign of possible respiratory exposure. Anthrax is not transmitted from one person to another.

Adult↗

PubMed2001

[Female patient with cutaneous anthrax in Belgium].

A 23-year-old Turkish woman was admitted with an infection of the left thumb. The clinical picture was typical for cutaneous anthrax. Microbiological tests confirmed the diagnosis 'infection by Bacillus anthracis'. She recovered when treated with penicillin, although later tests revealed that the bacteria were resistant to this antibiotic. The patient became infected in Belgium as a result of wounding herself on the teeth of an illegally slaughtered sheep, which had possibly become infected in the pasture. Recognising the characteristic clinical picture of cutaneous anthrax is essential for prompt treatment and a favourable prognosis.

Adult↗

PubMed2001

[Optimizing antibiotics policy in the Netherlands. VI. SWAB advice: no selective decontamination of intensive care patients on mechanical ventilation].

The Working Party on Antibiotic Policy (Dutch acronym is SWAB) has issued a guideline in which the pro and cons of the routine use of selective decontamination (SD) in patients in intensive care (IC) on mechanical ventilation are compared in order to decide whether SD is indicated. The effectiveness of SD in IC patients was evaluated in 28 prospective, randomized studies. In most studies a significant reduction in the incidence of pneumonia was demonstrated. The incidence of pneumonia in the control groups varied from 5 to 85%. The reduction in the incidence of pneumonia seems to have no effect on duration of mechanical ventilation and IC unit stay or the use of antibiotics. No effect on IC mortality was demonstrated. However, only major reductions could have been demonstrated with the size of the studies carried out so far. A significant reduction of about 20% was suggested in two meta-analyses. The validity of these meta-analyses is questionable. Based on the data available, it is not possible to reach the conclusion that SD will be cost-effective. The size of the studies is too small and the study duration too short to prove that the use of SD, if applied on a large scale, might not eventually lead to development of resistance. Selection of micro-organisms that are already intrinsically resistant or had already acquired resistance to one of the agents used, has been demonstrated. In the absence of clearly demonstrated advantages (decrease in mortality, reduction in the use of antibiotics, cost-effectiveness), the routine use of SD in IC patients on mechanical ventilation is not recommended.

Antibiotic Prophylaxis↗

PubMed2001

Lethal Escherichia coli and Salmonella typhimurium endotoxemia is mediated through different pathways.

Despite the differences in the molecular structure between lipopolysaccharides (LPS) isolated from Escherichia coli, Klebsiella pneumoniae or Salmonella typhimurium, the potential differences in their biological effects in vivo have not been investigated. In the present study, TNF and LT double knock-out (TNF-/-LT-/-) mice were almost as susceptible as TNF+/+LT+/+ controls to S. typhimurium LPS, but they were significantly more resistant to lethal endotoxemia induced by E. coli or K. pneumoniae LPS. The effect was not due to endotoxin-associated proteins. In the knock-out mice, this difference in lethality was accompanied by decreased interleukin-1 (IL-1) and interferon-gamma (IFN-gamma) production after challenge with E. coli LPS, whereas after S. typhimurium LPS more IL-1 and IFN-gamma were produced. In contrast, more IL-10 was produced after challenge of mice with E. coli LPS than with S. typhimurium LPS. The hypothesis that a combination of pro-inflammatory cytokines is responsible for the mortality after S. typhimurium LPS was suggested by experiments in mice deficient in IL-1beta-converting enzyme (ICE-/- mice). ICE-/-mice, lacking mature IL-1beta and IL-18, but also defective in IFN-gamma and TNF production, were completely protected against both E. coli and S. typhimurium LPS. Experiments in Toll-like receptor (TLR)-4 defective mice suggested that the difference is not due to differential activation of TLR4. In conclusion, TNF and LT play a central role in the lethality due to E. coli LPS, whereas the lethal effects of S. typhimurium LPS are mediated through mechanisms also involving other cytokines such as IFN-gamma, IL-1 and IL-18.

Animals↗

PubMed2001

Pro-inflammatory cytokines in patients with essential hypertension.

BACKGROUND: It has been suggested that abnormalities in the immune response play a role in the pathogenesis of essential hypertension (EH). The aim of this study was to assess circulating concentrations and ex vivo production of the pro-inflammatory cytokines tumour necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta), and of the anti-inflammatory cytokines IL-1 receptor antagonist (IL-1ra) and IL-6, in patients with EH and compare them with healthy volunteers. PATIENTS AND METHODS: Plasma cytokine concentrations were measured in EH patients and control volunteers by specific radioimmunoassays and ELISA. Ex vivo cytokine production was assessed after stimulation of whole-blood with lipopolysaccharide. RESULTS: Circulating concentrations of TNF, IL-1 and IL-6 did not differ between EH patients and controls. In contrast, IL-1ra circulating levels were higher in EH patients. Hypertensive patients had an increased IL-1 and IL-6 production capacity when whole blood was stimulated ex vivo with lipopolysaccharide, while TNF production was lower. IL-1ra production capacity did not differ between patients and controls. CONCLUSIONS: Patients with EH have an altered profile of pro-and anti-inflammatory cytokines, consistent with monocyte activation in the circulation. The importance of these changes for the pathogenesis of EH and/or its secondary complications remains to be elucidated.

Adult↗

PubMed2001

Use of fluconazole in daily practice: still room for improvement.

One hundred courses of fluconazole treatment in a university hospital and 81 courses in a non-university teaching hospital have been analysed in a prospective audit to evaluate prescribing practices. The quality of treatments was assessed by an infectious disease specialist and a pharmacist according to standard guidelines. In the non-university hospital, prescribed dosages were lower than in the university hospital, and often below the recommended dose. Mean duration of treatment for oesophageal candidosis and disseminated infections was considerably shorter in the non-university hospital compared with the university hospital, and often judged too short. Microbiological samples were examined in 75% of the cases in both hospitals. The expert reviewers agreed with the indication to use fluconazole in 58-100% of cases in the university hospital and 42-80% in the non-university hospital, depending on the type of infection. There did not appear to be a major problem with inappropriate use of fluconazole. However, important issues for improvement could be identified, such as increasing the dosage and duration of treatment in cases of serious infections, and withholding treatment from patients with colonization rather than infection.

Adult↗

PubMed2001

Differential roles of interleukin-18 (IL-18) and IL12 for induction of gamma interferon by staphylococcal cell wall components and superantigens.

The roles of endogenous cytokines induced by either intact staphylococcal microorganisms or staphylococcal exotoxins were examined using human whole-blood cultures. To accomplish this, interleukin-18 binding protein (IL-18BP) and tumor necrosis factor binding protein (TNFbp) were used to neutralize IL-18 and TNF, respectively, whereas an anti-IL-12 monoclonal antibody was used to neutralize IL-12 and the IL-1 receptor antagonist (IL-1Ra) was used to block IL-1 receptors. Heat-killed Staphylococcus epidermidis and Staphylococcus aureus, as well as the staphylococcal superantigens toxic shock syndrome toxin-1 (TSST-1) and staphylococcus enterotoxin B (SEB) induced gamma interferon (IFN-gamma) production. Staphylococcus spp.-induced production of IFN-gamma required the presence of endogenous IL-18, IL-12, and TNF. In contrast, TSST-1-induced IFN-gamma was not significantly reduced in the presence of IL-18BP, anti-IL-12 antibodies, IL-1Ra, or anti-TNFbp. SEB-induced IFN-gamma was significantly inhibited only by anti-IL-12 antibodies, indicating that endogenous IL-18, IL-1, and TNF are not required for SEB-induced IFN-gamma. In conclusion, the mechanisms of IFN-gamma stimulation by intact staphylococcal microorganisms and by exotoxins differ, and this is likely due to the different receptors which are triggered on the cell membranes. In contrast to its role in the interactions between staphylococci and host cells, IL-18 does not appear to play a major role in superantigen-induced IFN-gamma.

Antigens, Bacterial↗

PubMed2000

[Optimizing antibiotics policy in the Netherlands. V. SWAB guidelines for perioperative antibiotic prophylaxis. Foundation Antibiotics Policy Team].

The Stichting Werkgroep Antibioticabeleid (SWAB, Foundation Antibiotics Policy Team) has issued guidelines for perioperative antibiotic prophylaxis in Dutch hospitals. Antibiotic prophylaxis is generally recommended for surgical procedures with relatively high postoperative infection rates and those in which consequences of infection are really serious. Studies have revealed that prophylaxis given within two hours before incision is most effective. Short-term, preferably single-dose prophylaxis, is as effective as multiple-dose prophylaxis in most procedures. For reasons of cost effectiveness and prevention of induction of resistance, single-dose prophylaxis is recommended. The antimicrobial agent of choice for perioperative prophylaxis should not be widely used as a therapeutic agent, should be selectively active against micro-organisms most frequently isolated from surgical site infections, and should have a plasma-half-life that makes single-dosing possible for most operations. Therefore cefazoline is an agent that is widely used for perioperative prophylaxis.

Antibiotic Prophylaxis↗