Nijmegen Institute for Infection

Nijmegen, Netherlands

Nijmegen Institute for Infection

Nijmegen, Netherlands
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Seyedmousavi S.,Radboud University Nijmegen | Seyedmousavi S.,Nijmegen Institute for Infection | Guillot J.,National Veterinary School of Alfort | de Hoog G.S.,Fungal Biodiversity Center | And 3 more authors.
Clinical Microbiology Reviews | Year: 2013

Emerging fungal diseases due to black yeasts and relatives in domestic or wild animals and in invertebrates or cold- and warmblooded vertebrates are continually being reported, either as novel pathogens or as familiar pathogens affecting new species of hosts. Different epidemiological situations can be distinguished, i.e., occurrence as single infections or as zoonoses, and infection may occur sporadically in otherwise healthy hosts. Such infections are found mostly in mammals but also in cold-blooded animals, are frequently subcutaneous or cerebral, and bear much similarity to human primary disorders. Infections of the nervous system are mostly fatal, and the source and route of infection are currently unknown. A third epidemiological situation corresponds to pseudoepidemics, i.e., infection of a large host population due to a common source. It is often observed and generally hypothesized that the susceptible animals are under stress, e.g., due to poor housing conditions of mammals or to a change of basins in the case of fishes. The descriptions in this article represent an overview of the more commonly reported and recurring black fungi and the corresponding diseases in different types of animals. © 2013, American Society for Microbiology. All Rights Reserved.

Mouton J.W.,Radboud University Nijmegen | Mouton J.W.,Nijmegen Institute for Infection | Mouton J.W.,Canisius Wilhelmina Hospital | Ambrose P.G.,Institute for Clinical Pharmacodynamics Inc. | And 6 more authors.
Drug Resistance Updates | Year: 2011

There is a growing need to optimize the use of old and new antibiotics to treat serious as well as less serious infections. The topic of how to use pharmacokinetic and pharmacodynamic (PK/PD) knowledge to conserve antibiotics for the future was elaborated on in a workshop of the conference (The conference "The Global Need for Effective Antibiotics - moving towards concerted action", ReAct, Uppsala, Sweden, 2010). The optimization of dosing regimens is accomplished by choosing the dose and schedule that results in the antimicrobial exposure that will achieve the microbiological and clinical outcome desired while simultaneously suppressing emergence of resistance. PK/PD of antimicrobial agents describe how the therapeutic drug effect is dependent on the potency of a drug against a microorganism and the exposure (the concentration of antimicrobial available for effect over time). The description and modeling of these relationships quantitatively then allow for a rational approach to dose optimization and several strategies to that purpose are described. These strategies include not only the dosing regimen itself but also the duration of therapy, preventing collateral damage through inappropriate use and the application of PK/PD in drug development. Furthermore, PK/PD relationships of older antibiotics need to be urgently established. The need for global harmonization of breakpoints is also suggested and would add efficacy to antibiotic therapy. For each of the strategies, a number of priority actions are provided. © 2011 Elsevier Ltd. All Rights Reserved.

Levy O.,Boston Childrens Hospital | Levy O.,Harvard University | Netea M.G.,Radboud University Nijmegen | Netea M.G.,Nijmegen Institute for Infection
Pediatric Research | Year: 2014

Unique features of immunity early in life include a distinct immune system particularly reliant on innate immunity, with weak T helper (Th)1-polarizing immune responses, and impaired responses to certain vaccines leading to a heightened susceptibility to infection. To these important aspects, we now add an increasingly appreciated concept that the innate immune system displays epigenetic memory of an earlier infection or vaccination, a phenomenon that has been named "trained immunity." Exposure of neonatal leukocytes in vitro or neonatal animals or humans in vivo to specific innate immune stimuli results in an altered innate immune set point. Given the particular importance of innate immunity early in life, trained immunity to early life infection and/or immunization may play an important role in modulating both acute and chronic diseases. © 2014 International Pediatric Research Foundation, Inc.

Gresnigt M.S.,Radboud University Nijmegen | Gresnigt M.S.,Nijmegen Institute for Infection | Van de Veerdonk F.L.,Radboud University Nijmegen | Van de Veerdonk F.L.,Nijmegen Institute for Infection | Van de Veerdonk F.L.,University of Colorado at Denver
Seminars in Immunology | Year: 2013

IL-36α, IL-36β, IL-36γ, and IL-36Ra, collectively called IL-36 cytokines, are part of the IL-1 family. IL-36α, IL-36β, and IL-36γ are IL-36 receptor (IL-36R) agonists, while IL-36Ra is a receptor antagonist that blocks the activation of IL-36R signaling. IL-36 cytokines require processing in order to become fully active, however the protease(s) responsible for this are currently not known. The IL-36 receptor pathway activates dendritic cells and plays a role in polarizing T-helper responses. The skin is the predominant site where IL-36 cytokines are expressed and several reports have established that they play a significant role in the pathogenesis of skin diseases. In this review the discovery and biological function of the cytokines IL-36α, IL-36β, IL-36γ and IL-36Ra will be discussed, and their role in the pathogenesis of a wide variety of diseases. © 2013 Elsevier Ltd.

Ene I.V.,Aberdeen Group | Cheng S.-C.,Radboud University Nijmegen | Cheng S.-C.,Nijmegen Institute for Infection | Netea M.G.,Radboud University Nijmegen | And 2 more authors.
Infection and Immunity | Year: 2013

Candida albicans is a normal resident of the human gastrointestinal and urogenital tracts and also a prevalent fungal pathogen. During both commensalism and infection, it must match the immunological defenses of its host while adapting to environmental cues and the local nutrient status. C. albicans regularly colonizes glucose-poor niches, thereby depending upon alternative carbon sources for growth. However, most studies of host immune responses to C. albicans have been performed on fungal cells grown on glucose, and the extent to which alternative physiologically relevant carbon sources impact innate immune responses has not been studied. The fungal cell wall is decorated with multifarious pathogen-associated molecular patterns and is the main target for recognition by host innate immune cells. Cell wall architecture is both robust and dynamic, and it is dramatically influenced by growth conditions. We found that growth of C. albicans cells on lactate, a nonfermentative carbon source available in numerous anatomical niches, modulates their interactions with immune cells and the resultant cytokine profile. Notably, lac-tate-grown C. albicans stimulated interleukin-10 (IL-10) production while decreasing IL-17 levels, rendering these cells less visible to the immune system than were glucose-grown cells. This trend was observed in clinical C. albicans isolates from different host niches and from different epidemiological clades. In addition, lactate-grown C. albicans cells were taken up by macrophages less efficiently, but they were more efficient at killing and escaping these phagocytic cells. Our data indicate that carbon source has a major impact upon the C. albicans interaction with the innate immune system. © 2013, American Society for Microbiology.

Leentjens J.,Radboud University Nijmegen | Leentjens J.,Nijmegen Institute for Infection | Kox M.,Radboud University Nijmegen | Kox M.,Nijmegen Institute for Infection | And 5 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2013

Sepsis is the leading cause of death in the intensive care unit and ranks in the top 10 causes of death in general worldwide. Proinflammatory mediators are related to symptoms observed early in patients with sepsis, such as fever and hemodynamic instability. However, in recent years it has become clear that most septic patientsdonot diefromanoverwhelmingproinflammatoryimmune response but in an immunosuppressive state, which can last for days or even weeks, and that results in increased susceptibility to secondary (opportunistic) infections. Although infection control and supportive therapies will remain the cornerstone of treatment, especially in the early phase of sepsis, the identification of this so-called "immunoparalysis" is currently causing a paradigm shift in the adjunctive treatment of sepsis from therapies that suppress the immune system toward immunostimulation. In this Critical Care Perspective we give an overview of the pathophysiology of sepsis, with a focus on immunosuppressive mechanisms that play an important role in outcome. In addition,we present an appraisal of the recent advances in immunotherapy as an adjunctive treatment for sepsis. Copyright © 2013 by the American Thoracic Society.

Van Poppel P.C.M.,Radboud University Nijmegen | Netea M.G.,Radboud University Nijmegen | Netea M.G.,Nijmegen Institute for Infection | Smits P.,Radboud University Nijmegen | Tack C.J.,Radboud University Nijmegen
Diabetes Care | Year: 2011

OBJECTIVE - To investigate whether the dipeptidyl peptidase-4 inhibitor vildagliptin improves endothelium-dependent vasodilatation in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS - Sixteen subjects with type 2 diabetes (age 59.8 ± 6.8 years, BMI 29.1 ± 4.8 kg/m 2, HbA 1c 6.97 ± 0.61) on oral blood glucose-lowering treatment were included. Participants received vildagliptin 50 mg b.i.d. or acarbose 100 mg t.i.d. for four consecutive weeks in a randomized, double-blind, cross-over design. At the end of each treatment period, we measured forearm vasodilator responses to intra-arterially administered acetylcholine (endothelium-dependent vasodilator) and sodium nitroprusside (endotheliumin-dependent vasodilator). RESULTS - Infusion of acetylcholine induced a dose-dependent increase in forearm blood flow in the experimental arm, which was higher during vildagliptin (3.1 ± 0.7, 7.9 ± 1.1, and 12.6 ± 1.4 mL · dL -1 · min -1 in response to three increasing dosages of acetylcholine) than during acarbose (2.0 ± 0.7, 5.0 ± 1.2, and 11.7 ± 1.6 mL · dL -1 · min -1, respectively; P = 0.01 by two-way ANOVA). Treatment with vildagliptin did not significantly change the vascular responses to sodium nitroprusside. CONCLUSIONS - Four weeks' treatment with vildagliptin improves endothelium-dependent vasodilatation in subjects with type 2 diabetes. This observationmight have favorable cardiovascular implications. © 2011 by the American Diabetes Association.

Kouijzer I.J.E.,Radboud University Nijmegen | Bleeker-Rovers C.P.,Radboud University Nijmegen | Bleeker-Rovers C.P.,Nijmegen Institute for Infection | Oyen W.J.G.,Nijmegen Institute for Infection | Oyen W.J.G.,Radboud University Nijmegen
Seminars in Nuclear Medicine | Year: 2013

Fever of unknown origin (FUO) is commonly defined as fever higher than 38.3 C on several occasions during at least 3 weeks with uncertain diagnosis after a number of obligatory tests. FUO remains a clinical challenge as no diagnosis is reached in up to 50% of cases. In general, infection accounts for one-fourth of cases of FUO, followed by neoplasm and noninfectious inflammatory diseases. FDG-PET is a sensitive diagnostic technique for the evaluation of FUO. Especially integrated imaging combining PET and CT facilitates anatomical localization of focally increased FDG uptake, thereby guiding further diagnostic tests to achieve a final diagnosis. FDG-PET/CT appears to be a more sensitive diagnostic tool in FUO than stand-alone FDG-PET, because of the precise anatomical localization of small lesions and better differentiation between physiological and pathologic metabolic foci. With FDG-PET/CT becoming widely available, FDG-PET/CT should be a routine procedure in the workup of FUO. © 2013 Elsevier Inc. All rights reserved.

Kox M.,Radboud University Nijmegen | Kox M.,Nijmegen Institute for Infection | Pickkers P.,Radboud University Nijmegen
JAMA Internal Medicine | Year: 2013

The current view in intensive care medicine is that very sick patients need very intensive treatment. However, in this group of highly vulnerable patients, more intensive reatment may promote the chances of unwanted adverse effects and hence, iatrogenic damage. Therefore, we state that critically ill patients probably benefit from a more cautious approach. Using data from large clinical trials of previous years, we exemplify that less intensive treatment is associated with a better outcome in intensive care patients and suggest that we reappraise patient management as well as trial design in intensive care medicine while bearing in mind the "less is more" paradigm.We illustrate our case by describing the intensity of the most relevant treatment options for patients with septic shock, including mechanical ventilation, fluid management, blood pressure-targeted therapy, corticosteroids, patient monitoring, sedation, and nutrition.We conclude that treatment of critically ill patients while keeping in mind the "le s is more" paradigm might not only benefit the patient but could also have a notable impact on the ever-increasing intensive care-related health care costs.

Colbers A.,Radboud University Nijmegen | Colbers A.,Nijmegen Institute for Infection | Greupink R.,Radboud University Nijmegen | Burger D.,Radboud University Nijmegen
Current Opinion in Infectious Diseases | Year: 2013

PURPOSE OF REVIEW: Treatment with combination antiretroviral therapy during pregnancy reduces the chance of mother to child transmission of HIV. Physiological changes during pregnancy can lead to lower exposure to antiretrovirals, possibly resulting in virological failure. For most antiretrovirals, data on exposure during pregnancy and transplacental passage are limited. This review summarizes the most recent information on pharmacokinetics (including transplacental passage), efficacy, as well as the safety of antiretrovirals during pregnancy. RECENT FINDINGS: Intensive-sampling pharmacokinetic studies as well as observational studies using sparse sampling were performed to explore the exposure to antiretrovirals during pregnancy. Transplacental passage, efficacy (viral load at delivery and infection status of the newborn) and safety information were evaluated for several antiretrovirals. SUMMARY: For most nucleoside/nucleotide reverse transcriptase inhibitors and protease inhibitors, recent research shows a decreased exposure during pregnancy. However, the advantage of a general dose increase during pregnancy still remains unclear. For newer compounds and efavirenz, limited or no data on pharmacokinetics during pregnancy or transplacentally are available, while the mechanisms of transplacental passage also remain unknown. For safety reasons, it will be important to monitor pregnancy outcomes in resource-limited settings during the implementation of the WHO guidelines (including the use of efavirenz during pregnancy). © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

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