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Systemic Candida albicans infection causes high morbidity and mortality and is associated with neutropenia; however, the roles of other innate immune cells in pathogenesis are poorly defined. Here, using a [...]

Humans with chronic granulomatous diseases (CGDs) due to mutations in p47-phox have defective NADPH activity and thus cannot generate NADPH-dependent reactive Oxygen species (ROS). The role of ROS in inflammation is controversial; some in vitro studies suggest that ROS are crucial for secretion of IL-1[beta] via inflammasome activation, whereas mice defective for ROS and patients with CGD have a proinflammatory phenotype. In this study, we evaluated activation of the IL-1[beta] inflammasome in cells from CGD patients. In contrast to previous studies using the small molecule diphenylene iodonium (DPI) as a ROS inhibitor, we found no decrease in either caspase-1 activation or secretion of IL-1[beta] and IL-18 in primary CGD monocytes. Moreover, activation of CGD monocytes by uric acid crystals induced a 4-fold higher level of IL-1[beta] secretion compared with that seen in monocytes from unaffected subjects, and this increase was not due to increased synthesis of the IL-1[beta] precursor. In addition, Western blot analysis of CGD cells revealed that caspase-1 activation was not decreased, but rather was increased compared with control cells. Examination of the effects exerted by the inhibition of ROS activity by DPI revealed that the decrease in IL-1[beta] secretion by DPI was actually due to inhibition of IL-1[beta] gene expression. Thus, inconsistent with the proinflammatory role of ROS, the present findings support the concept that ROS likely dampen inflammasome activation. The absence of ROS in CGD monocytes may explain the presence of an inflammatory phenotype characterized by granulomas and inflammatory bowel disease occurring in CGD patients. antioxidants | colitis | gout | inflammation | uric acid www.pnas.org/cgi/doi/10.1073/pnas.0914795107

The article discusses the specific role that human dectin-1 deficiency plays in the prevention of mucocutaneous fungal infections. The findings of the dectin-1 mutation in persons from Europe and Africa reveal that it is an ancient mutation that emerged more than 60,000 years ago and also that the infection is genetic.

Byline: Benoit P. Guery (1), Maiken C. Arendrup (2), Georg Auzinger (3), Elie Azoulay (4), Marcio Borges Sa (5), Elizabeth M. Johnson (6), Eckhard Muller (7), Christian Putensen (8), Coleman Rotstein (9), Gabriele Sganga (10), Mario Venditti (11), Rafael Zaragoza Crespo (12), Bart Jan Kullberg (13) Keywords: Antifungal; Azole; Candida; Candidiasis; Echinocandins; Invasive candidiasis; Intensive care; Polyenes Abstract: Background Invasive candidiasis and candidemia are frequently encountered in the nosocomial setting particularly in the intensive care unit (ICU). Objective and methods To review the current management of invasive candidiasis and candidemia in non-neutropenic adult ICU patients based on a review of the literature and an European expert panel discussion. Results and conclusions Empiric and directed treatment for invasive candidiasis are predicated on the hemodynamic status of the patient. Unstable patients may benefit from broad-spectrum antifungal agents, which can be narrowed once the patient has stabilized and the identity of the infecting species is established. In stable patients, a more classical approach using fluconazole may be satisfactory provided that the patient is not colonized with fluconazole resistant strains or there has been recent past exposure to an azole ( Author Affiliation: (1) Infectious Diseases, SGRIVI, Hopital Huriez, CHRU Lille, 59045, Lille Cedex, France (2) Unit of Mycology, Department Bacteriology, Mycology and Parasitology, Statens Serum Institut, Building 43/117, 2300, Copenhagen, Denmark (3) Liver Intensive Care, Institute of Liver Studies, King's College Hospital, Denmark Hill, London, SE5 9RS, UK (4) Service de Reanimation Medicale, Hopital Saint-Louis, 1, avenue Claude-Bellefaux, 75010, Paris, France (5) Sepsis Unit, Intensive Care Department, Hospital Son Llatzer, Palma de Mallorca, Spain (6) Mycology Reference Laboratory, National Collection of Pathogenic Fungi, The HPA Centre for Infections, HPA South West Laboratory, Myrtle Road, Kingsdown, Bristol, BS2 8EL, UK (7) Universitatsklinik fur Anasthesiologie, Intensivmedizin und Schmerztherapie, Knappschaftskrankenhaus Bochum, Langendreer, Klinikum der Ruhr-Universitat, In der Schornau 23--25, 44892, Bochum, Germany (8) Operative Intensivmedizin, Klinik und Poliklinik fur Anasthesiologie und Operative Intensivmedizin, Rheinische-Friedrich-Wilhelms Universitat Bonn, Sigmund-Freud Str. 25, 53127, Bonn, Germany (9) Division of Infectious Diseases, University Health Network, Toronto General Hospital, NCSB 11-1212, 200 Elizabeth Street, Toronto, ON, M5G 2C4, Canada (10) Department of Surgery, Division of General Surgery and Organ Transplantation, Policlinico 'A Gemelli', Catholic University, Largo Gemelli, 8, 00168, Rome, Italy (11) Internal Medicine, Clinical Medicine Department, 'La Sapienza' University, Rome, Viale dell' Universita, 37, 00185, Rome, Italy (12) Secretario GTEI-SEMICYUC, Medicina Intensiva, Hospital Universitario Dr. Peset, Avenida Gaspa Aguilar, 90, 46107, Valencia, Spain (13) Department of Medicine (463), Nijmegen Institute for Infection, Inflammation, and Immunity (N4i), Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB, Nijmegen, The Netherlands Article History: Registration Date: 10/10/2008 Received Date: 09/10/2008 Accepted Date: 09/10/2008 Online Date: 30/10/2008 Article note: Part I is published at: doi: 10.1007/s00134-008-1338-7. Electronic supplementary material The online version of this article (doi: 10.1007/s00134-008-1339-6) contains supplementary material, which is available to authorized users.

Byline: Benoit P. Guery (1), Maiken C. Arendrup (2), Georg Auzinger (3), Elie Azoulay (4), Marcio Borges Sa (5), Elizabeth M. Johnson (6), Eckhard Muller (7), Christian Putensen (8), Coleman Rotstein (9), Gabriele Sganga (10), Mario Venditti (11), Rafael Zaragoza Crespo (12), Bart Jan Kullberg (13) Keywords: Antifungal; Azole; Candida; Candidiasis; Echinocandins; Invasive candidiasis; Intensive care; Polyenes Abstract: Background Invasive candidiasis and candidemia are frequently encountered in the nosocomial setting, particularly in the intensive care unit (ICU). Objectives and methods To review the current management of invasive candidiasis and candidemia in non-neutropenic adult ICU patients based on a review of the literature and a European expert panel discussion. Results and conclusions Candida albicans remains the most frequently isolated fungal species followed by C. glabrata. The diagnosis of invasive candidiasis involves both clinical and laboratory parameters, but neither of these are specific. One of the main features in diagnosis is the evaluation of risk factor for infection which will identify patients in need of pre-emptive or empiric treatment. Clinical scores were built from those risk factors. Among laboratory diagnosis, a positive blood culture from a normally sterile site provides positive evidence. Surrogate markers have also been proposed like 1,3 [beta]-d glucan level, mannans, or PCR testing. Invasive candidiasis and candidemia is a growing concern in the ICU, apart from cases with positive blood cultures or fluid/tissue biopsy, diagnosis is neither sensitive nor specific. The diagnosis remains difficult and is usually based on the evaluation of risk factors. Author Affiliation: (1) Infectious Diseases, SGRIVI, Hopital Huriez, CHRU Lille, 59045, Lille Cedex, France (2) Unit of Mycology, Department of Bacteriology, Mycology and Parasitology, Statens Serum Institut, Building 43/117, 2300, Copenhagen, Denmark (3) Liver Intensive Care, Institute of Liver Studies, King's College Hospital, Denmark Hill, London, SE5 9RS, UK (4) Service de Reanimation Medicale, Hopital Saint-Louis, 1, Avenue Claude-Bellefaux, 75010, Paris, France (5) Sepsis Unit, Intensive Care Department, Hospital Son Llatzer, Palma de Mallorca, Spain (6) Mycology Reference Laboratory, National Collection of Pathogenic Fungi, The HPA Centre for Infections, HPA South West Laboratory, Myrtle Road, Kingsdown, Bristol, BS2 8EL, UK (7) Universitatsklinik fur Anasthesiologie, Intensivmedizin und Schmerztherapie, Knappschaftskrankenhaus Bochum, Langendreer, Klinikum der Ruhr, Universitat, In der Schornau 23-25, 44892, Bochum, Germany (8) Operative Intensivmedizin, Klinik und Poliklinik fur Anasthesiologie und Operative Intensivmedizin, Rheinische-Friedrich-Wilhelms Universitat Bonn, Sigmund-Freud Str. 25, 53127, Bonn, Germany (9) Division of Infectious Diseases, University Health Network, Toronto General Hospital, NCSB 11-1212, 200 Elizabeth Street, Toronto, ON, M5G 2C4, Canada (10) Division of General Surgery and Organ Transplantation, Policlinico 'A Gemelli', Department of Surgery, Catholic University, Largo Gemelli, 8, 00168, Rome, Italy (11) Internal Medicine, Clinical Medicine Department, 'La Sapienza' University, Rome, Viale dell' Universita, 37, 00185, Rome, Italy (12) Secretario GTEI-SEMICYUC, Medicina Intensiva Hospital Universitario Dr. Peset, Avenida Gaspa Aguilar, 90, 46107, Valencia, Spain (13) Department of Medicine (463), Nijmegen Institute for Infection, Inflammation, and Immunity (N4i), Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB, Nijmegen, The Netherlands Article History: Registration Date: 10/10/2008 Received Date: 22/04/2008 Accepted Date: 05/10/2008 Online Date: 30/10/2008 Article note: Part II is published at: doi: 10.1007/s00134-008-1339-6.

Infectious diseases exert a constant evolutionary pressure on the genetic makeup of our innate immune system. Polymorphisms in Toll-like receptor 4 (TLR4) have been related to susceptibility to Gram-negative infections and septic shock. Here we show that two polymorphisms of TLR4, Asp299Gly and Thr39911e, have unique distributions in populations from Africa, Asia, and Europe. Genetic and functional studies are compatible with a model in which the nonsynonymous polymorphism Asp299Gly has evolved as a protective allele against malaria, explaining its high prevalence in subSaharan Africa. However, the same allele could have been disadvantageous after migration of modern humans into Eurasia, putatively because of increased susceptibility to severe bacterial infections. In contrast, the Asp299Gly allele, when present in cosegregation with Thr39911e to form the Asp299Gly/Thr39911e haplotype, shows selective neutrality. Polymorphisms in TLR4 exemplify how the interaction between our innate immune system and the infectious pressures in particular environments may have shaped the genetic variations and function of our immune system during the out-of-Africa migration of modern humans. cytokines | human migration | innate immunity | Toll-like receptor 4 | sepsis

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[sup.-/-] mice resulted from accumulation of fat tissue based on increased food intake. Il18[sup.-/-] 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[sup.-/-] mice involved an enhanced expression of genes associated with gluconeogenesis in the liver of Il18[sup.-/-] 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[sup.-/-] mice through activation of STAT3 phosphorylation. These findings indicate a new role of IL-18 in the homeostasis of energy intake and insulin sensitivity., Author(s): Mihai G Netea (corresponding author) [1, 2, 8]; Leo A B Joosten [3, 8]; Eli Lewis [2]; Dalan R Jensen [4]; Peter J Voshol [5]; Bart Jan Kullberg [1]; [...]

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 [...]