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Patients with primary immunodeficiency disease (PIDD) typically require life-long intravenous (IV) or subcutaneous (SC) immunoglobulin (Ig) replacement therapy to prevent recurrent infections. The efficacy, safety, and pharmacokinetics of a highly concentrated (20 %) Ig preparation for SC administration (IGSC 20 %) were evaluated in a prospective trial in patients with PIDD. A total of 74 patients (aged 3-83 years) received 4327 IGSC 20 % infusions over a median of 380.5 days. The rate of validated serious bacterial infections was 0.012 event/patient-year ( p < 0.0001 compared with the historical control), and the annualized rate of infection was 2.41 events/patient. Median IgG trough levels were >14.5 g/l. The median maximum infusion rate was 60 ml/h/site (range 4.4-180), resulting in a median infusion duration of 0.95 h. A volume ≥30 ml was infused per site in 74.8 % of IGSC 20 % infusions. Most (84.9 %) infusions were administered using ≤2 infusion sites; for 99.8 % of infusions, there was no need to interrupt/stop administration or reduce the infusion rate. No related serious adverse event (AE) occurred during IGSC 20 % treatment; related non-serious AEs occurred at a rate of 0.036 event/infusion. The incidence of related local AEs was 0.015 event/infusion and of related systemic AEs was 0.021 event/infusion; most were mild in severity, none severe. Increased infusion rates or volumes were not associated with higher AE rates. The investigated IGSC 20 % treatment was shown to be effective and safe, enabling higher infusion rates and volumes per site compared to conventional SC treatments, resulting in fewer infusion sites and shorter infusion durations. [ABSTRACT FROM AUTHOR]

Hundred-thousands of fungal species are present in our environment, including normal colonizers that constitute part of the human microbiota. The homeostasis of host-fungus interactions encompasses efficient fungal sensing, tolerance at mucosal surfaces, as well as antifungal defenses. Decrease in host immune fitness or increase in fungal burden may favor pathologies, ranging from superficial mucocutaneous diseases to invasive life-threatening fungal infections. Toll-like receptors (TLRs) are essential players in this balance, due to their ability to control both inflammatory and anti-inflammatory processes upon recognition of fungal-specific pathogen-associated molecular patterns (PAMPs). Certain members of the TLR family participate to the initial recognition of fungal PAMPs on the cell surface, as well as inside phagosomes of innate immune cells. Active signaling cascades in phagocytes ultimately enable fungus clearance and the release of cytokines that shape and instruct other innate immune cells and the adaptive immune system. Some TLRs cooperate with other pattern recognition receptors (PRRs) (e.g., C-type lectins and Galectins), thus allowing for a tailored immune response. The spatio-temporal and physiological contributions of individual TLRs in fungal infections remains ill-defined, although in humans, TLR gene polymorphisms have been linked to increased susceptibility to fungal infections. This review focuses entirely on the role of TLRs that control the host susceptibility to environmental fungi (e.g., Aspergillus, Cryptoccocus, and Coccidoides), as well as to the most frequent human fungal pathogens represented by the commensal Candida species. The emerging roles of TLRs in modulating host tolerance to fungi, and the strategies that evolved in some of these fungi to evade or use TLR recognition to their advantage will also be discussed, as well as their potential suitability as targets in vaccine therapies. [ABSTRACT FROM AUTHOR]

Invasive fungal infections by Candida albicans (Ca) are a frequent cause of lethal sepsis in intensive care unit patients. While a contribution of type I interferons (IFNs-I) in fungal sepsis remains unknown, these immunostimulatory cytokines mediate the lethal effects of endotoxemia and bacterial sepsis. Using a mouse model lacking a functional IFN-I receptor (Ifnar1-/-), we demonstrate a remarkable protection against invasive Ca infections. We discover a mechanism whereby IFN-I signaling controls the recruitment of inflammatory myeloid cells, including Ly6Chi monocytes and neutrophils, to infected kidneys by driving expression of the chemokines CCL2 and KC. Within kidneys, monocytes differentiate into inflammatory DCs but fail to functionally mature in Ifnar1-/- mice, as demonstrated by the impaired upregulation of the key activation markers PDCA1 and iNOS. The increased activity of inflammatory monocytes and neutrophils results in hyper-inflammation and lethal kidney pathology. Pharmacological diminution of monocytes and neutrophils by treating mice with pioglitazone, a synthetic agonist of the nuclear receptor peroxisome proliferator-activated receptor-γ (PPAR-γ), strongly reduces renal immunopathology during Ca infection and improves mouse survival. Taken together, our data connect for the first time the sepsis-promoting functions of IFNs-I to the CCL2-mediated recruitment and the activation of inflammatory monocytes/DCs with high host-destructing potency. Moreover, our data demonstrate a therapeutic relevance of PPAR-γ agonists for microbial infectious diseases where inflammatory myeloid cells may contribute to fatal tissue damage. [ABSTRACT FROM AUTHOR]

Mammalian innate immune cells produce reactive oxygen species (ROS) in the oxidative burst reaction to destroy invading microbial pathogens. Using quantitative real-time ROS assays, we show here that both yeast and filamentous forms of the opportunistic human fungal pathogen Candida albicans trigger ROS production in primary innate immune cells such as macrophages and dendritic cells. Through a reverse genetic approach, we demonstrate that coculture of macrophages or myeloid dendritic cells with C. albicans cells lacking the superoxide dismutase (SOD) Sod5 leads to massive extracellular ROS accumulation in vitro. ROS accumulation was further increased in coculture with fungal cells devoid of both Sod4 and Sod5. Survival experiments show that C. albicans mutants lacking Sod5 and Sod4 exhibit a severe loss of viability in the presence of macrophages in vitro. The reduced viability of sod5Δ/Δ and sod4Δ/Δ sod5Δ/Δ mutants relative to wild type is not evident with macrophages from gp91phox −/− mice defective in the oxidative burst activity, demonstrating a ROS-dependent killing activity of macrophages targeting fungal pathogens. These data show a physiological role for cell surface SODs in detoxifying ROS, and suggest a mechanism whereby C. albicans, and perhaps many other microbial pathogens, can evade host immune surveillance in vivo. [ABSTRACT FROM AUTHOR]

The work presented in this paper was aimed at detecting, understanding and modeling some critical behavior aspects of zeolite-containing diesel catalysts. An already available mathematical model for precious metal catalysts was used as a starting point. A specially designed set of experiments provided the information needed to improve certain modeling features. New submodels were introduced to account for hydrocarbon and H2O adsorption, as well as diffusion limitations in the zeolite. The effect of flow maldistribution during real world operation was investigated experimentally and computationally. Although a number of issues (especially regarding the DeNOx mechanisms) are not yet fully resolved, significant progress was achieved as regards the understanding and computational prediction of diesel catalyst operation. [ABSTRACT FROM AUTHOR]

The kinetics of CO oxidation over two catalytic sites, either 100% zero-valent or 100% oxidised rhodium atoms, were studied. It was shown that an oxidised rhodium species exhibits a significant higher turnover rate in CO oxidation (factor 25) than the corresponding zero-valent one. This noticeable difference, interpreted with respect to mechanistic considerations, led us to conclude that one of the promoting effects of ceria–zirconia is to stabilise rhodium atoms as oxidised species. [ABSTRACT FROM AUTHOR]