Gadolinium and nephrogenic systemic fibrosis: time to tighten practice

Nephrogenic systemic fibrosis (NSF) is a relatively new entity, first described in 1997. Few cases have been reported, but the disease has high morbidity and mortality. To date it has been seen exclusively in patients with renal dysfunction. There is an emerging link with intravenous injection of gadolinium contrast agents, which has been suggested as a main triggering factor, with a lag time of days to weeks. Risk factors include the severity of renal impairment, major surgery, vascular events and other proinflammatory conditions. There is no reason to believe that children have an altered risk compared to the adult population. It is important that the paediatric radiologist acknowledges emerging information on NSF but at the same time considers the risk:benefit ratio prior to embarking on alternative investigations, as children with chronic kidney disease require high-quality diagnostic imaging

The Urokinase Receptor (uPAR) Facilitates Clearance of Borrelia burgdorferi

The causative agent of Lyme borreliosis, the spirochete Borrelia burgdorferi, has been shown to induce expression of the urokinase receptor (uPAR); however, the role of uPAR in the immune response against Borrelia has never been investigated. uPAR not only acts as a proteinase receptor, but can also, dependently or independently of ligation to uPA, directly affect leukocyte function. We here demonstrate that uPAR is upregulated on murine and human leukocytes upon exposure to B. burgdorferi both in vitro as well as in vivo. Notably, B. burgdorferi-inoculated C57BL/6 uPAR knock-out mice harbored significantly higher Borrelia numbers compared to WT controls. This was associated with impaired phagocytotic capacity of B. burgdorferi by uPAR knock-out leukocytes in vitro. B. burgdorferi numbers in vivo, and phagocytotic capacity in vitro, were unaltered in uPA, tPA (low fibrinolytic activity) and PAI-1 (high fibrinolytic activity) knock-out mice compared to WT controls. Strikingly, in uPAR knock-out mice partially backcrossed to a B. burgdorferi susceptible C3H/HeN background, higher B. burgdorferi numbers were associated with more severe carditis and increased local TLR2 and IL-1β mRNA expression. In conclusion, in B. burgdorferi infection, uPAR is required for phagocytosis and adequate eradication of the spirochete from the heart by a mechanism that is independent of binding of uPAR to uPA or its role in the fibrinolytic system

Exacerbated Innate Host Response to SARS-CoV in Aged Non-Human Primates

The emergence of viral respiratory pathogens with pandemic potential, such as severe acute respiratory syndrome coronavirus (SARS-CoV) and influenza A H5N1, urges the need for deciphering their pathogenesis to develop new intervention strategies. SARS-CoV infection causes acute lung injury (ALI) that may develop into life-threatening acute respiratory distress syndrome (ARDS) with advanced age correlating positively with adverse disease outcome. The molecular pathways, however, that cause virus-induced ALI/ARDS in aged individuals are ill-defined. Here, we show that SARS-CoV-infected aged macaques develop more severe pathology than young adult animals, even though viral replication levels are similar. Comprehensive genomic analyses indicate that aged macaques have a stronger host response to virus infection than young adult macaques, with an increase in differential expression of genes associated with inflammation, with NF-κB as central player, whereas expression of type I interferon (IFN)-β is reduced. Therapeutic treatment of SARS-CoV-infected aged macaques with type I IFN reduces pathology and diminishes pro-inflammatory gene expression, including interleukin-8 (IL-8) levels, without affecting virus replication in the lungs. Thus, ALI in SARS-CoV-infected aged macaques developed as a result of an exacerbated innate host response. The anti-inflammatory action of type I IFN reveals a potential intervention strategy for virus-induced ALI

Dialysis-associated peritonitis in children

Peritonitis remains a frequent complication of peritoneal dialysis in children and is the most common reason for technique failure. The microbiology is characterized by a predominance of Gram-positive organisms, with fungi responsible for less than 5% of episodes. Data collected by the International Pediatric Peritonitis Registry have revealed a worldwide variation in the bacterial etiology of peritonitis, as well as in the rate of culture-negative peritonitis. Risk factors for infection include young age, the absence of prophylactic antibiotics at catheter placement, spiking of dialysis bags, and the presence of a catheter exit-site or tunnel infection. Clinical symptoms at presentation are somewhat organism specific and can be objectively assessed with a Disease Severity Score. Whereas recommendations for empiric antibiotic therapy in children have been published by the International Society of Peritoneal Dialysis, epidemiologic data and antibiotic susceptibility data suggest that it may be desirable to take the patient- and center-specific history of microorganisms and their sensitivity patterns into account when prescribing initial therapy. The vast majority of patients are treated successfully and continue peritoneal dialysis, with the poorest outcome noted in patients with peritonitis secondary to Gram-negative organisms or fungi and in those with a relapsing infection

Succinate is an inflammatory signal that induces IL-1 beta through HIF-1 alpha

Macrophages activated by the Gram-negative bacterial product lipopolysaccharide switch their core metabolism from oxidative phosphorylation to glycolysis1. Here we show that inhibition of glycolysis with 2-deoxyglucose suppresses lipopolysaccharide-induced interleukin-1β but not tumour-necrosis factor-α in mouse macrophages. A comprehensive metabolic map of lipopolysaccharide-activated macrophages shows upregulation of glycolytic and downregulation of mitochondrial genes, which correlates directly with the expression profiles of altered metabolites. Lipopolysaccharide strongly increases the levels of the tricarboxylic-acid cycle intermediate succinate. Glutamine-dependent anerplerosis is the principal source of succinate, although the ‘GABA (γ-aminobutyric acid) shunt’ pathway also has a role. Lipopolysaccharide-induced succinate stabilizes hypoxia-inducible factor-1α, an effect that is inhibited by 2-deoxyglucose, with interleukin-1β as an important target. Lipopolysaccharide also increases succinylation of several proteins. We therefore identify succinate as a metabolite in innate immune signalling, which enhances interleukin-1β production during inflammation

Computer-aided prediction of RNA secondary structures.

A brief survey of computer algorithms that have been developed to generate predictions of the secondary structures of RNA molecules is presented. Two particular methods are described in some detail. The first utilizes a thermodynamic energy minimization algorithm that takes into account the likelihood that short-range folding tends to be favored over long-range interactions. The second utilizes an interactive computer graphic modelling algorithm that enables the user to consider thermodynamic criteria as well as structural data obtained by nuclease susceptibility, chemical reactivity and phylogenetic studies. Examples of structures for prokaryotic 16S and 23S ribosomal RNAs, several eukaryotic 5S ribosomal RNAs and rabbit beta-globin messenger RNA are presented as case studies in order to describe the two techniques. Anm argument is made for integrating the two approaches presented in this paper, enabling the user to generate proposed structures using thermodynamic criteria, allowing interactive refinement of these structures through the application of experimentally derived data