Re-Infection Outcomes following One- and Two-Stage Surgical Revision of Infected Hip Prosthesis:A Systematic Review and Meta-Analysis

The two-stage revision strategy has been claimed as being the "gold standard" for treating prosthetic joint infection. The one-stage revision strategy remains an attractive alternative option; however, its effectiveness in comparison to the two-stage strategy remains uncertain.To compare the effectiveness of one- and two-stage revision strategies in treating prosthetic hip infection, using re-infection as an outcome.Systematic review and meta-analysis.MEDLINE, EMBASE, Web of Science, Cochrane Library, manual search of bibliographies to March 2015, and email contact with investigators.Cohort studies (prospective or retrospective) conducted in generally unselected patients with prosthetic hip infection treated exclusively by one- or two-stage revision and with re-infection outcomes reported within two years of revision. No clinical trials were identified.Data were extracted by two independent investigators and a consensus was reached with involvement of a third. Rates of re-infection from 38 one-stage studies (2,536 participants) and 60 two-stage studies (3,288 participants) were aggregated using random-effect models after arcsine transformation, and were grouped by study and population level characteristics.In one-stage studies, the rate (95% confidence intervals) of re-infection was 8.2% (6.0-10.8). The corresponding re-infection rate after two-stage revision was 7.9% (6.2-9.7). Re-infection rates remained generally similar when grouped by several study and population level characteristics. There was no strong evidence of publication bias among contributing studies.Evidence from aggregate published data suggest similar re-infection rates after one- or two-stage revision among unselected patients. More detailed analyses under a broader range of circumstances and exploration of other sources of heterogeneity will require collaborative pooling of individual participant data.PROSPERO 2015: CRD42015016559

Evidence for a lack of a direct transcriptional suppression of the iron regulatory peptide hepcidin by hypoxia-inducible factors.

BACKGROUND: Hepcidin is a major regulator of iron metabolism and plays a key role in anemia of chronic disease, reducing intestinal iron uptake and release from body iron stores. Hypoxia and chemical stabilizers of the hypoxia-inducible transcription factor (HIF) have been shown to suppress hepcidin expression. We therefore investigated the role of HIF in hepcidin regulation. METHODOLOGY/PRINCIPAL FINDINGS: Hepcidin mRNA was down-regulated in hepatoma cells by chemical HIF stabilizers and iron chelators, respectively. In contrast, the response to hypoxia was variable. The decrease in hepcidin mRNA was not reversed by HIF-1alpha or HIF-2alpha knock-down or by depletion of the HIF and iron regulatory protein (IRP) target transferrin receptor 1 (TfR1). However, the response of hepcidin to hypoxia and chemical HIF inducers paralleled the regulation of transferrin receptor 2 (TfR2), one of the genes critical to hepcidin expression. Hepcidin expression was also markedly and rapidly decreased by serum deprivation, independent of transferrin-bound iron, and by the phosphatidylinositol 3 (PI3) kinase inhibitor LY294002, indicating that growth factors are required for hepcidin expression in vitro. Hepcidin promoter constructs mirrored the response of mRNA levels to interleukin-6 and bone morphogenetic proteins, but not consistently to hypoxia or HIF stabilizers, and deletion of the putative HIF binding motifs did not alter the response to different hypoxic stimuli. In mice exposed to carbon monoxide, hypoxia or the chemical HIF inducer N-oxalylglycine, liver hepcidin 1 mRNA was elevated rather than decreased. CONCLUSIONS/SIGNIFICANCE: Taken together, these data indicate that hepcidin is neither a direct target of HIF, nor indirectly regulated by HIF through induction of TfR1 expression. Hepcidin mRNA expression in vitro is highly sensitive to the presence of serum factors and PI3 kinase inhibition and parallels TfR2 expression

Defects in tRNA Modification Associated with Neurological and Developmental Dysfunctions in Caenorhabditis elegans Elongator Mutants

Elongator is a six subunit protein complex, conserved from yeast to humans. Mutations in the human Elongator homologue, hELP1, are associated with the neurological disease familial dysautonomia. However, how Elongator functions in metazoans, and how the human mutations affect neural functions is incompletely understood. Here we show that in Caenorhabditis elegans, ELPC-1 and ELPC-3, components of the Elongator complex, are required for the formation of the 5-carbamoylmethyl and 5-methylcarboxymethyl side chains of wobble uridines in tRNA. The lack of these modifications leads to defects in translation in C. elegans. ELPC-1::GFP and ELPC-3::GFP reporters are strongly expressed in a subset of chemosensory neurons required for salt chemotaxis learning. elpc-1 or elpc-3 gene inactivation causes a defect in this process, associated with a posttranscriptional reduction of neuropeptide and a decreased accumulation of acetylcholine in the synaptic cleft. elpc-1 and elpc-3 mutations are synthetic lethal together with those in tuc-1, which is required for thiolation of tRNAs having the 5′methylcarboxymethyl side chain. elpc-1; tuc-1 and elpc-3; tuc-1 double mutants display developmental defects. Our results suggest that, by its effect on tRNA modification, Elongator promotes both neural function and development

Iota-Carrageenan Is a Potent Inhibitor of Influenza A Virus Infection

The 2009 flu pandemic and the appearance of oseltamivir-resistant H1N1 influenza strains highlight the need for treatment alternatives. One such option is the creation of a protective physical barrier in the nasal cavity. In vitro tests demonstrated that iota-carrageenan is a potent inhibitor of influenza A virus infection, most importantly also of pandemic H1N1/2009 in vitro. Consequently, we tested a commercially available nasal spray containing iota-carrageenan in an influenza A mouse infection model. Treatment of mice infected with a lethal dose of influenza A PR8/34 H1N1 virus with iota-carrageenan starting up to 48 hours post infection resulted in a strong protection of mice similar to mice treated with oseltamivir. Since alternative treatment options for influenza are rare, we conclude that the nasal spray containing iota-carrageenan is an alternative to neuraminidase inhibitors and should be tested for prevention and treatment of influenza A in clinical trials in humans

HJV gene mutations in European patients with juvenile hemochromatosis

A large variety of mutations within the genes encoding hepcidin (HAMP) and hemojuvelin (HJV) have been identified in patients with the severe iron overload disorder juvenile hemochromatosis (JH). The aim of the present study was to evaluate the molecular background of JH in patients from central parts of Europe. Sequence analyses of HAMP and HJV were performed in seven JH patients from six families from Germany, Slovakia, and Croatia. For detection of the G320V mutation in HJV, a rapid polymerase chain reaction-based assay was developed. No mutations were found within the HAMP gene. Six of seven (86%) JH patients carried at least one copy of the G320V mutation within the HJV gene. Four of these patients were homozygous for the G320V mutation. In addition, two novel HJV mutations were identified (C119F and S328fsX337). Taken together, the present study demonstrates that molecular analysis of the HJV gene is a powerful tool for an early and reliable diagnosis of JH. As in affected patients from Greece, the G320V mutation seems to be widely distributed among JH patients from central parts of Europe. Therefore, detection of the G320V mutation could identify the majority of JH cases from these regions non-invasively