Pentoxifylline did not improve survival in patients with alcoholic hepatitis. Prednisolone was associated with a reduction in 28-day mortality that did not reach significance and with no improvement in outcomes at 90 days or 1 year. (Funded by the National Institute for Health Research Health Technology Assessment program; STOPAH EudraCT number, 2009-013897-42 , and Current Controlled Trials number, ISRCTN88782125 ).

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Osteoarthritis is a prevalent and disabling disease affecting an increasingly large swathe of the world population. While clinical osteoarthritis is a late-stage condition for which disease-modifying opportunities are limited, osteoarthritis typically develops over decades, offering a long window of time to potentially alter its course. The etiology of osteoarthritis is multifactorial, showing strong associations with highly modifiable risk factors of mechanical overload, obesity and joint injury. As such, characterization of pre-osteoarthritic disease states will be critical to support a paradigm shift from palliation of late disease towards prevention, through early diagnosis and early treatment of joint injury and degeneration to reduce osteoarthritis risk. Joint trauma accelerates development of osteoarthritis from a known point in time. Human joint injury cohorts therefore provide a unique opportunity for evaluation of pre-osteoarthritic conditions and potential interventions from the earliest stages of degeneration. This review focuses on recent advances in imaging and biochemical biomarkers suitable for characterization of the pre-osteoarthritic joint as well as implications for development of effective early treatment strategies.

We applied genetic tools available in Drosophila to identify candidate substrates of the UBE3A ubiquitin ligase, the gene responsible for Angelman syndrome (AS). Human UBE3A was expressed in Drosophila heads to identify proteins differentially regulated in UBE3A-expressing versus wild-type extracts. Using two-dimensional gel and MALDI-TOF analysis, we detected 20 proteins that were differentially regulated by over-expression of human UBE3A in Drosophila heads. One protein responsive to UBE3A was the Rho-GEF pebble (pbl). Here, we present three lines of evidence suggesting that UBE3A regulates Pbl. First, we show genetic evidence that UBE3A and the Drosophila de-ubiquitinase fat facets (faf) exert opposing effects on Pbl function. Secondly, we find that both Pbl and ECT2, the mammalian orthologue of Pbl called epithelial cell transforming sequence 2 oncogene, physically interact with their respective ubiquitin E3 ligases. Finally, we show that Ect2 expression is regulated by Ube3a in mouse neurons as the pattern of Ect2 expression is dramatically altered in the hippocampus and cerebellum of Ube3a null mice. These results suggest that an orthologous UBE3A post-translational regulatory pathway regulates neuronal outgrowth in the mammalian brain and that dysregulation of this pathway may result in neurological phenotypes including AS and possibly other autism spectrum disorders.

In silico analysis of the Listeria monocytogenes genome revealed lmo0292, a gene predicted to encode a HtrA-like serine protease. A stable insertion mutant was constructed, revealing a requirement for htrA in the listerial response to heat, acid, and penicillin stress. Transcriptional analysis revealed that htrA is not induced in response to heat shock but is induced in response to low pH and penicillin G stress. Furthermore, htrA expression was shown to be dependent upon the LisRK two-component sensor-kinase, a system known to respond to changes in integrity of the cell envelope. In addition, we demonstrated that a second in-frame start codon, upstream of that previously annotated for L. monocytogenes htrA, incorporating a putative signal sequence appears to influence virulence potential. Finally, a significant virulence defect was observed for the htrA mutant, indicating that this gene is required for full virulence in mice. Our findings suggest that L. monocytogenes lmo0292 encodes an HtrA-like serine protease that is not part of the classical heat shock response but is involved in stress responses and virulence.L. monocytogenes is a food-borne pathogen with an ability to sense and appropriately respond to hostile changes in its environment, an adaptive response, which is pivotal to mounting a successful infection. To overcome stresses encountered in food and during infection, L. monocytogenes has evolved elaborate systems for sensing and responding to a variety of adverse environments (2,9,15,28).The publication of the complete chromosomal sequence of L. monocytogenes EGDe (11) facilitated significant advancements in the identification and characterization of loci which potentially play important roles in listerial growth and survival in foods and during infection, one such locus is lmo0292 (encoding an HtrA-like homologue). Initially characterized in Escherichia coli, HtrA is one of several proteins, collectively known as heat shock proteins, whose expression is essential for survival of bacteria at high temperatures (17). In addition, htrA has been shown to be essential for the pathogenicity of several gram-negative and gram-positive bacteria, namely, Salmonella enterica serovar Typhimurium (13), Klebsiella pneumoniae (3), Streptococcus pyogenes (14), and Streptococcus pneumoniae (12), as well as the antibiotic stress response in Lactococcus lactis (7) and Staphylococcus aureus (30).Three HtrA homologues-HtrA, YvtA, and YycK-are encoded in Bacillus subtilis (22,23). In silico analysis revealed that the immediate genomic organization of the region encoding the HtrA-like serine protease in L. monocytogenes corresponds to the B. subtilis six-gene operon (yycF-yycK). The B. subtilis yycF gene and its ortholog in S. aureus encode a response regulator that is essential for cell growth (6, 21). Fukuchi et al. (8) showed that the two-component system encoded by yycF and yycG is essential and has the potential to modulate expression of the cell division operon ftsAZ in B. subtilis. Attempts to disrupt the correspo...