This led to a smaller than expected proportion of patients receiving alternative therapy that differed inhibitor Imatinib from standard therapy, adding to the complexity of interpreting the safety results. There were also a relatively small number of patients exposed to higher doses because fewer patients were classified with severe protein C deficiency at 24 hours than predicted from the PROWESS data [14], which limits the conclusions that can be drawn from this subgroup. The reliance on local protein C assays to stratify patients led to some misclassification of protein C values between local and central laboratories and the potential relevance of this warrants further investigation.

Although mortality differences were noted, the study was not primarily designed or powered to detect 28-day mortality differences be
Respiratory infection is the single largest contributor to the global burden of disease and the leading cause of death in children worldwide [1,2]. Streptococcus pneumoniae (the pneumococcus) remains the most common cause of community-acquired pneumonia in Europe and the United States [3]. In addition to pneumonia, pneumococcal infection may also manifest as invasive disease, defined by the isolation of S. pneumoniae from a normally sterile site such as blood (bacteraemia) or cerebrospinal fluid (meningitis). Although asymptomatic colonisation of the nasopharynx by the pneumococcus is widespread in the population, invasive pneumococcal disease (IPD) occurs in only a minority of individuals [4,5].

The factors that influence development of invasive disease remain poorly understood, although increasing evidence points towards a role for genetic variation in the host’s immune response [5]. In particular, recent insights from the study of animal models, rare human primary immunodeficiency states, and population-based genetic epidemiology have focused attention on the control of the proinflammatory transcription factor NF-��B in the development of IPD [5-10].NF-��B plays a key regulatory role in a diverse array of cellular processes, including innate and adaptive immune responses [11,12]. In unstimulated cells, NF-��B transcription factor subunits are prevented from binding DNA through associations with the inhibitor of NF-��B (I��B) protein family.

Stimulation of a variety of immune receptors (including Toll-like receptors, T-cell and B-cell antigen receptors and members of the IL-1 and TNF receptor superfamilies) leads to phosphorylation and degradation of the I��B inhibitors and release of NF-��B, which induces transcription of proinflammatory target genes [11,12]. Genes that are activated by Entinostat NF-��B include those encoding cytokines (for example, IL-1, IL-2, IL-6, TNF��) and chemokines (for example, IL-8, RANTES), as well as acute phase response proteins, adhesion molecules, antimicrobial peptides and inducible enzymes [11,12].