Drosophila Enhancer of Polycomb, E(Pc), is a suppressor of position-effect variegation and an enhancer of both Polycomb and trithorax mutations. A homologous yeast protein, Epl1, is a subunit of the NuA4 histone acetyltransferase complex. Epl1 depletion causes cells to accumulate in G2/M and global loss of acetylated histones H4 and H2A. In relation to the Drosophila protein, mutation of Epl1 suppresses gene silencing by telomere position effect. Epl1 protein is found in the NuA4 complex and a novel highly active smaller complex named Piccolo NuA4 (picNuA4). The picNuA4 complex contains Esa1, Epl1, and Yng2 as subunits and strongly prefers chromatin over free histones as substrate. Epl1 conserved N-terminal domain bridges Esa1 and Yng2 together, stimulating Esa1 catalytic activity and enabling acetylation of chromatin substrates. A recombinant picNuA4 complex shows characteristics similar to the native complex, including strong chromatin preference. Cells expressing only the N-terminal half of Epl1 lack NuA4 HAT activity, but possess picNuA4 complex and activity. These results indicate that the essential aspect of Esa1 and Epl1 resides in picNuA4 function. We propose that picNuA4 represents a nontargeted histone H4/H2A acetyltransferase activity responsible for global acetylation, whereas the NuA4 complex is recruited to specific genomic loci to perturb locally the dynamic acetylation/deacetylation equilibrium.

NuA4 is an essential histone H4/H2A acetyltransferase complex that interacts with activators and stimulates transcription in vitro. We have identified three novel NuA4 subunits: Act3/Arp4, an actin-related protein implicated in epigenetic control of transcription, Act1, and Epl1, a protein homologous to Drosophila Enhancer of Polycomb. Act3/Arp4 binds nucleosomes in vitro and is required for NuA4 integrity in vivo. Mutations in ACT3 and acetyltransferase-encoding ESA1 cause gene-specific transcription defects. Accordingly, NuA4 is localized in precise loci within the nucleus and does not overlap with the silent chromatin marker Sir3. These data along with the known epigenetic roles of Act3/Arp4 and homologs of Epl1 and Esa1 strongly support an essential role for chromatin structure modification by NuA4 in transcription regulation in vivo.

It is not known whether pandemic 2009 influenza A/H1N1 (2009 H1N1) leads to more serious disease than seasonal influenza in hematopoietic cell transplant (HCT) recipients. In a retrospective study in HCT recipients with virologically proven influenza virus infection, a total of 161 HCT recipients (18 2009 H1N1, 103 seasonal influenza A, and 40 seasonal influenza B) were analyzed. In multivariable analyses, more patients with 2009 H1N1 had lower respiratory tract disease (LRD), hypoxemia, and prolonged viral shedding compared with seasonal influenza A. Seasonal influenza A and B outcomes were similar. There was no difference in overall and influenza-associated mortality among influenza virus types. Both early and delayed administration of antiviral therapy was shown to be beneficial in terms of decreased rates of development of LRD, although earlier intervention appeared to be more effective. Profound lymphopenia and lack of early antiviral therapy were associated significantly with LRD, hypoxemia, and death. High-dose corticosteroid treatment (≥ 1 mg/kg) given at the time of influenza diagnosis was associated with a reduced risk for mechanical ventilation. Thus, our data suggest that infection with 2009 influenza A/H1N1 resulted in more severe respiratory disease in HCT recipients compared with seasonal influenza.

The impact of cytokines induced during influenza infection has been described, but the effect of corticosteroids on clinical outcomes is unclear. Although antiviral therapy has been well studied in immunocompetent subjects, few data exist on its clinical efficacy in immunocompromised populations. Data from 143 hematopoietic cell transplant recipients with documented seasonal influenza infection were reviewed to examine the impact of different corticosteroid regimens and antiviral therapy on clinical outcomes. In multivariable analyses, there was no observed difference between patients who received no, low doses (< 1 mg/kg/d) or high doses (≥ 1 mg/kg/d) of corticosteroids with regards to the development of lower respiratory tract disease (LRD), hypoxemia, need for mechanical ventilation or death. However, treatment with high dose steroids was associated with prolonged viral shedding (OR, 3.3; 95% CI, 1.0-11; p = 0.05). In multivariable analyses, antiviral therapy initiated to treat upper respiratory tract infection (URI) was associated with fewer cases of LRD (OR, 0.04; 95% CI, 0-0.2; p < 0.01) and fewer hypoxemia episodes (OR, 0.3; 95% CI, 0.1-0.9; p = 0.03). Our results suggest that corticosteroids are not associated with adverse clinical outcomes in hematopoietic cell transplant recipients infected with influenza, although use of higher doses may delay viral clearance. Antiviral therapy initiated during the URI phase reduced the risk of LRD and hypoxemia.

Most oseltamivir-resistant pandemic (H1N1) 2009 viruses have been isolated from immunocompromised patients. To describe the clinical features, treatment, outcomes, and virologic data associated with infection from pandemic (H1N1) 2009 virus with H275Y mutation in immunocompromised patients, we retrospectively identified 49 hematology–oncology patients infected with pandemic (H1N1) 2009 virus. Samples from 33 of those patients were tested for H275Y genotype by allele-specific real-time PCR. Of the 8 patients in whom H275Y mutations was identified, 1 had severe pneumonia; 3 had mild pneumonia with prolonged virus shedding; and 4 had upper respiratory tract infection, of whom 3 had prolonged virus shedding. All patients had received oseltamivir before the H275Y mutation was detected; 1 had received antiviral prophylaxis. Three patients excreted resistant virus for >60 days. Emergence of oseltamivir resistance is frequent in immunocompromised patients infected with pandemic (H1N1) 2009 virus and can be associated with a wide range of clinical disease and viral kinetics.

Background Cytomegalovirus (CMV) disease occurs frequently after cessation of antiviral prophylaxis in CMV-seronegative kidney transplant recipients from seropositive donors (D+ R−), and the risk factors are incompletely defined. Methods We retrospectively assessed the incidence, clinical features, and risk factors for CMV disease in a cohort of D+ R− kidney transplant recipients who received antiviral prophylaxis at a single US transplant center using descriptive statistics and Cox proportional hazards models. Results CMV disease developed in 29 of 113 (26%) D+ R− patients at a median of 185 days (interquartile range 116–231 days) post transplant, including CMV syndrome (66%) and tissue invasive disease (34%). The incidence of CMV disease was higher in patients who underwent re-transplantation (57% vs. 24%) and this factor was independently associated with a higher risk of CMV disease in multivariable analysis (hazard ratio, 4.02; 95% confidence interval, 1.3–13; P = 0.016). Other demographic and transplant variables were not independently associated with a risk of late-onset CMV disease. Conclusions Despite a comprehensive analysis of patient and transplant variables, only re-transplantation was identified as a risk factor for CMV disease in D+ R− kidney transplant recipients who received antiviral prophylaxis, but had limited clinical predictive value. The development of novel laboratory markers to identify patients at greatest risk for CMV disease should be a priority for future studies.

Influenza RNA in blood (viremia) was detected in 9 of 79 (11.4%) hematopoietic cell transplant recipients with influenza, and was less frequently observed in patients with upper respiratory tract disease only and more frequently in patients infected with 2009 pandemic influenza A/H1N1 strain (versus seasonal strains). Viremia increased the risk of progression to lower respiratory tract disease (LRD), hypoxemia, respiratory failure, and overall and influenza-related death. Among patients with LRD, viremia was associated with increased hazards of overall and influenza-associated death (hazard ratio 3.5, 1.1-12). Thus, influenza viremia may serve as marker for overall poor outcome.

Overall, all first-line antimicrobials remain acceptable choices for empirical treatment of uncomplicated UTIs in women in Quebec. The regional variability in susceptibility data within a single province emphasizes the importance of local susceptibility data to inform the development of empirical treatment guidelines for UTIs.