IMPORTANCE Surgical site infections increase patient morbidity and health care costs. The Centers for Disease Control and Prevention emphasize improved basic preventive measures to reduce bacterial transmission and infections among patients undergoing surgery. OBJECTIVE To assess whether improved basic preventive measures can reduce perioperative Staphylococcus aureus transmission and surgical site infections.

The human cytomegalovirus (HCMV) major immediate-early (MIE) enhancer contains five functional cyclic AMP (cAMP) response elements (CRE

. We speculate that neurohormonal stimulation via this signaling cascade is a possible means for reversing HCMV silence in vivo.Persons with impaired cellular immunity risk tissue-invasive disease from reactivation of latent human cytomegalovirus (HCMV). HCMV reactivation in tissues or blood of immunocompetent patients suffering illness from another cause also occurs but usually goes unnoticed and is self-limiting. For instance, nearly one-third of patients who are critically ill or in septic shock have detectable findings of HCMV reactivation in their bloodstream (12,26,43,45,80). HCMV reactivation infection in intestinal tissues with preexisting inflammatory disease (e.g., inflammatory bowel disease) is also well described for immunocompetent patients (28,39,40,51). The precise triggering mechanisms that underlie HCMV reactivation are unknown.So far, only cells of myeloid lineage have been determined to fulfill criteria for cellular sites of HCMV latency in vivo. In healthy HCMV-seropositive persons, precursors of macrophages and dendritic cells, including CD34ϩ hematopoietic progenitor cells, carry latent HCMV genomes at a low frequency (75). The terminal differentiation of these cells into a macrophage-or dendritic cell-like phenotype is a prerequisite for HCMV reactivation ex vivo (67, 76). However, this reactivation appears to be a rare event, suggesting that other, as yet unidentified factors may promote HCMV reactivation. Stimulation with tumor necrosis factor alpha (TNF-␣) or gamma interferon may promote HCMV reactivation from differentiated counterparts of monocytic-dendritic cell precursors that had been infected latently in vitro or in vivo (25,66,67,76).For both HCMV and murine CMV, viral major immediateearly (MIE) gene expression is greatly restricted or shut off during viral latency, and the productive viral life cycle cannot advance without this expression (57,74,75,78). The MIE enhancer/promoter controlling expression is regulated by the coordinated actions of multiple types of cis-acting elements (57). These elements are bound by cellular transcription factors whose functions are modulated by input supplied by the cell, the virus, and the external surrounding (57). Higher-order chromatin structure contributes to this regulation. Heterochromatin components amass on the inactive MIE enhancer/promoter in viral latency, whereas the chromatin signatures of transcriptional activity predominate at the active MIE enhancer/ promoter in acute and reactivation infections (47,67). MIE enhancer/promoter silencing is also favored by innate antiviral mechanisms that partly involve the repressive actions of nuclear ND10 domain components (e.g., hDAXX, PML, ATRX, and histone deacetylase [HDAC]) (52) but does not involve CpG methylation of the MIE enhancer/promoter (29).Quiescent HCMV infection of human NTera2/D1 cells (NT2 cells) is a tractable model system for studying the regulation of HCMV MIE enhancer/promoter reactivation (37, 54). NT2 cells share many phenotypic features with pluripotent

Novel strategies to mitigate the disease burden resulting from human cytomegalovirus (CMV) (HCMV) reactivation are needed. Knowledge about the ways in which HCMV major immediate-early (MIE) gene expression breaks silence from latency to start the viral replicative cycle has the potential to inform the development of new therapies to preempt viral replication. However, the molecular mechanisms that regulate the switch from HCMV MIE gene silence to activation are poorly understood.The expression of viral MIE genes is required to initiate the productive life cycles of human and animal CMV species, whereas expression is greatly restricted or absent during the latency of these viruses (39,52,53,57). The 550-bp MIE enhancer is the vital regulatory center for the transcriptional activation of the MIE gene locus (39). The enhancer's function is attributed to assorted cis-acting elements that are consensus binding sites for different specific cellular transcription factors (9,22,31,37); several types of cis-acting elements are repeated. Signaling networks relay and integrate information from the cell, the virus, and the extracellular environment to dynamically modulate the functional activities of these cellular transcription factors (9, 24). The composite configuration of the specific cis-acting elements in the HCMV MIE enhancer differs greatly from that of evolutionarily distant cytomegalovirus relatives (39). This may explain why the replacement of this enhancer with the MIE enhancer from murine CMV (MCMV) renders HCMV poorly competent at executing both MIE gene expression and viral genome replication in lytically infected cells (21).HCMV infection of human pluripotent embryonal NTera2/D1 (NT2) cells is a tractable model with which to molecularly characterize the regulatory mechanisms that break HCMV MIE gene expression silence in a setting of viral quiescence (25, 36). These cells become either neurons and astrocytes after treatment with retinoic acid (RA) (2, 3) or epithelial and smooth muscle-like cells after treatment with bone morphogenetic protein 2 (10). Keeping NT2 cells in an undifferentiated state, partly by propagation under progenitor cell growth conditions (36), promotes quiescent HCMV infection and results in greater than 98% of NT2 nuclei containing HCMV pp65 at 1 h postinfection (p.i.) with a multiplicity of infection (MOI) of 3 to 5 (25) and approximately 3 HCMV genome equivalents per nucleus at 24 h p.i. with an MOI of 10 (38). At 48 h p.i., the NT2 cells contain a subset of nonreplicating HCMV genomes having a DNA structure of covalently closed circles with superhelical twists (36).