We sought to determine whether an intact bone marrow is essential to lung repair following bleomycin-induced lung injury in mice, and the mechanisms of any protective effects conferred by bone marrow-derived mesenchymal stem cell (BMDMSC) transfer. We found that myelosupression increased susceptibility to bleomycin injury and that BMDMSC transfer was protective. Protection was associated with the differentiation of engrafted BMDMSC into specific and distinct lung cell phenotypes, with an increase in circulating levels of G-CSF and GM-CSF (known for their ability to promote the mobilization of endogenous stem cells) and with a decrease in inflammatory cytokines. In vitro, cells from injured, but not from normal, mouse lung produced soluble factors that caused BMDMSC to proliferate and migrate toward the injured lung. We conclude that bone marrow stem cells are important in the repair of bleomycin-injured lung and that transfer of mesenchymal stem cells protects against the injury. BMDMSC localize to the injured lung and assume lung cell phenotypes, but protection from injury and fibrosis also involves suppression of inflammation and triggering production of reparative growth factors.

BACKGROUND The treatment of symptomatic congenital cytomegalovirus (CMV) disease with intravenous ganciclovir for 6 weeks has been shown to improve audiologic outcomes at 6 months, but the benefits wane over time. METHODS We conducted a randomized, placebo-controlled trial of valganciclovir therapy in neonates with symptomatic congenital CMV disease, comparing 6 months of therapy with 6 weeks of therapy. The primary end point was the change in hearing in the better ear (“best-ear” hearing) from baseline to 6 months. Secondary end points included the change in hearing from baseline to follow-up at 12 and 24 months and neurodevelopmental outcomes, with each end point adjusted for central nervous system involvement at baseline. RESULTS A total of 96 neonates underwent randomization, of whom 86 had follow-up data at 6 months that could be evaluated. Best-ear hearing at 6 months was similar in the 6-month group and the 6-week group (2 and 3 participants, respectively, had improvement; 36 and 37 had no change; and 5 and 3 had worsening; P = 0.41). Total-ear hearing (hearing in one or both ears that could be evaluated) was more likely to be improved or to remain normal at 12 months in the 6-month group than in the 6-week group (73% vs. 57%, P = 0.01). The benefit in total-ear hearing was maintained at 24 months (77% vs. 64%, P = 0.04). At 24 months, the 6-month group, as compared with the 6-week group, had better neurodevelopmental scores on the Bayley Scales of Infant and Toddler Development, third edition, on the language-composite component (P = 0.004) and on the receptive-communication scale (P = 0.003). Grade 3 or 4 neutropenia occurred in 19% of the participants during the first 6 weeks. During the next 4.5 months of the study, grade 3 or 4 neutropenia occurred in 21% of the participants in the 6-month group and in 27% of those in the 6-week group (P = 0.64). CONCLUSIONS Treating symptomatic congenital CMV disease with valganciclovir for 6 months, as compared with 6 weeks, did not improve hearing in the short term but appeared to improve hearing and developmental outcomes modestly in the longer term. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT00466817.)

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Bone marrow-derived mesenchymal stem cells (BMDMSCs) appear to be important in repair of the chronic lung injury caused by bleomycin in mice. To determine effects of these BMDMSCs on an acute inflammatory response, we injected C57BL/6 mice intraperitoneally with 1 mg/kg endotoxin followed either by intravenous infusion of 5 x 10(5) BMDMSCs, the same number of lung fibroblasts, or an equal volume of normal saline solution. Lungs harvested 6, 24, and 48 h and 14 days after endotoxin showed that BMDMSC administration prevented endotoxin-induced lung inflammation, injury, and edema. Although we were able to detect donor cells in the lungs at 1 day after endotoxin, by 14 days no donor cells were detected. BMDMSC administration suppressed the endotoxin-induced increase in circulating proinflammatory cytokines without decreasing circulating levels of anti-inflammatory mediators. Ex vivo cocultures of BMDMSC and lung cells from endotoxemic animals demonstrated a bilateral conversation in which lung cells stimulated proliferation and migration of stem cells and suppressed proinflammatory cytokine production by lung cells. We conclude that BMDMSCs decrease both the systemic and local inflammatory responses induced by endotoxin. These effects do not require either lung engraftment or differentiation of the stem cells and are due at least in part to the production of stem cell chemoattractants by the lungs and to humoral and physical interactions between stem cells and lung cells. We speculate that mobilization of this population of BMDMSCs may be a general mechanism for modulating an acute inflammatory response.

This guideline addresses the evaluation and management of wellappearing, term infants, 8 to 60 days of age, with fever $38.0 C. Exclusions are noted. After a commissioned evidence-based review by the Agency for Healthcare Research and Quality, an additional extensive and ongoing review of the literature, and supplemental data from published, peer-reviewed studies provided by active investigators, 21 key action statements were derived. For each key action statement, the quality of evidence and benefit-harm relationship were assessed and graded to determine the strength of recommendations. When appropriate, parents' values and preferences should be incorporated as part of shared decision-making. For diagnostic testing, the committee has attempted to develop numbers needed to test, and for antimicrobial administration, the committee provided numbers needed to treat. Three algorithms summarize the recommendations for infants 8 to 21 days of age, 22 to 28 days of age, and 29 to 60 days of age. The recommendations in this guideline do not indicate an exclusive course of treatment or serve as a standard of medical care. Variations, taking into account individual circumstances, may be appropriate. BACKGROUNDEfforts to develop an evidence-based approach to the evaluation and management of young febrile infants have spanned more than 4 decades. 1 In the 1970s, concerns arose about the emergence and rapid progression of group B Streptococcus (GBS) infection in neonates, whose clinical appearance and preliminary laboratory evaluations did not always reflect the presence of serious disease. 2 Such concerns led to extensive evaluations, hospitalizations, and antimicrobial treatment of all febrile infants younger than 60 days, 3 with many institutions extending complete sepsis workups to 90 days. However, the seminal