Occult bacteremia in children with simple febrile seizure in the post-pneumococcal conjugate vaccine era

Purpose The authors aimed to investigate the utility of blood culture (BC) for children with simple febrile seizure (SFS) in the emergency department (ED) in the post-10/13-valent pneumococcal conjugate vaccine (PCV) era. Methods This study was performed at the ED of a tertiary care university-affiliated women and children’s hospital, and involved 3,237 previously healthy children aged 6-60 months who visited the ED with SFS from January 2013 through December 2017. The SFS was defined according to the International Classification of Diseases, 11th Revision codes related to seizure. The children were divided into 2 groups according to the vaccination rates of the period of their visit: the 70-PCV (70%, 2013-2014) and 97-PCV (97%, 2015-2017) groups. The primary outcome was the yield, defined as a true positivity of BC. In addition, we collected information on baseline characteristics, ED length of stay, inflammatory biomarkers, and ED outcomes. Results Of the 1,578 children with SFS who underwent BC, 1,357 belonged to the 97-PCV group. The median age of the study population was 22 months (interquartile range, 16.0-30.0), and 935 children (59.3%) were boys. Of the 41 children (2.6%) with positive BC results, 3 had the yield (0.2%): Staphylococcus aureus in 2 children and Streptococcus pneumoniae in the other. All 3 children belonged to the 97-PCV group. There were 38 contaminated BCs (2.4%; 95% confidence interval, 1.6%-3.2%). The 97-PCV group showed a shorter median ED length of stay (166.0 minutes [108.0-279.5] vs. 143.0 [109.5-209.5]; P = 0.010) and a lower rate of hospitalization (39.4% vs. 12.8%; P < 0.001). No differences between the 2 groups were found in the baseline characteristics and biomarkers. Conclusion This study suggests a low utility of BC in previously healthy children with SFS in emergency settings in the post-10/13-valent PCV era

A case of peritoneal dialysis-associated peritonitis by Rothia mucilaginosa

Rothia muciliaginosa (R. mucilaginosa) is a facultative, Gram-positive coccus that is considered to be part of the normal flora of the mouth and respiratory tract. There are sporadic reports of the organism causing endocarditis in patients with heart valve abnormalities, as well as meningitis, septicemia, and pneumonia associated with intravenous drug abuse. However, it is an unusual pathogen in cases of peritoneal dialysis (PD)-associated peritonitis. Although R. mucilaginosa is generally susceptible to penicillin, ampicillin, cefotaxime, imipenem, rifampicin, and glycopeptides, there are no guidelines for the treatment of PD-associated peritonitis. Herein, we report a case of PD-associated peritonitis due to R. mucilaginosa that was resolved with intraperitoneal antibiotic treatment

The Boston-type Craniosynostosis Mutation MSX2 (P148H) Results in Enhanced Susceptibility of MSX2 to Ubiquitin-dependent Degradation

Boston-type craniosynostosis is caused by a single amino acid substitution, P148H, in the transcription factor MSX2. The increased binding affinity of MSX2 (P148H) to the response element has led many to hypothesize that the substitution is a gain-of-function mutation. However, there have been conflicting reports on the function of MSX2, and by extension, the nature of the P148H mutation remains unclear. In this study, we have examined the molecular mechanism of MSX2 function and the nature of the P148H mutation. During cranial suture closure of rodent, Msx2 expression was detected in the suture space. Overexpression of wild type MSX2 in mesenchymal cells stimulated cell proliferation and cyclin D1 expression, whereas P148H mutant did not. These results indicated that MSX2 is involved in maintaining the suture space by stimulating suture mesenchymal cell proliferation and that P148H is defective in this process. The protein levels of P148H were lower than wild type Msx2 (Msx2-WT), and pulse-chase experiments indicated that the mutant protein has a shorter half-life than the Msx2-WT protein. The ubiquitylation level of P148H was greater than that of Msx2-WT. The degradation of Msx2 was mediated by Praja1, and the P148H mutant was degraded more effectively than WT. The ubiquitylation of Msx2-WT was higher in the presence of Msx2 (P148H), which indicated that P148H functions as a dominant-negative mutant. Collectively, the primary function of MSX2 in suture closure is the induction of cell proliferation and suture maintenance, and the mutation results in an increased susceptibility of both wild type and mutant MSX2 to proteasomal degradation

Msx2 mediates the inhibitory action of TNF-α on osteoblast differentiation

TNF-α, a proinflammatory cytokine, inhibits osteoblast differentiation under diverse inflammatory conditions; however, the underlying mechanisms in terms of the TNF-α signaling pathway remain unclear. In this study, we examined the role of Msx2 in TNF-α-mediated inhibition of alkaline phosphatase (ALP) expression and the signaling pathways involved. TNF-α down-regulated ALP expression induced by bone morphogenetic protein 2 (BMP2) in C2C12 and Runx2-/- calvarial cells. Over-expression of Msx2 suppressed BMP2-induced ALP expression. Furthermore, TNF-α induced Msx2 expression, and the knockdown of Msx2 by small interfering RNAs rescued ALP expression, which was inhibited by TNF-α. TNF-α activated the NF-κB and the JNK pathways. Inhibition of NF-κB or JNK activation reduced the inhibitory effect of TNF-α on ALP expression, whereas TNF-α-induced Msx2 expression was only suppressed by the inhibition of the NF-κB pathway. Taken together, these results indicate that Msx2 mediates the inhibitory action of TNF-α on BMP2-regulated osteoblast differentiation and that the TNF-α-activated NF-κB pathway is responsible for Msx2 induction

BMP2-activated Erk/MAP Kinase Stabilizes Runx2 by Increasing p300 Levels and Histone Acetyltransferase Activity*

Runx2 is a critical transcription factor for osteoblast differentiation. Regulation of Runx2 expression levels and transcriptional activity is important for bone morphogenetic protein (BMP)-induced osteoblast differentiation. Previous studies have shown that extracellular signal-regulated kinase (Erk) activation enhances the transcriptional activity of Runx2 and that BMP-induced Runx2 acetylation increases Runx2 stability and transcriptional activity. Because BMP signaling induces Erk activation in osteoblasts, we sought to investigate whether BMP-induced Erk signaling regulates Runx2 acetylation and stability. Erk activation by overexpression of constitutively active MEK1 increased Runx2 transcriptional activity, whereas U0126, an inhibitor of MEK1/2, suppressed basal Runx2 transcriptional activity and BMP-induced Runx2 acetylation and stabilization. Overexpression of constitutively active MEK1 stabilized Runx2 protein via up-regulation of acetylation and down-regulation of ubiquitination. Erk activation increased p300 protein levels and histone acetyltransferase activity. Knockdown of p300 using siRNA diminished Erk-induced Runx2 stabilization. Overexpression of Smad5 increased Runx2 acetylation and stabilization. Erk activation further increased Smad-induced Runx2 acetylation and stabilization, whereas U0126 suppressed these functions. On the other hand, knockdown of Smad1 and Smad5 by siRNA suppressed both basal and Erk-induced Runx2 protein levels. Erk activation enhanced the association of Runx2 with p300 and Smad1. Taken together these results indicate that Erk signaling increases Runx2 stability and transcriptional activity, partly via increasing p300 protein levels and histone acetyltransferase activity and subsequently increasing Runx2 acetylation by p300. In addition to the canonical Smad pathway, a BMP-induced non-Smad Erk signaling pathway cooperatively regulates osteoblast differentiation partly via increasing the stability and transcriptional activity of Runx2

Analysis of Outcomes in Ischemic vs Nonischemic Cardiomyopathy in Patients With Atrial Fibrillation A Report From the GARFIELD-AF Registry

IMPORTANCE Congestive heart failure (CHF) is commonly associated with nonvalvular atrial fibrillation (AF), and their combination may affect treatment strategies and outcomes