Current Status and Survival Impact of Infectious Disease Consultation for Multidrug-Resistant Bacteremia in Ventilated Patients: A Single-Center Experience in Korea

Background We evaluated the current status and survival impact of infectious disease consultation (IDC) in ventilated patients with multidrug-resistant (MDR) bacteremia. Methods One hundred sixty-one consecutive patients from a single tertiary care hospital were enrolled over a 5-year period. Patients with at least one of the following six MDR bacteremias were included: methicillin-resistant Staphylococcus aureus, extended-spectrum β-lactamase-producing gram-negative bacteria (Escherichia coli and Klebsiella pneumonia), carbapenem-resistant gram-negative rods (Acinetobacter baumannii and Pseudomonas aeruginosa), and vancomycin-resistant Enterococcus faecium. Results Median patient age was 66 years (range, 18 to 95), and 57.8% of subjects were male. The 28-day mortality after the day of blood culture was 52.2%. An IDC was requested for 96 patients based on a positive blood culture (59.6%). Patients without IDC had significantly higher rate of hemato-oncologic diseases as a comorbidity (36.9% vs. 11.5%, P < 0.001). Patients without an IDC had higher Acute Physiology and Chronic Health Evaluation (APACHE) II score (median, 20; range, 8 to 38 vs. median, 16; range, 5 to 34, P < 0.001) and Sequential Organ Failure Assessment (SOFA) score (median, 9; range, 2 to 17 vs. median, 7; range, 2 to 20; P = 0.020) on the day of blood culture and a higher 28-day mortality rate (72.3% vs. 38.5%, P < 0.001). In patients with SOFA ≥9 (cut-off level based on Youden’s index) on the day of blood culture and gram-negative bacteremia, IDC was also significantly associated with lower 28-day mortality (hazard ratio [HR], 0.298; 95% confidence interval [CI], 0.167 to 0.532 and HR, 0.180; 95% CI, 0.097 to 0.333; all P < 0.001) based on multivariate Cox regression analysis. Conclusions An IDC for MDR bacteremia was requested less often for ventilated patients with greater disease severity and higher 28-day mortality after blood was drawn. In patients with SOFA ≥9 on the day of blood culture and gram-negative bacteremia, IDC was associated with improved 28-day survival after blood draw for culture

CAGE Binds to Beclin1, Regulates Autophagic Flux and CAGE-Derived Peptide Confers Sensitivity to Anti-cancer Drugs in Non-small Cell Lung Cancer Cells

The objective of this study was to determine the role of CAGE, a cancer/testis antigen, in resistance of non-small cell lung cancers to anti-cancer drugs. Erlotinib-resistant PC-9 cells (PC-9/ER) with EGFR mutations (ex 19 del + T790M of EGFR), showed higher level of autophagic flux than parental sensitive PC-9 cells. Erlotinib and osimertinib increased autophagic flux and induced the binding of CAGE to Beclin1 in PC-9 cells. The inhibition or induction of autophagy regulated the binding of CAGE to Beclin1 and the responses to anti-cancer drugs. CAGE showed binding to HER2 while HER2 was necessary for binding of CAGE to Beclin1. CAGE was responsible for high level of autophagic flux and resistance to anti-cancer drugs in PC-9/ER cells. A peptide corresponding to the DEAD box domain of CAGE, 266AQTGTGKT273, enhanced the sensitivity of PC-9/ER cells to erlotinib and osimertinib, inhibited the binding of CAGE to Beclin1 and regulated autophagic flux in PC-9/ER cells. Mutant CAGE-derived peptide 266AQTGTGAT273 or 266AQTGTGKA273 did not affect autophagic flux or the binding of CAGE to Beclin1. AQTGTGKT peptide showed binding to CAGE, but not to Beclin1. FITC-AQTGTGKT peptide showed co-localization with CAGE. AQTGTGKT peptide decreased tumorigenic potentials of PC-9/ER and H1975 cells, non-small cell lung cancer (NSCLC) cells with EGFR mutation (L885R/T790M), by inhibiting autophagic fluxand inhibiting the binding of CAGE to Beclin1. AQTGTGKT peptide also enhanced the sensitivity of H1975 cells to anti-cancer drugs. AQTGTGKT peptide showed tumor homing potential based on ex vivo homing assays of xenograft of H1975 cells. AQTGTGKT peptide restored expression levels of miR-143-3p and miR-373-5p, decreased autophagic flux and conferred sensitivity to anti-cancer drugs. These results present evidence that combination of anti-cancer drug with CAGE-derived peptide could overcome resistance of non-small cell lung cancers to anti-cancer drugs

EGR3-HDAC6-IL-27 Axis Mediates Allergic Inflammation and Is Necessary for Tumorigenic Potential of Cancer Cells Enhanced by Allergic Inflammation-Promoted Cellular Interactions

The objective of this study was to investigate mechanisms of allergic inflammation both in vitro and in vivo in details. For this, RNA sequencing was performed. Early growth response 3 gene (Egr3) was one of the most highly upregulated genes in rat basophilic leukemia (RBL2H3) cells stimulated by antigen. The role of Egr3 in allergic inflammation has not been studied extensively. Egr3 was necessary for passive cutaneous anaphylaxis (PCA) and passive systemic anaphylaxis (PSA). Egr3 promoter sequences contained potential binding site for NF-κB p65. NF-κB p65 directly regulated Egr3 expression and mediated allergic inflammation in vitro. Histone deacetylases (HDACs) is known to be involved in allergic airway inflammation. HDAC6 promoter sequences contained potential binding site for EGR3. EGR3 showed binding to promoter sequences of HDAC6. EGR3 was necessary for increased expression of histone deacetylase 6 (HDAC6) in antigen-stimulated RBL2H3 cells. HDAC6 mediated allergic inflammation in vitro and PSA. TargetScan analysis predicted that miR-182-5p was a negative regulator of EGR3. Luciferase activity assay confirmed that miR-182-5p was a direct regulator of EGR3. MiR-182-5p mimic inhibited allergic inflammation both in vitro and in vivo. Cytokine array showed that HDAC6 was necessary for increased interleukin-27 (IL-27) expression in BALB/C mouse model of PSA. Antigen stimulation did not affect expression of EBI3, another subunit of IL-27 in RBL2H3 cells or BALB/C mouse model of PCA or PSA. IL-27 receptor alpha was shown to be able to bind to HDAC6. IL-27 p28 mediated allergic inflammation in vitro, PCA, and PSA. Mouse recombinant IL-27 protein promoted features of allergic inflammation in an antigen-independent manner. HDAC6 was necessary for tumorigenic and metastatic potential enhanced by PSA. PSA enhanced the metastatic potential of mouse melanoma B16F1 cells in an IL-27-dependent manner. Experiments employing culture medium and mouse recombinant IL-27 protein showed that IL-27 mediated and promoted cellular interactions involving B16F1 cells, lung macrophages, and mast cells during allergic inflammation. IL-27 was present in exosomes of antigen-stimulated RBL2H3 cells. Exosomes from antigen-stimulated RBL2H3 cells enhanced invasion of B16F1 melanoma cells in an IL-27-dependemt manner. These results present evidence that EGR3-HDAC6-IL-27 axis can regulate allergic inflammation by mediating cellular interactions

Korean speech sound development in children from bilingual Japanese-Korean environments

PurposeThis study investigates Korean speech sound development, including articulatory error patterns, among the Japanese-Korean children whose mothers are Japanese immigrants to Korea.MethodsThe subjects were 28 Japanese-Korean children with normal development born to Japanese women immigrants who lived in Jeonbuk province, Korea. They were assessed through Computerized Speech Lab 4500. The control group consisted of 15 Korean children who lived in the same area.ResultsThe values of the voice onset time of consonants /ph/, /t/, /th/, and /k*/ among the children were prolonged. The children replaced the lenis sounds with aspirated or fortis sounds rather than replacing the fortis sounds with lenis or aspirated sounds, which are typical among Japanese immigrants. The children showed numerous articulatory errors for /c/ and /l/ sounds (similar to Koreans) rather than errors on /p/ sounds, which are more frequent among Japanese immigrants. The vowel formants of the children showed a significantly prolonged vowel /o/ as compared to that of Korean children (P<0.05). The Japanese immigrants and their children showed a similar substitution /n/ for /ɧ/ [Japanese immigrants (62.5%) vs Japanese-Korean children (14.3%)], which is rarely seen among Koreans.ConclusionThe findings suggest that Korean speech sound development among Japanese-Korean children is influenced not only by the Korean language environment but also by their maternal language. Therefore, appropriate language education programs may be warranted not only or immigrant women but also for their children

Clinical features and outcome of corneal opacity associated with congenital glaucoma

Background To investigate the clinical features of corneal opacity and the surgical outcome of penetrating keratoplasty (PK) in eyes with congenital glaucoma. Methods A retrospective review was made of the records from 320 eyes of 193 patients who were diagnosed with congenital glaucoma between January 1981 and January 2016. Anterior segment photographs at disease presentation were examined for the presence and severity of corneal opacity. Data on patient demographics, intraocular pressure (IOP), ocular and systemic comorbidities, ocular surgery and its outcome were collected. Results Overall, corneal opacification was observed in 248 of 320 eyes (77.5%). Out of 248 eyes with corneal opacification, 53 eyes had Haab striae alone, and 195 eyes presented with either nebulomacular corneal opacity (128 eyes, iris details visible through opacity) or leukomatous corneal opacity (67 eyes, iris details invisible through opacity). In 12 eyes with severe leukomatous corneal opacity, PK was performed at the mean age of 18.6 months (range 4–57 months). The grafts failed in 6 eyes (50%) due to endothelial rejection (4 eyes) or graft infection (2 eyes) during the mean 80.6 months of follow-up (range 15–228 months). The median survival time was 36 months. The graft failure was significantly associated with smaller corneal diameter at the time of surgery, but not with the age, IOP, combined aniridia, simultaneous glaucoma or lens surgery. Conclusion Congenital glaucoma was combined with corneal opacity in 77.5%. The corneal transplant survival was 50% in eyes with congenital glaucoma and total corneal opacity

Human Adipose Tissue-Derived Mesenchymal Stem Cells Attenuate Atopic Dermatitis by Regulating the Expression of MIP-2, miR-122a-SOCS1 Axis, and Th1/Th2 Responses

The objective of this study was to investigate the effect of human adipose tissue-derived mesenchymal stem cells (AdMSCs) on atopic dermatitis (AD) in the BALB/c mouse model. The AdMSCs attenuated clinical symptoms associated with AD, decreased numbers of degranulated mast cells (MCs), IgE level, amount of histamine released, and prostaglandin E2 level. Atopic dermatitis increased the expression levels of cytokines/chemokines, such as interleukin-5 (IL-5), macrophage inflammatory protein-1ß (MIP-1ß), MIP-2, chemokine (C-C motif) ligand 5 (CCL5), and IL-17, in BALB/c mouse. The AdMSCs showed decreased expression levels of these cytokines in the mouse model of AD. In vivo downregulation of MIP-2 attenuated the clinical symptoms associated with AD. Atopic dermatitis increased the expression levels of hallmarks of allergic inflammation, induced interactions of FcRIβ with histone deacetylase 3 (HDAC3) and Lyn, increased ß-hexosaminidase activity, increased serum IgE level, and increased the amount of histamine released in an MIP-2-dependent manner. Downregulation of MIP-2 increased the levels of several miRNAs, including miR-122a-5p. Mouse miR-122a-5p mimic inhibited AD, while suppressor of cytokine signaling 1 (SOCS1), a predicted downstream target of miR-122a-5p, was required for AD. The downregulation of SOCS1 decreased the expression levels of MIP-2 and chemokine (C-X-C motif) ligand 13 (CXCL13) in the mouse model of AD. The downregulation of CXCL13 attenuated AD and allergic inflammation such as passive cutaneous anaphylaxis. The role of T cell transcription factors in AD was also investigated. Atopic dermatitis increased the expression levels of T-bet and GATA-3 [transcription factors of T-helper 1 (Th1) and T-helper 2 (Th2) cells, respectively] but decreased the expression of Foxp3, a transcription factor of regulatory T (Treg) cells, in an SOCS1-dependent manner. In addition to this, miR-122a-5p mimic also prevented AD from regulating the expression of T-bet, GATA-3, and Foxp3. Atopic dermatitis increased the expression of cluster of differentiation 163 (CD163), a marker of M2 macrophages, but decreased the expression of inducible nitric oxide synthase (iNOS), a marker of M1 macrophages. Additionally, SOCS1 and miR-122a-5p mimic regulated the expression of CD163 and iNOS in the mouse model of AD. Experiments employing conditioned medium showed interactions between MCs and macrophages in AD. The conditioned medium of AdMSCs, but not the conditioned medium of human dermal fibroblasts, negatively inhibited the features of allergic inflammation. In summary, we investigated the anti-atopic effects of AdMSCs, identified targets of AdMSCs, and determined the underlying mechanism for the anti-atopic effects of AdMSCs

MiR-135-5p-p62 Axis Regulates Autophagic Flux, Tumorigenic Potential, and Cellular Interactions Mediated by Extracellular Vesicles During Allergic Inflammation

The objective of this study was to investigate the relationship between autophagy and allergic inflammation. In vitro allergic inflammation was accompanied by an increased autophagic flux in rat basophilic leukemia (RBL2H3) cells. 3-MA, an inhibitor of autophagic processes, negatively regulated allergic inflammation both in vitro and in vivo. The role of p62, a selective receptor of autophagy, in allergic inflammation was investigated. P62, increased by antigen stimulation, mediated in vitro allergic inflammation, passive cutaneous anaphylaxis (PCA), and passive systemic anaphylaxis (PSA). P62 mediated cellular interactions during allergic inflammation. It also mediated tumorigenic and metastatic potential of cancer cells enhanced by PSA. TargetScan analysis predicted that miR-135-5p was a negative regulator of p62. Luciferase activity assay showed that miR-135-5p directly regulated p62. MiR-135-5p mimic negatively regulated features of allergic inflammation and inhibited tumorigenic and metastatic potential of cancer cells enhanced by PSA. MiR-135-5p mimic also inhibited cellular interactions during allergic inflammation. Extracellular vesicles mediated allergic inflammation both in vitro and in vivo. Extracellular vesicles were also necessary for cellular interactions during allergic inflammation. Transmission electron microscopy showed p62 within extracellular vesicles of antigen-stimulated rat basophilic leukemia cells (RBL2H3). Extracellular vesicles isolated from antigen-stimulated RBL2H3 cells induced activation of macrophages and enhanced invasion and migration potential of B16F1 mouse melanoma cells in a p62-dependent manner. Extracellular vesicles isolated from PSA-activated BALB/C mouse enhanced invasion and migration potential of B16F1 cells, and induced features of allergic inflammation in RBL2H3 cells. Thus, miR-135-5p-p62 axis might serve as a target for developing anti-allergy drugs

Clinical Characteristics and Etiology of Travelers' Diarrhea among Korean Travelers Visiting South-East Asia

The morbidity of travelers' diarrhea (TD) is still high. This study examined the incidence of common pathogens and characteristics of TD among Korean travelers who visited South-East Asian countries. We performed a prospective study involving 479 Korean travelers with diarrheal disease from February 2009 to April 2009 and stool samples were examined and questionnaire surveys were done after arrival. Enterotoxigenic Escherichia coli (ETEC) was found in 36.0% of TD cases, as were the following: Enteroaggregative Escherichia coli (EAEC) in 27.0%, Vibrio parahaemolyticus in 13.1%, and Norovirus in 11.5%. The detected rate of classic TD was higher in men (P = 0.007), in patients who had a shorter duration trip (P = 0.023) and in patients who drank more than 1 liter of water per day (P = 0.037). Positive stool culture rates were higher in men (P = 0.005), in hospitalized patients (P = 0.013). and in those who consumed impure water or raw foods (P = 0.033). A higher severity of disease corresponded to a significantly higher culture positivity rate (P = 0.029). We should consider the possibility of other pathogens in addition to ETEC in patients with TD who visit South-East Asia. Travelers need to educate about risk factors associated with TD

Complete Genome Sequence of Brucella abortus A13334, a New Strain Isolated from the Fetal Gastric Fluid of Dairy Cattle

Brucella abortus is a major pathogen that infects livestock and humans. A new strain of B. abortus (A13334) was isolated from the fetal gastric fluid of a dairy cow, with the aim of using it to compare genetic properties, analyze virulence factor, and survey the epidemiological relationship to other Brucella species. Here, we report the complete and annotated genome sequence of B. abortus A13334.open2

Complete Genome Sequence of Brucella canis Strain HSK A52141, Isolated from the Blood of an Infected Dog

Brucella canis infection can be clinically inapparent in dogs, and when infection goes unnoticed, there is a chance for dog-to-human transmission. A new strain of B. canis was isolated from the blood of an infected dog in order to analyze the pathogenic mechanism, compare genetic properties, and develop new genetic tools for early diagnosis of canine brucellosis. Herein, we report the complete genome sequence of the strain B. canis HSK A52141. This is the second complete genome sequence and biological annotation available for a member of B. canis.open2