Regional and annual patterns in respiratory virus co-infection etiologies and antibiotic prescriptions for pediatric mycoplasma pneumoniae pneumonia.

OBJECTIVE: Mycoplasma pneumoniae (M. pneumoniae) pneumonia is the second-most common cause of community-acquired pneumonia (CAP). This study aimed at investigating into the prevalence of macrolide-resistant M. pneumoniae (MRMP) with respiratory virus co-infection and the antibiotic prescriptions in children with CAP in four provinces in Korea, and to assess the variations in the findings across regions and throughout the year. PATIENTS AND METHODS: This prospective study was conducted in 29 hospitals in Korea between July 2018 and June 2020. Among the enrolled 1,063 children with CAP, all 451 patients with M. pneumoniae underwent PCR assays of M. pneumoniae and respiratory viruses, and the presence of point mutations of residues 2063 and 2064 was evaluated. RESULTS: Gwangju-Honam (88.6%) showed the highest prevalence of MRMP pneumonia, while Daejeon-Chungcheong (71.3%) showed the lowest, although the differences in prevalence were not significant (p=0.074). Co-infection of M. pneumoniae pneumonia and respiratory virus was observed in 206 patients (45.4%), and rhinovirus co-infection (101 children; 22.2%) was the most frequent. The prevalence of MRMP pneumonia with respiratory virus co-infection and the antibiotic prescriptions differed significantly among the four provinces (p < 0.05). The monthly rate of MRMP pneumonia cases among all cases of M. pneumoniae pneumonia and tetracycline or quinolone prescriptions did not differ significantly among the four regions (trend p > 0.05) during the study period. CONCLUSIONS: The prevalence of M. pneumoniae pneumonia with virus co-infection and antibiotic prescriptions could differ according to region, although the MRMP pneumonia rate showed no difference within Korea.

Fasting plasma glucose variability in midlife and risk of Parkinson's disease: A nationwide population-based study.

AIM: Despite the recognized association between type 2 diabetes (T2D) and Parkinson's disease (PD), the implications of glycaemic variability for patients with PD are as yet unknown. For this reason, our study assessed the future risk of incident PD according to visit-to-visit fasting plasma glucose (FPG) variability, as calculated by standard deviation (FPG-SD), coefficient variance (FPG-CV) and variability independent of the mean (FPG-VIM). METHODS: Using the Korean National Health Insurance Service Health Screening Cohort, 131,625 Korean adults without diabetes were followed. They were divided into a midlife group (age<65 years) and an elderly group (age≥65 years) throughout a median follow-up of 8.4 years. RESULTS: Adjusted hazard ratios (HRs) were calculated using multivariable Cox proportional-hazards analysis. In the midlife group, HRs for incident PD in the highest quartile of FPG variability (as measured by SD, CV and VIM) were 1.37 [95% confidence interval (CI): 1.09-1.73], 1.33 (95% CI: 1.06-1.68) and 1.35 (95% CI: 1.07-1.70), respectively, vs the lowest variability quartile group. However, while incident PD did not differ according to FPG variability in the elderly group, Kaplan-Meier curves of PD probability in the midlife group showed a progressively increasing risk of PD the higher the FPG variability. According to a multivariable adjusted model, every 1-SD unit increment in glycaemic variability was associated with a 9% higher risk of incident PD in the midlife group. CONCLUSION: Increased long-term glycaemic variability may be a precipitating risk factor for developing PD in the midlife population without diabetes.

Association of Antibody-Secreting Cells With Allograft Rejection After Renal Transplantation.

BACKGROUND: Donor-specific antibodies (DSA) are measured at the time of transplantation to predict renal allograft outcome, but pretransplantation DSA are sometimes not adequate to predict antibody-mediated rejection (AMR). We previously developed a flow cytometric assay that could measure the number of antibody-secreting cells (ASCs) instead of DSA. Here, we evaluated the performance of the flow cytometric ASC assay in predicting renal allograft rejection and compared it with that of the enzyme-linked immunospot (ELISpot) assay. METHODS: We enrolled 25 patients who received renal transplantation between May 2017 and August 2017 at Seoul National University Hospital. Mononuclear cells separated from patient peripheral blood obtained on pretransplantation day 1 were incubated with CpG 2006, human CD40L, interleukin-21, and donor or autologous lymphocyte lysates for 6 days. Flow cytometry and ELISpot assay (Mabtech) were performed to measure the ASCs and their association with graft rejection. RESULTS: The number of donor-reactive ASCs, as measured by flow cytometry, was higher in the rejection group than in the nonrejection group (mean ± standard deviation [SD], 3688.9 ± 3875.3 vs 257.9 ± 297.3, P = .014), and no significant difference was observed in the ELISpot assay. Multiple linear regression analysis showed that the number of donor-reactive ASCs measured by flow cytometry was independently and negatively associated with the number of rejection-free days (P = .008, partial R2 = 0.368, adjusted R2 = 0.496). CONCLUSION: After renal transplantation, an increased number of donor-reactive ASCs, as measured by flow cytometry, was associated with allograft rejection. This may be useful to predict renal allograft rejection by measuring the sensitization status of patients who are awaiting renal transplantation.

Moderate hearing loss is related with social frailty in a community-dwelling older adults: The Korean Frailty and Aging Cohort Study (KFACS).

OBJECTIVES: To determine whether hearing loss is associated with social frailty in older adults. METHODS: Cross-sectional analysis of cohort study data. Hearing was measured using of Pure-tone audiometry. Hearing loss was determined based on the average of hearing thresholds at 0.5, 1, and 2 kHz in the ear that had better hearing. Social frailty was defined based on the summation of the following 5 social components (1. Neighborhood meeting attendance 2. Talking to friend(s) sometimes 3.Someone gives you love and affection 4. Living alone 5. Meeting someone every day). Participants who had no correspondence to the components were considered non-social frailty; those with 1-2 components were considered social prefrailty; and those having 3 or more components were considered social frailty. RESULTS: The prevalence of non-social frailty, social prefrailty, social frailty was 27.6%, 60.7% and 11.7% respectively. Of the five questions, two components (Neighborhood meeting attendance and Presence of someone who shows love and affection to the participants) were associated with hearing loss (p < 0.001). Compared to non-social frailty, the odds ratio of social frailty for hearing loss was 2.24 (95% CI 1.48-3.38) after adjusting for age, residential area, economic status, smoking, depressive disorder and MMSE, and 2.17 (95% CI 1.43-3.30) after further adjustments with physical frailty. CONCLUSION: Hearing loss was associated with social frailty even after controlling confounding factors even including physical frailty.

Comparison of Flow-cytometric Antibody Secreting Cell Assay and Mabtech Immunoglobulin ELISpot Assay.

BACKGROUND: The increase of donor-specific antibodies (DSA) after transplantation could be a more important marker than the level of DSA in pre-transplantation sera. The assessment of sensitized cells that can secrete DSA is needed. We developed an assay for antibody-secreting cells (ASCs) measured with the use of flow cytometry and compared it with the Mabtech immunoglobulin (IgG) ELISpot assay. METHODS: Thirteen patients who were awaiting or received organ transplantation and 15 healthy control subjects were included. All subjects were positive for anti-cytomegalovirus (CMV) IgG. Peripheral blood mononuclear cells (PBMCs) were seeded with CpG 2006 (5'-TCGTCGTTTTGTCGTTTTGTCGTT-3'), 500 ng/mL human CD40 ligand, and 50 ng/mL interleukin-21 in complete RPMI media. Eight micrograms of CMV pp28 antigen were added to test wells and compared with nonstimulated PBMCs. After 72 hours, analysis with the use of the human IgG ELISpot kit (Mabtech) and flow cytometry with anti-CD19-PE, CD27-PE-Cy7, CD38-APC, IgG-FITC antibodies was performed. RESULTS: The flow-cytometric ASC assay was moderately correlated with Mabtech IgG ELISpot assay (r = 0.554; P < .001). The ASCs measured by means of flow cytometry were significantly higher in healthy control subjects compared with patients (P < .001). ASCs measured by means of flow cytometry in CMV antigen-stimulated PBMCs were significantly higher compared with nonstimulated PBMCs (P < .001). The IgG-secreting cells measured by means of Mabtech ELISpot assay was not different between healthy control subjects and patients nor between CMV antigen-stimulated and nonstimulated PBMCs. CONCLUSIONS: Flow-cytometric ASC assay can differentiate ASCs for CMV antigen better than Mabtech IgG ELISpot assay. Flow-cytometric ASC assay might be useful for assessing sensitization status in patients awaiting organ transplantation.

Evaluation of Changes in New Calculated Panel Reactive Antibody Adopting HLA-Cw, DR51/52/53, and DQ Antigens in Koreans.

BACKGROUND: Calculated panel reactive antibody (cPRA) (%) is percentage of donors that would be incompatible with the candidate, based on the candidate's unacceptable HLA antigens. cPRA based on antigen frequencies of HLA-A, B, and DR has been used in Korea. We developed new cPRA including HLA-Cw, DR51/52/53, and DQ. Changes in new-cPRA were evaluated. METHODS: We analyzed the differences between cPRA based on HLA-A, -B, and -DR antigens (old-cPRA) from cPRA based on HLA-A, -B, -Cw, -DR, -DR51/52/53, and -DQ antigens (new-cPRA) on 125 waitlisted candidates for renal transplantation in Seoul National University Hospital. cPRA for unacceptable antigens was calculated according to 3 different cut-off values (MFI <1000, 3000, and 10000 for cPRAw, cPRAm, and cPRAs, respectively). RESULTS: For HLA class I, cPRAw and cPRAm were significantly increased in new-cPRA compared to old-cPRA (median 78.3% vs 71.7%, P < .001; 34.0% vs 23.5%, P = .029, respectively). For HLA class II, cPRAw, cPRAm, and cPRAs were significantly increased in new-cPRA compared to old-cPRA (median 86.8% vs 42.6%; 58.0% vs 0.0%; 0.0% vs 0.0%, P < .001 for all). CONCLUSIONS: cPRA (%) including HLA-Cw, -DR51/52/53, and -DQ showed remarkable increase, especially in HLA class II antigens. The meaning of this should be carefully interpreted through further studies considering clinical outcomes.

Fyn is a redox sensor involved in solar ultraviolet light-induced signal transduction in skin carcinogenesis.

Solar ultraviolet (UV) light is a major etiological factor in skin carcinogenesis, with solar UV-stimulated signal transduction inducing pathological changes and skin damage. The primary sensor of solar UV-induced cellular signaling has not been identified. We use an experimental system of solar simulated light (SSL) to mimic solar UV and we demonstrate that Fyn is a primary redox sensor involved in SSL-induced signal transduction. Reactive oxygen species (ROS) generated by SSL exposure directly oxidize Cys488 of Fyn, resulting in increased Fyn kinase activity. Fyn oxidation was increased in mouse skin after SSL exposure and Fyn-knockout mice formed larger and more tumors compared with Fyn wild-type mice when exposed to SSL for an extended period of time. Murine embryonic fibroblasts (MEFs) lacking Fyn and cells in which Fyn expression was knocked down were resistant to SSL-induced apoptosis. Furthermore, cells expressing mutant Fyn (C448A) were resistant to SSL-induced apoptosis. These findings suggest that Fyn acts as a regulatory nexus between solar UV, ROS and signal transduction during skin carcinogenesis.

Estimation of size of cord blood inventory based on high-resolution typing of HLAs.

Methods for estimating the cord blood (CB) inventory size required vary according to the ethnic diversity of the HLA, degree of HLA matching and HLA-typing resolution. We estimated the CB inventory size required using 7190 stored CB units (CBU) and 2450 patients who were awaiting or underwent allogeneic hematopoietic stem cell transplantation. With high-resolution typing of HLA-A, B and DRB1, 94.6% of Korean patients could find CBUs in 100 000 CBUs with a 5/6 match, and 95.7% could find CBUs in 5000 CBUs with a 4/6 match. With low-resolution typing of HLA-A and B and high-resolution typing of leukocyte antigen-DRB1, 95% of patients could find CBUs in 50 000 CBUs with a 5/6 match, and 96.7% could find CBUs in 3000 CBUs  with a 4/6 match. With additional high-resolution typing for HLA-A and B, which could improve transplantation outcome, the size of the CB inventory would need to increase twofold for Koreans.

The effectiveness of a brochure describing an acceptable method of sputum collection for tuberculosis testing.

We evaluated the effectiveness of an educational brochure explaining proper sputum collection techniques for tuberculosis (TB) diagnosis. Patients with suspected pulmonary TB (PTB) were randomly assigned to either the brochure-using group or the non-using group. No significant difference in positive TB culture rates was observed between the brochure-using and non-using groups (33.1% vs. 35.6%, P = 0.690). The proportions of acceptable specimen samples for bacterial pneumonia were also similar between the two groups (37.1% vs. 35.6%). An educational brochure provided by the attending physician explaining an acceptable specimen collection method for TB testing did not result in a higher detection rate of PTB.

Phase I study of sunitinib plus capecitabine/cisplatin or capecitabine/oxaliplatin in advanced gastric cancer.

BACKGROUND: We evaluated the maximum tolerated dose (MTD) and safety of sunitinib plus capecitabine/cisplatin (XP) or capecitabine/oxaliplatin (XELOX) in Korean patients with advanced gastric cancer (GC). METHODS: Sunitinib (37.5 or 25 mg/day) was administered on a 2-week-on/1-week-off schedule with chemotherapy. Assessments included dose-limiting toxicity (DLT), safety, pharmacokinetics, and antitumor activity. RESULTS: Twenty-eight patients received sunitinib/XP; 48 received sunitinib/XELOX. The MTDs were: sunitinib 25 mg/day, cisplatin 80 mg/m(2), and capecitabine 1,000 mg/m(2); sunitinib 37.5 mg/day, oxaliplatin 110 mg/m(2), and capecitabine 800 mg/m(2); and sunitinib 25 mg/day, oxaliplatin 110 mg/m(2), and capecitabine 1,000 mg/m(2). DLTs at the MTDs comprised grade (G) 4 febrile neutropenia plus G3 diarrhea (n = 1; sunitinib/XP), dose delays due to hematologic toxicity (n = 2; both sunitinib/XP), G3 bleeding (menorrhagia; n = 1; sunitinib/XELOX), and G3 increased alanine aminotransferase levels (n = 1; sunitinib/XELOX). There was a high frequency of G3/4 hematologic adverse events observed with both treatment regimens, particularly with sunitinib/XP. Frequent non-hematologic, G3/4 adverse events were nausea, stomatitis, and hypophosphatemia with sunitinib/XP and hypophosphatemia and pulmonary embolism with sunitinib/XELOX. No drug-drug interactions were apparent. At the MTDs, median progression-free survival was 6.4 months and 5.5-8.0 months for sunitinib/XP and sunitinib/XELOX, respectively; and the objective response rate was 46.7% and 43.5-45.5% for sunitinib/XP and sunitinib/XELOX, respectively. CONCLUSIONS: At the MTD, sunitinib/XELOX had an acceptable safety profile in patients with advanced GC.

HLA-A, -B, -DRB1 allele frequencies and haplotypic association from DNA typing data of 7096 Korean cord blood units.

Human leukocyte antigen (HLA) distribution in 7096 Korean cord blood (CB) units preserved at the public CB bank was analyzed by using the polymerase chain reaction with sequence-specific oligonucleotide probe (PCR-SSOP) method. A total of 14 HLA-A, 33 HLA-B, 13 HLA-DRB1 alleles and 2470 three-locus haplotypes were identified. The results are generally similar to those from the previous Korean studies, but the frequencies of less frequent haplotypes < 0.1% are more relevant and infrequent haplotypes with strong linkage disequilibrium were newly found because of the large sample size. Our results showed some similarities to those of other Asians but also some differences, suggesting a rationale for an Asian network for a hematopoietic stem-cell donor registry. Results from this large-scale analysis will be useful in Korean and Asian registry planning.

The benzoxathiolone LYR-71 down-regulates interferon-gamma-inducible pro-inflammatory genes by uncoupling tyrosine phosphorylation of STAT-1 in macrophages.

BACKGROUND AND PURPOSE: Benzoxathiolone derivatives have shown anti-inflammatory and immunomodulatory potential in acne and psoriatic disorders. However, little is known about the molecular basis for these pharmacological effects. In this study, we decided to investigate the anti-inflammatory actions of a benzoxathiolone derivative LYR-71, 6-methyl-2-propylimino-6,7-dihydro-5H-benzo[1,3]oxathiol-4-one, in interferon (IFN)-gamma-activated macrophages. EXPERIMENTAL APPROACH: RAW 264.7 macrophages or primary macrophages, derived from bone marrow of C3H/HeJ mice, were stimulated with IFN-gamma in the presence of LYR-71. Nitric oxide (NO) or chemokine production was measured by Griess reaction or enzyme-linked immunosorbent assay. RAW 264.7 cells were used to examine the molecular mechanisms of LYR-71 in modulating IFN-gamma-induced inflammatory responses. KEY RESULTS: LYR-71 down-regulated IFN-gamma-induced transcription of inducible NO synthase, IFN-gamma-inducible protein-10 and the monokine induced by IFN-gamma genes in macrophages. This effect was mediated by uncoupling tyrosine phosphorylation of the signal transducer and activator of transcription (STAT)-1 in response to IFN-gamma. LYR-71 directly inhibited the in vitro catalytic activity of Janus kinase (JAK)-2. Further, the inhibitory actions of LYR-71 on IFN-gamma-induced STAT-1 phosphorylation and NO production were consistently abolished in the presence of peroxyvanadate, implying another target dependent on protein tyrosine phosphatase. CONCLUSIONS AND IMPLICATIONS: Taken together, LYR-71 could restrain IFN-gamma-induced inflammatory responses through uncoupling the tyrosine phosphorylation of STAT-1, an activation index of JAK-STAT-1 signalling, in macrophages. These results may provide a molecular mechanism underlying anti-inflammatory actions shown by benzoxathiolone derivatives.

A new HLA-B*51 variant, B*5158, identified by sequence-based typing in a Korean individual.

A novel human leukocyte antigen (HLA)-B*51 allele, officially named HLA-B*5158, was identified in the cord blood from Korean. HLA-B*5158 allele shows single nucleotide difference from B*510101 in exon 2 at nucleotide position 214 (C/T), resulting in an amino acid substitution, Trp48Arg.

Cerebellar alterations induced by chronic hypoxia: an immunohistochemical study using a chick embryonic model.

A model of fetal aerogenic hypoxia was developed in which fertilized chicken eggs were half-painted with melted wax and incubated under normal conditions. The cerebellum of the hypoxic chick embryos at a later stage of development (E18-20) was analyzed immunochemically. Hypoxic insult resulted in considerable neurocytological deficits of the Purkinje cells and altered glial fibrillary acid protein (GFAP) immunoreactivity in the fetal cerebellum. Purkinje cells in the hypoxic embryos were marked by small cell size, poorly developed dendrites, low cell density, deletion and ectopia. On the other hand, enhanced GFAP immunoreactivity was found in astrocytes and Bergmann glia of the hypoxic embryos. Our results indicate that chronic hypoxia in the chick fetus can cause severe disorders of neuronal development as well as glial activation. We suggest that our hypoxic model of chick embryos could be an accessible animal model for further elucidating fetal hypoxia.

Radiolabeling of paclitaxel with electrophilic 123I.

123I-Labeled paclitaxel, [123I]-1 was prepared by electrophilic aromatic radioiodination of 3'-N-(p-trimethylstannylbenzoyl)-3'-debenzoylpaclitaxel 2 with 123I- in the presence of peracetic acid.

Synthesis and in vitro cytotoxicity of hexacyclic camptothecin analogues.

A series of C(7)-N-alkylaminoethyl-C(10), C(11)-methylenedioxy- and ethylenedioxy-camptothecin (3a-g, 4a-b) were prepared. Their syntheses and in vitro cytotoxicity were reported. Among 15 derivatives, 3a and 3b showed more potent cytotoxicity than Camptothecin, especially in CAOV-3 cell line.

Synthesis and biology of 3'-N-acyl-N-debenzoylpaclitaxel analogues.

The, 3'-N-acyl-N-debenzoylpaclitaxel analogues 1a-d were synthesized and evaluated on biological systems. Some of the analogues 1a-d exhibited higher cytotoxicities (up to 20-fold) and stronger abilities to induce apoptosis than paclitaxel. In an in vivo experiment against i.p. implanted B16 melanoma, the most cytotoxic compound 1b in vitro caused tumor growth inhibition more than paclitaxel.

Distribution of transferrin binding protein immunoreactivity in the chicken central and peripheral nervous systems.

Transferrin binding protein (TfBP) is a glycoprotein originally purified from chicken oviduct that exhibits transferrin binding activity. Recent work has shown that TfBP is a post-translationally modified form of the heat shock protein (HSP108), the avian homologue of a glucose regulated protein, GRP94. The function of this protein, however, has not yet been clearly defined. Antiserum to TfBP was found to selectively stain oligodendrocytes of the avian brain. In this study, we further describe these oligodendrocytes and other cell types positive to anti-TfBP in the chick nervous system. In accordance with previous studies, the most prominent cell type that labels with antiserum to TfBP is the oligodendrocyte. At the electron microscopic level, the immunoreactive product is confined to the perinuclear cytoplasm and fine processes of the oligodendrocytes, whereas myelin and axoplasm are devoid of staining. The immunoreactive product is found both in the cytoplasmic matrix and bound to the endoplasmic reticulum and plasma membrane, suggesting that TfBP may have properties of both a soluble and an integral membrane protein. There is great variability in the number of TfBP-oligodendrocytes in different areas of the central nervous system (CNS); large numbers of cells are associated with the white matter regions and are found in the myelinated tracts, whereas few cells are present in the gray matter regions. In the retina, TfBP is localized specifically in the cells, that are morphologically oligodendrocytic and is present in the optic nerve fiber layer and the ganglion cell layer. Obvious staining is also seen in the Bergmann glial cells of the cerebellum and in the Schwann cells of the sciatic nerve. Furthermore, the choroid plexus cells similarly exhibit a strong reaction. The association of TfBP in these specific cell types responsible for myelination and sequestering iron and transferrin implies that TfBP may be involved in myelination and iron metabolism of the chick nervous system, perhaps through a role in transferrin concentration in these cells. A putative role of TfBP, as HSP108, is considered.