Correlation of serum interleukin-31 with pruritus and blood eosinophil markers in children with atopic dermatitis.

Background: Atopic dermatitis (AD) is chronic pruritic inflammatory skin disease in children. Interleukin (IL) 31 is a recently discovered cytokine associated with chronic skin inflammation and pruritus. Objectives: The aims of this study were to determine whether serum IL-31 levels are increased in children with AD and to examine the relationship between IL-31 and other clinical biomarkers in AD. Methods: Serum cytokine levels, including IL-31, IL-4, and IL-12, were measured in 38 patients with AD and 10 healthy children. Peripheral blood eosinophils, serum immunoglobulin E levels, eosinophil cationic protein, and thymic stromal lymphopoietin (TSLP) were measured. We also estimated the clinical severity of AD by using the Scoring Atopic Dermatitis (SCORAD) index by a single clinician. Results: The serum IL-31 levels were significantly higher in the patients with AD than in the healthy children. IL-31 correlated well with the SCORAD index and blood eosinophilic inflammatory markers. The serum level of TSLP was also higher in patients with AD than in the healthy children; however, levels of IL-4 and IL-12 were not different between AD and healthy children. There was no significant difference in serum IL-31 levels between patients with atopic AD and nonatopic AD. Conclusion: This study showed that serum IL-31 levels were significantly elevated in patients with AD than in the healthy children and correlated well with disease severity. IL-31 seemed to be one of the cytokines that induce pruritus and eosinophilic inflammation in AD. Serum IL-31 correlated with pruritic symptoms and disease course of AD.

Effect of platelet-rich plasma on the degenerative rotator cuff tendinopathy according to the compositions.

BACKGROUND: There are controversies about platelet-rich plasma (PRP) as an established treatment option for rotator cuff (RC) tendinopathy. The purpose of the study was to find the relation of cellular component with clinical efficacy in RC tendinopathy and to find the composition of PRP in treating RC tendinopathy. METHODS: A total 30 patients were recruited and divided into PRP and control groups. In the PRP group, 2 ml of PRP solution was injected to the hypoechoic lesion of degenerative supraspinatus via 22-gauge syringe with peppering technique. Patients in the control group were taught rotator cuff strengthening exercises. American Shoulder and Elbow Surgeons (ASES), Constant-Murley score, and numeric rating scale (NRS) were measured before, 6 weeks after, 12 weeks after, and 24 weeks after the procedure. PRP compositions were analyzed using the 1 ml of PRP solution. RESULTS: Linear regression analysis showed no significant difference of ASES and Constant-Murley scores between the groups at 6 weeks (P = 0.582 and 0.258) and at 12 weeks (P = 0.969 and 0.795) but showed a significant difference at 24 weeks (P = 0.050 and 0.048). Independent t test showed significant group difference of NRS at 6 weeks (P = 0.031) but not at 12 and 24 weeks (P = 0.147 and 0.935). 5.19 pg/ml in IL-1ß and 61.79 µg/ml in TGF-ß1 were acquired as cutoff values to predict meaningful improvement. The PRP subgroup above IL-1ß or TGF-ß1 cutoff value showed significant differences in all clinical outcomes compared with the exercise group while the PRP subgroup below the cutoff value showed no significant differences in linear regression analysis. CONCLUSIONS: Our study can help to find the optimal PRP condition and to enhance the effect of PRP on RC tendinopathy. TRIAL REGISTRATION: All the patients were registered in our Institutional Ethics Committee (approval number 2014-05-009).

Parents' Perspectives and Clinical Effectiveness of Cranial-Molding Orthoses in Infants With Plagiocephaly.

OBJECTIVE: To investigate the clinical effectiveness of and parents' perspectives on cranial-molding orthotic treatment. METHODS: Medical charts were reviewed for 82 infants treated for plagiocephaly with cranial-molding orthoses in our clinic from April 2012 to July 2016 retrospectively. Infants who were clinically diagnosed with positional plagiocephaly and had a Cranial Vault Asymmetry Index (CVAI) of more than 3.5% were included. Pre- and post-treatment CVAI was obtained by three-dimensional head-surface laser scan. Parents' perceptions of good outcome (satisfaction) were evaluated with the Goal Attainment Scale (GAS). The GAS score assessed how much the parent felt that his or her initial goal for correcting the skull asymmetry was achieved after the treatment. RESULTS: The compliance with cranial-molding orthoses was 90.2% (74 of 82 infants). There were 53 infants (65% of the 82 infants) who had adverse events with the cranial-molding orthoses during the study. Heat rash was found in 29 cases (35.4%) and was the most common adverse event. The mean GAS T-score was 51.9±10.2. A GAS T-score of 0 or more was identified for 71.6% of parents. The GAS T-score was significantly related to the age (p<0.001), the initial CVAI, and the difference of CVAI during the treatment (p<0.001). CONCLUSION: Parents' perception of good outcome was correlated with the anthropometric improvement in cranialmolding orthotic treatment in infants with plagiocephaly. A high percentage of parents felt that the treatment met their initial goals in spite of a high occurrence of adverse events.

Novel treatments for inflammatory bowel disease.

Increased understanding of the immunopathology of inflammatory bowel disease (IBD) has led to the development of targeted therapies and has unlocked a new era in IBD treatment. The development of treatment options aimed at a variety of pathological mechanisms offers new hope for customized therapies. Beyond anti-tumor necrosis factor agents, selective lymphocyte trafficking inhibitors have been proposed as potent drugs for IBD. Among these, vedolizumab has recently been approved for both Crohn's disease and ulcerative colitis. Numerous other agents for IBD treatment are currently under investigation, including Janus kinase inhibitors, anti-mucosal vascular addressin cell adhesion molecule-1 agents, an anti-SMAD7 antisense oligonucleotide, an anti-interleukin-12/23 monoclonal antibody, and a sphingosine-1-phosphate receptor-1 selective agonist. These agents will likely expand the treatment options available for the management of IBD patients in the future. In this review, we discuss the efficacy and safety of novel agents currently under investigation in IBD clinical trials.

Lidocaine Test Increases the Success Rates of Corticosteroid Injection in Impingement Syndrome.

OBJECTIVE: To determine whether lidocaine test injections would increase the success rate of corticosteroid injection for treatment of impingement syndrome. METHODS: Two hundred thirty-nine patients diagnosed with impingement syndrome were allocated to the lidocaine test (LC) group (N = 139) and the subacromial (SA) group (N = 100). The LC group received 1 ml of 1% lidocaine injection into the subacromial bursa under ultrasound guidance and a second injection of the steroid solution into the subacromial bursa or glenohumeral joint according to the response. The SA group received the same amount of steroid injection into the subacromial bursa without a prior lidocaine injection. Categorical outcomes were utilized and subjects were grouped based on percentage pain relief. Clinical improvement was expressed in terms of the patient's global impression of change (PGIC) as 'not improved,' 'slightly improved,' and 'much improved. RESULTS: In the LC group, 76 of the 139 patients (54% [95 CI 46-63%]) showed '50-80% improvement' and 15 (11% [95% CI 6.6-17%]) patients showed 'more than 80% improvement' at 3 weeks after the injection. While in the SA group, 29 of the 100 patient (29% [95% CI 21-39%]) showed '50-80% improvement' and 13 (13% [95% CI 7.7-21%]) showed 'more than 80% 3 weeks after the injection (χ2 = 15.073, P = 0.001). This difference persisted at 3 months (χ2 = 8.015, P = 0.018). The chi-square test of PGIC at 3 weeks also showed significant differences (P < 0.001). CONCLUSIONS: This was the first study to show that a lidocaine pre-injection increases the success rate of steroid injection in patients suspected of having impingement syndrome.

Effect of Pitavastatin Treatment on ApoB-48 and Lp-PLA2 in Patients with Metabolic Syndrome: Substudy of PROspective Comparative Clinical Study Evaluating the Efficacy and Safety of PITavastatin in Patients with Metabolic Syndrome.

BACKGROUND: Apolipoprotein (Apo) B-48 is an intestinally derived lipoprotein that is expected to be a marker for cardiovascular disease (CVD). Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a vascular-specific inflammatory marker and important risk predictor of CVD. The aim of this study was to explore the effect of pitavastatin treatment and life style modification (LSM) on ApoB-48 and Lp-PLA2 levels in metabolic syndrome (MS) patients at relatively low risk for CVD, as a sub-analysis of a previous multi-center prospective study. METHODS: We enrolled 75 patients with MS from the PROPIT study and randomized them into two treatment groups: 2 mg pitavastatin daily+intensive LSM or intensive LSM only. We measured the change of lipid profiles, ApoB-48 and Lp-PLA2 for 48 weeks. RESULTS: Total cholesterol, low density lipoprotein cholesterol, non-high density lipoprotein cholesterol, and ApoB-100/A1 ratio were significantly improved in the pitavastatin+LSM group compared to the LSM only group (P≤0.001). Pitavastatin+LSM did not change the level of ApoB-48 in subjects overall, but the level of ApoB-48 was significantly lower in the higher mean baseline value group of ApoB-48. The change in Lp-PLA2 was not significant after intervention in either group after treatment with pitavastatin for 1 year. CONCLUSION: Pitavastatin treatment and LSM significantly improved lipid profiles, ApoB-100/A1 ratio, and reduced ApoB-48 levels in the higher mean baseline value group of ApoB-48, but did not significantly alter the Lp-PLA2 levels.

The Relationship between 10-Year Cardiovascular Risk Calculated Using the Pooled Cohort Equation and the Severity of Non-Alcoholic Fatty Liver Disease.

BACKGROUND: We investigated the association between the severity of non-alcoholic fatty liver disease (NAFLD) and the estimated 10-year risk of cardiovascular disease (CVD) calculated by Pooled Cohort Equation (PCE) and Framingham risk score (FRS). METHODS: A total of 15,913 participants (mean age, 46.3 years) in a health screening program were selected for analysis. The presence and severity of fatty liver was assessed by abdominal ultrasonogram. Subjects who drank alcohol more than three times a week were excluded from the study. RESULTS: Among the participants, 57.6% had no NAFLD, 35.4% had grade I, 6.5% had grade II, and 0.5% had grade III NAFLD. Mean estimated 10-year CVD risk was 2.59%, 3.93%, 4.68%, and 5.23% calculated using the PCE (P for trend <0.01) and 4.55%, 6.39%, 7.33%, and 7.13% calculated using FRS, according to NAFLD severity from none to severe (P for trend <0.01). The odds ratio for ≥7.5% estimated CVD risk calculated using the PCE showed a higher correlation with increasing severity of NAFLD even after adjustment for conventional CVD risk factors (1.52, 2.56, 3.35 vs. the no NAFLD group as a reference, P<0.01) compared with calculated risk using FRS (1.65, 1.62, 1.72 vs. no NAFLD group as a reference, P<0.01). CONCLUSION: In our study of apparently healthy Korean adults, increasing severity of NAFLD showed a higher correlation with estimated 10-year CVD risk when calculated using the PCE than when calculated using FRS.

Efficacy and safety of ifosfamide in combination with carboplatin and etoposide in small cell lung cancer.

PURPOSE: Ifosfamide, a potent alkylating agent, is rarely incorporated into small cell lung cancer (SCLC) treatment. The aim of this study was to assess the efficacy and safety of ifosfamide in combination with carboplatin and etoposide (ICE) in previously untreated patients with SCLC. METHODS: From January 2002 to January 2014, we consecutively enrolled 69 patients with SCLC who were treated with ICE as initial chemotherapy at Kangbuk Samsung Hospital. The modified ICE regimen consists of ifosfamide 1200 mg/m(2)/day on days 1, 2, and 3 with mesna, etoposide 80 mg/m(2)/day on days 1, 2, and 3, and carboplatin AUC 6 on day 1. Treatment was repeated every 3 weeks and continued for up to nine cycles. Response assessments were performed every three cycles with computed tomography. RESULTS: Among 69 patients with SCLC, the median age was 69 years (range 51-88 years). Sixteen (23 %) patients had limited disease (LD), and 53 (77 %) had extensive disease (ED). The overall response rate was 73 %. Stable disease rate was 20 %. The median overall survival was 11.3 months [95 % confidence interval (CI) 8.9-14.1] in the overall population, 20.6 months (95 % CI 14.2-21.2) for LD and 9.1 months (95 % CI 7.8-11.6) for ED. The median number of administered cycles was 6 (range 1-9). Grade ≥3 hematological toxicities included neutropenia (34 %), anemia (59 %), and thrombocytopenia (31 %). Grade ≥3 non-hematological toxicities included peripheral neuropathy in 2 %. CONCLUSION: In chemonaïve patients with SCLC, modified ICE is well tolerated and shows favorable efficacy.

Metabolic Health Is More Important than Obesity in the Development of Nonalcoholic Fatty Liver Disease: A 4-Year Retrospective Study.

BACKGROUND: The aim of this study is to compare the risk for future development of nonalcoholic fatty liver disease (NAFLD) according to different status of metabolic health and obesity. METHODS: A total of 3,045 subjects without NAFLD and diabetes at baseline were followed for 4 years. Subjects were categorized into four groups according to the following baseline metabolic health and obesity statuses: metabolically healthy, non-obese (MHNO); metabolically healthy, obese (MHO); metabolically unhealthy, non-obese (MUHNO); and metabolically unhealthy, obese (MUHO). Being metabolically healthy was defined as having fewer than two of the following five components: high blood pressure, high fasting blood glucose, high triglyceride, low high density lipoprotein cholesterol, and being in the highest decile of the homeostasis model assessment-insulin resistance index. Obesity was defined as a body mass index >25 kg/m². The presence of NAFLD was assessed by ultrasonography. RESULTS: The proportions of subjects included in the MHNO, MHO, MUHNO, and MUHO groups were 71.4%, 9.8%, 13.0%, and 5.8%, respectively. The proportions of subjects who developed NAFLD were 10.5%, 31.4%, 23.2%, and 42% in the MHNO, MHO, MUHNO, and MUHO groups, respectively. The risk for developing NAFLD was highest in subjects who were metabolically unhealthy both at baseline and after 4 years compared with subjects who were consistently metabolically healthy during the follow-up period (odds ratio, 2.862). Using the MHNO group as reference, the odds ratios for the MHO, MUHNO, and MUHO groups were 1.731, 1.877, and 2.501, respectively. CONCLUSION: The risk for NAFLD was lower in MHO subjects than in MUNO subjects.

Integrated analysis of microRNA and mRNA expression profiles highlights aldehyde-induced inflammatory responses in cells relevant for lung toxicity.

We have shown that aldehydes impact the bronchial airway gene expression associated with inflammatory responses. In this study, we sought to determine whether microRNA (miRNA) plays a role in regulating the airway gene expression response to aldehyde exposure. We analyzed the whole genome miRNA and mRNA expression profiles of human alveolar epithelial cells exposed to 3 aldehydes (propanal, butanal, and pentanal) to identify aldehyde-sensitive miRNAs and to characterize the relationships between miRNAs and the expression of candidate cytokine-related genes, which are activated in response to inflammatory signals. Microarray analysis identified 15 miRNAs for propanal, 25 miRNAs for butanal, and 10 miRNAs for pentanal, which were differentially expressed in A549 human alveolar epithelial cells compared with vehicle control samples. Integrated analyses of miRNA and mRNA expression profiles identified significant miRNA-mRNA correlations. Gene ontology (GO) analysis of putative target genes (443 genes for propanal, 2166 genes for butanal, and 364 genes for pentanal) showed that the biological category "cytokine-cytokine receptor interaction" was prominently annotated. Moreover, we detected increased levels of interleukin (IL)-6 and IL-8 released in the 3 aldehyde exposure groups. Through an integrated analysis of the miRNA and mRNA expression profiles of aldehydes, we provide evidence that aldehyde can affect cytokine-induced toxicity signaling. Therefore, this study demonstrates the added value of an integrated miRNA-mRNA approach for identifying molecular events altered by environmental pollutants in an in vitro human model.

High prevalence of breast cancer in light polluted areas in urban and rural regions of South Korea: An ecologic study on the treatment prevalence of female cancers based on National Health Insurance data.

It has been reported that excessive artificial light at night (ALAN) could harm human health since it disturbs the natural bio-rhythm and sleep. Such conditions can lead to various diseases, including cancer. In this study, we have evaluated the association between ALAN and prevalence rates of cancer in females on a regional basis, after adjusting for other risk factors, including obesity, smoking, alcohol consumption rates and PM10 levels. The prevalence rates for breast cancer were found to be significantly associated with ALAN in urban and rural areas. Furthermore, no association was found with ALAN in female lung, liver, cervical, gastric and colon cancer. Despite the limitations of performing ecological studies, this report suggests that ALAN might be a risk factor for breast cancer, even in rural areas.

Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity.

In the current study, we aimed to investigate the transcriptomic responses and identify specific molecular signatures of low-molecular-weight saturated aliphatic aldehydes (LSAAs). To evaluate the change in gene expression levels, A549 human alveolar epithelial cells were exposed to six LSAAs (propanal, butanal, pentanal, hexanal, heptanal, and octanal) for 48 h. Clustering analysis of gene expression data show that the low carbon number group (LCG; propanal, butanal, and pentanal) was distinguished from the high carbon number group (HCG; hexanal, heptanal, and octanal). Also, transcriptomic profiling indicates that the LCG exposure group was more sensitive in gene alterations than the HCG group. Supervised analysis revealed 703 LCG specific genes and 55 HCG specific genes. After gene ontology (GO) analysis on LCG specific genes, we determined several key pathways which are known as being related to increase pulmonary toxicity such as cytokine-cytokine receptor interaction and chemokine signaling pathway. However, we did not find pulmonary toxicity-related pathways through GO analysis on HCG specific genes. Genes that are expressed in only the low carbon LSAA exposure group were regarded as biomarkers of aldehyde-induced pulmonary toxicity. In conclusion, this study describes changes in gene expression profiles in the in vitro respiratory system in response to exposure to 6 LSAAs with different carbon numbers and relates these gene alterations to pulmonary toxicity-related pathways. Moreover, novel carbon number-specific genes and pathways can be more widely implemented in combination with the traditional technique for assessment and prediction of exposure to environmental toxicants.

Analysis of microRNA and mRNA expression profiles highlights alterations in modulation of the MAPK pathway under octanal exposure.

Previous environmental microRNA (miRNA) studies have investigated a limited number of candidate miRNAs and have not evaluated functional effects on gene expression. In this study, we aimed to identify octanal (OC)-sensitive miRNAs and to characterize the relationships between miRNAs and expression of candidate genes involved in OC-induced toxicity. Microarray analysis identified 15 miRNAs that were differentially expressed in OC-exposed A549 human alveolar cells. Integrated analyses of miRNA and mRNA expression profiles identified significant miRNA-mRNA anti-correlations. GO analysis of 101 putative target genes showed that the biological category 'MAPK signaling pathway' was prominently annotated. Moreover, we detected increased phosphorylation of p38 MAPK in the OC-exposed group. By integrating the transcriptome and microRNAome, we provide evidence that OC can affect MAPK-induced toxicity signaling. Therefore, this study demonstrates the added value of an integrated miRNA-mRNA approach for identifying molecular events induced by environmental pollutants in an in vitro human model.

New algorithm for the identification of intact disulfide linkages based on fragmentation characteristics in tandem mass spectra.

Identifying the sites of disulfide bonds in a protein is essential for thorough understanding of a protein's tertiary and quaternary structures and its biological functions. Disulfide linked peptides are usually identified indirectly by labeling free sulfhydryl groups with alkylating agents, followed by chemical reduction and mass spectral comparison or by detecting the expected masses of disulfide linked peptides on mass scan level. However, these approaches for determination of disulfide bonds become ambiguous when the protein is highly bridged and modified. For accurate identification of disulfide linked peptides, we present here an algorithmic solution for the analysis of tandem mass (MS/MS) spectra of disulfide bonded peptides under nonreducing condition. A new algorithm called "DBond" analyzes disulfide linked peptides based on specific features of disulfide bonds. To determine disulfide linked sites, DBond takes into account fragmentation patterns of disulfide linked peptides in nucleoside diphosphate kinase (NDPK) as a model protein, considering fragment ions including cysteine, cysteine thioaldehyde (-2 Da, C(T)), cysteine persulfide (+32 Da, C(S)) and dehydroalanine (-34 Da, C(Delta)). Using this algorithm, we successfully identified about a dozen novel disulfide bonds in a hexa EF-hand calcium binding protein secretagogin and in a methionine sulfoxide reductase. We believe that DBond, taking into account the disulfide bond fragmentation characteristics and post-translational modifications, offers a novel approach for automatic identification of unknown disulfide bonds and their sites in proteins from MS/MS spectra.

Characterization of vesicles secreted from insulinoma NIT-1 cells.

Insulinoma NIT-1, an insulin-secreting mouse cell line, secretes vesicles in response to glucose or calcium. These vesicles, like exosomes, are relatively homogeneous (30-100 nm). We analyzed their protein profiles employing one-dimensional SDS gel electrophoresis combined with nanoLC-ESI-q-TOF tandem mass spectrometry, and searched for post-translational modifications (PTMs) using MOD(i) algorithm. We identified 270 proteins which matched at least two peptides reproducibly in duplicate runs. These proteins included metabolic proteins, endocytosis/exocytosis related proteins, chaperones, cytoskeletal proteins, membrane transporters/ion channels, signaling molecules, and nucleic acid binding proteins. Over 200 of these are newly identified proteins for the first time in secreted vesicles, and included RNA- and translation-related proteins, ubiquitin- and protein-degradation related proteins and post-translationally modified proteins. The rest of the proteins identified in this study were similar to those reported by others to be present in exosomes of various origins. The present study demonstrates that vesicles secreted from insulinoma NIT-1 cells have some properties, common to exosomes from lymphocytes and cancer cells, and some differing from those of other types of exosomes. We believe that the modified and newly identified proteins we identified in secreted vesicles from insulinoma NIT-1 cells have the potential to provide insights into mechanisms of biogenesis and function of secreted vesicles and may help explain the impairment of insulin secretion in islets from type-2 diabetes.