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Colorectal cancer (CRC) develops from polyps in the inner large intestine or rectum and an increasing incidence and high mortality rate has been observed in humans. Currently, colonoscopy is the preferred modality for early CRC diagnosis. However, this technique has several limitations, such as high medical costs and intricate procedures, leading to increasing demands for the development of a new, simple, and affordable diagnostic method. In this study, an advanced electrochemical biosensor based on rationally designed affinity peptides was developed for discriminating adenoma to carcinoma progression. Amino acid-substituted and rationally designed synthetic peptides (BP3-1 to BP3-8) based on in silico modeling studies were chemically synthesized, and covalently immobilized onto a gold electrode using aromatic ring compounds through surface chemistry techniques. The binding performance of the developed sensor system was observed using square wave voltammetry (SWV). The peptide BP3-2 was selected depending on its relative binding affinity; SWV indicated the limit of detection of BP3-2 for LRG1 to be 0.025 μg/mL. This sensor could distinguish the adenoma-carcinoma transition with improved binding abilities (specificity and selectivity), and stability in plasma samples spiked with LRG1 and real samples from patients with CRC. These results indicate that this electrochemical sensor system can be used for early monitoring of the colorectal adenoma to carcinoma progression.

Immunoglobulin A nephropathy (IgAN) is one of the most common primary glomerulopathies diagnosed in children and adolescents. This study aimed to evaluate the clinical features in and outcomes of pediatric IgAN over the last 30 years. Patients who were diagnosed before age of 18 at 20 centers in Korea were evaluated retrospectively. Of the 1154 patients (768 males, 386 females) with a median follow-up of 5 years, 5.6% (n = 65) progressed to stage 3&ndash, 5 chronic kidney disease (CKD). The 10- and 20-year CKD-free survival rates were 91.2% and 75.6%, respectively. Outcomes did not differ when comparing those in Korea who were diagnosed prior to versus after the year 2000. On multivariate analysis, combined asymptomatic hematuria and proteinuria as presenting symptoms and decreased renal function at the time of biopsy were associated with progression to CKD, while remission of proteinuria was negatively associated with this outcome. Patients who presented with gross hematuria or nephrotic syndrome tended toward positive outcomes, especially if they ultimately achieved remission. While remission of proteinuria might imply that the disease is inherently less aggressive, it also can be achieved by management. Therefore, more aggressive management might be required for pediatric-onset IgAN.

Dengue virus type 2 NS1 (DENV2 NS1) is a specific and sensitive protein biomarker for dengue fever diagnosis. In this study we used polyvalent phage display to identify unique affinity peptides that can bind NS1 protein. Cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) were used to investigate the binding interactions. The potential affinity peptide-displayed phage from these methods was selected; its sequence was EHDRMHAYYLTR (R3#10). Amino acid sequence analysis showed that the peptide was rich in basic residues (two His and Arg). Among all the peptides tested, R3#10 showed the greatest decrease in current in CV and increase in impedance in EIS upon binding to NS1 proteins. EIS revealed that R3#10 phage clones were more specific towards NS1 proteins, as compared to bovine serum albumin or the M13 wild type used as control. Detection of NS1 proteins is in accordance with the electron-transfer resistance (Rct) value of the sensor layer, which is confirmed by EIS, and the Kd value of the R3#10 peptide while binding to the phage particles was measured. To the best of our knowledge, this is the first example of identification and characterization of NS1 binding affinity peptides using phage display technology and electrochemical methods. We concluded that these new peptide-displayed phages or free peptides from phages may have potential applications in dengue diagnosis.

Renal cell carcinoma is the most common primary renal neoplasm in adults. Although renal cell carcinoma is known to spread to unusual sites, the ampulla of Vater is considered a rare site for metastasis. Here we present a case of renal cell carcinoma metastasized to the ampulla of Vater along with literature review. A 62-year-old Korean male had a history of hypertension and right-sided renal cell carcinoma diagnosed in September 2004, for which he underwent right radical nephrectomy in October 2004. The patient eventually underwent laparoscopic pylorus-preserving total pancreaticoduodenectomy in January 2017. The surgery was successful without postoperative complications. Previous studies have shown that surgical resection for solitary metastases of renal cell carcinoma can provide favorable survival rates. Our case report provides evidence that pancreaticoduodenectomy may be a treatment of choice for suitable patients with solitary renal cell carcinoma ampullary metastasis. A minimally invasive approach may result in early recovery of patient to be suitable for subsequent chemotherapy. Further evidence is needed to address the exact role of minimally invasive pancreaticoduodenectomy in renal cell carcinoma metastasized to the ampulla of Vater.

Purpose To investigate the relationship between topical glaucoma medications and meibomian gland dysfunction (MGD) in early middle-aged patients with glaucoma. Methods In this cross-sectional study, 50 patients with glaucoma younger than 50 years who had used topical glaucoma medications for more than 6 months and 40 normal controls of similar age were included. Patients in each group were graded for MGD (0-4) using slit-lamp microscopy. Tear film breakup time (BUT), ocular surface staining, and Marx line scores were also evaluated. Differences between both groups were analyzed statistically. Results The prevalence of MGD was 82% in the group using topical glaucoma medications and 52.5% in the control group. The average period of topical glaucoma medication use was 27.4 months. There were significant differences in the breakup time and Marx line score according to the presence of MGD. Although the duration of topical glaucoma medication use and the severity of MGD did not show a significant correlation, the degree of MGD and the Marx line score were significantly correlated. Conclusions Glaucoma eye drops may be one factor affecting the eyelid changes associated with MGD. The Marx line score may be used as an index to evaluate MGD in patients with glaucoma.

An electrochemical peptide sensor employing a sensitive synthetic peptide was designed for the diagnosis of sepsis. A series of synthetic peptides were chemically synthesized, and the binding events and performance of the sensor were monitored by CV and EIS. PCT BP3, selected as a potential high-affinity peptide, was found to have a Kd value of 0.39 ± 0.11 nM for procalcitonin.

Transmembrane p24 trafficking protein 3 (TMED3) is a metastatic suppressor in colon cancer and hepatocellular carcinoma. However, its function in the progression of clear cell renal cell carcinoma (ccRCC) is unknown. Here, we report that TMED3 could be a new prognostic marker for ccRCC. Patient data were extracted from cohorts in the Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC). Differential expression of TMED3 was observed between the low stage (Stage I and II) and high stage (Stage III and IV) patients in the TCGA and ICGC cohorts and between the low grade (Grade I and II) and high grade (Grade III and IV) patients in the TCGA cohort. Further, we evaluated TMED3 expression as a prognostic gene using Kaplan-Meier survival analysis, multivariate analysis, the time-dependent area under the curve (AUC) of Uno’s C-index, and the AUC of the receiver operating characteristics at 5 years. The Kaplan-Meier analysis revealed that TMED3 overexpression was associated with poor prognosis for ccRCC patients. Analysis of the C-indices and area under the receiver operating characteristic curve further supported this. Multivariate analysis confirmed the prognostic significance of TMED3 expression levels (P = 0.005 and 0.006 for TCGA and ICGC, respectively). Taken together, these findings demonstrate that TMED3 is a potential prognostic factor for ccRCC.

Dengue virus (DENV) nonstructural 1 (NS1) protein is a specific and sensitive biomarker for the diagnosis of dengue. In this study, an efficient electrochemical biosensor that uses chemically modified affinity peptides was developed for the detection of dengue virus NS1. A series of amino acid-substituted synthetic peptides was rationally designed, chemically synthesized and covalently immobilized to a gold sensor surface. The sensor performance was monitored via square wave voltammetry (SWV) and electrochemical impedance spectroscopy (EIS). Potential affinity peptides specific for NS1 were chosen according to the dynamic current decrease in SWV experiments. Using circular dichroism, the molar ellipticity of peptides (DGV BP1–BP5) was determined, indicating that they had a mostly similar in random coil structure, not totally identical. Using SWV, DGV BP1 was selected as a promising recognition peptide and limit of detection for NS1 was found to be 1.49 μg/mL by the 3-sigma rule. DGV BP1 showed good specificity and stability for NS1, with low signal interference. The validation of the sensor to detect NS1 proteins was confirmed with four dengue virus culture broth (from serotype 1 to 4) as proof-of-concept. The detection performance of our sensor incorporating DGV BP1 peptides showed a statistically significant difference. These results indicate that this strategy can potentially be used to detect the dengue virus antigen, NS1, and to diagnosis dengue fever within a miniaturized portable device in point-of-care testing.

Inflammasomes are caspase-1-activating molecular platforms that produce active interleukin (IL)-1β and are implicated in various central nervous system (CNS) diseases. These multi-protein complexes can be activated by exposure of cells to low osmolality. The inflammasome nucleotide-binding and oligomerization domain-like receptor pyrin domain-containing protein 3 (NLRP3) is hereby the main sensor of cellular osmolality. IL-1β was found to stimulate the secretion of antidiuretic hormone (ADH) from the posterior pituitary gland either by action of prostaglandins or indirectly by causing the release of IL-6. Based on these findings, we hypothesize that the hyponatremia caused by a wide range of CNS diseases is able to induce significant cell swelling with induction of a hyposmotic intracellular environment, which activates the NLRP3 inflammasome, causing the release of IL-1β and induced by IL-1β, IL-6, which increases the production of ADH that leads to more profound hyponatremia. Supportive evidence for this hypothesis is the finding that IL-1 injection can induce ADH release and hyposmotic effect of ADH induced hyponatremia can, via the mechanical effect of cell swelling, activate transient receptor potential channels, which via transforming growth factor β-activated kinase 1 activate NLRP3. Implications of this hypothesis, if confirmed, would include that hyponatremia can be exacerbated through this vicious cycle but also that the inflammasomes are key mediators of this process. Confirmation of this hypothesis would have implications for prevention and clinical management of changes in patients sodium levels related to syndrome of inappropriate antidiuretic hormone secretion (SIADH) with interventions targeting inflammatory mediator production and function of inflammasomes with the potential of prevention of permanent brain damage in a wide range of CNS diseases.

Recently, the prevalence of infant Kawasaki disease (KD) has increased. However, the myocardial functional analysis of infant KD can be difficult and rarely reported. The purpose of this study was to investigate layer specific myocardial strain analysis for better assessment of the acute period in infant KD. The study retrospectively reviewed the echocardiographic data of 25 infant patients with KD at the acute phase. With advanced imaging, pulsed tissue Doppler velocity data, myocardial strain with three layers specific analysis was performed. Then the data were compared with 25 age-matched healthy control infants. The measures of longitudinal strain and radial strain were decreased in infant KD compared to healthy controls. The circumferential strain was significantly decreased in infant KD at all three myocardial layers, especially in the endocardial layer (KD: −20.5 ± 6.4 % vs. control: −25.6 ± 7.6 %, endocardium, p = 0.00001; −14.6 ± 4.4 % vs. −18.1 ± 4.0 %; middle myocardium, p = 0.01; −9.7 ± 3.3 % vs. −11.4 ± 3.8 %; epicardium, p = 0.04). The acute phase of infant KD demonstrated decreased myocardial strain measurement. Circumferential strain was the lowest in the endocardial layer. Further continuous long-term follow up for myocardial assessment should be recommended even after recovery with appropriate treatment.

Purpose Acute pyelonephritis (APN) is a serious bacterial infection that can cause renal scarring in children. Early identification of APN is critical to improve treatment outcomes. The neutrophil-lymphocyte ratio (NLR) is a prognostic marker of many diseases, but it has not yet been established in urinary tract infection (UTI). The aim of this study was to determine whether NLR is a useful marker to predict APN or vesicoureteral reflux (VUR). Methods We retrospectively evaluated 298 pediatric patients (age≤36 months) with febrile UTI from January 2010 to December 2014. Conventional infection markers (white blood cell [WBC] count, erythrocyte sedimentation rate [ESR], C-reactive protein [CRP]), and NLR were measured. Results WBC, CRP, ESR, and NLR were higher in APN than in lower UTI (P

This study evaluated the effect of a booster vaccination of a new, live attenuated, Japanese encephalitis chimeric vaccine (JE-CV). Previously this vaccine has been used as a booster 12 months after priming with an inactivated vaccine and at24 months after priming with the same JE-CV. This study evaluates the immunogenicity and safety of the JE-CV given at 12-24 months after JE-CV priming.Phase III, open-label study in the Republic of Korea in which 119 children previously vaccinated with JE-CV at 12-24 months of age received a JE-CV booster at 12-24 months after primary vaccination. JE neutralizing antibody titers were measured using50% plaque reduction neutralization test prebooster and 1 month postbooster vaccination. Seroprotection (SP) was defined as ≥10 (1/dil). Safety was assessed for 28 days postvaccination by parental reports. Serious adverse events were monitored for 6 months postvaccination.Antibody persistence was high prebooster (SP rate 93.5%). There was a strong anamnestic response postbooster vaccination, with an SP rate of 100% and a50-fold increase in geometric mean titer from the prebooster level. Both antibody persistence and the booster response were independent of whether the booster was given at 12-17 or 18-24 months. The safety profile was good and comparable with the primary vaccination; there were no vaccine-related serious adverse events and no deaths.This study confirms the suitability of a JE-CV booster vaccination at 12-24 months after a primary dose of the same vaccine given at 12-24 months of age in children in the Republic of Korea.

목적: 본 연구의 목적은 방광 요관 역류(vesicoureteral reflux) 환아에서 재발성 요로감염의 임상양상을 조사하고, 첫 번째 및 재발성 요로감염 간의 원인균과 항생제 감수성 결과를 비교하는 것이다. 방법: 방관 요관 역류로 진단된 소아 환자 중에서 요로감염이 발생한 환자의 의무기록을 후향적으로 검토하였다. 첫 번째와 두 번째 요로감염 건에서 같은 균종이 동정된 경우를 1군으로, 다른 균종이 동정된 경우를 2군으로 분류하여 분석하였다. 결과: 2005년 4월부터 2018년 2월까지 총 13년 간의 연구 기간 동안, 총 77명의 방관 요관 역류 환아가 적어도 한 번 이상의 요로감염을 경험하였다. 이 중 47명의 환자(61.0%)가 재발성 요로감염 소견을 보였다. 재발성 요로감염 환자 중에서 1군은 19명(40.4%)이었고, 2군은 28명(59.6%)이었다. Escherichia coli (n=37, 39.4%)는 재발성 요로감염 환자의 첫 번째 및 두 번째 요로감염 건에서 가장 흔하게 분리된 원인균이었고, 그 다음으로는 Klebsiella pneumoniae (n=18, 19.1%), Enterococcus faecalis (n=14, 14.9%), Enterobacter aerogenes (n=7, 7.4%), 및 Pseudomonas aeruginosa (n=4, 4.3%) 순이었다. 비록 통계적 차이는 없었지만, E. coli에 의한 재발 시, 같은 균에 의한 재발 임에도 ceftazidime, piperacillin/tazobactam과 trimethoprim-sulfamethoxazole에 대한 항생제 내성의 비율이 첫 번째보다 두 번째 감염에서 증가하였고, E. aerogenes에 의한 재발에서도 cefotaxime, ceftazidime, piperacillin/tazobactam 및 meropenem에 대한 항생제 내성의 비율이 첫 번째보다 두 번째 감염에서 증가하였다. 결론: 방관 요관 역류 환아의 재발성 요로감염에서 경험적 항생제를 선택할 때, 이전 감염의 병원균 및 항균제 감수성 결과가 재발 시에 항상 동일하지는 않다는 점을 염두에 두어야 한다.

Background and Aim. ROHHADNET (rapid-onset obesity with hypoventilation, hypothalamic, autonomic dysregulation, neuroendocrine tumor) syndrome is a rare disease with grave outcome. Although early recognition is essential, prompt diagnosis may be challenging due to its extreme rarity. This study aimed to systematically review its clinical manifestation and to identify genetic causes. Materials and Methods. We firstly conducted a systematic review on ROHHAD/NET. Electronic databases were searched using related terms. We secondly performed whole exome sequencing (WES) and examined copy number variation (CNV) in two patients to identify genetic causes. Results. In total, 46 eligible studies including 158 patients were included. There were 36 case reports available for individual patient data (IPD; 48 patients, 23 ROHHAD, and 25 ROHHADNET) and 10 case series available for aggregate patient data (APD; 110 patients, 71 ROHHAD, and 39 ROHHADNET). The median age at onset calculated from IPD was 4 years. Gender information was available in 100 patients (40 from IPD and 60 from APD) in which 65 females and 35 males were showing female preponderance. Earliest manifestation was rapid obesity, followed by hypothalamic symptoms. Most common types of neuroendocrine tumors were ganglioneuromas. Patients frequently had dysnatremia and hyperprolactinemia. Two patients were available for WES. Rare variants were identified in PIK3R3, SPTBN5, and PCF11 in one patient and SRMS, ZNF83, and KMT2B in another patient, respectively. However, there was no surviving variant shared by the two patients after filtering. Conclusions. This study systematically reviewed the phenotype of ROHHAD/NET aiming to help early recognition and reducing morbidity. The link of variants identified in the present WES requires further investigation.

A necrotizing retinitis in children is a rare but vision-threatening ocular complication of chickenpox. We report a 10-year-old girl who developed chickenpox 1 month before presenting with panuveitis and necrotizing retinitis. After prompt antiviral treatment, her inflammatory signs were resolved. Early detection and treatment of varicella zoster-associated necrotizing retinitis after chickenpox can achieve good visual outcome.

D-dimer, as well as other biomarkers related to coagulation, is significantly increased during severe bacterial infection and sepsis. The aim of this study was to evaluate the usefulness of serum D-dimer as a biological marker in diagnosing acute pyelonephritis (APN) and in predicting vesicoureteric reflux (VUR) in infants with urinary tract infection (UTI). We retrospectively analyzed the data of 177 young infants (

Delta neutrophil index (DNI) is the fraction of circulating immature granulocytes, which reflects severe bacterial infections and septic condition but has not been studied in urinary tract infection (UTI). Here, we evaluated the value of DNI in predicting acute pyelonephritis (APN) or vesicoureteral reflux (VUR) using the data of 288 patients. Conventional inflammatory markers (white blood cell [WBC] count, erythrocyte sedimentation rate [ESR], C-reactive protein [CRP]), and DNI were measured. WBC, CRP, ESR and DNI were higher in APN than in lower UTI (p P P P P

PURPOSE To evaluate choroidal changes in eyes with acute anterior uveitis associated with human leukocyte antigen (HLA)-B27. METHODS In 44 patients with first-onset, unilateral, acute-onset (

Various cytokines activated by the inhalation of coal dust may mediate inflammation and lead to tissue damage. Objective of this study was to examine the relationships between coal work- ers' pneumoconiosis (CWP) progression over a 3 yr period and the serum levels of cytokines in 85 retired coal workers. To investigate the relevance of serum cytokines in CWP, serum levels of inter- leukin-8 (IL-8), tumor necrosis factor-alpha (TNF-α), transforming growth factor-beta1 (TGF-β1), and monocyte chemotactic protein-1 (MCP-1) as progressive CWP biomarkers were studied in re- lation to the progression of pneumoconiosis over a 3 yr period in 85 patients with CWP. CWP pro- gression was evaluated through paired comparisons of chest radiographs. Median levels of TGF-β1 and MCP-1 were significantly higher in subjects with progressive CWP than in those without CWP progression. The area under the ROC curve for TGF-β1 (0.693) and MCP-1 (0.653) indicated that these cytokines could serve as biomarkers for the progression of CWP. Serum TGF-β1 levels were related to the progression of CWP (β=0.247, p=0.016). The results suggest that high serum levels of TGF-β1 and MCP-1 are associated with the progression of CWP.

Background: Tissue microarray analysis (TMA) is a high-throughput method for histologic evaluation, immunohistochemistry, and in situ hybridization using paraffin embedded tissue. Despite its high efficiency as an experimental tool, TMA is limited because it only contains a very small tissue fragment from each case. Therefore, the purpose of this study was to evaluate the validity of TMA in a study of nephrotoxicity caused by immunosuppressants. Methods: Male Sprague-Dawley rats were treated with vehicle (n=16), cyclosporine (n=23), and cyclosporine plus losartan (n=13) for a maximum of 7 weeks. After animal sacrifice, renal tissues were embedded in paraffin and processed into slides for microscopic examination using conventional methods and the TMA technique. Acute tubular injury, vascular hyaline change, and interstitial fibrosis were scored in both conventional and TMA slides. The number of interstitial macrophages was counted after ED-1 immunohistochemistry and the results also compared between conventional and TMA slides. Results: The degree of acute tubular injury and interstitial fibrosis showed a significant agreement between conventional and TMA methods (κ value, 0.79 and 1.00, respectively). The number of interstitial macrophages counted in conventional and TMA slides showed a significant correlation as well (r=0.934, P

We performed a nationwide epidemiological study to evaluate the prevalence and characteristics of nocturnal enuresis (NE) in Korean adolescents and adults. A questionnaire was sent via e-mail to 51,073 people aged 16-40 yr by stratified sampling according to age, sex, and region among a 200,000 internet survey panel pool. The questionnaire included following information; presence or absence of NE, frequency of NE, possible risk factors for NE, self-esteem scale score and depression score results, and measures for the treatment of NE. Among the 2,117 responders, 54 (2.6%) had NE (≥1 enuretic episode within 6 months). Of 54 bedwetters, 9.3% wet ≥1 night per week and 20.5% wet ≥1 per month. The prevalence rates remained relatively stable with no apparent trend of reduction with age. The presence of sleep disturbance, family history, urgency, or urge incontinence increased the probability of NE episode significantly. The self-esteem score was lower (P=0.053) and the depression scale score was higher (P=0.003) in bedwetters compared with non-bedwetters. Overall 2.6% of Korean aged 16-40 yr have NE. The higher rate of urgency and urge incontinence in adolescent and adult enuretics suggests that bladder function has an important role in adolescent and adult NE.

Objectives/Hypothesis The study evaluated the relationship between the position that initially provoked vertigo and the affected semicircular canal (SCC) in patients with benign paroxysmal positional vertigo (BPPV), and aimed to predict the side affected by BPPV through history taking regarding the provoking position. Study Design Prospective study at a tertiary hospital. Methods A total of 521 patients with BPPV involving the posterior or horizontal SCCs performed questionnaires at initial visit asking to choose the initial provoking position among the 10 positions corresponding to one of the three planes (roll, pitch, or yaw). After excluding 45 patients showing signs of simultaneous multiple canal or anterior canal involvement, the frequency of the provoking positions and the correlation between the side of the provoking position and the ear affected by BPPV were analyzed. Results There were 239 patients with posterior SCC BPPV (p-BPPV) and 237 patients with horizontal SCC BPPV (h-BPPV). The waking-up position was the most common provoking position in both types of BPPV. Statistically significant correlation was demonstrated between the side of the provoking position at the onset of vertigo and the affected side by BPPV (P < .01) in patients with p-BPPV as well as h-BPPV (geotropic type [Geo]), but not in patients with h-BPPV (apogeotropic type [Apo]). Conclusions History taking regarding the side of provoking position at the onset of vertigo may help predict the side affected by BPPV in p-BPPV and h-BPPV (Geo). When h-BPPV (Apo) is suspected, further detailed examinations using additional localization methods should be performed. Level of Evidence 2b. Laryngoscope, 123:2259–2263, 2013

The aim of this study was to determine whether decreased serum sodium concentration could be associated with the disease activity in SLE. We retrospectively analyzed the data of the two independent cohorts of children and adults with SLE in two centers. Hyponatremia was associated with serum chloride (p = 0.004), albumin (p = 0.002) and SLE disease activity index (SLEDAI) (p = 0.026) in children with SLE. Serum sodium levels were correlated negatively with ESR (p =0.001) and positively with serum albumin levels (p

The aim of this study was to evaluate the influence of cyclosporine A (CsA) on glomerular growth and the effect of mizoribine (MZR) and losartan (LSAR) on CsA-induced nephropathy in young rats. Six-week-old male Sprague-Dawley rats maintained on a low salt diet were given CsA (15 mg/kg), CsA and LSRT (30 mg/kg/day), CsA and MZR (5 mg/kg), or a combination of CsA, LSRT, and MZR for 4 and 7 weeks (two experiments) and compared with control group (olive oil-treated). Histopathology and glomerular size, inflammatory and fibrotic factors were studied. The score of acute CsA toxicity significantly decreased in the CsA + MZR group compared to the CsA group (p

Background The UBA6-specific E2 conjugating enzyme 1 (USE1) ubiquitin enzyme cascade is a poorly characterized arm of the ubiquitin-proteasome system. We investigated whether the UBA6-USE1 enzyme cascade plays a role in lung cancer tumorigenesis. Methods USE1 expression was assessed in tumor-normal paired samples from 106 lung cancer patients by immunoblot. USE1 was stably overexpressed and knocked down in lung cancer cell lines to evaluate cell proliferation, colony formation, and invasion. Xenograft models were used to determine the effects of USE1 on tumor growth (n = 7). Proteomics analysis was used to identify proteins interacting with USE1. The USE1 gene was sequenced in lung cancer patients, and missense mutations of USE1 were generated to evaluate its function. All statistical tests were two-sided. Results USE1 proteins were frequently overexpressed in lung cancer patients (92.5%) Stable overexpression of USE1 increased cell proliferation ( P = .002), migration ( P < .001), and invasion ( P < .001), whereas knockdown of USE1 reduced cell proliferation ( P < .001), migration ( P = .003), and invasion in lung cancer cells and xenograft models ( P < .001). USE1 was found to have a conserved D-box domain, and the level of the protein was regulated by the anaphase-promoting complex. Several missense mutations in USE1 identified in patients prolong the stability of the protein. Conclusions USE1 proteins are frequently overexpressed in lung cancer, and missense mutations in USE1 prolong the half-life of the protein, promoting tumor formation. Our findings reveal novel roles for USE1 in lung cancer and the possible use of USE1 as a novel biomarker and therapeutic target for lung cancer treatment.

Little information is currently available on the development of tubulointerstitial lesions in children with Henoch–Schonlein nephritis (HSN). To identify the impact of the development of tubulointerstitial changes in HSN, we retrospectively analyzed renal biopsies obtained from children with HSN. Twenty-eight children with HSN from whom serial renal biopsies had been obtained before and after immunosuppressive therapy were enrolled in the study. The patients were divided into two groups according to the observed change in tubulointerstitial lesion development: group I (n = 15), with stable or improved tubulointerstitial lesions, and group II (n = 13), with worsened tubulointerstitial lesions. Group II patients had longer duration of proteinuria than group I patients (3.7 ± 3.7 years vs. 1.7 ± 1.7 years, p = 0.052). The change in serum albumin level was negatively correlated with the change in tubulointerstitial scores before and after treatment (γ = −0.444, p = 0.018). Group II patients showed a significant decrease in immunoglobulin G (IgG) and IgA deposits after treatment (p = 0.039 and 0.003, respectively), while group II patients did not (p = 0.458 and 0.506, respectively). Although the International Study of Kidney Disease in Children classification of HSN does not include tubulointerstitial lesions, they can progress during treatment and could have significant clinical implications in association with the duration of proteinuria.

Objectives/Hypothesis: The aim of this study was to evaluate the relationship between the head position during sleep and the affected semicircular canal (SCC) in patients with benign paroxysmal positional vertigo (BPPV). Study Design: Prospective study at a tertiary hospital. Methods: We conducted a prospective study in patients with BPPV involving posterior or horizontal SCCs. Of a total of 425 patients diagnosed with BPPV, 83 patients showing signs of simultaneous multiple canal involvement, and those having combined otologic diseases in the same ear were excluded from the study. All patients included in the study were asked to define their preferred head-lying side at the beginning of sleep among the following choices: supine, lateral (right or left), or no predominant side. Results: Our study included 174 patients with posterior SCC BPPV (p-BPPV) and 168 patients with horizontal SCC BPPV (h-BPPV). Patients habitually adopted a lateral head position during sleep in 105 cases of p-BPPV and 109 cases of h-BPPV. Statistically significant correlation was demonstrated between the head-lying side during sleep and the affected side by BPPV (P < .01) in patients with p-BPPV as well as h-BPPV. Conclusions: There is significant correlation between the head-lying side during sleep and the side affected by BPPV in h-BPPV and p-BPPV, which may provide additional clues about the pathophysiology of BPPV. Clinically, this information may be used to provide helpful guidelines for patients with BPPV concerning their sleeping positions to prevent recurrence of BPPV. Laryngoscope, 2012

Objectives: Various cytokines induced by inhalation of coal dust may mediate inflammation and lead to tissue damage or fibrosis, such as coal workers' pneumoconiosis (CWP). Methods: To investigate the relevance of serum cytokines in CWP, the levels of serum interleukin-8 (IL-8) and tumor necrosis factor-alpha (TNF-α) as CWP biomarkers in 110 retired coal miners (22 controls and 88 CWP subjects) were related to cross sectional findings and 1-year progressive changes of the pneumoconiosis. Progressive changes of CWP were evaluated by paired comparison of chest radiographs. Analysis by a receiver operating characteristic (ROC) curve assessed the biomarker potential of each cytokine. Results: The mean serum IL-8 level was significantly higher in CWP compared to controls and IL-8 levels correlated with the degree of CWP. The median serum TNF-α level was significantly higher in subjects with progressive CWP compared to subjects without CWP progression. The area under the ROC curve for IL-8 (0.70) and TNF-α (0.72) for CWP identification and progression, respectively, indicated the biomarker potential of the two cytokines. Serum cutoff values of IL-8 and TNF-α were 11.63 pg/ml (sensitivity 69%; specificity 64%) and 4.52 pg/ml (sensitivity 67%; specificity 79%), respectively. Conclusion: The results suggest that high levels of serum IL-8 are associated with the presence of CWP and those of serum TNF-α are associated with the progression of CWP.

Rationale: Non-arteritic anterior ischemic optic neuropathy (NAION) is characterized by sudden, painless visual loss and optic disc edema. NAION occurs mainly in the presence of cardiovascular disease and hypercoagulability, mainly in patients over 50 years of age. We experienced a case of NAION associated with central retinal vein occlusion (CRVO) in a young man with no underlying disease. Patient concerns: A 46-year-old man was referred to our clinic following a sudden loss of vision in his right eye. The patient exhibited no underlying disease and reported no ongoing medication. Significant visual loss and visual disturbance of the right eye were observed. The pupil of the right eye was enlarged and an afferent pupillary defect was observed. On fundus examination, retinal hemorrhage was observed in the peripheral retina; macular edema was observed in optical coherence tomography analysis. However, optic disc edema was not evident. No abnormal findings were found in routine blood tests for hypercoagulability. After 3 days of steroid intravenous injection, macular edema disappeared and visual acuity was improved, but optic disc edema began to appear. One week later, optic disc edema was evident and visual acuity was significantly reduced; thus, the patient was diagnosed with NAION. In fluorescein angiography, peripheral retinal ischemia was observed, suggesting that CRVO was complicated. Blood tests, including analysis of coagulation factors, were performed again, showing that coagulation factors IX and XI were increased. Diagnoses: Anomalous coagulation factors in non-arteritic anterior ischemic optic neuropathy with central retinal vein occlusion. Interventions: Systemic steroids were administered. Outcomes: One month later, optic disc edema and retinal hemorrhage gradually diminished and eventually disappeared; however, visual acuity did not recover. Conclusion: In young patients without underlying disease, cases of NAION require careful screening for coagulation disorders. Even if there is no abnormality in the test for routine coagulation status, it may be necessary to confirm a coagulation defect through an additional coagulation factor assay.

Aim: Mitochondrial disorders with respiratory chain complex defect are known to show a broad spectrum of clinical phenotypes, though their contribution to renal disease has not received much attention. The aim of this study was to evaluate renal function using different markers of the glomerular filtration rate (GFR) in children with mitochondrial respiratory chain complex (MRC) defects. Methods: Twenty-two patients with MRC I defect confirmed by biochemical enzyme assays using muscle tissue, were evaluated for renal function with diethylenetriaminepentaacetic acid (DTPA) renal scintigraphy, urine creatinine clearance, serum creatinine (Scr) and cystatin C (Cys C) levels. Results: All patients showed lower levels within normal range of Scr (0.4–0.7 mg/dL, mean 0.47 mg/dL), and with no significant correlation with DTPA–GFR. Cys C showed significant correlation with DTPA–GFR (p < 0.01) providing higher diagnostic accuracy than creatinine in patients with MRC defect. Conclusion: In mitochondrial disorder with MRC defect, Scr could not fully reflect renal function due to the relatively small body mass of patients. Considering the limited clinical availability of DTPA renal scintigraphy, Cys C should be taken as the first step to evaluate GFR in mitochondrial disorders.

Cyclosporine (CsA) treatment in immunoglobulin A nephropathy (IgAN) is controversial and has not been widely studied. The aim of this study was to investigate the effects of CsA on renal histology and the expression of interstitial fibrosis-associated molecules in childhood IgAN. The subjects were 18 children (age 4.2-13.9 years; male:female 13:5) who had been treated with CsA for 8 or 12 months and who had renal biopsies before and after treatment. Renal biopsies were assessed by routine histology and immunohistochemistry against osteopontin (OPN), transforming growth factor-beta (TGF-beta), CD68, and CD34. The degree of proteinuria and mesangial IgA deposits decreased or disappeared after treatment in all cases, and the percentage of patients with diffuse mesangial proliferation decreased from 44.4 to 22.2%. However, interstitial fibrosis developed or was aggravated in nine patients (50%) after treatment and was associated with an increased degree of interstitial inflammation in five patients. Tubular OPN expression (45.3 +/- 23.4 vs. 37.6 +/- 19.3%) and the degree of CD68-positive macrophage infiltration (136.1 +/- 88.2 vs. 132 +/- 86.0/mm(2)) were not increased after CsA treatment, but TGF-beta expression was significantly increased (6.4 +/- 4.2 vs. 13.3 +/- 9.9%; p = 0.025). Microvascular density was increased and peritubular capillaries were of small caliber in inflamed areas. We conclude that increased levels of TGF-beta and the development of interstitial fibrosis limit the long-term use of CsA in IgAN patients. Osteopontin and macrophages may be indirectly involved in renal fibrosis by prolonging interstitial inflammation rather than by directly increasing TGF-beta expression.

Background: Oral squamous cell carcinomas (OSCCs) are characterized by a high degree of local invasion and a high rate of metastases to cervical lymph nodes. Downregulation of CXCR-4 by siRNA inhibits invasion and growth of breast and colon cancer cells. However, there have been no reports on the downregulation of CXCR-4 by small interfering RNA (siRNA) in oral cancer cells. Methods: We generated two stable CXCR-4-knockdown clones (KBsi and KOSCC-25Bsi) from the KB and KOSCC-25B OSCC cell lines by lentiviral delivery. In vitro invasion and cell proliferation assays were used to investigate the effect of CXCR-4 downregulation on cell proliferation and invasiveness in KBsi and KOSCC-25Bsi. Immunohistochemistry was performed to evaluate the correlation between CXCR-4 expression and proliferation in 26 OSCC tissue samples. Results: CXCR4-knockdown OSCC cells showed reduced invasiveness. The invasiveness of KBsi decreased to 29.5% of the vector-infected controls, and KOSCC-25Bsi decreased to 38.1% of the control vector-infected cells (P

Surface iron on a mineral particle may be a major mediator of mineral-dust-induced toxicity, because iron on the surface of the particle acts as a Fenton catalyst to produce hydroxyl radical from hydrogen peroxide. Desferrioxamine (DF), an iron chelator, might inhibit the process of silica-induced pulmonary reaction. To test this assumption, we investigated the protective effect of DF on lipid peroxidation of cell membrane, production of inflammatory cytokine, and fibroblast proliferation by crystalline silica for an in vitro model. The Fenton activity of silica was decreased by preincubation with DF. Marked decreases in malondialde-hyde (MDA) levels were seen in the DF-treated silica group compared with the untreated group. DF inhibited not only silica-induced release of tumor necrosis factor-α (TNF-α) and interleukin-8 (IL-8) from A549, but also fibroblast proliferation. The therapeutic effect of DF on experimental silicosis in rat was also studied using total cell count with differential percentage in bronchoaiveoiar lavage fluid, the amount of hydroxyproline in lung, and examination of a histologic section. DF significantly reduced inflammation and fibrosis compared with the untreated control. From these results, we concluded that DF might play a role in the inhibition of silica-induced pulmonary reaction.

Sinonasal type hemangiopericytomas are very rare tumors, and are often called glomangiopericytoma. They are believed to be derived from perivascular modified smooth muscle cells. Their origin is similar to glomus tumors but some distinct differences exist. Glomangiopericytomas are indolent tumors and overall survival rates are higher after complete surgical excision. Recurrence rates are as high as 30%. We present a case of glomangiopericytoma which involves the orbital wall, noteworthy because such bone-dissolving glomangiopericytomas are extremely rare.

Purpose Kawasaki disease (KD) is an immune-related multisystemic vasculitis that occurs in children, especially ensuing from a coronary artery abnormality. Sodium level is known to be related to vascular injury, which could affect the progress of KD. The purpose of this study was to determine the serum sodium levels that could predict the occurrence of cardiac and coronary artery events in KD. Methods We conducted a retrospective review of medical records for 104 patients with KD from January 2015 to December 2015. Patients with serum Na levels of

Tubulointerstitial nephritis and uveitis (TINU) syndrome is a rare disease, often underdiagnosed or misdiagnosed in children. We describe the case of a 12-year-old boy who presented to Severance Hospital with a 1-month history of bilateral conjunctival injection. He was first evaluated by an Ophthalmologist in another hospital and diagnosed with panuveitis. Laboratory tests indicated renal failure, and a renal biopsy confirmed the diagnosis of acute tubulointerstitial nephritis. An extensive exclusion of all possible causes allowed a diagnosis of TINU syndrome. The patient was treated with a systemic corticosteroid (initially prednisolone, 2 mg/kg and later deflazacort 1 mg/kg) and topical steroid drops for 1 month. Azathioprine was later added to the treatment regimen and the systemic steroid was slowly tapered. The final outcome of renal-ocular disease was favorable in the patient. However, long-term follow-up is necessary to properly manage frequent relapses and incomplete renal recovery. TINU should be considered as a differential diagnosis in children with uveitis or acute renal failure.

Background Preoperative liver stiffness (LS) measurement using transient elastography (TE) is useful for predicting late recurrence after curative resection of hepatocellular carcinoma (HCC). We developed and validated a novel LS value-based predictive model for late recurrence of HCC. Methods Patients who were due to undergo curative resection of HCC between August 2006 and January 2010 were prospectively enrolled and TE was performed prior to operations by study protocol. The predictive model of late recurrence was constructed based on a multiple logistic regression model. Discrimination and calibration were used to validate the model. Results Among a total of 139 patients who were finally analyzed, late recurrence occurred in 44 patients, with a median follow-up of 24.5 months (range, 12.4–68.1). We developed a predictive model for late recurrence of HCC using LS value, activity grade II-III, presence of multiple tumors, and indocyanine green retention rate at 15 min (ICG R15), which showed fairly good discrimination capability with an area under the receiver operating characteristic curve (AUROC) of 0.724 (95% confidence intervals [CIs], 0.632–0.816). In the validation, using a bootstrap method to assess discrimination, the AUROC remained largely unchanged between iterations, with an average AUROC of 0.722 (95% CIs, 0.718–0.724). When we plotted a calibration chart for predicted and observed risk of late recurrence, the predicted risk of late recurrence correlated well with observed risk, with a correlation coefficient of 0.873 (P

To the Editor: We read with interest the contribution by Varaprasad, et al 1. They studied patients with systemic lupus erythematosus (SLE) and posterior reversible encephalopathy syndrome (PRES) and suggested that PRES occurs in young patients with lupus at the early stage of the disease. However, they did not explain the exact mechanism of the disease. We would like to add the possible pathomechanism in the development of PRES in SLE. PRES is an uncommon condition that … Address correspondence to Dr. J.I. Shin, 250 Seongsan-ro, Seodaemun-gu, CPO Box 8044, Department of Pediatrics, Yonsei University College of Medicine, Seoul 120-752, Korea. E-mail: shinji{at}yuhs.ac

To the Editor: We read with interest the recent contribution by Drs. Fernandez-Fernandez and Sesma1. They introduced 2 significant studies: the IFIGENIA trial (Idiopathic Pulmonary Fibrosis International Group Exploring N-Acetylcysteine I Annual study)2 and the study by Guilpain, et al 3 showing that antimyeloperoxidase (MPO) antibodies generated a reactive oxygen species that was highly harmful to endothelial cells, and that N-acetylcysteine (NAC) … Address correspondence to Dr. J. Shin, 250 Sungsanno, Seodaemun-gu, CPO Box 8044, Department of Pediatrics, Yonsei University College of Medicine, Seoul 120-752, Korea. E-mail: shinji{at}yuhs.ac

A petrified auricle is a rare condition in which the structure becomes partially or completely rigid. It arises as a consequence of calcification or ossification of the auricular cartilage. An ossified auricle is much more rare than a calcified cartilage, and it can be diagnosed only by histology. To the best of our knowledge, only 18 cases of ossification of the auricle have been previously reported in the literature. We report a new case of auricular ossification in a 72-year-old woman who had taken calcium for the previous 8 years. We also review the relevant literature.

We read with great interest the contribution by Bazso et al. [1]. They reported the case of a 12-year-old girl with juvenile idiopathic arthritis (JIA) who developed systemic lupus erythematosus (SLE) after 10 years and speculated a few hypotheses of “shared autoimmunity,” the complete dysregulation of the immune system, and the side eVect of the anti-TNF therapy. However, we would like to suggest a diVerent and possible pathomechanism of the overlapping JIA and SLE case. The patient presented Escherichia coli (E. coli) septicemia at the age of 22 and subsequently developed clinical, immunological, and pathological manifestations fulWlling the diagnostic criteria of SLE within the following 8 weeks. SigniWcantly, Uthman et al. [2] also reported a case of SLE following E. coli sepsis in a 72-year-old woman, postulating three plausible pathomechanisms. Firstly, Robertson and Pisetsky [3] reported that Wve of the eight patients with E. coli bacteremia demonstrated increased levels of antibodies to single-stranded (ss) DNA from E. coli. Secondly, Gilkeson et al. [4] showed that normal mice immunized with ssDNA derived from E. coli developed an immune-mediated proliferative glomerulonephritis secondary to renal deposition of anti-DNA antibodies as in SLE. Thirdly, E. coli is known to produce heat shock protein (HSP), and Schultz et al. [5] suggested a role of HSP in the pathogenesis of rheumatic diseases like SLE. The host initially reacts to microbial infections with an enhanced cellular and humoral response to the microbial HSP, and cross-reactivity may occur with the HSP of the stressed host because of structural similarities to the microbial HSP [5]. Therefore, there is a possibility that E. coli septicemia might play a critical role as an inducer in the development of SLE in the Bazso et al.’s patient. However, further studies are necessary to elucidate the exact relationship and molecular pathogenic pathway between the JIA and SLE overlap in the future.

Background Unlike Caucasian populations, genetic factors contributing to the risk of type 2 diabetes mellitus (T2DM) are not well studied in Asian populations. In light of this, and the fact that copy number variation (CNV) is emerging as a new way to understand human genomic variation, the objective of this study was to identify type 2 diabetes–associated CNV in a Korean cohort. Methodology/Principal Findings Using the Illumina HumanHap300 BeadChip (317,503 markers), genome-wide genotyping was performed to obtain signal and allelic intensities from 275 patients with type 2 diabetes mellitus (T2DM) and 496 nondiabetic subjects (Total n = 771). To increase the sensitivity of CNV identification, we incorporated multiple factors using PennCNV, a program that is based on the hidden Markov model (HMM). To assess the genetic effect of CNV on T2DM, a multivariate logistic regression model controlling for age and gender was used. We identified a total of 7,478 CNVs (average of 9.7 CNVs per individual) and 2,554 CNV regions (CNVRs; 164 common CNVRs for frequency>1%) in this study. Although we failed to demonstrate robust associations between CNVs and the risk of T2DM, our results revealed a putative association between several CNVRs including chr15:45994758–45999227 (P = 8.6E-04, Pcorr = 0.01) and the risk of T2DM. The identified CNVs in this study were validated using overlapping analysis with the Database of Genomic Variants (DGV; 71.7% overlap), and quantitative PCR (qPCR). The identified variations, which encompassed functional genes, were significantly enriched in the cellular part, in the membrane-bound organelle, in the development process, in cell communication, in signal transduction, and in biological regulation. Conclusion/Significance We expect that the methods and findings in this study will contribute in particular to genome studies of Asian populations.

AimsTo identify the predictive factors for ciclosporin A (CyA)-associated nephrotoxicity (CAN) in children with minimal change nephrotic syndrome (MCNS).MethodsThe clinical and laboratory findings of 58 children (median age 3.2 years, range 1.1–13.1 years, male:female 48:10) with MCNS who were treated with CyA from 1992 to 2002 were analysed retrospectively. Forty-eight (83%) of them were steroid dependent and 10 (17%) were steroid resistant. The starting dose of CyA was 5 mg/kg per day, and the desired drug level was kept at 100–200 ng/ml. Serial renal biopsies were performed before and after CyA therapy.ResultsTwenty-two patients (38%) had CAN (group I) and 36 (62%) did not (group II). There were no differences in the age at onset, sex, initial response to steroids, duration of CyA therapy and relapse rates. However, the median CyA trough levels were significantly higher in group I than in group II (218.0±15.2 vs 171.8±6.7 ng/ml, p=0.01). Changes in creatinine clearance were more decreased in group I than in group II (−39.4±8.2 vs 2.7±4.3 ml/min per 1.73 m2, pConclusionsThe median CyA trough level was an independent and significant risk factor for the development of CAN in children with MCNS receiving moderate-dose CyA.

Coal dust inhalation can result in industrial bronchitis and coal workers’ pneumoconiosis (CWP) presenting as either simple pneumoconiosis or complicated CWP. With prolonged excessive exposure, small opacities in simple pneumoconiosis may coalesce and form larger opacities, recognized as progressive massive fibrosis (PMF) greater than 1 cm in diameter on a chest X-ray. Even though the degree of respiratory impairment or the presence of symptoms does not always correlate well with the extent of PMF, most workers frequently describe dyspnea, a cough and sputum production. It may be caused by deviation of the prominent area of coalescence, loss of upper zone lung volume, elevation of the hila, and basilar emphysema. We present a case of large opacity in pneumoconiosis which included a finding of ischemic necrosis. Rapid change in the solitary mass caused a diagnostic dilemma in attempting to distinguish a primary or metastatic neoplasm from an unusual presentation of PMF.

Inhaled inorganic dusts, such as coal, can cause inflammation and fibrosis in the lungs, known as pneumoconiosis. Diagnosis of pneumoconiosis depends on morphological changes by radiological findings and functional change by pulmonary function test (PFT) . Unfortunately, current diagnostic findings are limited only to lung fibrosis, which is usually irreversibly progressive. Therefore, it is important that research on potential and prospective biomarkers for pneumoconiosis should be conducted prior to initiation of irreversible radiological or functional changes in the lungs. Analytical techniques using exhaled breath condensate (EBC) or exhaled gas are non-invasive methods for detection of various respiratory diseases. The objective of this study is to investigate the relationship between inflammatory biomarkers, such as EBC pH or fractional exhaled nitric oxide (FENO) , and pneumoconiosis among 120 retired coal miners (41 controls and 79 pneumoconiosis patients) . Levels of EBC pH and FENO did not show a statistically significant difference between the pneumoconiosis patient group and pneumoconiosis patients with small opacity classified by International Labor Organization (ILO) classification. The mean concentration of FENO in the low percentage FEV1 (< 80%) was lower than that in the high percentage (80% ≤) (p = 0.023) . The mean concentration of FENO in current smokers was lower than that in non smokers (never or past smokers) (p = 0.027) . Although there was no statistical significance, the levels of FENO in smokers tended to decrease, compared with non smokers, regardless of pneumoconiosis. In conclusion, there was no significant relationship between the level of EBC pH or FENO and radiological findings or PFT. The effects between exhaled biomarkers and pneumoconiosis progression, such as decreasing PFT and exacerbation of radiological findings, should be monitored.