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Objective: We provide evidence-based recommendations regarding screening for interstitial lung disease (ILD) and the monitoring for ILD progression in people with systemic autoimmune rheumatic diseases (SARDs), specifically rheumatoid arthritis, systemic sclerosis, idiopathic inflammatory myopathies, mixed connective tissue disease, and Sjögren disease., Methods: We developed clinically relevant population, intervention, comparator, and outcomes questions related to screening and monitoring for ILD in patients with SARDs. A systematic literature review was performed, and the available evidence was rated using the Grading of Recommendations, Assessment, Development, and Evaluation methodology. A Voting Panel of interdisciplinary clinician experts and patients achieved consensus on the direction and strength of each recommendation., Results: Fifteen recommendations were developed. For screening people with these SARDs at risk for ILD, we conditionally recommend pulmonary function tests (PFTs) and high-resolution computed tomography of the chest (HRCT chest); conditionally recommend against screening with 6-minute walk test distance (6MWD), chest radiography, ambulatory desaturation testing, or bronchoscopy; and strongly recommend against screening with surgical lung biopsy. We conditionally recommend monitoring ILD with PFTs, HRCT chest, and ambulatory desaturation testing and conditionally recommend against monitoring with 6MWD, chest radiography, or bronchoscopy. We provide guidance on ILD risk factors and suggestions on frequency of testing to evaluate for the development of ILD in people with SARDs., Conclusion: This clinical practice guideline presents the first recommendations endorsed by the American College of Rheumatology and American College of Chest Physicians for the screening and monitoring of ILD in people with SARDs., (© 2024 American College of Rheumatology.)

Objective: We provide evidence-based recommendations regarding the treatment of interstitial lung disease (ILD) in adults with systemic autoimmune rheumatic diseases (SARDs)., Methods: We developed clinically relevant population, intervention, comparator, and outcomes questions. A systematic literature review was then performed, and the available evidence was rated using the Grading of Recommendations, Assessment, Development, and Evaluation methodology. A panel of clinicians and patients reached consensus on the direction and strength of the recommendations., Results: Thirty-five recommendations were generated (including two strong recommendations) for first-line SARD-ILD treatment, treatment of SARD-ILD progression despite first-line ILD therapy, and treatment of rapidly progressive ILD. The strong recommendations were against using glucocorticoids in systemic sclerosis-ILD as a first-line ILD therapy and after ILD progression. Otherwise, glucocorticoids are conditionally recommended for first-line ILD treatment in all other SARDs., Conclusion: This clinical practice guideline presents the first recommendations endorsed by the American College of Rheumatology and American College of Chest Physicians for the treatment of ILD in people with SARDs., (© 2024 American College of Rheumatology.)

Pulmonary hypertension (PH) is a frequent complication of interstitial lung disease (ILD). Although PH has mostly been described in idiopathic pulmonary fibrosis, it can manifest in association with many other forms of ILD. Associated pathogenetic mechanisms are complex and incompletely understood but there is evidence of disruption of molecular and genetic pathways, with panvascular histopathologic changes, multiple pathophysiologic sequelae, and profound clinical ramifications. While there are some recognized clinical phenotypes such as combined pulmonary fibrosis and emphysema and some possible phenotypes such as connective tissue disease associated with ILD and PH, the identification of further phenotypes of PH in ILD has thus far proven elusive. This statement reviews the current evidence on the pathogenesis, recognized patterns, and useful diagnostic tools to detect phenotypes of PH in ILD. Distinct phenotypes warrant recognition if they are characterized through either a distinct presentation, clinical course, or treatment response. Furthermore, we propose a set of recommendations for future studies that might enable the recognition of new phenotypes., Competing Interests: Dr. Lucilla Piccari has received research funding from and served as a speaker for Janssen and Ferrer, advised Janssen, Ferrer and United Therapeutics as well as received support for attending congresses from Janssen, MSD and Ferrer, all of which not related to this manuscript. Prof Katerina Antoniou has a consultant role for Roche, Boehringer‐Ingelheim, GSK, honoraria for lecturing for Roche, Boehringer‐Ingelheim, GSK, Astra‐Zeneca, Chiesi & Menarini. Dr. Paul M. Hassoun serves on a scientific advisory board for Merck, an activity unrelated to the current work. Dr. Sylvia M. Nikkho is an employee of Bayer AG. Dr. Rajan Saggar has a Consulting and Advisory Role for United Therapeutics, Third Pole, Novartis, Acceleron, Aerovate, and Janssen. Dr. Oksana A. Shlobin has consulted for UT, Bayer, Altavant, Aerovate, Jenssen&Jenssen and Merck, and is on the speaker bureau for UT, Bayer, and JJ. Dr. Steven D. Nathan is a consultant for United Therapeutics, Bellerophon, Third Pole, Roche, Boehringer‐Ingelheim, Merck and Daewoong. Dr. Stephen John Wort received honoraria from Janssen, MSD, Bayer and Acceleron for advisory boards; received honoraria from Janssen for educational activity, received unrestricted research grants from Janssen and Bayer, and travel grants, conference registration, and accommodation from Actelion and GSK. The remaining authors declare no conflict of interest., (© 2023 The Authors. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Purpose: Phyllodes tumors (PTs) of the breast are rare fibroepithelial neoplasms, and factors associated with the recurrence of PTs are poorly understood. This study sought to identify clinicopathological factors associated with the recurrence of PTs., Method: From January 2009 to December 2019, we identified 100 patients who underwent definitive surgery for PT. Clinicopathological risk factors associated with the recurrence of PT were assessed., Results: The median age of the patients was 44 y (range, 19-62 y), and the median tumor size was 4 cm (0.8-30 cm). At a median follow-up of 26.7 mo (0-103 mo), 22 of the 100 patients experienced local recurrence. In the univariate and multivariate analyses, body mass index ≥ 23 kg/m 2 ( P  = 0.042 in the univariate analysis; P  = 0.039 in the multivariate analysis), tumor size ≥ 5 cm ( P  = 0.006 in the univariate analysis; P  = 0.036 in the multivariate analysis), and the presence of stromal overgrowth ( P  = 0.032 in the univariate analysis; P  = 0.040 in the multivariate analysis) were associated with an increased risk of local recurrence. Resection margins and grade were not associated with local recurrence., Conclusion: Normal- or underweight patients and those with larger tumor sizes were more prone to local recurrence. Further larger, multicenter studies with a long-term follow-up are required., Competing Interests: All authors report no conflicts of interest., (Copyright © 2022 Yong Yeup Kim et al.)

Objective: To determine the association between insufficient sleep in the prenatal period and postpartum depression (PPD), and whether changes in sleep patterns during pregnancy increase the risk of PPD., Methods: A prospective cohort study was conducted between March 2013 and November 2017. Participants completed a sleep questionnaire pre-pregnancy and at 12, 24 and 36 gestational weeks (GW). Depressive symptoms were assessed by the Edinburgh Postnatal Depression Scale (EPDS) at 4 weeks postpartum, and the cut-off score for PPD was 10 or more., Results: Of 2512 participants, 410 (16.3%) were identified as having PPD. Only insufficient sleep at 36 GW was significantly associated with PPD after adjusting for confounding factors (odds ratio 1.79, 95% confidence interval 1.40-2.27, P < 0.001). Both Group 1 (change from sufficient to insufficient) and Group 3 (sustained insufficient) demonstrated a significant risk of PPD at all starting time-points in the multivariate analysis, but no significant association was evident between Group 2 (change from insufficient to sufficient) and PPD., Conclusion: Insufficient sleep at 36 GW was associated with a significant risk of developing PPD. Additionally, regardless of whether women had sufficient sleep, a shift towards worsening sleep at 36 GW was highly associated with PPD., (© 2021 International Federation of Gynecology and Obstetrics.)

There is a considerable need for cell-based in vitro skin models for studying dermatological diseases and testing cosmetic products, but current in vitro skin models lack physiological relevance compared to human skin tissue. For example, many dermatological disorders involve complex immune responses, but current skin models are not capable of recapitulating the phenomena. Previously, we reported development of a microfluidic skin chip with a vessel structure and vascular endothelial cells. In this study, we cocultured dermal fibroblasts and keratinocytes with vascular endothelial cells, human umbilical vascular endothelial cells. We verified the formation of a vascular endothelium in the presence of the dermis and epidermis layers by examining the expression of tissue-specific markers. As the vascular endothelium plays a critical role in the migration of leukocytes to inflammation sites, we incorporated leukocytes in the circulating media and attempted to mimic the migration of neutrophils in response to external stimuli. Increased secretion of cytokines and migration of neutrophils was observed when the skin chip was exposed to ultraviolet irradiation, showing that the microfluidic skin chip may be useful for studying the immune response of the human tissue., (© 2020 Wiley Periodicals, Inc.)

Objective: The aim of this study was to investigate the clinical implications of diabetes for the management of idiopathic sudden sensorineural hearing loss (ISSNHL)., Study Design: Retrospective study., Setting: Tertiary referral center., Subjects and Methods: ISSNHL patients (N = 403) who received inpatient management between January 2015 and December 2018 were analyzed. All were managed by a uniform treatment protocol of high-dose steroid therapy and salvage intratympanic steroid injections. Treatment results were evaluated according to the American Academy of Otolaryngology-Head and Neck Surgery's criteria 3 months after the start of treatment. We compared the clinical parameters and treatment outcomes of ISSNHL with and without diabetes. We also evaluated the influence of diabetes on the prognosis of ISSNHL by propensity score matching., Results: Overall, of the 403 ISSNHL patients, 94 (23.3%) had diabetes, and 11 were newly diagnosed with diabetes. The patients with diabetes were older than those without diabetes ( P < .001), and their initial hearing threshold was significantly higher ( P < .001). The diabetic patients were hospitalized for a longer period, and their hearing recovery rate was lower. However, when age, sex, and initial hearing level were adjusted by propensity score matching, the diabetic patients and matched controls yielded similar treatment results., Conclusions: ISSNHL with diabetes usually presents with severe hearing loss and requires longer hospitalization. However, diabetes itself may not influence the prognosis of ISSNHL. Proper management must be provided in ISSNHL with diabetes.

Background and Purpose: Bleeding is one of the most critical adverse effects of antithrombotic drugs, and many efforts have been made to discover novel antiplatelet agents without bleeding complications. Shear stress-induced platelet aggregation (SIPA), where the interaction of von Willebrand factor (vWF) and platelet glycoprotein (GP) Ib constitutes the initial step, is a promising target to overcome bleeding problems, as SIPA occurs only in pathological conditions. Here, we describe SP-8008, a novel modulator of vWF-GP Ib interactions and evaluated its antiplatelet/antithrombotic effects., Experimental Approach: Newly synthesized compounds were screened for antiplatelet effects in vitro, using human platelets exposed to high shear stress. Aggregation, intracellular calcium level, granule secretion, and integrin activation were assessed. Molecular modelling using virtual docking and flow cytometry were used to evaluate effects on vWF-GP Ib interactions. Antithrombotic effects in vivo were determined in rats, using arterial thrombosis and shear stress-specific thrombosis. Transection tail bleeding time was used to evaluate adverse effects., Key Results: SP-8008 was a potent inhibitor of SIPA, with IC 50 of 1.44 ± 0.09 μM. SP-8008 effectively and broadly blocked shear stress-induced platelet activation events, without any significant toxicity. Importantly, SP-8008 was highly selective against SIPA, effectively interfering with vWF-GP Ib engagement. Most importantly, SP-8008 exerted significant antithrombotic effects in vivo in both shear stress-specific and arterial thrombosis, without prolonging bleeding time., Conclusions and Implications: Our results demonstrated that SP-8008 can be a novel selective antiplatelet agent with improved safety profile., (© 2019 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Chronic prostatitis typically occurs in aging men, and its symptoms include frequent and painful urination. In recent study, several studies have shown that Korean red ginseng (KRG) can be used in the prevention and treatment of various diseases. The objective of this study is to investigate whether KRG can play a role in repressing the development of chronic nonbacterial prostatitis (CNP) in male Wistar rats. To induce CNP, rats were castrated and beta-estradiol (0.25 mg/kg) was subcutaneously (s.c.) injected daily. 7-week-old male Wistar rats were divided into 5 groups (the normal group, CNP group, positive group, and KRG group (0.25g/kg) and another KRG (0.50g/kg) group. After 4 weeks, all rats were sacrificed and their prostate and serum were analyzed. Compared to the positive group, the KRG groups (0.25g/kg and 0.50g/kg) showed similar protective properties on CNP based on the histopathologic morphology of the prostate and the inflammation cytokines in the prostate tissue. Also, results of the immunohistochemistry staining showed that expression levels of vascular endothelial growth factor A (VEGFA), interleukin 6 (IL6), interleukin 1 beta (IL-1ß), tumor necrosis factor (TNF-alpha), and cytochrome c oxidase subunit II (COX2) were also decreased in KRG group (0.25g/kg) and KRG group (0.50g/kg). These results suggested that KRG inhibited the development of CNP and might a useful herbal treatment or functional food for CNP.

The aim of the present study was to compare bone-collecting capacity of bone harvesting device and minimally irrigated low-speed drilling using three implant systems. One bone harvesting device and three commercially available drill systems were compared using the osteotomies on bovine rib bones. The amount of the collected bone particle and particle size (<500  μ m: small, 500-1000  μ m: medium, and >1000  μ m: large) were measured. Total wet (1.535 ± 0.232 mL) and dry volume (1.147 ± 0.425 mL) of the bone particles from bone harvesting device were significantly greater than three drill systems (wet volume: 1.225 ± 0.187-1.27 ± 0.29 mL and dry volume: 0.688 ± 0.163-0.74 ± 0.311 mL) ( P < 0.05). In all groups, the amount of large sized particles in wet and dry state was the greatest compared to that of medium and small particles. The dry weight of the bone particles showed the same tendency to volumetric measurement. In conclusion, total bone particles and large sized particles (>1000  μ m) were harvested significantly greater by bone harvesting device than minimally irrigated low-speed drilling. The composition of particle size in all harvesting methods was similar to each other.

The relationship between polymorphism of the angiotensin I converting enzyme ( ACE ) gene and chronic obstructive pulmonary disease (COPD) has been examined in many previous studies. However, their results were controversial. Therefore, we performed a meta-analysis to evaluate the relationship between the ACE gene and the risk of COPD. Fourteen case-control studies were included in this meta-analysis. The pooled p value, odds ratio (OR), and 95% confidence interval (95% CI) were used to investigate the strength of the association. The meta-analysis was performed using comprehensive meta-analysis software. Our meta-analysis results revealed that ACE polymorphisms were not related to the risk of COPD ( p > 0.05 in each model). In further analyses based on ethnicity, we observed an association between insertion/deletion polymorphism of the ACE gene and risk of COPD in the Asian population (codominant 2, OR = 3.126, 95% CI = 1.919-5.093, p < 0.001; recessive, OR = 3.326, 95% CI = 2.190-5.050, p < 0.001) but not in the Caucasian population ( p > 0.05 in each model). In conclusion, the present meta-analysis indicated that the insertion/deletion polymorphism of the ACE gene may be associated with susceptibility to COPD in the Asian population but not in the Caucasian population. However, the results of the present meta-analysis need to be confirmed in a larger sample.

Introduction: The objective of this study was to compare postoperative pain between single-port access total laparoscopic hysterectomy (SPA-TLH) using a transumbilical single-port system and conventional multi (three)-port access total laparoscopic hysterectomy (MPA-TLH)., Material and Methods: A randomized controlled trial was conducted on 60 women who underwent SPA-TLH and MPA-TLH for benign gynecologic diseases between March 2014 and January 2015. Patients were randomly assigned to undergo SPA-TLH (n = 30) or MPA-TLH (n = 30). The variables measured included surgical outcomes and postoperative pain at 30 min and 1, 12, 24, and 48 h after surgery, assessed by the visual analog scale, bolus requirement of intravenous patient-controlled analgesia, and additional analgesic use., Results: The two study groups did not differ in terms of patient demographics or surgical outcomes except for operative time. The SPA-TLH group had a longer operative time (p < 0.0001) compared with the MPA-TLH groups. There were no differences in pain scores between the two groups. The SPA-TLH group had significantly more intravenous analgesia requests during the 12-24 h after surgery (2.17 ± 3.05 vs. 0.79 ± 1.99; p = 0.047), more 24-48 h postoperative analgesics (0.21 ± 0.41 vs. 0.03 ± 0.19; p = 0.045), and more total additional analgesics (0.97 ± 0.94 vs. 0.45 ± 0.87; p = 0.034)., Conclusion: SPA-TLH was feasible compared with MPA-TLH but the SPA-TLH group had a longer operative time. Although there is no difference in pain based on the visual analog scale pain score, the SPA-TLH group required more analgesia to give the same postoperative pain control., (© 2015 Nordic Federation of Societies of Obstetrics and Gynecology.)

Objectives: To explore the role of antiapoptotic and apoptotic processes in the development of cholesteatoma by investigating the expression of an antiapoptotic (c-FLIP) and apoptotic (p53) protein relative to the expression of a proliferation marker (Ki-67)., Study Design: Basic science study., Setting: Tertiary referral center., Subjects and Methods: An immunohistochemical investigation was performed on 35 cholesteatoma specimens (21 acquired, 14 congenital) and 10 normal retroauricular skins to evaluate the expression of c-FLIP, p53, and Ki-67. The expression rate of each marker was measured to assess the difference between retroauricular skin and cholesteatoma, as well as between congenital and acquired cholesteatoma., Results: c-FLIP expression was significantly higher in the cholesteatoma specimens than in retroauricular skin (P < .05), while the expression of p53 did not significantly differ between the two. Ki-67 expression in cholesteatoma was significantly higher than in retroauricular skin (P < .001). The c-FLIP expression rate was positively correlated with that of Ki-67 (r = 0.47, P = .001), and there was no significant correlation between the expression level of p53 and that of Ki-67 (r = 0.152, P = .319). In addition, no differences in c-FLIP, p53, and Ki-67 expression rates were evident between congenital and acquired cholesteatoma., Conclusions: The upregulation of c-FLIP together with unchanged p53 suggests an altered equilibrium between apoptosis and antiapoptosis, favoring antiapoptosis, and may play a role in the pathogenesis of cholesteatoma., (© American Academy of Otolaryngology—Head and Neck Surgery Foundation 2015.)

Purpose: This study proposes a simple and noninvasive instrument called the "Rotatometer" to measure tibiofemoral rotation and investigates its clinical applicability to the assessment of static rotational knee laxity., Methods: The degree of tibiofemoral rotation was measured for a sample of 94 healthy volunteers with 188 knees by using the Rotatometer. The measurement was made by two independent and blinded examiners in three sessions at one-month intervals. The normative rotational profile and its relationship with gender and age were evaluated, and inter-observer reliability and intra-observer reliability were calculated., Results: Males showed 62° ± 5° of external rotation, whereas females, 64° ± 5°. Males showed 44° ± 5° of internal rotation, whereas females, 49° ± 4°. Females showed significantly higher degrees of rotation than males. Tibiofemoral rotation was not correlated with age, and external rotation and internal rotation had a moderate positive relationship. Inter-observer reliability ranged from 0.84 to 0.91 for external rotation and 0.90 to 0.95 for internal rotation, and intra-observer reliability ranged from 0.69 to 0.89 for external rotation and 0.87 to 0.95 for internal rotation., Conclusions: The results suggest the Rotatometer to be a simple and noninvasive device with high inter- and intra-observer reliability. The device can provide a normative rotational profile for reference purposes and thus can be used to determine the preoperative and postoperative rotational status of knees with anterior cruciate ligament injuries and compare results from different reconstruction techniques.

Background: Thyroid cancer affects relatively young adults, and its overall survival is excellent. With long life expectancy, the development of subsequent cancers is an important concern for survivors of thyroid cancer. The objective of this study was to investigate the incidence and types of second primary malignancies in Korean patients with thyroid cancer., Methods: The study cohort included 178,844 registrants with thyroid cancer from the Korea Central Cancer Registry (KCCR) database between 1993 and 2010. Standardized incidence ratios (SIRs) were calculated using a statistical software program (SEER*Stat 8.0.4)., Results: Among 178,844 patients with thyroid cancer, 2895 (1.6%) were diagnosed with subsequent second primary malignancies. The overall risks of a second primary cancer were elevated by 6% in patients who had thyroid cancer compared with the general population during the same period. The elevated risks for developing second cancers were observed in all sites except the stomach and cervix. The elevated risk of second primary cancers was observed within the first 10 years of follow-up. Leukemia and cancers of the salivary gland, kidney, prostate, lung, and breast had the most significantly elevated risks as secondary cancers and presented as early as during the first 5 years after the initial diagnosis of thyroid cancer., Conclusions: This is the largest, standardized, population-based study to date using nationwide data from the entire Korean population. The risks of several cancers were elevated significantly during follow-up, thus alerting physicians to pay special attention in their care of patients with thyroid cancer and long-term survivors., (© 2014 American Cancer Society.)

Background: FOS has been implicated in the progression of renal disease including IgAN. In this study, we investigated whether polymorphisms of FOS family genes [FOS, FOSB, FOS-like antigen 1 (FOSL1), and FOSL2] were associated with immunoglobulin A nephropathy (IgAN) and the clinical phenotypes of IgAN patients., Methods: We genotyped single nucleotide polymorphisms (SNPs) of FOS family genes (rs2239615 and rs7101 for FOS, rs12373539 and rs2282695 for FOSB, rs637571 for FOSL1, and rs925255 for FOSL2) using direct sequencing in 198 IgAN patients and 290 control subjects., Results: No SNPs were associated with IgAN; however, in the analysis of clinical phenotypes, we found that rs637571 of FOSL1 was associated with podocyte foot process effacement of IgAN in additive (CT vs. TT vs. CC, P = 0.0031, OR = 2.08, 95% CI = 1.27-3.40) and dominant models (CT/TT vs. CC, P = 0.0034, OR = 2.50, 95% CI = 1.35-4.64). The frequency of genotypes containing the T allele was increased in IgAN patients with podocyte foot process effacement, compared to those without podocyte foot process effacement., Conclusion: These results suggest that FOSL1 may be related to IgAN severity., (© 2014 Wiley Periodicals, Inc.)

Background and Purpose: Dysregulated tonic tension and calcium sensitization in blood vessels has frequently been observed in many cardiovascular diseases. Despite a huge therapeutic potential, little is known about natural products targeting tonic tension and calcium sensitization., Experimental Approach: We screened natural products for inhibitory effects on vasoconstriction using the rat isolated thoracic aorta and found that an anthraquinone derivative, emodin, attenuated tonic tension. Organ bath system, primary vascular smooth muscle cells, confocal microscopy and Western blot analysis were employed to demonstrate the suppressive effects of emodin on PKCδ-mediated myosin phosphatase inhibition., Key Results: Emodin, an active ingredient of Polygonum multiflorum extract, inhibited phenylephrine-induced vasoconstriction in rat isolated thoracic aorta, and inhibited vasoconstriction induced by 5-HT and endothelin-1. It also generally suppressed vasoconstrictions mediated by voltage-operated, store-operated calcium channels and intracellular calcium store. However, emodin did not affect agonist-induced calcium increases in primary smooth muscle cells. In contrast, post-treatment with emodin following phenylephrine stimulation potently suppressed tonic tension in rat aortic rings. Western blot analysis revealed that emodin inhibited phenylephrine-induced phospho-myosin light chain (pMLC) and the phosphorylation of myosin-targeting subunit and C-kinase-activated protein phosphatase-1 inhibitor (CPI-17). This was mediated by selective inhibition of PKCδ, whereas PKCα was not involved., Conclusion and Implications: Emodin attenuates tonic tension through the blockade of PKCδ and CPI-17-mediated MLC-phosphatase inhibition. This new mode of action for the suppression of tonic tension and structural insights into PKCδ inhibition revealed by emodin may provide new information for the development of modulators of tonic tension and for the treatment of hypertension., (© 2014 The British Pharmacological Society.)

Cellular behavior is dependent on a variety of physical cues required for normal tissue function. In order to mimic native tissue environments, human alveolar bone-derived mesenchymal stem cells (hABMSCs) were exposed to orbital shear stress (OSS) in a low-speed orbital shaker. The synergistic effects of OSS on proliferation and differentiation of hABMSCs were investigated. In particular, we induced the osteoblastic differentiation of hABMSCs cultured in the absence of OM by exposing hABMSCs to OSS (0.86-1.51 dyne/cm(2)). Activation of Cx43 was associated with exposure of hABMSCs to OSS. The viability of cells stimulated for 10, 30, 60, 120, and 180 min/day increased by approximately 10% compared with that of control. The OSS groups with stimulation of 10, 30, and 60 min/day had more intense mineralized nodules compared with the control group. In quantification of vascular endothelial growth factor (VEGF) and bone morphogenetic protein-2 (BMP-2) protein, VEGF protein levels under stimulation for 10, 60, and 180 min/day and BMP-2 levels under stimulation for 60, 120, and 180 min/day were significantly different compared with those of the control. In conclusion, the results indicated that exposing hABMSCs to OSS enhanced their differentiation and maturation.

Background: Although differentiated thyroid carcinoma (DTC) rarely develops distant metastases, the present study was performed to evaluate factors that affect the survival of patients with DTC who present with distant metastasis., Methods: Among 4,989 patients who underwent thyroid surgery for DTC, 82 presenting with distant metastasis were analyzed. Based on radioiodine ((131)I) avidity and the thyroid-stimulating hormone-stimulated serum thyroglobulin (sTg) level at the time of metastasis, patients were divided into three groups: group 1 ((131)I uptake + sTg ≤ 215 ng/mL, n = 46), group 2 ((131)I uptake + sTg > 215 ng/mL, n = 24), group 3 (no (131)I uptake, n = 12). Disease-specific survival (DSS) was estimated using the Kaplan-Meier method. Factors predicting the outcome were evaluated using Cox proportional hazard regression analysis., Results: The age of patients (p = 0.04), frequency of follicular thyroid carcinoma (p = 0.002), tumor size (p < 0.001), and number of multiple metastatic sites (p = 0.004) differed significantly among the groups. With a median follow-up after surgery of 72 months, the 5- and 10-year DSSs for all patients were 84 and 69 %, respectively. The predictors of survival were age (p = 0.004), symptoms at the time of presentation (p = 0.045), histology (p = 0.01), sites of metastasis (p = 0.03), and (131)I avidity and sTg level at the time of metastasis (p = 0.002). In the multivariate analysis, age, histology, and (131)I avidity and sTg level at the time of metastasis remained significant factors for survival., Conclusions: Certain DTC patients with distant metastasis demonstrate favorable outcomes dependent on age, histology, and (131)I avidity and sTg level at the time of metastasis.

Aims: The aim of this study was to assess patient outcome after discontinuation of alfuzosin treatment in patients with benign prostatic hyperplasia (BPH)., Methods: This study included 200 BPH patients. Alpha-blockers were discontinued after 12 weeks of treatment when the International Prostatic Symptom Score (IPSS) was reduced to < 8 points, peak urine flow rate (Q(max)) was increased to ≥ 15 ml/s, the postvoiding residual (PVR) urine volume was ≤ 100 ml and the patient agreed to discontinue treatment. Urinary symptoms of the patients were assessed at 4, 8, 12 and 24 weeks after discontinuation of medication, and surveys were performed asking whether patients wanted to restart administration of medication., Results: Of 200 enrolled patients, 142 (71.00%) received 12 weeks of treatment with 10 mg of alfuzosin. The medication was discontinued in 58 of 142 patients (40.85%) because urinary symptoms had improved. Among these patients, follow-up observations were performed for 49 patients up to 24 weeks after treatment discontinued. Of these 49 patients, 28 (57.14%) showed correct urination without a need to restart treatment up to 24 weeks after the medication was discontinued. The discontinuation group demonstrated improved voiding symptoms, including Q(max) and PVR, relative to the re-administration group at baseline. Furthermore, the discontinuation group showed a smaller prostate volume than the re-administration group (p = 0.045)., Conclusion: When patients with BPH displayed symptomatic improvement upon treatment with alpha-blockers, the improvements were maintained in a select subpopulation of patients without the need to re-administer the alpha-blockers., (© 2013 John Wiley & Sons Ltd.)

Background: Although papillary thyroid carcinoma (PTC) often presents as multifocal or bilateral tumors, but whether multifocality or bilaterality is associated with disease recurrence/persistence is controversial. We evaluated the association between multifocality and bilaterality of PTC and disease recurrence/persistence. We also analyzed the location and number of tumors in multifocal PTC., Methods: We reviewed the medical records of 2,095 patients who underwent total thyroidectomy for PTC. Tumors were classified as solitary or multifocal PTC according to the number of tumors present. Multifocal PTCs were subdivided into multifocal-unilateral and multifocal-bilateral PTC based on the tumor location. Solitary tumor or multifocal tumors located in one lobe were classified as unilateral PTC, and tumors in both lobes were classified as bilateral PTC. We analyzed the clinicopathologic features and clinical outcomes in each classification. Logistic regression models were used to assess the relation between multifocality or bilaterality and disease recurrence/persistence., Results: Extrathyroidal invasion, cervical lymph node metastasis, and advanced TNM stage were significantly more frequent in multifocal PTC than in solitary PTC. Extrathyroidal invasion, cervical lymph node metastasis, advanced TNM stage, and distant metastasis were significantly more frequent in bilateral PTC than in unilateral PTC. The clinicopathologic parameters did not differ significantly between patients with multifocal-unilateral and multifocal-bilateral PTC. Multifocality was found to be an independent predictor of disease recurrence/persistence [odds ratio (OR) 1.45, 95 % confidence interval (CI) 1.01-2.10, p = 0.04]. However, there was no association between bilaterality and disease recurrence/persistence (OR 0.98, 95 % CI 0.64-1.48, p = 0.92). In multifocal PTC, the number of tumors (OR 1.75, 95 % CI 1.04-2.97, p = 0.04), but not the location of tumors (OR 0.56, 95 % CI 0.31-1.02, p = 0.06), was significantly associated with disease recurrence/persistence., Conclusions: Although multifocal and bilateral PTC had aggressive pathologic features, only multifocality was associated with an increased risk of disease recurrence/persistence. This suggests that the number of tumor foci, but not their location, is a significant predictor of clinical outcomes.

Ultrasound stimulation produces significant multifunctional effects that are directly relevant to alveolar bone formation, which is necessary for periodontal healing and regeneration. We focused to find out effects of specific duty cycles and the percentage of time that ultrasound is being generated over one on/off pulse period, under ultrasound stimulation. Low-intensity pulsed ultrasound ((LIPUS) 1 MHz) with duty cycles of 20% and 50% was used in this study, and human alveolar bone-derived mesenchymal stem cells (hABMSCs) were treated with an intensity of 50 mW/cm(2) and exposure time of 10 min/day. hABMSCs exposed at duty cycles of 20% and 50% had similar cell viability (O.D.), which was higher (*P < 0.05) than that of control cells. The alkaline phosphatase (ALP) was significantly enhanced at 1 week with LIPUS treatment in osteogenic cultures as compared to control. Gene expressions showed significantly higher expression levels of CD29, CD44, COL1, and OCN in the hABMSCs under LIPUS treatment when compared to control after two weeks of treatment. The effects were partially controlled by LIPUS treatment, indicating that modulation of osteogenesis in hABMSCs was related to the specific stimulation. Furthermore, mineralized nodule formation was markedly increased after LIPUS treatment than that seen in untreated cells. Through simple staining methods such as Alizarin red and von Kossa staining, calcium deposits generated their highest levels at about 3 weeks. These results suggest that LIPUS could enhance the cell viability and osteogenic differentiation of hABMSCs, and could be part of effective treatment methods for clinical applications.

This study was performed to investigate the effects of extremely low frequency pulsed electromagnetic fields (ELF-PEMFs) on the proliferation and differentiation of human alveolar bone-derived mesenchymal stem cells (hABMSCs). Osteogenesis is a complex series of events involving the differentiation of mesenchymal stem cells to generate new bone. In this study, we examined not merely the effect of ELF-PEMFs on cell proliferation, alkaline phosphatase (ALP) activity, and mineralization of the extracellular matrix but vinculin, vimentin, and calmodulin (CaM) expressions in hABMSCs during osteogenic differentiation. Exposure of hABMSCs to ELF-PEMFs increased proliferation by 15% compared to untreated cells at day 5. In addition, exposure to ELF-PEMFs significantly increased ALP expression during the early stages of osteogenesis and substantially enhanced mineralization near the midpoint of osteogenesis within 2 weeks. ELF-PEMFs also increased vinculin, vimentin, and CaM expressions, compared to control. In particular, CaM indicated that ELF-PEMFs significantly altered the expression of osteogenesis-related genes. The results indicated that ELF-PEMFs could enhance early cell proliferation in hABMSCs-mediated osteogenesis and accelerate the osteogenesis.

Fibroblast growth factors (FGFs) and their receptors (FGFRs) have been implicated in prostate growth and are overexpressed in benign prostatic hyperplasia (BPH). In this study, we investigated whether single nucleotide polymorphisms (SNPs) of the FGFR genes (FGFR1 and FGFR2) were associated with BPH and its clinical phenotypes in a population of Korean men. We genotyped four SNPs in the exons of FGFR1 and FGFR2 (rs13317 in FGFR1; rs755793, rs1047100, and rs3135831 in FGFR2) using direct sequencing in 218 BPH patients and 213 control subjects. No SNPs of FGFR1 or FGFR2 genes were associated with BPH. However, analysis according to clinical phenotypes showed that rs1047100 of FGFR2 was associated with prostate volume in BPH in the dominant model (GA/AA versus GG, P = 0.010). In addition, a significant association was observed between rs13317 of FGFR1 and international prostate symptom score (IPSS) in the additive (TC versus CC versus TT, P = 0.0022) and dominant models (TC/CC versus TT, P = 0.005). Allele frequency analysis also showed significant association between rs13317 and IPSS (P = 0.005). These results suggested that FGFR genes could be related to progression of BPH.

Quercetin, an abundant flavonol found in fruits and vegetable, has been implicated in lowering the risk of cardiovascular disease that is often associated with high plasma levels of low density lipoprotein (LDL) cholesterol. Here we investigated whether quercetin could modulate the expression of LDL receptors (LDLR) in HepG2 cells and the possible underlying mechanisms to exert quercetin's effects. We found that quercetin was able to induce LDLR expression with at least a 75 µ m concentration, which was accompanied by an increase in nuclear sterol regulatory element binding protein 2 (SREBP2). This effect was mediated by activation of c-jun-N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) signalling pathways as implicated by experiments using chemical inhibitors of each pathway. When cells were challenged with protein synthesis inhibitors in quercetin-activated LDLR transcription, LDL mRNA levels were not significantly affected by cycloheximide but puromycin abolished quercetin-induced LDLR transcription. Taken together, we conclude that quercetin can initiate LDLR transcription by enhancing SREBP2 processing, but new protein synthesis might be necessary to exert a maximum effect of quercetin in the up-regulation of the LDLR gene. Our findings demonstrate that quercetin strongly up-regulated LDLR gene expression, which might elicit hypolipidemic effects by increasing the clearance of circulating LDL cholesterol levels from the blood., (Copyright © 2012 John Wiley & Sons, Ltd.)

Aim:  To compare the improvement in erectile dysfunction (ED) and lower urinary tract symptoms (LUTS) as well as safety of tadalafil dosed at 20 mg on-demand and 5 mg once daily among ED patients. Materials and methods:  A total of 194 ED patients visited between March 2010 and June 2011 were recruited. Out of 194 individuals, 168 (86.6%) met inclusion criteria after completing the two-week screening period (V0). The Patients were randomly allocated into two groups: (i) 20 mg of tadalafil as needed (Group 1: n = 84, 50.0%) and (ii) 5 mg of tadalafil once daily (Group 2: n = 84, 50.0%). Blood pressure (BP), heart rate (HR) and the five-item version of the International Index of Erectile Function (IIEF-5) were assessed immediately before initiation of treatment (V1) and after four (V2) and twelve weeks of treatment (V3). In men with an IPSS of ≥ 8 at V1, IPSS, maximal flow rate (Qmax) and post-void residual volume (PVR) were also assessed. Results:  Of the 168 patients, 134 (79.8%; Group 1: n = 68, 81.0%; Group 2: n = 66, 78.6%) patients completed the trial. IIEF-5 improved in both groups, and the mean change was larger in Group 2 at V3 (4.9 ± 4.2 vs. 6.5 ± 4.5; p = 0.032) Similarly, though IPSS (with ≥ 8, n = 88, 65.7%; Group 1: n = 44, 64.7%; Group 2: n = 44, 66.7%) improved in both groups, the mean change was larger in Group 2 at V3 (-2.8 ± 4.3 vs. -4.8 ± 4.1; p = 0.026). Qmax and PVR did not differ significantly in either group. Conclusions:  Once daily tadalafil was more efficacious in treating both ED and LUTS than on-demand dosing. However, no differences were observed between the two dosing schedules with regard to the improvement in LUTS when stratified by improvement in ED. The side effects were insignificant for both dosing schedules., (© 2012 Blackwell Publishing Ltd.)

Background: The objectives of this study were to determine the proportions of major oncogenic alterations and to examine survival in genotype-specific subsets of never-smokers with nonsmall cell lung cancer (NSCLC)., Methods: The authors concurrently analyzed mutations in the epidermal growth factor receptor (EGFR) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) genes and investigated anaplastic lymphoma kinase (ALK) gene rearrangements in samples from 229 never-smokers with NSCLC. ALK rearrangements were identified by fluorescent in situ hybridization and were confirmed by immunohistochemistry. Mutations in EGFR (exons 18 to 21) and KRAS (codons 12 and 13) were determined by direct sequencing., Results: Of 229 tumors, the frequency of EGFR mutations, ALK rearrangements, KRAS mutations, and no mutations (wild type [WT]) in any of the 3 genes (WT/WT/WT) was 48%, 8.3%, 3.5%, and 40.2%, respectively. All genetic alterations were mutually exclusive. The median progression-free survival after treatment with EGFR tyrosine kinase inhibitors (TKIs) was 12.8 months, 6.3 months, 2.1 months, and 1.6 months in patients with EGFR mutations, the WT/WT/WT genotype, KRAS mutations, and ALK rearrangements, respectively. In a Cox regression model, the adjusted hazard ratio for the risk of disease progression after treatment with EGFR TKIs was 0.59 (95% confidence interval [CI], 0.40-0.87; P = .008) for patients with EGFR mutations, 4.58 (95% CI, 2.07-10.15; P < .001) for patients with ALK rearrangements, and 4.23 (95% CI, 1.65-10.8; P = .003) for patients with KRAS mutations. Overall survival also differed significantly among genotypes., Conclusions: To the authors' knowledge, this was the largest comprehensive and concurrent analysis to date of 3 major oncogenic alterations in a cohort of East Asian never-smokers with NSCLC. Because survival outcomes differed among genotypes, and drugs that target specific alterations currently are available, genetic profiling to identify genotype-specific subsets can lead to successful treatment with appropriate kinase inhibitors., (Copyright © 2011 American Cancer Society.)

Background. To examine the results of treatment of Extramammary Paget's disease (EMPD) in ethnic Chinese. Method. Between 1990 and 2010, patients treated for EMPD were reviewed. Data were analyzed retrospectively. Results. Forty-eight patients were treated by surgical resection. Local recurrence rate was 14.6%. The postresection defects were repaired by primary closure (8.3%), partial thickness skin graft (72.9%), or local/regional flaps (18.8%). Dermal invasion was found in 9 patients (18.8%). Seven patients (14.6%) developed regional lymph node metastasis (concurrent with surgery, n = 1; subsequent to surgery, n = 6), and 3 patients (6.3%) had systemic metastasis after surgery. The presence of dermal invasion was associated with significantly higher incidence of regional lymph nodes and systemic metastasis. The incidence of associated internal malignancy was 8.3%. Conclusion. The mainstay of treatment for EMPD is surgery. Pathological dermal invasion increases the chance of regional lymph node as well as systemic metastasis. The association with internal malignancy warrants preoperative endoscopic examination in all patients.

Objectives. This study aims to report our experience in the management of HNBCC in ethnic Chinese over a 10-year period. Methods. A retrospective review of all ethnic Chinese patients with HNBCC treated in a tertiary centre from 1999 to 2009. Results. From 1999 to 2009, 225 patients underwent surgical excision for HNBCC. Majority were elderly female patients. Commonest presentation was a pigmented (76.2%) ulcer (64.8%) over the nose (31.6%). Median skin margin taken on tumour excision was 2.0 mm; primary skin closure was achieved in 51.8%. Postresection skin margin was clear in 75.4%. Of those with inadequate skin margins, 56.7% opted for further treatment, 43.4% for observation. Recurrence rates were 2.6% and 13.8%, respectively (P = 0.106). Overall recurrence rate was 5.5%. Conclusions. HNBCC commonly presented as pigmented ulcers over the nose of elderly female patients in our locality. Adequate tumour excision ± reconstruction offered the best chance of cure. Reexcision of those with inadequate skin margins improved local tumour control.

Chronic kidney disease (CKD) is a common cause of end-stage renal disease. Antihypertensive agents are used clinically to inhibit the progression of CKD, but cannot prevent eventual renal failure. This study investigated the effect of Tanshinone IIA, an active component of Salvia miltiorrhiza, in rats suffering from CKD induced by 5/6 nephrectomy. After development of renal insufficiency, the rats were treated with Tanshinone IIA (10 mg/kg) for 8 weeks. Serum creatinine, angiotensin II (Ang II), transforming growth factor β1 (TGF-β1) and collagen IV levels were significantly reduced in Tanshinone IIA treated rats compared with a control group. In addition, Tanshinone IIA suppressed increases in urinary protein excretion in CKD rats. These findings suggest that chronic oral administration of Tanshinone IIA can improve renal dysfunction associated with CKD., (Copyright © 2010 John Wiley & Sons, Ltd.)

This study aimed to investigate the inhibitory effect of Bupleurum falcatum and its combination with angiotensin II receptor blocker (ARB) on cytokine and chemokine production in cultured human mesangial cells. Human mesangial cells were isolated and cultured in Dulbecco's modified Eagle's medium culture medium. Bupleurum falcatum, ARB, and the combination of the two were added to human mesangial cells. Cytokine and chemokine levels were analysed using an enzyme-linked immunosorbent assay. There were no significant differences in the expression of IL-1ss, IL-2 or TNF-a between controls and the experimental groups. However, IL-11 and monocyte chemoattractant protein-1 (MCP-1) levels were significantly reduced in response to ARB, Bupleurum falcatum, or their combination when compared with controls. IL-8 expression was reduced significantly only in cells treated with ARB. Both Bupleurum falcatum and ARB treatments alone reduced the cytokine concentration, but there was not a stronger reduction when the two drugs were combined. It was shown that Bupleurum falcatum inhibited cytokine production in human mesangial cells. However, there were no additive effects on the suppression of cytokine production when Bupleurum falcatum was combined with ARB. Further studies are needed to elucidate the renoprotective effects of Bupleurum falcatum., ((c) 2009 John Wiley & Sons, Ltd.)

Objective: To determine the significance of laryngopharyngeal reflux (LPR) in benign vocal mucosal lesions., Study Design and Setting: A case-control study at the tertiary referral medical center., Subjects and Methods: From April 2003 to December 2006, we studied 110 patients with benign vocal mucosal lesions who had undergone 24-hour ambulatory double pH monitoring. The control group included 200 patients who had undergone ambulatory 24-hour double-probe pH monitoring due to laryngopharyngeal reflux-related symptoms without specific findings of benign vocal mucosal lesions. Reflux symptom index and reflux finding score were measured. We compared the prevalence of pathologic laryngopharyngeal reflux and various parameters of the pH monitoring such as total reflux number, fraction time of pH below 4 in various positions, and DeMeester scores., Results: The prevalence of pathologic laryngopharyngeal reflux was 65 percent in the control group, 66 percent in vocal nodule group, 75 percent in the vocal polyp group, and 90 percent in the Reinke's edema group. Patients with Reinke's edema had a significantly higher prevalence of pathologic laryngopharyngeal reflux than controls (P = 0.016). LPR was associated with a significantly increased risk of Reinke's edema (odds ratio: 4.846, 95% confidence interval 1.093 approximately 21.492). Total reflux number and DeMeester scores in the Reinke's edema group and fraction time of pH below 4 in the supine position in the vocal polyp group were significantly higher than those in the control group., Conclusion: Laryngopharyngeal reflux might play a role as an etiologic factor in Reinke's edema and vocal polyps.

The excessive proliferation and migration of synoviocytes are well-characterized phenomena that play key roles in the pathophysiology of rheumatoid arthritis (RA). Melatonin has been shown to have potent anti-proliferative effect in various cancer cells such as breast and prostate cancer cells. In this study, we examined the role of melatonin on synoviocyte proliferation in primary cultured human fibroblast-like synoviocytes (FLSs) by analyzing protein expression of P21(CIP1) (P21) and P27(KIP1) (P27), the cyclin-dependent kinase inhibitors that are important in cell cycle control, and the phosphorylation of mitogen-activated protein kinases (MAPKs). RA-FLS proliferation was determined by a [(3)H]-thymidine incorporation assay. Western blot analysis was applied to examine the underlying mechanisms of melatonin's effect. Melatonin inhibited RA-FLS proliferation in a dose-dependent manner. It reduced proliferation of passage 2 FLSs by 25% at 10 microm and by nearly 40% at 100 microm concentrations. The inhibitory effect of melatonin on RA-FLS proliferation was also observed in passages 4 and 6. Melatonin upregulated the expression levels of P21 and P27 dose-dependently (24 hr), induced the phosphorylation of extracellular signal-regulated protein kinase (ERK) time-dependently (10 microm), but did not affect phosphorylation of P38 in RA-FLSs. In addition, the expression of P21 and P27 triggered by melatonin was inhibited by the pretreatment of the ERK inhibitor, PD98059 (10 microm). The anti-proliferative action of melatonin in RA-FLSs was also blocked by PD98059. Taken together, these results suggest that melatonin exerts the inhibitory effect of the proliferation of RA-FLSs through the activation of P21 and P27 mediated by ERK. Hence we suggest that melatonin could be used as a therapeutic agent for the treatment of RA.

Objective: This study aimed to analyze the differences of soluble endoglin (sEng) and transforming growth factor-beta1 (TGF-beta1) according to preeclamptic complications and to investigate the correlation between these factors and the clinical symptoms of preeclampsia., Method: We estimated the levels of sEng and TGF-beta1 in plasma collected in the second trimester at the time of genetic amniocentesis from 60 women who subsequently developed preeclampsia and 124 contemporaneous normotensive women., Results: sEng levels were higher in cases than in controls, whereas TGF-beta1 levels were lower (P < 0.001). sEng levels, but not TGF-beta1 levels, were higher in cases with severe or preterm delivery than in cases with mild preeclampsia or term delivery (P < 0.001) and were increased in cases destined to deliver a small gestational age neonate (P < 0.001). Moreover, sEng levels, but not TGF-beta1 levels, showed a positive correlation with maximum diastolic and systolic blood pressure (r = 0.57, P < 0.001; and r = 0.33, P < 0.001, respectively) and proteinuria (r = 0.42, P < 0.001)., Conclusion: Early midtrimester plasma levels of sEng are predictive of subsequence occurrence and severity of preeclampsia, in terms of severity of hypertension and proteinuria, prematurity, and association with small for gestational age neonates., ((c) 2009 John Wiley & Sons, Ltd.)

Verapamil is known to be a P-glycoprotein (P-gp) substrate and norverapamil is formed via hepatic cytochrome P450 (CYP 3A) in the rat. Epigallocatechin gallate (EGCG), a flavonoid, was reported to be an inhibitor of both P-gp and CYP3A. Hence, it could be expected that EGCG could alter the pharmacokinetics of verapamil. In this study, 9 mg/kg verapamil was administered orally to Sprague-Dawley rats 30 min after the oral administration of 2 and 10 mg/kg of oral EGCG. Compared with the controls, the AUC values of both verapamil (74.3% and 111% increase for 2 and 10 mg/kg EGCG, respectively) and norverapamil (51.5% and 87.2% increase for 2 and 10 mg/kg EGCG, respectively) were significantly greater in the presence of EGCG. However, compared with the controls, both the AUC and the relative bioavailability of verapamil were significantly (p<0.01) increased by 74.3-111% in the presence of EGCG. The likely explanation is inhibition of P-gp. Inhibition of CYP3A would increase the AUC of verapamil but decrease the AUC of norverampil. However, inhibition of P-gp would lead to an increase of AUC of both verapamil and norverapamil., (2009 John Wiley & Sons, Ltd.)

Background and Purpose: Inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) have been suggested as key components in various inflammatory diseases. Here we examined the effects of new quinolinedione derivatives, 6-(4-fluorophenyl)-amino-5,8-quinolinedione (OQ1) and 6-(2,3,4-trifluorophenyl)-amino-5,8-quinolinedione (OQ21) on activity and expression of iNOS and COX-2 to explore their anti-inflammatory properties., Experimental Approach: The effects of OQ1 and OQ21 were assessed on lipopolysaccharide (LPS)-induced iNOS and COX-2 in murine macrophage cell line (RAW264.7), along with isolated enzyme assays to measure enzyme inhibition. Nuclear factor-kappaB (NFkappaB) activation pathways were investigated to elucidate mechanisms underlying OQ-mediated suppression of the expression of iNOS and COX-2. In vivo anti-inflammatory activities of OQ compounds were evaluated in mouse ear oedema, induced by topical 12-O-tetradecanoylphorbol-13-acetate (TPA)., Key Results: LPS-induced NO production in RAW264.7 cells was inhibited by OQ1 and OQ21 through the attenuation of iNOS expression as well as iNOS activity. Down-regulation of iNOS followed blocking of NFkappaB activation, as assessed by inhibitory kappaB degradation and electrophoretic mobility shift assay for NFkappaB. Synthesis and accumulation of prostaglandin E(2) were also suppressed by OQ1 and OQ21. LPS-induced COX-2 expression and cellular COX-2 activities were attenuated by OQ1 and OQ21. Consistent with these results, OQ1 showed potent anti-inflammatory effects in mouse ear oedema induced by TPA., Conclusions and Implications: The novel quinolinedione derivatives, OQ1 and OQ21, showed potent anti-inflammatory activity through dual inhibitory effects on iNOS and COX-2, suggesting that OQ derivatives might provide a new therapeutic modality for chronic inflammatory diseases, refractory to conventional drug therapies.

Objective: This study aimed to identify the prognostic value of tumor markers in olfactory neuroblastoma (ONB)., Study Design and Setting: Seventeen patients with ONB (23 tumor specimens) were included. Each specimen was studied for bcl-2, p53, MIC-2 by immunohistochemistry and for N-myc by chromogenic in situ hybridization., Results: Twelve (70%) of 17 patients and 15 (65%) of 23 specimens showed positive reactivity for bcl-2. Of seven patients who were treated with neoadjuvant chemotherapy, one patient with diffuse bcl-2 expression achieved complete remission. Another patient without bcl-2 expression had no response to chemotherapy. Five patients who showed partial positivity achieved partial remission. Survival and bcl-2 expression tended to correlate, but it was not statistically significant (P = 0.06). All of the ONB specimens were negative for N-myc. Positive immunoreactivity for MIC-2 or p53 was found only in one specimen., Conclusion: Bcl-2 expression was commonly found in ONB and the immunoreactivity for bcl-2 might predict response to neoadjuvant chemotherapy. In addition, Bcl-2 expression tended to be associated with worse survival.

Melatonin possesses a number of important biologic activities including oncostatic, anti-oxidant, and immunostimulatory actions. This study was designed to assess the effects of melatonin on inflammation-related gene expression in lipopolysaccharide (LPS)-stimulated human peripheral blood mononuclear cells (PBMCs), using CombiMatrix 2K Human Inflammation chip. After pretreatment with melatonin (100 microm) for 4 hr, cells were incubated with LPS (1 microg/mL) for 24 hr. We compared gene expression profiles between LPS-treated, melatonin-treated, LSP/melatonin-treated, and control groups. LPS induced the upregulation of 95 genes, compared with controls. Melatonin pretreatment in LPS-stimulated PBMCs suppressed the expression of 23 genes more than twofold. Interestingly, melatonin showed a suppressive effect on the expression of CC chemokine subfamily genes, including CCL2/MCP1, CCL3/MIP1 alpha, CCL4/MIP1 beta, CCL5/RANTES, CCL8/MCP2, CCL20/MDC, and CCL22/MIP3 alpha, in LPS-stimulated PBMCs. This result was confirmed by reverse transcriptase polymerase chain reaction. Among the CC chemokine subfamily genes, particularly, the expression of CCL2 and CCL5 was markedly downregulated by melatonin in LPS-stimulated PBMCs. The secretion levels of CCL2 and CCL5 were measured using enzyme-linked immunosorbent assay. Stimulation of PBMCs by LPS induced the secretion of CCL2 (2334.3 +/- 161.4 pg/mL, mean +/- S.E.M.), whereas melatonin pretreatment (153.0 +/- 3.8 pg/mL) inhibited the LPS-induced secretion of CCL2. Melatonin pretreatment (2696.2 +/- 385.3 pg/mL) also inhibited the LPS-induced secretion of CCL5 (4679.6 +/- 107.5 pg/mL). Taken together, these results suggest that melatonin may have a suppressive effect on LPS-induced expression of CC chemokine genes, especially CCL2 and CCL5, which may explain its beneficial effects in the treatment of various inflammatory conditions.

Objectives: The aim of this study was to evaluate the role of nasal bone assessment in first-trimester screening for Down syndrome (DS) in the Korean population., Methods: From July 2004 to March 2006, we prospectively evaluated the fetal nasal bones at 11-14 weeks' gestation in the Korean population., Results: A successful evaluation was possible in 6490 of 6787 fetuses (95.6%). Absent, hypoechoic, and short nasal bones were seen in 4 (26.7%), 4 (26.7%), and 1 (6.7%) of 15 fetuses with DS, respectively, whereas in 5 (0.1%), 11 (0.2%), and 246 (3.8%) of 6456 normal fetuses. The incidence of absent and hypoechoic nasal bone showed significant differences between normal fetuses and fetuses with DS (P < 0.0005, both). Screening for DS using an absent or hypoechoic nasal bone resulted in a sensitivity of 53.3%, a specificity of 99.8%, a positive likelihood ratio of 215.2, and a negative likelihood ratio of 0.5., Conclusion: Our study showed that nasal bone abnormality at 11-14 weeks of gestation had a high association with DS in the Korean population. This suggests that nasal bone assessment can be used to supplement the current first-trimester screening for DS in the Korean population., (2007 John Wiley & Sons, Ltd)

Objective: To construct new reference charts and equations for fetal biparietal diameter (BPD), head circumference (HC), abdominal circumference (AC) and femur diaphysis length (FDL) from Korean fetuses at 12-40 weeks., Method: Prospective cross-sectional data obtained in one center for 5 years from a population of pregnant women undergoing ultrasound examination between the 12th and 40th week of gestation. Exclusion criteria comprised all maternal and fetal conditions possibly affecting fetal biometry. No fetuses were excluded on the basis of abnormal biometry. For each measurement, regression models were fitted to estimate both the mean and the standard deviation at each menstrual age., Results: Biometric measurements were obtained for 10 455 fetuses. New charts and reference equations are reported for BPD, HC, AC and FDL. Reference equations are cubic models., Conclusion: We present new Korean reference charts and equations for fetal biometry. They can be easily used in obstetric ultrasound studies for the Korean population., ((c) 2007 John Wiley & Sons, Ltd.)

The prevalence of diabetes has exponentially increased in recent decades due to environmental factors such as nocturnal lifestyle and aging, both of which influence the amount of melatonin produced in the pineal gland. The present study investigated the effect of melatonin on signaling pathways of glucose transport in C2C12 mouse skeletal muscle cells. Intriguingly, treatment of C2C12 cells with melatonin (1 nm) stimulated glucose uptake twofold increase. Melatonin-stimulated glucose transport was inhibited with co-treatment with the melatonin receptor antagonist luzindole. Furthermore, treatment of stably over-expressed melatonin receptor type 2B containing C2C12 myotubes with melatonin amplified glucose transport c. 13-fold. Melatonin also increased the phosphorylation level of insulin receptor substrate-1 (IRS-1) and the activity of phosphoinositide 3-kinase (PI-3-kinase). However, 3',5'-cyclic adenosine monophosphate-activated protein kinase (AMPK), another important glucose transport stimulatory mediator via an insulin-independent pathway, was not influenced by melatonin treatment. Activity of p38 mitogen-activated protein kinase (MAPK), a downstream mediator of AMPK, was also not changed by melatonin. In addition, melatonin increased the expression level of forkhead box A2, which was recently discovered to regulate fatty acid oxidation and to be inhibited by insulin. In summary, melatonin stimulates glucose transport to skeletal muscle cells via IRS-1/PI-3-kinase pathway, which implies, at the molecular level, its role in glucose homeostasis and possibly in diabetes. Additionally, exposure to light at night and aging, both of which lower endogenous melatonin levels may contribute to the incidence and/or development of diabetes.

The existence of specific melatonin-binding sites in lymphoid cells led to the discovery of signal transduction pathway for melatonin in human lymphocytes and immunomodulatory role of melatonin in immune cells. In recent years, transcriptional regulation of melatonin on various transcription factors has been demonstrated. Therefore, this study was designed to assess by cDNA microarray analysis the regulatory effects of melatonin on transcription factors in human peripheral blood mononuclear cells (PBMCs). Forty-six genes were upregulated and 23 were downregulated more than twofold in melatonin-treated PBMCs. Of the more than twofold upregulated transcription factor genes, homeo box A4 (HOXA4), forkhead box O1A (FOXO1A), transcription elongation factor B (SIII), polypeptide 3 (TCEB3), and peroxisome proliferative activated receptor delta (PPARD) were identified. Of the more than twofold downregulated genes, PHD finger protein 15 (PHF15) and zinc finger protein 33a (ZNF33A) were identified. In summary, identification of these genes by cDNA microarray analysis in response to melatonin administration may provide a foundation for further studies on the function of melatonin in human PBMCs.

Objective: To evaluate the relation between fetal nasal bone length (NBL) and biparietal diameter (BPD) at 15-19.9 (20) weeks of gestation by ultrasonography in the Korean population., Methods: The study population included 1268 Korean women (aged between 19 and 45 years) with a singleton pregnancy who registered at the Maternal Fetal Medicine Unit of Samsung Cheil Hospital between September 2003 and February 2005. Ultrasound measurements of NBL were performed using a strict sagittal plan of the fetal head. Other fetal biometry profiles were conducted before amniocentesis for fetal karyotyping., Results: NBL and fetal biometry profiles were measured successfully in 77.9% (988/1268) of the fetuses. NBL was found to increase linearly as a function of BPD (P < 0.001) with a median NBL of 4.4 mm (range 1.9-7.9). NBL increases through 15-19.9 (20) weeks of gestation were given by the equation NBL (mm) = 0.0836 x BPD (mm) + 1.368 (R2 = 0.1, P < 0.001)., Conclusions: Fetal NBL and BPD are linearly related in the second trimester. Fetal NBL in the Korean population is likely to be shorter than that reported for Caucasians and African-Americans., (Copyright 2006 John Wiley & Sons, Ltd.)

Melatonin is reported to be an anti-inflammatory agent. No genetic study concerning the association between melatonin and inflammatory disease has yet been reported. Here we performed a polymorphism study on the melatonin receptor type 1B (MTNR1B) in Korean rheumatoid arthritis (RA) patients and controls. The polymorphism of MTNR1B located in 3'-untranslated region (rs 1562444) was selected for its higher rate of heterozygosity among other single nucleotide polymorphisms (SNPs) in both MTNR1A and MTNR1B genes and investigated in RA patients (n = 173) and healthy controls (n = 195) by polymerase chain reaction-restriction fragment length polymorphism assay using NlaIII restriction enzyme. No statistically significant difference in either genotype distribution or allele frequency was observed between RA patients and controls. The genotype distributions and allele frequencies of rheumatoid factor negative [RF(-)] patients were similar to those of controls. However, statistical analysis of genotype revealed a significant association (chi2 = 6.42, P = 0.04) is present between RF(+) and MTNR1B SNP (rs 1562444). Although no statistically significant difference in allele frequency between RF(+) and controls was observed (chi2 = 2.75, P = 0.10), the results might suggest that MTNR1B SNP (rs 1562444) is associated with the presence of RF in RA. This is the first study, to our knowledge, to report a positive genetic relationship between melatonin and RA.

Background: Methoxyacetic acid (MAA) causes fetal limb abnormalities when the substance is administrated on gestation day (GD) 11 in mice. Limb abnormalities are caused mainly by extensive cell death in the mesoderm of the limb plate. This investigation focused on identifying a protein that is linked with mouse limb teratogenicity., Methods: A single dose of MAA at 10 mmol/kg body weight was administered by gavage on GD 11; controls were administered vehicle only. Dams were killed by cervical dislocation 4 hr after treatment and forelimb buds were isolated from both the control and treated embryos. Proteins in forelimb buds GD 11 + 4 hr were precipitated out using 40-60% ammonium sulfate and were then analyzed by 2D SDS-PAGE. Excised protein spots were identified by mass spectrometry and amino acid internal sequence analysis. Identified protein was further confirmed by Western blotting., Results: Two-dimensional gel analysis indicated that 1 protein spot of 81.7 kDa/pI 7.3 was overexpressed, and the protein matched heat shock protein 70 (HSP70; accession no. P08109, SwissProt)., Conclusions: The results suggest that MAA, when administered to pregnant mice, upregulates HSP70 in the forelimb buds., ((c) 2005 Wiley-Liss, Inc.)

Apoptosis-modulating approaches offer an attractive opportunity for therapeutic use for many tumors. We investigated the effects of the roots of Coptis japonica var. dissecta (Ranunculaceae) on human gastric cancer cells, SNU-668. The cytotoxicity of Coptis japonica at 100 microg/ml (methanol extract) by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was 13.89 +/- 1.91% of control value. Considering the features by 4,6-diamidino-2-phenylindole (DAPI) staining and terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) assay, it was confirmed that the death of SNU-668 cells was due to apoptosis. In the apoptosis-regulating genes, BCL2 expression was diminished out, whereas BAX and CASP3 expressions were increased, compared with control. Furthermore, the activity of caspase3 was significantly increased by Coptis japonica treatment. These results suggest that Coptis japonica could induce apoptotic anticancer effect through caspase3 activation on SNU-668 human gastric cancer cells., (Copyright 2005 John Wiley & Sons, Ltd.)

Bioassay-guided fractionation has led to the isolation of two triterpenoid saponins 3-O-[O-beta-D-glucopyranosyl-(1 --> 3)-O-beta-D-glucopyranosyl] oleanolic acid (1), and 3-O-[O-beta-D-glucopyranosyl-(1 --> 2)-O-beta-D-glucopyranosyl] oleanolic acid (2) from the whole plants of Viola ibukiana Makino. Compound 2 showed matrix metalloproteinase-1 expression inhibition activities in a dose-dependent manner.

Objectives: To review the detection rate of the prenatal screening tests used for the diagnosis of the trisomy 18., Methods: From 1 October 1998 to 31 December 2001, we reviewed the database and medical records of 30 cases of trisomy 18. All were singletons and trisomy 18 was confirmed by amniocentesis in 19 cases, by cordocentesis in 6 cases, by chorionic villi sampling in 2 cases and by skin biopsy in 3 cases., Results: Of the 30 study cases, 23 cases (77%) were offered genetic study due to abnormal ultrasound (US) findings. Twelve (40%) out of the 23 cases were due to abnormal US findings detected before the triple test and 11 (37%) were due to abnormal US findings after the normal triple test. Six cases (20%) were offered genetic study because of an abnormal triple test, and one case was offered genetic study due to advanced maternal age only. Including the second targeted ultrasonogram, one or more abnormal US findings were found in all 30 fetuses., Conclusions: Abnormal US finding is the most sensitive screening test for trisomy 18. The most sensitive ultrasonographic finding for trisomy 18 at under 16 weeks of gestation is increased nuchal translucency (75%) and, after 16 weeks, is cardiac defect (83%)., (Copyright 2005 John Wiley & Sons, Ltd.)