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Find video protocols related to scientific articles indexed in Pubmed.
Variation Between Residents and Attending Staff Interpreting Radiographs to Verify Placement of Nutrition Access Devices in the Neonatal Intensive Care Unit.
Nutr Clin Pract
PUBLISHED: 11-12-2014
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Introduction: Although radiography is considered the standard for confirming the position of nutrition access devices, it is sometimes difficult to visualize their tips. The purpose of this study was to evaluate how well pediatric residents could confirm placement via radiography of feeding tubes and intravenous (IV) nutrition catheter support in a neonatal intensive care unit (NICU). Methods: Seventy radiographs in a NICU during May 2013 were retrospectively evaluated. Eight pediatric residents (mean NICU experience, 5 months; range, 0-12 months) recorded the location of feeding tubes and IV nutrition catheters and marked their tips on computerized radiographs. Consensus review of radiographs by a radiologist and a NICU expert using a picture archiving communication system monitor in a reading room served as the reference standard. Detection rates and correct tip localization percentages were evaluated. Results: Of the 70 neonates, 38 had nutrition access devices: orogastric tube (n = 36), oroduodenal tube (n = 4), or central venous catheter (CVC) (n = 8). Detection rates were 89.6% for orogastric tubes (range, 75.0%-100%), 90.6% for oroduodenal tubes (range, 50.0%-100%), and 46.9% for CVCs (range, 12.5%-75.0%). Percentage of correct tip localizations was 85.7% for orogastric tubes (range, 74.1%-100%), 86.2% for oroduodenal tubes (range, 25.0%-100%), and 70% for CVCs (range, 50.0%-100%). Conclusion: It is not easy for pediatrician residents to confirm the position of nutrition access devices in neonates by using radiographs. Reinforcement of radiology teaching, second opinions from radiologists or NICU experts, and other methods for verifying the positions of nutrition access devices are needed to minimize complications.
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miR-410 Inhibition Induces RPE Differentiation of Amniotic Epithelial Stem Cells via Overexpression of OTX2 and RPE65.
Stem Cell Rev
PUBLISHED: 10-30-2014
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The retinal pigment epithelium (RPE) is a highly specialized cell type located between the choroid and neural retina of the eye. RPE degeneration causes irreversible visual impairment, extending to blindness. Cell therapy has recently emerged as a potential therapeutic approach for retinal degeneration. MicroRNA-based differentiation of stem cells is a new strategy for producing tissue-specific cell types. In this study, we developed a novel microRNA-based strategy for RPE induction from human amniotic epithelial stem cells (AESCs). We identified microRNAs involved in RPE development in AESCs. Of 29 putative human RPE-relevant microRNAs, microRNA-410 (miR-410) was predicted to target multiple RPE development-relevant genes. Inhibition of miR-410 induces overexpression of immature and mature RPE-specific factors, including OTX2, RPE65, Bestrophin and EMMPRIN. These RPE-like cells were morphologically altered toward a cobblestone-like shape and were able to phagocytize microbeads. We showed that miR-410 directly regulates predicted target genes OTX2 and RPE65. Our microRNA-based strategy demonstrated RPE differentiation in AESCs by treatment of an antisense microRNA-410 (anti-miR-410), without the use of additional factors or exogenous transduction. These findings suggest that miR-410 inhibition can be a useful tool for directed cell differentiation and an attractive method for cell therapy in human retinal degenerative diseases.
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Risk Assessment of Volatile Organic Compounds Benzene, Toluene, Ethylbenzene, and Xylene (BTEX) in Consumer Products.
J. Toxicol. Environ. Health Part A
PUBLISHED: 10-25-2014
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Exposure and risk assessment was performed by evaluating levels of volatile organic compounds (VOC) benzene, toluene, ethylbenzene, and xylene (BTEX) in 207 consumer products. The products were categorized into 30 different items, consisting of products of different brands. Samples were analyzed for BTEX by headspace-gas chromatography/mass spectrometry (headspace-GC/MS) with limit of detection (LOD) of 1 ppm. BTEX were detected in 59 consumer products from 18 item types. Benzene was detected in whiteout (ranging from not detected [ND] to 3170 ppm), glue (1486 ppm), oil-based ballpoint pens (47 ppm), and permanent (marking) pens (2 ppm). Toluene was detected in a leather cleaning product (6071 ppm), glue (5078 ppm), whiteout (1130 ppm), self-adhesive wallpaper (15-1012 ppm), shoe polish (806 ppm), permanent pen (609 ppm), wig adhesive (372 ppm), tapes (2-360 ppm), oil-based ballpoint pen (201 ppm), duplex wallpaper (12-52 ppm), shoes (27 ppm), and air freshener (13 ppm). High levels of ethylbenzene were detected in permanent pen (ND-345,065 ppm), shoe polish (ND-277,928 ppm), leather cleaner (42,223 ppm), whiteout (ND-2,770 ppm), and glue (ND-792 ppm). Xylene was detected in permanent pen (ND-285,132 ppm), shoe polish (ND-87,298 ppm), leather cleaner (12,266 ppm), glue (ND-3,124 ppm), and whiteout (ND-1,400 ppm). Exposure assessment showed that the exposure to ethylbenzene from permanent pens ranged from 0 to 3.11 mg/kg/d (men) and 0 to 3.75 mg/kg/d (women), while for xylene, the exposure ranges were 0-2.57 mg/kg/d and 0-3.1 mg/kg/d in men and women, respectively. The exposure of women to benzene from whiteout ranged from 0 to 0.00059 mg/kg/d. Hazard index (HI), defined as a ratio of exposure to reference dose (RfD), for ethylbenzene was 31.1 (3.11 mg/kg/d/0.1 mg/kg/d) and for xylene (2.57 mg/kg/d/0.2 mg/kg/d) was 12.85, exceeding 1 for both compounds. Cancer risk for benzene was calculated to be 3.2 × 10(-5) based on (0.00059 mg/kg/d × 0.055 mg/kg-d(-1), cancer potency factor), assuming that 100% of detected levels in some products such as permanent pens and whiteouts were exposed in a worst-case scenario. These data suggest that exposure to VOC via some consumer products exceeded the safe limits and needs to be reduced.
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Potential Application of Benzo(a)Pyrene-Associated Adducts (Globin or Lipid) as Blood Biomarkers for Target Organ Exposure and Human Risk Assessment.
J. Toxicol. Environ. Health Part A
PUBLISHED: 10-25-2014
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In order to investigate the potential application of blood biomarkers as surrogate indicators of carcinogen-adduct formation in target-specific tissues, temporal formation of benzo[a]pyrene (BaP)-associated DNA adducts, protein adducts, or lipid damage in target tissues such as lung, liver, and kidney was compared with globin adduct formation or plasma lipid damage in blood after continuous intraperitoneal (ip) injection of [(3)H]BaP into female ICR mice for 7 d. Following treatment with [(3)H]BaP, formation of [(3)H]BaP-DNA or -protein adducts in lung, liver, and kidney increased linearly, and persisted thereafter. This finding was similar to the observed effects on globin adduct formation and plasma lipid damage in blood. The lungs contained a higher level of DNA adducts than liver or kidneys during the treatment period. Further, the rate of cumulative adduct formation in lung was markedly greater than that in liver. Treatment with a single dose of [(3)H]BaP indicated that BaP-globin adduct formation and BaP-lipid damage in blood reached a peak 48 h after treatment. Overall, globin adduct formation and lipid damage in blood were significantly correlated with DNA adduct formation in the target tissues. These data suggest that peripheral blood biomarkers, such as BaP-globin adduct formation or BaP-lipid damage, may be useful for prediction of target tissue-specific DNA adduct formation, and for risk assessment after exposure.
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Comparative efficacy and bioequivalence of novel h1-antihistamine bepotastine salts (nicotinate and salicylate).
J. Toxicol. Environ. Health Part A
PUBLISHED: 10-25-2014
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Bepotastine salts (nicotinate and salicylate) were investigated for their physicochemical properties to develop novel salt forms of bepotastine, bioequivalent to the bepotastine besilate-loaded tablet (Talion). These bepotastine salts of either nicotinate- or salicylate-loaded tablets were prepared by conventional wet granulation method, and dissolution profiles and pharmacokinetics in beagle dogs were compared to those of Talion. A novel bepotastine nicotinate has a higher solubility at varying pH levels (1.2, 4, or 6.8) than salicylate-loaded or besilate-loaded salt. In addition, those bepostastine salt forms (nicotinate and salicylate) are stable in heat, light, and water. Further, the novel nicotinate- and salicylate-loaded tablets showed similar dissolution rates to Talion in several selected dissolution media and were bioequivalent to Talion in beagle dogs in terms of area under the concentration-time curve (AUC) and maximum observed concentration (Cmax). A pharmacokinetic study performed in beagle dogs demonstrated that test and reference products were found to be bioequivalent in terms of safety, efficacy, and pharmacokinetic properties. These results suggest that bepostastine nicotinate and salicylate formulations are considered applicable candidates and are well tolerated versus the conventional bepostastine besilate formulation.
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A One-Generation Reproductive Toxicity Study of 3,4-Methylenedioxy-N-Methamphetamine (MDMA, Ecstasy), an Amphetamine Derivative, in C57BL/6 Mice.
J. Toxicol. Environ. Health Part A
PUBLISHED: 10-25-2014
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3,4-Methylenedioxy-N-methamphetamine (MDMA, ecstasy) is an amphetamine derivative and is a popular type of drug that is abused due to its effects on the central nervous system (CNS), including alertness and euphoria. However, life-threatening (brain edema, heart failure, and coma) and fatal hyperthermia sometimes occur in some individuals taking MDMA. In a one-generation reproductive toxicity study, the potential toxicity of chronic exposure of MDMA was investigated on the reproductive capabilities of parental mice (F0), as well as the survival/development of their subsequent offspring (F1). Male and female C57BL/6 mice were administered orally MDMA at 0, 1.25, 5 or 20 mg/kg body weight (b.w.) throughout the study, beginning at the premating period, through mating, gestation, and lactation periods. MDMA did not produce any apparent clinical signs in F0 or F1 mice, and produced no significant changes in body weight, feed/water intake, or organ weights. In contrast, administration of MDMA produced external abnormalities in fetuses, stillbirth and labored delivery, and diminished viability and weaning indices in offspring, but these data were not significant. In addition, physical development of F1 mice was not markedly influenced by MDMA treatment. Nonetheless, serum biochemistry markers showed that levels of alkaline phosphatase (ALP), aspartate aminotransferase (AST), and blood urea nitrogen (BUN) were markedly elevated in a dose-dependent manner from 5 mg and higher MDMA/kg b.w., whereas levels of triglycerides (TG), potassium (K), and uric acid (UA) were reduced. Data suggest that MDMA may exert a weak reproductive and developmental toxicity, and the no-observed-adverse-effect level (NOAEL) of MDMA is estimated to be 1.25 mg/kg b.w./d.
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Evaluation of cadmium-induced nephrotoxicity using urinary metabolomic profiles in sprague-dawley male rats.
J. Toxicol. Environ. Health Part A
PUBLISHED: 10-25-2014
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The aim of this study was to investigate urinary metabolomic profiles associated with cadmium (Cd)-induced nephrotoxicity and their potential mechanisms. Metabolomic profiles were measured by high-resolution (1)H-nuclear magnetic resonance (NMR) spectroscopy in the urine of rats after oral exposure to CdCl2 (1, 5, or 25 mg/kg) for 6 wk. The spectral data were further analyzed by a multivariate analysis to identify specific urinary metabolites. Urinary excretion levels of protein biomarkers were also measured and CdCl2 accumulated dose-dependently in the kidney. High-dose (25 mg/kg) CdCl2 exposure significantly increased serum blood urea nitrogen (BUN), but serum creatinine (sCr) levels were unchanged. High-dose CdCl2 (25 mg/kg) exposure also significantly elevated protein-based urinary biomarkers including osteopontin, monocyte chemoattractant protein-1 (MCP-1), kidney injury molecules-1 (Kim-1), and selenium-binding protein 1 (SBP1) in rat urine. Under these conditions, six urinary metabolites (citrate, serine, 3-hydroxyisovalerate, 4-hydroxyphenyllactate, dimethylamine, and betaine) were involved in mitochondrial energy metabolism. In addition, a few number of amino acids such as glycine, glutamate, tyrosine, proline, or phenylalanine and carbohydrate (glucose) were altered in urine after CdCl2 exposure. In particular, the metabolites involved in the glutathione biosynthesis pathway, including cysteine, serine, methionine, and glutamate, were markedly decreased compared to the control. Thus, these metabolites are potential biomarkers for detection of Cd-induced nephrotoxicity. Our results further indicate that redox metabolomics pathways may be associated with Cd-mediated chronic kidney injury. These findings provide a biochemical pathway for better understanding of cellular mechanism underlying Cd-induced renal injury in humans.
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Nephrotoxic potential and toxicokinetics of melamine combined with cyanuric Acid in rats.
J. Toxicol. Environ. Health Part A
PUBLISHED: 10-25-2014
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To investigate the nephrotoxic potential of melamine (MEL) and cyanuric acid (CA) in male Sprague-Dawley rats, 7-d repeated-dose studies were performed. The experimental groups of MEL100 and CA100 were orally administered with MEL and CA at 100 mg/kg/d for 7 d, respectively. In groups dosed with MEL-CA mixtures, melamine and cyanuric acid (1:1) were simultaneously administered at 4, 20, or 100 mg/kg/d for 7 d (i.e., MEL-CA4, MEL-CA20, or MEL-CA100, respectively). Body weights were not markedly affected in MEL100, CA100, and MEL-CA4 groups, but significantly reduced in MEL-CA 20 and 100 rats. Most parameters determined in sera and tissues were not markedly altered in MEL100, CA100, and MEL-CA4-treated rodents. However, BUN, creatinine, total protein, and kidney weights were significantly increased in MEL-CA20- and MEL-CA100-treated animals. Renal histopathologic findings also revealed signs of toxicity, including tubular dilatation, crystal deposition, granulomatous tubulo-interstitial inflammation, and tubular necrosis with regeneration. Data suggested that the combination of MEL and CA might be responsible for observed nephrotoxicity that was not seen following individual exposure to either MEL or CA alone. Subsequently, the concentrations of MEL and CA were determined in serum, urine, and kidney tissues by using liquid chromatography-mass spectrometry. Toxicokinetic studies indicated that MEL or CA alone might be eliminated almost completely within 24 h after dosing showing no accumulation in kidney. However, the combined MEL-CA dose produced marked accumulation of chemicals in blood and kidneys. These results suggested that combined MEL and CA might produce renal toxicity due to significant chemical accumulation in kidney accompanied by low excretion.
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The No-Observed-Adverse-Effect Level (NOAEL) of Baby Aloe Powder (BAP) for Nutraceutical Application Based Upon Toxicological Evaluation.
J. Toxicol. Environ. Health Part A
PUBLISHED: 10-25-2014
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Aloe has been used in versatile herbal medications and nutraceuticals throughout history. Aloe is widely considered to be generally safe for humans and used globally. The effectiveness and pharmacological properties of aloe are dependent upon when the plant is collected. However, little is known about the toxicology of whole-body aloe collected within less than 1 yr. Based upon widespread exposure to aloe, it is important to determine a daily intake level of this chemical to ensure its safety for humans. To determine the no-observed-adverse-effect level (NOAEL) of baby aloe powder (BAP) for clinical application, Sprague-Dawley (SD) rats were treated orally for 4 wk with 4 different concentrations: 0, 0.125, 0.5, and 2 g/kg body weight (bw). In this study, no significant or dose-dependent toxicological effects of BAP were observed in biochemical or hematological parameters, urinalysis, clinical signs, body weight, and food and water consumption. There were changes in some biomarkers in certain treated groups compared to controls; however, all values were within their reference ranges and not dose-dependent. Based on these results, the NOAEL of BAP was estimated to be greater than 2 g/kg bw in male and 2 g/kg bw in female SD rats. Collectively, these data suggest that BAP used in this study did not produce any marked subacute toxic effects up to a maximum concentration of 2 g/kg bw, and thus use in nutraceuticals and in pharmaceutical and cosmetic applications at a concentration of >2 g/kg is warranted.
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Autocrine stimulation of IL-10 is critical to the enrichment of IL-10-producing CD40hiCD5+ regulatory B cells in vitro and in vivo.
BMB Rep
PUBLISHED: 10-25-2014
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IL-10-producing B (Breg) cells regulate various immune responses. However, their phenotype remains unclear. CD40 expression was significantly increased in B cells by LPS, and the Breg cells were also enriched in CD40hiCD5+ B cells. Furthermore, CD40 expression on Breg cells was increased by IL-10, CD40 ligand, and B-cell activating factor, suggesting that CD40hi is a common phenotype of Breg cells. LPS-induced CD40 expression was largely suppressed by an anti-IL-10 receptor antibody and in IL-10-/-CD5+CD19+ B cells. The autocrine effect of IL-10 on the CD40 expression was largely suppressed by an inhibitor of JAK/STAT3. In vivo, the LPS treatment increased the population of CD40hiCD5+ Breg cells in mice. However, the population of CD40hiCD5+ B cells was minimal in IL-10-/- mice by LPS. Altogether, our findings show that Breg cells are largely enriched in CD40hiCD5+ B cells and the autocrine effect of IL-10 is critical to the formation of CD40hiCD5+ Breg cells.
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Ru(II)-catalyzed selective C-H amination of xanthones and chromones with sulfonyl azides: synthesis and anticancer evaluation.
J. Org. Chem.
PUBLISHED: 09-24-2014
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A ketone-assisted ruthenium-catalyzed selective amination of xanthones and chromones C-H bonds with sulfonyl azides is described. The reactions proceed efficiently with a broad range of substrates with excellent functional group compatibility. This protocol provides direct access to 1-aminoxanthones, 5-aminochromones, and 5-aminoflavonoid derivatives known to exhibit potent anticancer activity.
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Development of a simultaneous vibration and pressure stimulation system for cognitive studies.
Biomed Mater Eng
PUBLISHED: 09-18-2014
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In this study, a tactile stimulator that could separately or simultaneously display the vibrotactile and pressure sense was developed. The developed system consisted of a control unit, a drive unit, and an actuator, and can be operated with PC or manually. This system quantitatively controls the stimulation parameters such as the stimulation intensity, duration, frequency, and stimulation type. A preliminary electroencephalogram (EEG) experiment for three types of stimulation (vibrotactile, pressure sense, vibrotactile + pressure sense) highlights that the system could be used in complex tactile cognitive studies. An event-related desynchronization (ERD) and synchronization (ERS) were measured at the area of C3 and C4 for all three types of stimulation, and a clear response was identified in the contralateral somatosensory area from the brain topology. Therefore, it is expected that this system could be widely used in single and complex human tactile cognition and perception studies for vibrotactile and pressure sensation.
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Effects of distraction task on driving: a functional magnetic resonance imaging study.
Biomed Mater Eng
PUBLISHED: 09-18-2014
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This study investigated neuronal activation differences under two conditions: driving only and distracted driving. Driving and distraction tasks were performed using a Magnetic Resonance (MR)-compatible driving simulator with a driving wheel and pedal. The experiment consisted of three blocks, and each block had both a Rest phase (1 min) and a Driving phase (2 min). During the Rest phase, drivers were instructed to simply look at the stop screen without performing any driving tasks. During the Driving phase, each driver was required to drive at 110 km/h under two conditions: driving only and driving while performing additional distraction tasks. The results show that the precuneus, inferior parietal lobule, supramarginal gyrus, middle frontal gyrus, cuneus, and declive are less activated in distracted driving than in driving only. These regions are responsible for spatial perception, spatial attention, visual processing and motor control. However, the cingulate gyrus and sub-lobar regions (lentiform nucleus and caudate), which are responsible for error monitoring and control of unnecessary movement, show increased activation during distracted driving compared with driving only.
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Dinuclear [{(p-cym)RuCl}2(?-phpy)](PF6)2 and heterodinuclear [(ppy)2Ir(?-phpy)Ru(p-cym)Cl](PF6)2 complexes: synthesis, structure and anticancer activity.
Dalton Trans
PUBLISHED: 08-28-2014
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Phpy bridged homodinuclear Ru-Ru () and heterodinuclear Ir-Ru complexes () have been developed. Complex induces autophagy towards the cisplatin resistant human breast cancer (MCF7) cell line, whereas is inactive.
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Excessive microglial activation aggravates olfactory dysfunction by impeding the survival of newborn neurons in the olfactory bulb of Niemann-Pick disease type C1 mice.
Biochim. Biophys. Acta
PUBLISHED: 08-15-2014
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Progressive olfactory impairment is one of the earliest markers of neurodegeneration. However, the underlying mechanism for this dysfunction remains unclear. The present study investigated the possible role of microgliosis in olfactory deficits using a mouse model of Niemann-Pick disease type C1 (NPC1), which is an incurable neurodegenerative disorder with disrupted lipid trafficking. At 7weeks of age, NPC1 mutants showed a distinct olfactory impairment in an olfactory test compared with age-matched wild-type controls (WT). The marked loss of olfactory sensory neurons within the NPC1 affected olfactory bulb (NPC1-OB) suggests that NPC1 dysfunction impairs olfactory structure. Furthermore, the pool of neuroblasts in the OB was diminished in NPC1 mice despite the intact proliferative capacity of neural stem/progenitor cells in the subventricular zone. Instead, pro-inflammatory proliferating microglia accumulated extensively in the NPC1-OB as the disease progressed. To evaluate the impact of abnormal microglial activation on olfaction in NPC1 mice, a microglial inhibition study was performed using the anti-inflammatory agent Cyclosporin A (CsA). Importantly, long-term CsA treatment in NPC1 mice reduced reactive microgliosis, restored the survival of newly generated neurons in the OB and improved overall performance on the olfactory test. Therefore, our study highlights the possible role of microglia in the regulation of neuronal turnover in the OB and provides insight into the possible therapeutic applications of microglial inhibition in the attenuation or reversal of olfactory impairment.
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Extraction and Analysis of Risk Elements for Korean Homecare Patients with Senile Dementia.
J Behav Health Serv Res
PUBLISHED: 07-23-2014
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The purpose of this study is to provide information for the protection of Korean homecare patients with senile dementia by investigating accident cases using a survey. With the survey of accident cases, the caregivers of 55 Korean homecare patients with senile dementia (75.9?±?7.0 years) were administered the short form of the Samsung Dementia Questionnaire (S-SDQ) and an activities of daily living (ADL) test. Twelve risk elements were extracted. The order of frequency of occurrence from highest to lowest was "egress," "fall," "violence," "collision," "gas accident," "slip," "faucet misuse," "overeating," "drop," "discharge," "weird eating," and "self-injury." The percentage of risk elements resulting in physical harm was 40.1% across all risk elements. The risk elements resulting in the most physical harm were "fall," "collision," "slip," and "drop," respectively. Regarding the location of occurrence of risk elements, risk elements resulting in physical harm showed no significant differences between indoors and outdoors. Some risk elements, such as "egress," "fall," and "gas accident" happened concurrently with more than four other elements, while "collision," "drop," and "violence" happened together with more than two other elements. "Slip" happened significantly more often in the low ADL score group, while "gas accident" happened significantly more often in the high ADL score group. This study provides basic information about monitoring factors to protect senior homecare patients with senile dementia.
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Cumulative effective dose associated with computed tomography examinations in adolescent trauma patients.
Pediatr Emerg Care
PUBLISHED: 07-01-2014
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The aims of this study were to analyze cumulative effective dose (cED) and to assess lifetime attributable risk (LAR) of cancer due to radiation exposure during computed tomography (CT) examinations in adolescent trauma patients.
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Identification of noninvasive biomarkers for nephrotoxicity using HK-2 human kidney epithelial cells.
Toxicol. Sci.
PUBLISHED: 06-30-2014
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The kidney is an important site of xenobiotic-induced toxicity. Because the traditional markers of renal injury indicate only severe renal damage, new biomarkers are needed for a more sensitive and reliable evaluation of renal toxicity. This study was designed to identify in vitro noninvasive biomarkers for efficient assessment of nephrotoxicity by using cisplatin as a model of nephrotoxic compounds. To this end, a comparative proteomic analysis of conditioned media from HK-2 human kidney epithelial cells treated with cisplatin was performed. Here, we identified pyruvate kinase M1/M2 isoform M2 (PKM2) and eukaryotic translation elongation factor 1 gamma (EF-1?) as potential biomarker candidates for evaluation of nephrotoxicity. PKM2 and EF-1? were increased by cisplatin in a kidney cell-specific manner, most likely due to cisplatin-induced apoptosis. The increase of PKM2 and EF-1? levels in conditioned media was also observed in the presence of other nephrotoxic agents with different cytotoxic mechanisms such as CdCl2, HgCl2, and cyclosporine A. Rats treated with cisplatin, CdCl2, or HgCl2 presented increased levels of PKM2 and EF-1? in the urine and kidney tissue. Taken together, this study identified two noninvasive biomarker candidates, PKM2 and EF-1?, by comparative proteomic analysis. These new biomarkers may offer an alternative to traditional renal markers for efficient evaluation of nephrotoxicity.
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Viriditoxin regulates apoptosis and autophagy via mitotic catastrophe and microtubule formation in human prostate cancer cells.
Int. J. Oncol.
PUBLISHED: 06-26-2014
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Microtubule targeting chemicals are considered excellent antitumor drugs through their binding to tubulin, which affects the instability of microtubules resulting in arrest of cancer cells. The present study was designed to investigate the antitumor effects of viriditoxin (VDT) against human prostate cancer cells. VDT, isolated from Paecilomyces variotii fungus, which was derived from the jellyfish Nemopilema nomurai, offers a new approach for controlling resistant bacterial infections by blocking bacterial cell division proteins. VDT produced dose-dependent cytotoxicity against human prostate cancer cells. Treatment with VDT promoted both apoptosis and autophagy in LNCaP cells. Annexin V/FITC staining indicated that apoptosis occurred in VDT-treated LNCaP cells. DAPI staining revealed morphological changes in the cell nuclei indicative of mitotic catastrophe in LNCaP cells. VDT caused cell growth inhibition via G2/M phase arrest. Moreover, VDT also increased autophagic cell death in LNCaP cells by induction of several autophagy-related proteins such as LC3  II, Atg5, Atg7 and beclin-1 protein, which are essential for autophagy induction. These results were also confirmed by acridine orange staining. This study indicates that VDT could potentially be effective against prostate cancer by promoting multiple modes of growth arrest and cell death coupled with apoptosis and autophagy.
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Cerebral activation and lateralization due to the cognition of a various driving speed difference: an fMRI study.
Biomed Mater Eng
PUBLISHED: 06-24-2014
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This study investigated the changes of cerebral activation and lateralization due to the cognition of three driving speeds in comparison to a reference driving speed using functional magnetic resonance imaging fMRI. A driving video as a visual stimulation source was recorded with four different driving speeds in a real driving situation. The experiment consisted of three blocks and each block included a one-minute control phase and a one-minute stimulation phase. The activation area and the lateralization index were analyzed by subtracting high speed data from low speed data. Such areas as occipital, parietal and frontal lobes, which is related to visual cognition, high order visual and spatial attention (or vigilance), were activated due to the cognition of various driving speed differences. As the driving speed difference increased, the activation area increased in the areas related to spatial attention (or vigilance), such as the frontal lobe, however, changes of neuronal activation in the occipital and parietal lobes were inconsistent. As the driving speed difference increased, the absolute value of cerebral lateralization decreased. These results may provide some basic data for elucidating the brain-function mechanism related to the cognition of a various driving speed difference based on a realistic visual stimulation.
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Response time of visual matching task and heart rate in children with Attention Deficit Hyperactivity Disorder (ADHD).
Biomed Mater Eng
PUBLISHED: 06-24-2014
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The purpose of this study was to investigate the relation between response time of visual matching task and heart rate (HR) in children with Attention Deficit Hyperactivity Disorder (ADHD). Thirty boys who were diagnosed with ADHD and are under treatment participated in the study. The experiment consisted of three phases, a total of 5 min with rest phase, control phase, and visual matching task phase. HR was measured during each phase. The HR in visual matching task phase increased, compared to that in rest phase. There was a negative correlation between response time of visual matching task and magnitude of the HR in the visual matching task phase. In other words, as HR increased, response time of the visual matching task decreased. This means that increasing in HR increased the supply of oxygen by fast circulation of blood for cognitive processing and this induced the improvement of cognitive ability in the ADHD children. This means that increasing HR increased the supply of oxygen by fast circulation of blood for cognitive processing and this induced the improvement of cognitive ability in the ADHD children. The result of this study supports previous studies that the administration of high oxygen concentration can positively affect the cognitive performance of the ADHD children. The results of the present and previous studies also may provide scientific evidence that can be used for treating patients with cognitive problems such as ADHD.
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?-Linolenic acid: nutraceutical, pharmacological and toxicological evaluation.
Food Chem. Toxicol.
PUBLISHED: 05-08-2014
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?-Linolenic acid (ALA), a carboxylic acid with 18 carbons and three cis double bonds, is an essential fatty acid needed for human health and can be acquired via regular dietary intake of foods that contain ALA or dietary supplementation of foods high in ALA, for example flaxseed. ALA has been reported to have cardiovascular-protective, anti-cancer, neuro-protective, anti-osteoporotic, anti-inflammatory, and antioxidative effects. ALA is the precursor of longer chain omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), but its beneficial effects on risk factors for cardiovascular diseases are still inconclusive. The recommended intake of ALA for cardiovascular health is reported to be 1.1-2.2g/day. Although there are limited toxicological data for ALA, no serious adverse effects have been reported. The evidence on an increased prostate cancer risk in association with dietary ALA is not conclusive. Based on the limited data currently available, it may be concluded that ALA may be beneficial as a nutraceutical/pharmaceutical candidate and is safe for use as a food ingredient.
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Thoraco-abdominal CT examinations for evaluating cause of cardiac arrest and complications of chest compression in resuscitated patients.
Emerg Radiol
PUBLISHED: 04-27-2014
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The objective of the study is to describe the causes of cardiac arrest and complications of cardiopulmonary resuscitation (CPR) on thoraco-abdominal CT examinations for resuscitated patients in our institution. We evaluated the causes of cardiac arrest on thoraco-abdominal CT scans, which was compared with the final diagnosis (determined by consensus of two emergency physicians based on the clinical, imaging, and laboratory findings). Additionally, we evaluated the complications of CPR on thoraco-abdominal CT scans. From March 2005 to August 2011, 82 patients underwent CT of the thorax (n=77) and abdomen (n=23) within 24 h after CPR. Final diagnosis was as follows: cardiac (n=29), respiratory (n=28), metabolic (n=11), exsanguination (n=5), cerebral (n=2), sepsis (n=1), and indeterminate (n=6). In 25 patients (30 %), thoraco-abdominal CT scans made the role either as a definitive study (n=22) or as a supportive test (n=3) for the diagnosis. In particular, CT was critical in diagnosis of many respiratory causes (64 %) and all exsanguinations. The most common complications following CPR were skeletal chest injuries (n=48), followed by lung contusion (n=45). Thoraco-abdominal CT examinations are helpful for the diagnosis of cause of cardiac arrest and complications of CPR.
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Estrogenic endocrine-disrupting chemicals: molecular mechanisms of actions on putative human diseases.
J Toxicol Environ Health B Crit Rev
PUBLISHED: 04-23-2014
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Endocrine-disrupting chemicals (EDC), including phthalates, bisphenol A (BPA), phytoestrogens such as genistein and daidzein, dichlorodiphenyltrichloroethane (DDT), and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), are associated with a variety of adverse health effects in organisms or progeny by altering the endocrine system. Environmental estrogens, including BPA, phthalates, and phytoestrogens, are the most extensively studied and are considered to mimic the actions of endogenous estrogen, 17?-estradiol (E2). Diverse modes of action of estrogen and estrogen receptors (ER? and ER?) have been described, but the mode of action of estrogenic EDC is postulated to be more complex and needs to be more clearly elucidated. This review examines the adverse effects of estrogenic EDC on male or female reproductive systems and molecular mechanisms underlying EDC effects that modulate ER-mediated signaling. Mechanisms of action for estrogenic EDC may involve both ER-dependent and ER-independent pathways. Recent findings from systems toxicology of examining estrogenic EDC are also discussed.
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Detection of blebs and bullae in patients with primary spontaneous pneumothorax by multi-detector CT reconstruction using different slice thicknesses.
J Med Imaging Radiat Oncol
PUBLISHED: 03-31-2014
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The aim of this study was to compare the diagnostic performances of multi-detector computed tomography (MDCT) reconstruction at two different slice thicknesses (1?mm, 'high resolution' vs. 5?mm, 'routine') with respect to the detection of blebs and bullae (BBs) in patients with primary spontaneous pneumothorax (PSP).
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Evaluation of renal toxicity by combination exposure to melamine and cyanuric Acid in male sprague-dawley rats.
Toxicol Res
PUBLISHED: 03-29-2014
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Melamine-induced nephrotoxicity is closely associated with crystal formation in the kidney caused by combined exposure to melamine (Mel) and cyanuric acid (CA). However, there are few dosage-finding studies for toxicological evaluation of chronic co-exposure to Mel and CA. The objective of this study was to investigate the possible mechanism by which a Mel and CA mixture lead to renal toxicity in rats. Mel and CA were co-administered to rats via oral gavage for 50 days. Nephrotoxicity was determined by measuring blood urea nitrogen (BUN) and serum creatinine (sCr) levels. Relative kidney weights were significantly increased in rats after co-exposure to Mel+CA (63/6.3 or 630/6.3 mg/kg) mixtures. BUN and sCr levels were significantly increased after Mel and CA co-exposure. Taken together, significant increase in KIM-1, NGAL, and calbindin levels were observed in the urine of rats exposed to Mel+CA (63/6.3 or 630/6.3 mg/kg) compared with the corresponding control group. Histological analysis revealed epithelial degeneration and necrotic cell death in the proximal tubules of the kidney after co-exposure to Mel+CA (63/6.3 or 630/6.3 mg/kg). Our data suggest that Mel-mediated renal toxicity may be influenced by CA concentrations in Mel-contaminated milk or foods.
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Growth arrest and forced differentiation of human primary glioblastoma multiforme by a novel small molecule.
Sci Rep
PUBLISHED: 03-20-2014
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Glioblastoma multiforme is the most common malignant brain tumor in adults, with an average survival of less than one year due to its resistance to therapy. Recent studies reported that GBM initiates from CD133-expressing cancer stem cells (CSC). However, the efficacy of CSC targeting is limited. A newly developed approach in cancer treatment is the forced differentiation of cancer cells. Here, we show that the treatment of the novel small molecule, CG500354, into CD133-expressing human primary GBM cells induces growth arrest by cell cycle regulators, p53, p21, p27 and phase-specific cyclins, and neural differentiation, as confirmed by neural progenitor/precursor markers, nestin, GFAP and Tuj1. When GBM-derived cells caused the tumors in NOD/SCID mice, CG500354 induced GBM-derived cells differentiation into Tuj1 and GFAP expressing cells. We next demonstrated that CG500354 plays a tumor-suppressive role via cAMP/CREB signaling pathway. CG500354 increases not only the extracellular cAMP level but also the protein level of PKA and CREB. Additionally, both mimetic substances, Forskolin and Rolipram, revealed comparable results with CG500354. Our findings indicate that induction of growth arrest and neural differentiation via cAMP/CREB signaling pathway by CG500354 treatment suggests the novel targeting of PDE4D in the development of new drugs for brain tumor therapy.
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Intra- and inter-hemispheric effective connectivity in the human somatosensory cortex during pressure stimulation.
BMC Neurosci
PUBLISHED: 03-13-2014
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Slow-adapting type I (SA-I) afferents deliver sensory signals to the somatosensory cortex during low-frequency (or static) mechanical stimulation. It has been reported that the somatosensory projection from SA-I afferents is effective and reliable for object grasping and manipulation. Despite a large number of neuroimaging studies on cortical activation responding to tactile stimuli mediated by SA-I afferents, how sensory information of such tactile stimuli flows over the somatosensory cortex remains poorly understood. In this study, we investigated tactile information processing of pressure stimuli between the primary (SI) and secondary (SII) somatosensory cortices by measuring effective connectivity using dynamic causal modeling (DCM). We applied pressure stimuli for 3 s to the right index fingertip of healthy participants and acquired functional magnetic resonance imaging (fMRI) data using a 3T MRI system.
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Parametric response mapping of dynamic CT as an imaging biomarker to distinguish viability of hepatocellular carcinoma treated with transcatheter arterial chemoembolization.
Abdom Imaging
PUBLISHED: 02-13-2014
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Accurate assessment of viability of hepatocellular carcinoma (HCC) after transcatheter arterial chemoembolization (TACE) is important for therapy planning. The purpose of this study is to determine the diagnostic value of a novel image analysis method called parametric response mapping (PRM) in predicting viability of tumor in HCC treated with TACE for dynamic CT images.
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Successful endovascular treatment of bilateral intralobar pulmonary sequestration with a bridging isthmus in a child.
Pediatr. Pulmonol.
PUBLISHED: 02-05-2014
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Pulmonary sequestration refers to aberrant formation of segmental lung tissue that has no connection with the bronchial tree and receives a blood supply from a systemic artery. Bilateral pulmonary sequestration, especially with a bridging isthmus is extremely rare. Although endovascular treatment is regarded as the less invasive alternative for the treatment of pulmonary sequestration, all previously reported bilateral pulmonary sequestrations have been treated surgically. We report the case of a 13-year-old girl who underwent successful endovascular treatment for bilateral pulmonary sequestration with a bridging isthmus. Thoracic CT angiography showed a heterogeneous mass-like consolidation in the both lower lobes connected each other via a bridging isthmus behind the heart. CT also demonstrated an aberrant artery, which originated from the celiac trunk, supplied the sequestration of the left lower lobe, and that a branch from the aberrant artery traversed to the sequestration in the right lower lobe. After percutaneous endovascular embolization using microcoils and gelfoam, the patient had no complications and the bilateral sequestration showed markedly decrease in the size.
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Solution structure of a sponge-derived cystine knot peptide and its notable stability.
J. Nat. Prod.
PUBLISHED: 02-05-2014
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A novel cystine knot peptide, asteropsin E (ASPE), was isolated from an Asteropus sp. marine sponge. The primary, secondary, and tertiary structures of ASPE were determined by high-resolution 2D NMR spectroscopy (900 MHz). With the exception of an N-terminal modification, ASPE shares properties with the previously reported asteropsins A-D, that is, the absence of basic residues, a highly acidic nature, conserved structurally important residues (including two cis-prolines), and a highly conserved tertiary structural framework. ASPE was found to be remarkably stable to gastrointestinal tract enzymes (chymotrypsin, elastase, pepsin, and trypsin) and to human plasma.
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Donepezil enhances Purkinje cell survival and alleviates motor dysfunction by inhibiting cholesterol synthesis in a murine model of Niemann Pick disease type C.
J. Neuropathol. Exp. Neurol.
PUBLISHED: 02-04-2014
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Neurodegenerative processes are often accompanied by disruption of cholinergic systems; therefore, acetylcholinesterase (AChE) inhibitors (AChEIs) may have therapeutic potential in some neurological conditions. We evaluated the effects of administration of donepezil, a widely used AChEI, in the cerebellum in a murine model of Niemann-Pick disease type C (NPC). The NPC mice developed Purkinje cell loss at the age of 8 weeks; 4-week-old NPC mice given donepezil led to improvement of Purkinje cell survival that was associated with improvement of motor dysfunction in the mice. Because abnormal accumulation of cholesterol caused by impaired lipid homeostasis is the principal pathogenetic mechanism underlying NPC, we investigated the effects of donepezil on cholesterol metabolism in the NPC mice. Donepezil treatment reduced cholesterol accumulation in adult neural stem cells in vitro, and it downregulated the expression of the cholesterol synthesis factors' sterol regulatory element-binding proteins and 3-hydroxy-3-methylglutaryl-CoA reductase in the cerebellum, implying that AChE activity might be associated with cholesterol homeostasis. Taken together, our findings suggest the role of a cholinergic pathway as a novel regulator of NPC progression and the potential application of AChEIs for the treatment of human NPC.
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Synthesis of PPAR-? activators inspired by the marine natural product, paecilocin A.
Mar Drugs
PUBLISHED: 01-10-2014
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A series of N-substituted phthalimide derivatives were synthesized based on a pharmacophore study of paecilocin A (a natural PPAR-? agonist) and synthetic leads. The introduction of hydrophilic and hydrophobic groups to the phthalimide skeleton yielded compounds 3-14. Compound 7 showed significant PPAR-? activation in a luciferase assay using rat liver Ac2F cells. Docking simulations showed that a free hydroxyl group on the phthalimide head and a suitable hydrophilic tail, including a phenyl linker, were beneficial for PPAR-? activation. Compound 7 and rosiglitazone concentration-dependently activated PPAR-? with EC50 values of 0.67 ?M and 0.028 ?M, respectively. These phthalimide derivatives could be further investigated as a new class of PPAR-? ligands.
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Age-related differences in kidney injury biomarkers induced by cisplatin.
Environ. Toxicol. Pharmacol.
PUBLISHED: 01-07-2014
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Acute kidney injury (AKI) occurs in a half of cisplatin (CDDP)-treated patients. Traditional biomarkers including blood urea nitrogen (BUN) and serum creatinine (SCr) are still used for detection of CDDP-induced AKI, but these biomarkers are not specific or sensitive. The aim of this study was to identify the specific and sensitive biomarkers against CDDP-induced renal injury between young (3-week-old) and old (20-week-old) rats. All animals were intraperitoneally injected once with CDDP (6 mg/kg). After 3 days, all animals were sacrificed and serum, urine, and kidney tissues were collected. Urinary and serum biomarkers as well as histological changes were measured. CDDP-induced proximal tubular damage was apparent from histopathological examination, being more severe in 3-week-old rats accompanied by increased number of TUNEL-positive apoptotic cells. This was associated with elevated urinary kidney injury molecule-1 (KIM-1), glutathione-S-transferase alpha (GST-?), vascular endothelial growth factor (VEGF), and tissue inhibitor of metalloproteinases-1 (TIMP-1). In contrast, the levels of neutrophil gelatinase-associated lipocalin (NGAL) and osteopontin were significantly increased in 20-week-old rats after CDDP treatment. These results indicate that the use of age-specific urinary biomarkers is necessary to diagnosis of CDDP-induced AKI. Especially, urinary KIM-1, GST-?, TIMP-1, and VEGF levels may help in the early diagnosis of young patients with CDDP-induced AKI.
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A p38 MAPK-mediated alteration of COX-2/PGE2 regulates immunomodulatory properties in human mesenchymal stem cell aging.
PLoS ONE
PUBLISHED: 01-01-2014
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Because human mesenchymal stem cells (hMSC) have profound immunomodulatory effects, many attempts have been made to use hMSCs in preclinical and clinical trials. For hMSCs to be used in therapy, a large population of hMSCs must be generated by in vitro expansion. However, the immunomodulatory changes following the in vitro expansion of hMSCs have not been elucidated. In this study, we evaluated the effect of replicative senescence on the immunomodulatory ability of hMSCs in vitro and in vivo. Late-passage hMSCs showed impaired suppressive effect on mitogen-induced mononuclear cell proliferation. Strikingly, late-passage hMSCs had a significantly compromised protective effect against mouse experimental colitis, which was confirmed by gross and histologic examination. Among the anti-inflammatory cytokines, the production of prostaglandin E2 (PGE2) and the expression of its primary enzyme, cyclooxygenase-2 (COX-2), were profoundly increased by pre-stimulation with interferon gamma (IFN-?) and tumor necrosis factor alpha (TNF-?), and this response was significantly decreased with consecutive passages. We demonstrated that the impaired phosphorylation activity of p38 MAP kinase (p38 MAPK) in late-passage hMSCs led to a compromised immunomodulatory ability through the regulation of COX-2. In conclusion, our data indicate that the immunomodulatory ability of hMSCs gradually declines with consecutive passages via a p38-mediated alteration of COX-2 and PGE2 levels.
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Proper compression landmark and depth for cardiopulmonary resuscitation in patients with pectus excavatum: a study using CT.
Emerg Med J
PUBLISHED: 12-12-2013
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To determine by chest CT the proper compression landmark and depth for cardiopulmonary resuscitation in patients with pectus excavatum (PE).
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A novel oxiranylchromenone derivative, MHY336, induces apoptosis and cell cycle arrest via a p53- and p21-dependent pathway in HCT116 human colon cancer cells.
Int. J. Oncol.
PUBLISHED: 10-18-2013
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In this study, we compared cytotoxicity, cell cycle distribution, and apoptosis on MHY336 treatment in three human colorectal carcinoma HCT116 cells: p53+/+ (p53?wt), p53-/- (p53-null), and p21-/- (p21-null), as well as investigated the roles of p53 and p21 in cell death. Using these three isogenic variants, the roles of p53 and p21 in the cellular response to treatment with MHY336, a novel topoisomerase II? inhibitor, were investigated. Our results showed that MHY336 treatment increased the expression of p53 over time in cells with wild-type p53 status. This elevated levels of p53 is associated with increased DNA fragmentation, and cleavage of poly(ADP-ribose) polymerase, consistent with increased sensitivity of these cells to apoptotic stimuli. However, p53-null and p21-null cells were more resistant to the antiproliferative and apoptotic effects of MHY336 than p53-wt cells. The same result was achieved by knocking down p53 and p21 with siRNA in p53-wt cells, indicating that p53 and p21 play a crucial role in MHY336-induced cell cycle arrest and apoptosis. Taken together, these results suggest that MHY336 could be a potential candidate to be used in chemoprevention and/or treatment of colon cancer.
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Evaluation of somatosensory cortical differences between flutter and vibration tactile stimuli.
Conf Proc IEEE Eng Med Biol Soc
PUBLISHED: 10-11-2013
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In parallel with advances in haptic-based mobile computing systems, understanding of the neural processing of vibrotactile information becomes of great importance. In the human nervous system, two types of vibrotactile information, flutter and vibration, are delivered from mechanoreceptors to the somatosensory cortex through segregated neural afferents. To investigate how the somatosensory cortex differentiates flutter and vibration, we analyzed the cortical responses to vibrotactile stimuli with a wide range of frequencies. Specifically, we examined whether cortical activity changed most around 50 Hz, which is known as a boundary between flutter and vibration. We explored various measures to evaluate separability of cortical activity across frequency and found that the hypothesis margin method resulted in the greatest separability between flutter and vibration. This result suggests that flutter and vibration information may be processed by different neural processes in the somatosensory cortex.
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MicroRNA-141-3p plays a role in human mesenchymal stem cell aging by directly targeting ZMPSTE24.
J. Cell. Sci.
PUBLISHED: 10-07-2013
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Human mesenchymal stem cell (hMSC) aging may lead to a reduced tissue regeneration capacity and a decline in physiological functions. However, the molecular mechanisms controlling hMSC aging in the context of prelamin A accumulation are not completely understood. In this study, we demonstrate that the accumulation of prelamin A in the nuclear envelope results in cellular senescence and potential downstream regulatory mechanisms responsible for prelamin A accumulation in hMSCs. We show for the first time that ZMPSTE24, which is involved in the post-translational maturation of lamin A, is largely responsible for the prelamin A accumulation related to cellular senescence in hMSCs. Direct binding of miR-141-3p to the 3UTR of ZMPSTE24 transcripts was confirmed using a 3UTR-luciferase reporter assay. We also found that miR-141-3p, which is overexpressed during senescence as a result of epigenetic regulation, is able to decrease ZMPSTE24 expression levels, and leads to an upregulation of prelamin A in hMSCs. This study provides new insights into mechanisms regulating MSC aging and may have implications for therapeutic application to reduce age-associated MSC pool exhaustion.
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Development of a simple MR-compatible vibrotactile stimulator using a planar-coil-type actuator.
Behav Res Methods
PUBLISHED: 09-05-2013
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For this study, we developed a magnetic resonance (MR)-compatible vibrotactile stimulator using a planar-coil-type actuator. The newly developed vibrotactile stimulator consists of three units: control unit, drive unit, and planar-coil-type actuator. The control unit controls frequency, intensity, time, and channel, and transfers the stimulation signals to the drive unit. The drive unit operates the planar-coil-type actuator in response to commands from the control unit. The planar-coil-type actuator, which uses a planar coil instead of conventional electric wire, generates vibrating stimulation through interaction of the current of the planar coil with the static magnetic field of the MR scanner. Even though the developed tactile stimulating system is small, simple, and inexpensive, it has a wide range of stimulation frequencies (20 ~ 400 Hz, at 40 levels) and stimulation intensities (0 ~ 7 V, at 256 levels). The stimulation intensity does not change due to frequency changes. Since the transient response time is a few microseconds, the stimulation time can be controlled on a scale of microseconds. In addition, this actuator has the advantages of providing highly repeatable stimulation, being durable, being able to assume various shapes, and having an adjustable contact area with the skin. The new stimulator operated stably in an MR environment without affecting the MR images. Using functional magnetic resonance imaging, we observed the brain activation changes resulting from stimulation frequency and intensity changes.
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A novel anthracene derivative, MHY412, induces apoptosis in doxorubicin-resistant MCF-7/Adr human breast cancer cells through cell cycle arrest and downregulation of P-glycoprotein expression.
Int. J. Oncol.
PUBLISHED: 08-30-2013
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New potential chemotherapeutic strategies are required to overcome multidrug resistance (MDR) in cancer. This study investigated the anticancer effect of a novel anthracene derivative MHY412 on doxorubicin-resistant human breast cancer (MCF-7/Adr) cells. We measured cell viability and the expression of apoptosis-related genes; in addition, the antitumor activity of MHY412 was confirmed using an in vivo tumor xenograft model. MHY412 significantly inhibited the proliferation of MCF-7/Adr and MCF-7 cells in a concentration-dependent manner. Notably, the half?maximal inhibitory concentration (IC50) values of MHY412 in MCF-7/Adr (0.15 µM) and MCF-7 (0.26 µM) cells were lower than those of doxorubicin (MCF-7/Adr, 13.6 µM and MCF-7, 1.26 µM) after treatment for 48 h. MHY412 at low concentrations induced S phase arrest, but at high concentrations, the number of MCF-7/Adr cells in the sub-G1 phase significantly increased. MHY412-induced sub-G1 phase arrest was associated with inhibition of cyclin, cyclin?dependent kinase 2 (CDK2) and p21 expression in MCF-7/Adr cells. MHY412 markedly reduced P-glycoprotein (P-gp) expression and increased apoptotic cell death in MCF-7/Adr cells. Cleavage of poly-ADP ribose polymerase, reduced Bcl-2 expression, and increased in cytochrome c release in MCF-7/Adr cells confirmed the above results. In addition, MHY412 markedly inhibited tumor growth in a tumor xenograft model of MCF-7/Adr cells. Our data suggest that MHY412 exerts antitumor effects by selectively modulating the genes related to cell cycle arrest and apoptosis. In particular, MHY412 is a new candidate agent for the treatment of Bcl-2 overexpressed doxorubicin-resistant human breast cancer.
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SP600125 overcomes antimitotic drug-resistance in cancer cells by increasing apoptosis with independence of P-gp inhibition.
Eur. J. Pharmacol.
PUBLISHED: 08-19-2013
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The purpose of this study was to identify conditions that increase the sensitivity of resistant cancer cells to antimitotic drugs. Using MTS assays, microscopic observation, assessment of cleaved PARP, FACS analysis, and Hoechst staining, we found that the c-Jun N-terminal kinase (Jnk) inhibitor SP600125 (SP) sensitized the antimitotic drug-resistant KBV20C cancer cell line. The sensitization mechanism was independent of p-glycoprotein (P-gp) inhibition. Interestingly, SP-induced sensitization was greater in resistant KBV20C cancer cells than in KB parent cells. The mechanism of SP-induced sensitization involved G2 arrest. KBV20C cells treated with SP and antimitotic drugs were more sensitized than cells treated with SP alone. This suggests that SP can restore sensitization for antimitotic drugs in resistant cancer cells. Our findings may contribute to the development of SP-based combination therapies for patients receiving anti-cancer agents that target microtubules.
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Human Umbilical Cord Blood Mesenchymal Stem Cells Reduce Colitis in Mice by Activating NOD2 Signaling to COX2.
Gastroenterology
PUBLISHED: 08-14-2013
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Decreased levels or function of nucleotide-binding oligomerization domain 2 (NOD2) are associated with Crohns disease. NOD2 regulates intestinal inflammation, and also is expressed by human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs), to regulate their differentiation. We investigated whether NOD2 is required for the anti-inflammatory activities of MSCs in mice with colitis.
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A novel hydroxamic acid derivative, MHY218, induces apoptosis and cell cycle arrest through downregulation of NF-?B in HCT116 human colon cancer cells.
Int. J. Oncol.
PUBLISHED: 07-22-2013
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Colorectal cancer (CRC) is one of the most common malignant diseases and frequent cause of cancer deaths in the world. In spite of the significant advances in conventional therapeutic approaches to CRC, most patients ultimately die of their disease. There is a need to develop novel preventive approaches for this malignancy. This study was carried out to investigate the anticancer effect of MHY218, a hydroxamic acid derivative, in HCT116 human colon cancer cells. Treatment of cells with MHY218 resulted in growth inhibition and induction of apoptosis in a concentration-dependent manner. MHY218 induced G2/M phase arrest in the cell cycle progression which was observed by flow cytometry analysis, and a decrease in the protein expression of cyclin B1 and its activating partners Cdc25C and Cdc2. MHY218 also caused an increase in the expression levels of p21WAF1/CIP1, a G2/M phase inhibitor, in a p53-independent pathway. The induction of apoptosis was observed by decreased viability, DNA fragmentation, cleavage of poly(ADP-ribose) polymerase, alteration in the ratio of Bax/Bcl-2 protein expression, and activation of caspase-3, -8 and -9. In addition, MHY218 treatment showed downregulation of the expression levels of the transcription factor nuclear factor-kappa B (NF-?B) in the nucleus, which has been reported to be implicated in the apoptotic cell death of several types of cancer cells, suppression of TNF-?-induced NF-?B activation, inhibition of cyclooxygenase-2 expression, repression of matrix metalloproteinase-9 activation and decrease of 5-lipoxygenase in a concentration-dependent manner. These results suggest that MHY218 may be a useful candidate to be used in the chemoprevention and/or treatment of colon cancer.
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Uterotrophic and Hershberger assays for endocrine disruption properties of plastic food contact materials polypropylene (PP) and polyethylene terephthalate (PET).
J. Toxicol. Environ. Health Part A
PUBLISHED: 07-19-2013
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Plasticizers or plastic materials such as phthalates, bisphenol-A (BPA), and styrene are widely used in the plastic industry and are suspected endocrine-disrupting chemicals (EDC). Although plastic materials such as polypropylene (PP) and polyethylene terephthalate (PET) are not EDC and are considered to be safe, their potential properties as EDC have not been fully investigated. In this study, plastic samples eluted from plastic food containers (PP or PET) were investigated in Sprague-Dawley rats using Hershberger and uterotrophic assays. In the Hershberger assay, 6-wk-old castrated male rats were orally treated for 10 consecutive days with plastic effluent at 3 different doses (5 ml/kg) or vehicle control (corn oil, 1 ml/100 g) to determine the presence of both anti-androgenic and androgenic effects. Testosterone (0.4 mg/ml/kg) was subcutaneously administered for androgenic evaluation as a positive control, whereas testosterone (0.4 mg/ml/kg) and flutamide (3 mg/kg/day) were administered to a positive control group for anti-androgenic evaluation. The presence of any anti-androgenic or androgenic activities of plastic effluent was not detected. Sex accessory tissues such as ventral prostate or seminal vesicle showed no significant differences in weight between treated and control groups. For the uterotrophic assay, immature female rats were treated with plastic effluent at three different doses (5 ml/kg), with vehicle control (corn oil, 1 ml/100 g), or with ethinyl estradiol (3 ?g/kg/d) for 3 d. There were no significant differences between test and control groups in vagina or uterine weight. Data suggest that effluents from plastic food containers do not appear to produce significant adverse effects according to Hershberger and uterotrophic assays.
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Baicalein, an active component of Scutellaria baicalensis Georgi, induces apoptosis in human colon cancer cells and prevents AOM/DSS-induced colon cancer in mice.
Int. J. Oncol.
PUBLISHED: 07-09-2013
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Flavonoids have been demonstrated to provide health benefits in humans. Baicalein (5,6,7-trihydroxyflavone) is a phenolic flavonoid compound derived mainly from the root of Scutellaria baicalensis Georgi, a medicinal plant traditionally used in oriental medicine. Baicalein is widely used in Korean and Chinese herbal medicines as anti-inflammatory and anticancer therapy. However, the molecular mechanisms of its activity remain poorly understood and warrant further investigation. This study was performed to investigate the anticancer effect of baicalein on HCT116 human colon cancer cells and the tumor preventing capacity of baicalein on colitis-associated cancer in mice. In in vivo experiments, we induced colon tumors in mice by azoxymethane (AOM) and dextran sulfate sodium (DSS) and evaluated the effects of baicalein on tumor growth. Baicalein treatment on HCT116 cells resulted in a concentration-dependent inhibition of cell growth and induction of apoptotic cell death. The induction of apoptosis was determined by morphological changes and cleavage of poly(ADP-ribose) polymerase. Baicalein also suppressed the activation of NF-?B through PPAR? activation. These results indicate that the anti-inflammatory effects of baicalein may be mediated through PPAR? activation. Finally, administration with baicalein significantly decreased the incidence of tumor formation with inflammation. Our findings suggest that baicalein is one of the candidates for the prevention of inflammation-associated colon carcinogenesis.
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Low amount of salinomycin greatly increases Akt activation, but reduces activated p70S6K levels.
Int J Mol Sci
PUBLISHED: 07-08-2013
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The present study identified a novel salinomycin (Sal)-sensitization mechanism in cancer cells. We analyzed the signal proteins Akt, Jnk, p38, Jak, and Erk1/2 in cancer cell lines that had arrested growth following low amounts of Sal treatment. We also tested the signal molecules PI3K, PDK1, GSK3?, p70S6K, mTOR, and PTEN to analyze the PI3K/Akt/mTOR pathway. The results showed that Sal sensitization positively correlates with large reductions in p70S6K activation. Interestingly, Akt was the only signal protein to be significantly activated by Sal treatment. The Akt activation appeared to require the PI3K pathway as its activation was abolished by the PI3K inhibitors LY294002 and wortmannin. The Akt activation by Sal was conserved in the other cell lines analyzed, which originated from other organs. Both Akt activation and C-PARP production were proportionally increased with increased doses of Sal. In addition, the increased levels of pAkt were not reduced over the time course of the experiment. Co-treatment with Akt inhibitors sensitized the Sal-treated cancer cells. The results thereby suggest that Akt activation is increased in cells that survive Sal treatment and resist the cytotoxic effect of Sal. Taken together; these results indicate that Akt activation may promote the resistance of cancer cells to Sal.
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Characterization and clinical application of mesenchymal stem cells from equine umbilical cord blood.
J. Vet. Sci.
PUBLISHED: 06-28-2013
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Tendinitis of the superficial digital flexor tendon (SDFT) is a significant cause of lameness in horses; however, recent studies have shown that stem cells could be useful in veterinary regenerative medicine. Therefore, we isolated and characterized equine umbilical cord blood mesenchymal stem cells (eUCB-MSCs) from equine umbilical cord blood obtained from thoroughbred mares during the foaling period. Horses that had tendinitis of the SDFT were treated with eUCB-MSCs to confirm the therapeutic effect. After eUCB-MSCs transplantation, the core lesion in the SDFT was found to decrease. These results suggest that transplantation using eUCB-MSCs could be another source of cell treatment.
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Dynamic MRI findings and clinical features of benign hypervascular hepatic nodules in childhood-cancer survivors.
AJR Am J Roentgenol
PUBLISHED: 06-25-2013
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The purpose of this study is to investigate the dynamic MRI findings and clinical features of benign hypervascular hepatic nodules in childhood-cancer survivors.
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Changes in simple visual matching task performance and physiological signals in intellectually and developmentally disabled people due to administration of highly concentrated oxygen.
NeuroRehabilitation
PUBLISHED: 05-08-2013
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This study attempted to identify the effect of administration of highly concentrated oxygen on simple visual matching task performance, blood oxygen saturation [SpO2 (%)], and heart rate [HR (bpm)] of intellectually and developmentally disabled people.
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Changes of apoptosis in tumor tissues with time after irreversible electroporation.
Biochem. Biophys. Res. Commun.
PUBLISHED: 05-07-2013
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Irreversible electroporation is a novel method of ablating living tissues through its non-thermal effects, unlike radiofrequency ablation which has a severe problem of heat sink. It is due to high-energy direct current which leads to permanent disruption of lipid bilayer integrity in terms of exchanges between intra- and extracellular components via nano-sized pores. That finally causes irreversible damage to cellular homeostasis. Irreversibly damaged cells may undergo apoptosis followed by necrosis with time after electroporation. This damage can make it possible to monitor the ablated area with time post-IRE through MR imaging and an ultrasound system. Most previous studies have investigated the immediate response of undesired tissue to IRE. In our study, we showed changes of tumor tissues with time post-IRE by histological analysis and MR imaging. Tissues under IRE ablation showed a peak apoptotic rate at 24 h after IRE ablation with viable tissues at the peripheral rim of treated tissues in histological analysis. This phenomenon was also observed with no enhancement on contrast-enhanced MR images due to devascularization of IRE ablated zones.
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Evaluation of the growth pattern of carcinoma of colon and rectum by MDCT.
Acta Radiol
PUBLISHED: 04-30-2013
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BackgroundColorectal cancer is a leading cause of cancer morbidity and mortality worldwide. Knowledge of colorectal cancer tumor growth is of importance for basic understanding of tumor biology and for the clinical handling of the disease.PurposeTo conduct a retrospective evaluation of the growth pattern of colorectal cancer by multidetector computed tomography (MDCT).Material and MethodsPathologically proven adenocarcinomas of the colon and rectum in 44 patients were examined by MDCT on at least two separate occasions with an interval of >1 month in patients not receiving therapy. Maximal longitudinal diameters, wall thicknesses, and volume changes, as determined by serial CT scans, were used in calculation of growth rates.ResultsMean longitudinal diameters of tumors at initial and follow-up investigations were 3.8 cm (1.0-9.1 cm) and 5.4 cm (2.5-12.2 cm), respectively. The mean growth rate of longitudinal tumor diameter was 3.4 cm/year (0-13.8 cm/year). Mean axial wall thicknesses at initial and follow-up investigations were 1.4 cm (0.6-6.6 cm) and 1.9 cm (0.8-6.8 cm), respectively. Mean growth rate of tumor axial wall thickness was 1.0 cm/year (0-3.1 cm/year). Mean tumor volumes at initial and follow-up investigations were 1975 cm(3) (172-9756 cm(3); median, 1490) and 3545 cm(3) (442-15211 cm(3); median, 2846), respectively. Mean growth rate of tumor volume was 2912 cm(3)/year (216-12548 cm(3)/year; median, 1698), and volume doubling times varied from 0.05 to 7.1 years (mean, 1.2; median, 0.7). Significant correlations were observed between initial wall thickness and volume growth rate (p = 0.004). No significant difference was observed between other initial tumor size and growth rate.ConclusionThe tumor growth doubling time of colorectal cancer has a very broad aspect. The initial wall thickness of the tumor on MDCT appears to be the most powerful parameter showing correlation with the volume growth rate.
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Safety evaluation and risk assessment of d-Limonene.
J Toxicol Environ Health B Crit Rev
PUBLISHED: 04-12-2013
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d-Limonene, a major constituent of citrus oils, is a monoterpene widely used as a flavor/fragrance additive in cosmetics, foods, and industrial solvents as it possesses a pleasant lemon-like odor. d-Limonene has been designated as a chemical with low toxicity based upon lethal dose (LD50) and repeated-dose toxicity studies when administered orally to animals. However, skin irritation or sensitizing potential was reported following widespread use of this agent in various consumer products. In experimental animals and humans, oxidation products or metabolites of d-limonene were shown to act as skin irritants. Carcinogenic effects have also been observed in male rats, but the mode of action (MOA) is considered irrelevant for humans as the protein ?(2u)-globulin responsible for this effect in rodents is absent in humans. Thus, the liver was identified as a critical target organ following oral administration of d-limonene. Other than the adverse dermal effects noted in humans, other notable toxic effects of d-limonene have not been reported. The reference dose (RfD), the no-observed-adverse-effect level (NOAEL), and the systemic exposure dose (SED) were determined and found to be 2.5 mg/kg/d, 250 mg/kg//d, and 1.48 mg/kg/d, respectively. Consequently, the margin of exposure (MOE = NOAEL/SED) of 169 was derived based upon the data, and the hazard index (HI = SED/RfD) for d-limonene is 0.592. Taking into consideration conservative estimation, d-limonene appears to exert no serious risk for human exposure. Based on adverse effects and risk assessments, d-limonene may be regarded as a safe ingredient. However, the potential occurrence of skin irritation necessitates regulation of this chemical as an ingredient in cosmetics. In conclusion, the use of d-limonene in cosmetics is safe under the current regulatory guidelines for cosmetics.
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Development and application of risk management system for consumer products in compliance with global harmonization.
J Toxicol Environ Health B Crit Rev
PUBLISHED: 04-12-2013
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Exposure to the wide variety of chemicals used for manufacturing consumer products commonly occurs daily and the consequences to health are beneficial. However, some of these products are hazardous and exert deleterious effects on humans and the ecosystem. To protect consumers from exposure to hazardous chemicals, appropriate risk management systems are needed. Developed countries such as the United States and Canada have developed their own risk management systems for regulating hazardous agents. However, the risk management systems prepared by developed countries may not be readily applicable to developing or underdeveloped countries because of certain economic, political, cultural, or social factors in each country. In general, a risk management framework includes evaluation components of risk assessment, risk confrontation, risk intervention, risk communication, and risk management, but these may differ in specifics. The European Commission (EC) requires a socioeconomic analysis for formulating restrictions suggested by the European Chemicals Agency (ECHA). The EC has an early warning system for safety management termed the Rapid Alert System (RAPEX). Korea, Australia, and Japan also developed integrated network systems for risk management of consumer products. Monitoring entails the collection of information and evaluation. The risk assessment process includes scientific evaluation of potential adverse health effects. Risk communication tasks are to (1) identify stakeholders, (2) develop stakeholder analysis, (3) assess stakeholder acceptability, (4) consult with stakeholders, (5) inform stakeholders about their options, (6) evaluate control options, and (7) monitor changing issues. The risk management process involves weighing policy options and selecting regulatory options. The decision-making step is related to the determination of governmental or voluntary actions. This review examines the critical points of risk management system in Korea to effectively control hazardous agents for human safety and compliance with global harmonization.
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Triclosan exhibits a tendency to accumulate in the epididymis and shows sperm toxicity in male sprague-dawley rats.
Environ. Toxicol.
PUBLISHED: 04-08-2013
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Triclosan (TCS) is considered a potent endocrine disruptor that causes reproductive toxicity in non-mammals, but it is still unclear exactly whether TCS has adverse effects on the sperm or reproductive organs in mammals. In this study, we aimed to evaluate the distribution status of TCS in male reproductive organs of rats, and seek the correlation with the TCS-induced sperm toxicity or reproductive organ damage. Male rats were intragastrically administered with TCS at a dose of 50 mg/kg, the kinetics of TCS in the plasma and reproductive organs were investigated. TCS in testes and prostates both showed a lower-level distritbution compared to that in the plasma, which indicates it has no tendency to accumulate in those organs. However, TCS in the epididymides showed a longer elimination half-life (t1/2z ), a longer the mean retention time (MRT), and a lower clearance (CLZ /F) compared with those in the plasma. Besides, the ratios of mean area under the concentration-time curve (AUC)0-96h(epididymides/plasma) and AUC0-?(epididymides/plasma) were 1.13 and 1.51, respectively. These kinetic parameters suggest TCS has an accumulation tendency in the epididymides. Based on this, we investigated the TCS-induced sperm toxicity and histopathological changes of reproductive organs in rats. TCS was given intragastrically at doses of 10, 50, and 200 mg/kg for 8 weeks. Rats treated with the high dose (200 mg/kg) of TCS showed a significant decrease in daily sperm production (DSP), changes in sperm morphology and epididymal histopathology. Considering the histopathological change in the epididymides, TCS may induce the epididymal damage due to the epididymal accumulation of that. © 2013 Wiley Periodicals, Inc. Environ Toxicol, 2013.
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Resveratrol enhances chemosensitivity of doxorubicin in multidrug-resistant human breast cancer cells via increased cellular influx of doxorubicin.
Biochim. Biophys. Acta
PUBLISHED: 03-15-2013
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Multidrug resistance is a major problem in the treatment of breast cancer, and a number of studies have attempted to find an efficient strategy with which to overcome it. In this study, we investigate the synergistic anticancer effects of resveratrol (RSV) and doxorubicin (Dox) against human breast cancer cell lines.
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Diallyl disulfide impairs hippocampal neurogenesis in the young adult brain.
Toxicol. Lett.
PUBLISHED: 03-08-2013
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Garlic and garlic extracts are used as seasonings and are generally considered beneficial to human health, which include antioxidant and neuroprotective properties in neurological disorders. In the present study, we examined the effects of garlic sulfur components on the proliferation of neural progenitor cells (NPCs) and hippocampal neurogenesis. Of the sulfur compounds extracted, diallyl disulfide (DADS) significantly suppressed the proliferation of NPCs, whereas other sulfur containing components had no effect. In order to investigate the effect of DADS on adult hippocampal neurogenesis, DADS was administered orally to young (6 week-old) male C57BL/6 mice for 2 weeks. It was found that 10 mg/kg of DADS significantly decreased the proliferation of NPCs in the dentate gyrus without affecting the survival of newly generated cells. Furthermore, DADS decreased levels of hippocampal BDNF, phosphorylated CREB signaling, and phosphorylated ERKs, which are known to be related to hippocampal neurogenesis and NPCs proliferation. In addition, DADS induced significant memory defects as compared with controls. We report that DADS may have adverse effects on hippocampal neurogenesis and neurocognitive functions by modulating ERK and BDNF-CREB signaling, and suggest that the advisability of consuming large amounts of garlic products should be considered, particularly during the period of neural growth.
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Reduced radiation exposure of the female breast during low-dose chest CT using organ-based tube current modulation and a bismuth shield: comparison of image quality and radiation dose.
AJR Am J Roentgenol
PUBLISHED: 02-26-2013
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The objective of our study was to evaluate the effect of organ-based tube current modulation and bismuth shielding on image quality and breast radiation dose in women undergoing low-dose chest CT.
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Isolation and characterization of equine amniotic membrane-derived mesenchymal stem cells.
J. Vet. Sci.
PUBLISHED: 02-05-2013
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Recent studies have shown that mesenchymal stem cells (MSCs) are able to differentiate into multi-lineage cells such as adipocytes, chondroblasts, and osteoblasts. Amniotic membrane from whole placenta is a good source of stem cells in humans. This membrane can potentially be used for wound healing and corneal surface reconstruction. Moreover, it can be easily obtained after delivery and is usually discarded as classified waste. In the present study, we successfully isolated and characterized equine amniotic membrane-derived mesenchymal stem cells (eAM-MSCs) that were cultured and maintained in low glucose Dulbeccos modified Eagles medium. The proliferation of eAM-MSCs was measured based on the cumulative population doubling level (CPDL). Immunophenotyping of eAM-MSCs by flow cytometry showed that the major population was of mesenchymal origin. To confirm differentiation potential, a multi-lineage differentiation assay was conducted. We found that under appropriate conditions, eAM-MSCs are capable of multi-lineage differentiation. Our results indicated that eAM-MSCs may be a good source of stem cells, making them potentially useful for veterinary regenerative medicine and cell-based therapy.
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Frequency-dependent patterns of somatosensory cortical responses to vibrotactile stimulation in humans: a fMRI study.
Brain Res.
PUBLISHED: 02-02-2013
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In the human mechanosensation system, rapidly adapting afferents project sensory signals of flutter (5-50Hz) to the contralateral primary somatosensory cortex (S1) and bilateral secondary somatosensory cortex (S2) whereas Pacinian afferents project sensory signals of vibration (50-400Hz) to bilateral S2. However, it remains largely unknown how somatosensory cortical activity changes as a function of vibrotactile frequency. This functional magnetic resonance imaging (fMRI) study investigated frequency dependency of somatosensory cortical activity in humans by applying vibrotactile stimulation with various frequencies (20-200Hz) to the index finger. We found more frequency-dependent voxels in the upper bank of the lateral sulcus (LS) of S2 than in S1 and the posterior parietal cortex of S2. Our statistical spatial clustering analysis showed that two groups of positively or negatively frequency-dependent voxels formed distinct clusters, most clearly in the LS. Using a cortical separability index, we reaffirmed that somatosensory cortical activity was most separable at 50Hz, previously known to demarcate flutter and vibration. Our results suggest that the LS (S2) may play an important role in processing vibrotactile frequency information and that the somatosensory cortex may include spatially localized neural assemblies specialized to higher or lower vibrotactile frequency.
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The effects of hedgehog on RNA binding protein Msi1 during the osteogenic differentiation of human cord blood-derived mesenchymal stem cells.
Bone
PUBLISHED: 01-25-2013
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Human umbilical cord blood (UCB)-derived mesenchymal stem cells (MSCs) are useful tools for regenerative medicine due to their capacity for self-renewal and multi-lineage differentiation. The appropriate clinical application of MSCs for regenerative medicine requires an integrated understanding of multiple signaling pathways that regulate cell proliferation, stemness and differentiation. However, the potential molecular mechanisms mediating these functions are not completely understood. The effects of hedgehog (Hh) signaling on the osteogenic differentiation of MSCs are still controversial, and the underlying mechanisms are unclear. In the present study, we evaluated the direct effects of Hh signaling on the osteogenic differentiation of hUCB-MSCs and investigated potential downstream regulatory mechanisms responsible for Hh signaling. We observed that Hh signaling acts as a negative regulator of osteogenic differentiation through the suppression of RNA-binding Msi1, which in turn suppresses the expression of Wnt1 and the miR-148 family, especially miR-148b. Moreover, Hh and Msi1 are considered to be potential stemness markers of hUCB-MSCs due to their differentiation-dependent expression profiles. This study provides new insights into mechanisms regulating MSC differentiation and may have implications for a variety of therapeutic applications in the clinic.
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Morus bombycis extract suppresses mast cell activation and IgE-mediated allergic reaction in mice.
J Ethnopharmacol
PUBLISHED: 01-09-2013
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Morus bombycis Koidzumi (MB) is widely distributed throughout Korea, where it is used as a traditional folk remedy for the treatment of allergic diseases including asthma. However, the pharmacological effect and the mechanistic study of MB have not been investigated. We aimed to investigate the anti-allergic activity of MB in vitro and in vivo and the mechanism of its action on mast cells.
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Selective impairment on the proliferation of neural progenitor cells by oxidative phosphorylation disruption.
Neurosci. Lett.
PUBLISHED: 01-08-2013
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Mitochondria produce ATP, regulate apoptosis, and maintain calcium homeostasis, and thus, mitochondrial dysfunction critically impairs nervous system development. Furthermore, the disruption of oxidative phosphorylation (OXPHOS) in mitochondria could lead to energy depletion and elevate oxidative stress. In the present study, the authors investigated how perturbation of the respiratory chain and bioenergetics affects neural progenitor cells (NPCs). Mitochondrial OXPHOS was impaired by inhibiting electron transfer using the antimycin A and ATP synthase inhibitor oligomycin. It was found that oligomycin impaired NPCs proliferation and was toxic at high concentrations, whereas antimycin A-treated cells showed no changes in NPCs proliferation. Although ROS production was elevated concentration-dependently by both inhibitors, oligomycin-treated C17.2 NPCs, but not antimycin A-treated NPCs, showed a significantly higher cell death rate and lower levels of intracellular ATP. These findings suggest that bioenergetic considerations are critically important for cell viability regulation in NPCs. Taken together, the present study shows that OXPHOS disruption can have a neurotoxic effect on NPCs, and thus, adversely influence the developing brain and the neurogenic capacity of the adult brain.
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A novel histone deacetylase (HDAC) inhibitor MHY219 induces apoptosis via up-regulation of androgen receptor expression in human prostate cancer cells.
Biomed. Pharmacother.
PUBLISHED: 01-07-2013
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Histone deacetylase (HDAC) inhibitors are a new class of anticancer agents that act by inhibiting cancer cell proliferation and inducing apoptosis in various cancer cell lines. To investigate the anticancer effect of a novel histone deacetylase (HDAC) inhibitor MHY219, its efficacy was compared to that of suberoylanilide hydroxamic acid (SAHA) in human prostate cancer cells. The anticancer effects of MHY219 on cell viability, HDAC enzyme activity, cell cycle regulation, apoptosis and other biological assays were performed. MHY219 was shown to enhance the cytotoxicity on DU145 cells (IC??, 0.36 ?M) when compared with LNCaP (IC??, 0.97 ?M) and PC3 cells (IC??, 5.12 ?M). MHY219 showed a potent inhibition of total HDAC activity when compared with SAHA. MHY219 increased histone H3 hyperacetylation and reduced the expression of class I HDACs (1, 2 and 3) in prostate cancer cells. MHY219 effectively increased the sub-G1 fraction of cells through p21 and p27 dependent pathways in DU145 cells. MHY219 significantly induced a G2/M phase arrest in DU145 and PC3 cells and arrested the cell cycle at G0/G1 phase in LNCaP cells. Furthermore, MHY219 effectively increased apoptosis in DU145 and LNCaP cells, but not PC3 cells, according to Annexin V/PI staining and Western blot analysis. These results indicate that MHY219 is a potent HDAC inhibitor that targets regulating multiple aspects of cancer cell death and might have preclinical value in human prostate cancer chemotherapy, warranting further investigation.
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In vitro evaluation of biomarkers for cisplatin-induced nephrotoxicity using HK-2 human kidney epithelial cells.
Toxicol. Lett.
PUBLISHED: 01-05-2013
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The non-animal in vitro test methods, especially for assessment of kidney toxicity, have become invaluable tools due to the target organ-selective nature of many nephrotoxic xenobiotics. In vitro evaluation of biomarkers for nephrotoxicity assessment using human cell lines, which can provide more reliable information for toxicological risk evaluation in humans than animal cells, has not been well established to date. The present study investigated the potential use of biomarkers for cisplatin-induced nephrotoxicity assessment in vitro using HK-2 cells derived from human kidney proximal tubule epithelial cells. Cisplatin induced apoptosis of HK-2 cells in which down-regulation of Bcl-2 and activation of caspase-3 were possibly involved. We investigated the effect of cisplatin on the protein levels of kidney injury molecule (KIM)-1, clusterin, calbindin, tissue inhibitor of metalloproteinase (TIMP)-1, cystatin C (CysC), ??-microglobulin (??-M) and neutrophil gelatinase associated lipocalin (NGAL), which have been recently identified as in vivo biomarkers of nephrotoxicity. The protein levels of KIM-1, calbindin and TIMP-1 were significantly increased in the conditioned media of HK-2 cells treated with cisplatin, while ??-M, CysC, NGAL and clusterin were not affected by cisplatin treatment. The mRNA levels of KIM-1, calbindin and TIMP-1 were increased by cisplatin, indicating that cisplatin-induced up-regulation involves transcriptional activation. The levels of KIM-1, calbindin and TIMP-1 were significantly increased in urine of cisplatin-treated rats, providing in vivo validation of the in vitro results. Taken together, our results clearly demonstrate that among the known in vivo nephrotoxic biomarkers, KIM-1, calbindin and TIMP-1 can be effectively used as in vitro biomarkers for cisplatin-induced nephrotoxicity using a HK-2 human kidney cell system.
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Isolation and characterization of antler derivedmultipotent stem cells.
Cell Transplant
PUBLISHED: 01-02-2013
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Recent studies have reported that stem cells can be isolated from various tissues such as bone marrow, fatty tissue, umbilical cord blood, Whartons jelly and placenta. These types of stem cell studies have also arisen in veterinary medicine. Deer antlers show a seasonal re-growth of tissue, an unusual feature in mammals. Antler tissue therefore might offer a source of stem cells. To explore the possibility of stem cell populations within deer antlers, we isolated and successfully cultured antler-derived multipotent stem cells (MSCs). Antler MSCs were maintained in growth medium, and proliferation potential was measured via an assay called the cumulative population doubling level. Immunophenotyping and immunostaining revealed the intrinsic characteristic stem cell markers of antler MSCs. To confirm the ability to differentiate, we conducted osteogenic, adipogenic and chondrogenic induction under the respective differentiation conditions. We discovered that antler MSCs have the ability to differentiate into multiple lineages. In conclusion, our results show that deer antler tissue may contain MSCs and therefore may be a potential source for veterinary regenerative therapeutics.
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A mixture of Trachelospermi caulis and Moutan cortex radicis extracts suppresses collagen-induced arthritis in mice by inhibiting NF-?B and AP-1.
J. Pharm. Pharmacol.
PUBLISHED: 12-08-2011
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We aimed to determine the anti-arthritis effect and its mechanism of a combination of herbal extracts from Trachelospermi caulis (TC) and Moutan cortex radicis (MC) (TCMC).
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Development of a tactile stimulator with simultaneous visual and auditory stimulation using E-Prime software.
Comput Methods Biomech Biomed Engin
PUBLISHED: 12-08-2011
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In this study, a tactile stimulator was developed, which can stimulate visual and auditory senses simultaneously by using the E-Prime software. This study tried to compensate for systematic stimulation control and other problems that occurred with previously developed tactile stimulators. The newly developed system consists of three units: a control unit, a drive unit and a vibrator. Since the developed system is a small, lightweight, simple structure with low electrical consumption, a maximum of 35 stimulation channels and various visual and auditory stimulation combinations without delay time, the previous systematic problem is corrected in this study. The system was designed to stimulate any part of the body including the fingers. Since the developed tactile stimulator used E-Prime software, which is widely used in the study of visual and auditory senses, the stimulator is expected to be highly practical due to a diverse combination of stimuli, such as tactile-visual, tactile-auditory, visual-auditory and tactile-visual-auditory stimulation.
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The hepatoprotective effects of adenine nucleotide translocator-2 against aging and oxidative stress.
Free Radic. Res.
PUBLISHED: 11-22-2011
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Mitochondrial adenine nucleotide translocator (ANT) plays important roles in the regulation of mitochondrial permeability transition and cell bioenergetics. The mouse has three ANT isoforms (1, 2 and 4) showing tissue-specific expression patterns. Although ANT1 is known to have a pro-apoptotic property, the specific functions of ANT2 have not been well determined. In the present study, ANT2 expression was significantly lower in the aged rat liver and in a liver fibrosis model. To explore the protective role of ANT2 in the liver, we established a hepa1c1c7 cell line overexpressing ANT2. Overexpression of ANT2 caused hepa1c1c7 cells to be more resistant to oxidative stress, and mitochondrial membrane potential (MMP, ??m) was relatively intact in ANT2-overexpressing cells under oxidative stress. In addition, ANT2 was found to increase ATP production by influencing mitochondrial bioenergetics. These results imply that the hepatoprotective effect of ANT2 is due to the stabilization of MMP and enhanced ATP production, and thus, maintaining ANT2 levels in the liver might be important to enhance resistance to aging and oxidative stress.
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