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1.  A Solitary Malignant Schwannoma in the Choana and Nasal Septum 
Case Reports in Otolaryngology  2014;2014:202910.
Malignant schwannoma is an extremely rare tumor and the risk of malignant schwannoma increases in patients with von Recklinghausen's disease. Recently, we encountered a case of solitary malignant schwannoma in the choana and posterior nasal septum. Malignant schwannoma has not been previously reported in these locations. A 53-year-old man, who was immunologically healthy and showed no abnormal dermatological lesions, presented with a polypoid mass in the right nasal cavity and underwent endoscopic mass excision. The mass originated from the choana and the posterior portion of the right nasal septum. This mass was confirmed as a malignant schwannoma on histological examination and immunohistochemical staining. After endoscopic excision, postoperative adjuvant radiotherapy was administered, and there was no recurrence at 1 year after treatment. This case suggests that a solitary malignant schwannoma should be considered in the differential diagnosis of a mass in the posterior nasal cavity.
doi:10.1155/2014/202910
PMCID: PMC4172938  PMID: 25276456
3.  Incidence and Risk Factors for Early-Onset Hypertension after Allogeneic Hematopoietic Stem Cell Transplantation in Children 
Korean Circulation Journal  2013;43(12):804-810.
Background and Objectives
Survivors of pediatric hematopoietic stem cell transplantation (HSCT) are at risk for developing hypertension. The objectives of this study are to evaluate the prevalence and risk factors of early onset hypertension during the engraftment period after HSCT.
Subjects and Methods
This is a retrospective study of 157 consecutive patients (mean age at HSCT: 9.1±5.1 years) who underwent HSCT for acute myeloid leukemia (n=47), acute lymphoblastic leukemia (n=43), severe aplastic anemia (n=41), and other reasons (n=26). Blood pressure data were collected at five time points: 0, 7, 14, 21, and 28 days after HSCT. Hypertension was defined as having systolic and/or diastolic blood pressure ≥95th percentile according to age, gender, and height. To analyze the risk factors related to hypertension, data, including patients' demographic and transplant characteristics, were reviewed.
Results
Hypertension developed in 59 patients (38%), among whom 12 (7.6%) required long term therapy. Thirty-two (54%) patients had systolic and diastolic, 8 (14%) had only systolic, and 19 (32%) had only diastolic hypertension. Younger age, acute graft-versus-host disease, sinusoidal obstruction syndrome, treatment with antifungal agent, and greater increase in serum creatinine (Cr) levels were associated with hypertension. Multivariate analysis showed that younger age at HSCT and greater increase in serum Cr level were independent risk factors for hypertension.
Conclusion
Prevalence of hypertension during immediate post-HSCT period is high, especially in younger children. A greater increase in Cr after HSCT was significantly associated with hypertension. Further study is needed to elucidate long-term cardiovascular complications in pediatric HSCT survivors.
doi:10.4070/kcj.2013.43.12.804
PMCID: PMC3875696  PMID: 24385991
Hematopoletic stem cell transplantation; Child; Incidence; Blood pressure; Hypertension
4.  Risk Factors for Mortality in Patients with Acinetobacter baumannii Bacteremia 
Infection & Chemotherapy  2013;45(3):325-330.
Background
Acinetobacter baumannii, an opportunistic nosocomial pathogen that can cause significant morbidity and mortality, has emerged as a worldwide problem. The aim of this study was to evaluate the risk factors for mortality in patients with A. baumannii bacteremia.
Materials and Methods
We retrospectively evaluated 118 patients who had A. baumannii bacteremia between July 2003 and December 2011. The aim of this study was to identify the 30-day mortality in patients with A. baumannii bacteremia and relevant risk factors.
Results
The bacteremia-related 30-day mortality rate was 34.1%. Univariate analysis revealed that the risk factors for mortality included malignancy, longer hospital stay before bacteremia, intensive care unit (ICU) stay at the time of bacteremia, mechanical ventilation, use of a central venous catheter, unknown origin of bacteremia, bacteremia due to pneumonia, antimicrobial resistance to carbapenems, and elevated Acute Physiology and Chronic Health Evaluation II and Pitt bacteremia scores. Multivariate logistic regression analysis revealed that resistance to carbapenems (odds ratio [OR]: 4.01, 95% confidence interval [CI]: 1.51 to 0.68, P = 0.005), need for mechanical ventilation (OR: 3.97, 95% CI: 1.41 to 11.13, P = 0.005), and presence of malignancy (OR: 4.40, 95% CI: 1.60 to 12.08, P = 0.004) were significantly related to mortality risk.
Conclusions
Risk factors such as resistance to carbapenems, mechanical ventilation, and presence of malignancy were found to be associated with high mortality rates in the patients with A. baumannii bacteremia.
doi:10.3947/ic.2013.45.3.325
PMCID: PMC3848511  PMID: 24396634
Acinetobacter baumannii; Bacteremia; Mortality
5.  A Rare Case of Interdigitating Dendritic Cell Sarcoma in the Nasal Cavity 
Case Reports in Otolaryngology  2013;2013:913157.
Interdigitating dendritic cell sarcoma (IDCS) is an extremely rare neoplasm that mainly arises from the lymphoid tissues of the immune system. Although this neoplasm typically occurs anywhere along the lymph nodes, it can also be found at extranodal sites, especially in the head and neck. We experienced a rare case of extranodal IDCS in the nasal cavity, a location that has not been previously reported. A 73-year-old woman presented with a polyp-like mass in the nasal cavity and underwent endoscopic sinus surgery. A histologic study confirmed the mass as IDCS by immunohistochemistry with S-100 antibody, and postoperative adjuvant radiotherapy was administered. Although the incidence is extremely rare, this case suggests that extranodal IDCS should be considered in the differential diagnosis of nasal cavity masses.
doi:10.1155/2013/913157
PMCID: PMC3654715  PMID: 23710400
6.  A Case of Delayed Spontaneous Aneurismal Rupture after Ear Surgery Under General Anesthesia 
Korean Journal of Audiology  2012;16(2):83-86.
Many complications have been reported after ear surgery to treat chronic inflammation. These complications include facial nerve paralysis, perichondritis, injury of the dura or of the sigmoid sinus, cyst formation or mucocele in the healed mastoid cavity, and the recurrence of cholesteatoma, granulation tissue, or otorrhea. It might be believed that there could be no relation between ear surgery and spontaneous aneurysmal rupture, and only one other case of spontaneous aneurysmal rupture after ear surgery under general anesthesia has been previously reported in Korea. However, recently, the authors encountered a case of delayed spontaneous aneurysmal rupture 3 weeks after surgery. No problem was experienced during the operation, and it is suspected that an unidentified pre-existing aneurysm was responsible for the intracerebral hemorrhage.
doi:10.7874/kja.2012.16.2.83
PMCID: PMC3936562  PMID: 24653877
Intracerebral hemorrhage; Otologic surgical procedure; Complications; Aneurysm
7.  Primary Acinic Cell Carcinoma of the Breast: A Case Report with an Immunohistochemical and Ultrastructural Studies 
Journal of Breast Cancer  2011;14(2):160-164.
Acinic cell carcinoma (ACC) of the breast is extremely rare and is characterized by widespread acinar cell-like differentiation. We report of a 39-year-old woman presented with a palpable breast mass with significant morphological, immunohistochemical and ultrastructural findings. Histologically, ACC showed a diffuse glandular infiltrative pattern, with small acinar or glandular structures mixed with solid nests. Neoplastic cells were monotonous proliferation of cells with a granular or clear cytoplasm, resembling acinar cells of the salivary glands or Paneth cells. Both glandular and solid tumor cell populations were strongly positive for lysozyme and α-1-antitrypsin.
doi:10.4048/jbc.2011.14.2.160
PMCID: PMC3148534  PMID: 21847414
Acinic cell carcinoma; Breast neoplasms; Electron microscopy; Immunohistochemistry
8.  Early Left Ventricular Dysfunction in Children after Hematopoietic Stem Cell Transplantation for Acute Leukemia: A Case Control Study Using Speckle Tracking Echocardiography 
Korean Circulation Journal  2015;45(1):51-58.
Background and Objectives
Cardiovascular complications are the leading cause of morbidity and mortality in childhood cancer survivors. Hematopoietic stem cell transplantation (HSCT) is a curable therapy for pediatric cancer. However, changes in cardiac function in children after HSCT are not well known. We assessed left ventricular (LV) function in children after HSCT using speckle tracking echocardiography (STE).
Subjects and Methods
Forty consecutive patients with median age of 11.9 years (range, 1.5-16 years) who received HSCT for acute leukemia and had comprehensive echocardiography before and after (median 9.2 month) HSCT were included in this study. The LV function parameters including conventional tissue Doppler imaging (TDI) and STE data were collected from pre- and post-HSCT echocardiography. These data were compared to those of 39 age-matched normal controls.
Results
Compared to normal controls, post HSCT patients had similar (p=0.06) LV ejection fraction. However, the following three LV function parameters were significantly decreased in post HSCT patients: rate-corrected velocity of circumferential fiber shortening (p=0.04), mitral inflow E velocity (p<0.001), and mitral septal annular E' velocity (p=0.03). The following four STE parameters were also significantly decreased in post HSCT patients: LV global circumferential systolic strain (p<0.01), strain rate (SR, p=0.01), circumferential diastolic SR (p<0.01), and longitudinal diastolic SR (p<0.001). There was no significant change in TDI or STE parameters after HSCT compared to pre-HSCT. Patients with anthracycline cumulative dose >400 mg/m2 showed significantly (p<0.05) lower circumferential systolic strain and circumferential diastolic SR.
Conclusion
Subclinical cardiac dysfunction is evident in children after HSCT. It might be associated with pre-HSCT anthracycline exposure with little effect of conditioning regimens. Serial monitoring of cardiac function is mandatory for all children following HSCT.
doi:10.4070/kcj.2015.45.1.51
PMCID: PMC4310980  PMID: 25653704
Childhood leukemia; Stem cell transplantation; Heart function; Speckle tracking; Echocardiography; Strain rate
10.  The significance of ectopic crypt formation in the differential diagnosis of colorectal polyps 
Diagnostic Pathology  2014;9(1):212.
Background
Ectopic crypts, defined as abnormally positioned crypts that have lost their orientation toward the muscularis mucosae, have been suggested to be the best defining histologic feature of traditional serrated adenoma (TSA). However, the significance of ectopic crypt formation (ECF) in the distinction between TSA and conventional adenoma (CA) has rarely been studied.
Methods
We designed this study to determine if ECF can be found in CA and its presence is exclusive to TSA. We studied 107 TSAs and 191 CAs including 106 tubular adenomas (TAs), 66 tubulovillous adenomas (TVAs), and 19 villous adenomas (VAs).
Results
ECF was identified in most (79.4%) but not all TSAs. Additionally, ECF was not infrequent in CA (62 of 191, 32.5%), and its presence correlated with the presence of a villous component and larger tumor size (each p <0.001).
Conclusions
Based on its strong association with the presence of a villous component and larger tumor size, ECF appears to be involved in the protuberant growth of colorectal CA. Because ECF can be found in CA, particularly in cases with a villous component, the possibility of CA should be considered before making a diagnosis of TSA when encountering colorectal polyps with ECF.
Virtual Slides
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_212
doi:10.1186/s13000-014-0212-x
PMCID: PMC4247761  PMID: 25421018
Traditional serrated adenoma; Conventional adenoma; Colon; Ectopic crypt formation; BRAF; KRAS
12.  The burden of nosocomial staphylococcus aureus bloodstream infection in South Korea: a prospective hospital-based nationwide study 
BMC Infectious Diseases  2014;14(1):590.
Background
We estimated the nationwide burden of nosocomial S. aureus bloodstream infection (SA-BSI), a major cause of nosocomial infection, in South Korea.
Methods
To evaluate the nationwide incidence of nosocomial SA-BSI, cases of SA-BSI were prospectively collected from 22 hospitals with over 500 beds over 4 months. Data on patient-days were obtained from a national health insurance database containing the claims data for all healthcare facilities in South Korea. The additional cost of SA-BSI was estimated through a matched case–control study. The economic burden was calculated from the sum of the medical costs, the costs of caregiving and loss of productivity.
Results
Three hundred and thirty nine cases of nosocomial SA-BSI were included in the study: 254 cases of methicillin-resistant SA-BSI (MRSA-BSI) and 85 cases of methicillin-susceptible SA-BSI (MSSA-BSI). Death related to BSI occurred in 81 cases (31.9%) of MRSA-BSI and 12 cases (14.1%) of MSSA-BSI. The estimated incidence of nosocomial MRSA-BSI was 0.12/1,000 patient-days and that of nosocomial MSSA-BSI, 0.04/1,000 patient-days. The estimated annual cases of nosocomial BSI were 2,946 for MRSA and 986 for MSSA in South Korea. The additional economic burden per case of nosocomial SA-BSI was US $20,494 for MRSA-BSI and $6,914 for MSSA-BSI. Total additional annual cost of nosocomial SA-BSI was $67,192,559.
Conclusion
In view of the burden of nosocomial SA-BSI, a national strategy for reducing nosocomial SA-BSI is urgently needed in South Korea.
doi:10.1186/s12879-014-0590-4
PMCID: PMC4247623
Staphylococcus aureus; Bacteremia; Incidence; Hospital infections
13.  Design of a microscopic electrical impedance tomography system for 3D continuous non-destructive monitoring of tissue culture 
Background
Non-destructive continuous monitoring of regenerative tissue is required throughout the entire period of in vitro tissue culture. Microscopic electrical impedance tomography (micro-EIT) has the potential to monitor the physiological state of tissues by forming three-dimensional images of impedance changes in a non-destructive and label-free manner. We developed a new micro-EIT system and report on simulation and experimental results of its macroscopic model.
Methods
We propose a new micro-EIT system design using a cuboid sample container with separate current-driving and voltage sensing electrodes. The top is open for sample manipulations. We used nine gold-coated solid electrodes on each of two opposing sides of the container to produce multiple linearly independent internal current density distributions. The 360 voltage sensing electrodes were placed on the other sides and base to measure induced voltages. Instead of using an inverse solver with the least squares method, we used a projected image reconstruction algorithm based on a logarithm formulation to produce projected images. We intended to improve the quality and spatial resolution of the images by increasing the number of voltage measurements subject to a few injected current patterns. We evaluated the performance of the micro-EIT system with a macroscopic physical phantom.
Results
The signal-to-noise ratio of the developed micro-EIT system was 66 dB. Crosstalk was in the range of -110.8 to -90.04 dB. Three-dimensional images with consistent quality were reconstructed from physical phantom data over the entire domain. From numerical and experimental results, we estimate that at least 20 × 40 electrodes with 120 μm spacing are required to monitor the complex shape of ingrowth neotissue inside a scaffold with 300 μm pore.
Conclusion
The experimental results showed that the new micro-EIT system with a reduced set of injection current patterns and a large number of voltage sensing electrodes can be potentially used for tissue culture monitoring. Numerical simulations demonstrated that the spatial resolution could be improved to the scale required for tissue culture monitoring. Future challenges include manufacturing a bioreactor-compatible container with a dense array of electrodes and a larger number of measurement channels that are sensitive to the reduced voltage gradients expected at a smaller scale.
doi:10.1186/1475-925X-13-142
PMCID: PMC4196084  PMID: 25286865
Non-destructive monitoring; Label-free; Electrical impedance tomography; Three-dimensional impedance image; Tissue culture monitoring; Projected image reconstruction algorithm
14.  A Suggestion of Modified Classification of Trigeminal Schwannomas According to Location, Shape, and Extension 
Background
Comprehensive knowledge of the anatomical features of trigeminal schwannomas (TSs) is essential in planning surgery to achieve complete tumor resection. In the current report, we propose a modified classification of TSs according to their location of origin, shape, and extension into the adjacent compartment, and discuss appropriate surgical strategies with this classification.
Methods
We retrospectively analyzed 49 patients with TS who were treated surgically by a single neurosurgeon at the Asan Medical Center between 1993 and 2013.
Results
There were 22 males and 27 females, with the median age of 40 years (range, 21-75 years). Median tumor size was 4.0 cm in diameter (2.0-7.0 cm). Tumors were classified as follows: Type M (confined to the middle fossa; 8 cases, 19.0%), P (confined to the posterior fossa; 2 cases, 4.8%), MP (involving equally both middle and posterior fossae; 5 cases, 11.9%), Mp (predominantly middle fossa with posterior fossa extension; 6 cases, 14.3%), Pm (predominantly posterior fossa with middle fossa extension; 16 cases, 38.1%), Me (predominantly middle fossa with extracranial extension; 4 cases, 9.5%). Surgical approach was chosen depending on the tumor classification. More specifically, a frontotemporal craniotomy and extradural approach with or without zygomatic or orbitozygomatic osteotomy was applied to M- or Mp-type tumors; a lateral suboccipital craniotomy with or without suprameatal approach was applied to the majority of P- or Pm-type tumors; and a posterior transpetrosal approach was used in four tumors (three Pm and one MP). Gross total resection was achieved in 95.9% of patients, and the overall recurrence rate was 4.1% (2 patients). Postoperatively, trigeminal symptoms were improved or unchanged in 51.0% of cases (25 patients). Surgical complications included meningitis (5 patients) and cerebrospinal fluid leakage (3 patients). There was no mortality.
Conclusion
TSs are well to be classified with our modified classification and able to be removed effectively and safely by selecting appropriate surgical approaches.
doi:10.14791/btrt.2014.2.2.62
PMCID: PMC4231622  PMID: 25408927
Classification; Neurilemmoma; Surgical procedure; Trigeminal nerve
15.  Treatment and Outcomes for Gangliogliomas: A Single-Center Review of 16 Patients 
Background
Ganglioglioma is a rare and slowly growing benign tumor. We investigated the outcomes of patients who underwent different combination treatments.
Methods
Between 1998 and 2012, 16 patients, including 11 men and 5 women, with a median age of 12.5 years (range, 2.5-65 years) were treated for intracranial gangliogliomas at our institution. The median follow-up period was 5.7 years (range, 48 days-15.6 years). Fifteen cases were included in the outcome assessment because one patient was lost to follow-up. Complete resection was achieved in 8 (53%) patients. Six (40%) patients underwent incomplete resection with or without adjuvant radiotherapy, and one patient with a brainstem tumor underwent only stereotactic biopsy.
Results
Gangliogliomas predominantly affected young (87.5%), male patients and most frequently presented with seizures (64%). Of eight patients who underwent complete resection, seven did not show recurrence, whereas only three of six with incomplete resection showed no recurrence. Four patients with recurrence received salvage treatments (two repeat surgeries and two radiosurgeries). A tumor control rate of 93% (14/15) was achieved at the last follow-up. No recurrence or malignant changes were observed after a median follow-up of 12 and 4.5 years in four patients who received gamma knife (GK) radiosurgery as adjuvant and salvage treatment.
Conclusion
Complete resection produced the best outcomes and incomplete resection followed by adjuvant or salvage treatments showed favorable outcomes. In patients who are not eligible for complete resection because of tumor location or potential neurologic deficits following surgery, GK radiosurgery should be considered for the treatment of residual or recurrent tumors.
doi:10.14791/btrt.2014.2.2.49
PMCID: PMC4231627  PMID: 25408925
Ganglioglioma; Radiosurgery
16.  Regulation of retinal axon growth by secreted Vax1 homeodomain protein 
eLife  2014;3:e02671.
Retinal ganglion cell (RGC) axons of binocular animals cross the midline at the optic chiasm (OC) to grow toward their synaptic targets in the contralateral brain. Ventral anterior homeobox 1 (Vax1) plays an essential role in the development of the OC by regulating RGC axon growth in a non-cell autonomous manner. In this study, we identify an unexpected function of Vax1 that is secreted from ventral hypothalamic cells and diffuses to RGC axons, where it promotes axonal growth independent of its transcription factor activity. We demonstrate that Vax1 binds to extracellular sugar groups of the heparan sulfate proteoglycans (HSPGs) located in RGC axons. Both Vax1 binding to HSPGs and subsequent penetration into the axoplasm, where Vax1 activates local protein synthesis, are required for RGC axonal growth. Together, our findings demonstrate that Vax1 possesses a novel RGC axon growth factor activity that is critical for the development of the mammalian binocular visual system.
DOI: http://dx.doi.org/10.7554/eLife.02671.001
eLife digest
We see the world around us when light bounces off of objects and hits the retina at the back of our eyes. This triggers electrical signals in neurons called retinal ganglion cells (RGCs), which have long structures called axons that extend out from the retina and into the parts of the brain where the signals are interpreted. As the axons grow, various ‘guidance’ molecules direct the axons to the correct part of the brain.
One molecule that is important for the growth of retinal ganglion cells' axons is a protein called Vax1. This protein is a transcription factor and binds to DNA to control how and when the molecular templates used to make proteins are made—a process called transcription. Vax1 is not produced in retinal ganglion cells, but it does control the extension of these cells' axons into part of the brain called the ventral hypothalamus. In this study, the axons cross to the other side of the brain by forming a structure called optic chiasm. Humans and mice lacking Vax1 are unable to develop the optic chiasm, and the axons of their retinal ganglion cells do not reach their targets in the brain. These defects were thought to occur because the guidance molecules whose transcription is normally controlled by Vax1 were not produced in the correct amounts when Vax1 is absent.
Kim et al. now challenge this view by creating a mutant version of Vax1 that cannot bind to DNA or regulate the transcription of other proteins. Retinal ganglion cell axons could still grow correctly when they were put close to cells expressing this version of the Vax1 protein. This contradicts a hypothesis that Vax1 supports axonal growth by transcribing guidance molecules. Kim et al. followed up these results by examining developing mice and reached the unexpected conclusion that Vax1 is secreted from cells in the ventral hypothalamus and binds to a type of sugar molecule found on the surface of the axons. Once bound, Vax1 can enter the axons where it appears to stimulate the production of proteins inside axons, which helps the axons to grow.
These findings reveal unconventional functions for Vax1 that occur in addition to its role as a transcription factor. Vax1 is known to regulate the development of several structures in the brain, so the work of Kim et al. also raises new questions about how Vax1 controls these processes.
DOI: http://dx.doi.org/10.7554/eLife.02671.002
doi:10.7554/eLife.02671
PMCID: PMC4178304  PMID: 25201875
ventral anterior homeobox 1 (Vax1); retinal axon growth; optic chiasm; intercellular protein transfer; mouse
17.  Inhibition of IL-17A Suppresses Enhanced-Tumor Growth in Low Dose Pre-Irradiated Tumor Beds 
PLoS ONE  2014;9(9):e106423.
Ionizing radiation induces modification of the tumor microenvironment such as tumor surrounding region, which is relevant to treatment outcome after radiotherapy. In this study, the effects of pre-irradiated tumor beds on the growth of subsequently implanted tumors were investigated as well as underlying mechanism. The experimental model was set up by irradiating the right thighs of C3H/HeN mice with 5 Gy, followed by the implantation of HCa-I and MIH-2. Both implanted tumors in the pre-irradiated bed showed accelerated-growth compared to the control. Tumor-infiltrated lymphocyte (TIL) levels were increased, as well as pro-tumor factors such as IL-6 and transforming growth factor-beta1 (TGF-β1) in the pre-irradiated group. In particular, the role of pro-tumor cytokine interleukin-17A (IL-17A) was investigated as a possible target mechanism because IL-6 and TGF-β are key factors in Th17 cells differentiation from naïve T cells. IL-17A expression was increased not only in tumors, but also in CD4+ T cells isolated from the tumor draining lymph nodes. The effect of IL-17A on tumor growth was confirmed by treating tumors with IL-17A antibody, which abolished the acceleration of tumor growth. These results indicate that the upregulation of IL-17A seems to be a key factor for enhancing tumor growth in pre-irradiated tumor beds.
doi:10.1371/journal.pone.0106423
PMCID: PMC4152254  PMID: 25181290
18.  Comparison of the Effects of Matrix Metalloproteinase Inhibitors on TNF-α Release from Activated Microglia and TNF-α Converting Enzyme Activity 
Biomolecules & Therapeutics  2014;22(5):414-419.
Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that regulate cell-matrix composition and are also involved in processing various bioactive molecules such as cell-surface receptors, chemokines, and cytokines. Our group recently reported that MMP-3, -8, and -9 are upregulated during microglial activation and play a role as proinflammatory mediators (Lee et al., 2010, 2014). In particular, we demonstrated that MMP-8 has tumor necrosis factor alpha (TNF-α)-converting enzyme (TACE) activity by cleaving the prodomain of TNF-α and that inhibition of MMP-8 inhibits TACE activity. The present study was undertaken to compare the effect of MMP-8 inhibitor (M8I) with those of inhibitors of other MMPs, such as MMP-3 (NNGH) or MMP-9 (M9I), in their regulation of TNF-α activity. We found that the MMP inhibitors suppressed TNF-α secretion from lipopolysaccharide (LPS)-stimulated BV2 microglial cells in an order of efficacy: M8I>NNGH>M9I. In addition, MMP inhibitors suppressed the activity of recombinant TACE protein in the same efficacy order as that of TNF-α inhibition (M8I>NNGH>M9I), proving a direct correlation between TACE activity and TNF-α secretion. A subsequent pro-TNF-α cleavage assay revealed that both MMP-3 and MMP-9 cleave a prodomain of TNF-α, suggesting that MMP-3 and MMP-9 also have TACE activity. However, the number and position of cleavage sites varied between MMP-3, -8, and -9. Collectively, the concurrent inhibition of MMP and TACE by NNGH, M8I, or M9I may contribute to their strong anti-inflammatory and neuroprotective effects.
doi:10.4062/biomolther.2014.099
PMCID: PMC4201218  PMID: 25414771
Microglia; Inflammation; MMP inhibitor; TNF-α; TACE
19.  Astragalin inhibits airway eotaxin-1 induction and epithelial apoptosis through modulating oxidative stress-responsive MAPK signaling 
BMC Pulmonary Medicine  2014;14:122.
Background
Eotaxin proteins are a potential therapeutic target in treating the peribronchial eosinophilia associated with allergic airway diseases. Since inflammation is often associated with an increased generation of reactive oxygen species (ROS), oxidative stress is a mechanistically imperative factor in asthma. Astragalin (kaempferol-3-O-glucoside) is a flavonoid with anti-inflammatory activity and newly found in persimmon leaves and green tea seeds. This study elucidated that astragalin inhibited endotoxin-induced oxidative stress leading to eosinophilia and epithelial apoptosis in airways.
Methods
Airway epithelial BEAS-2B cells were exposed to lipopolysaccharide (LPS) in the absence and presence of 1–20 μM astragalin. Western blot and immunocytochemical analyses were conducted to determine induction of target proteins. Cell and nuclear staining was also performed for ROS production and epithelial apoptosis.
Results
When airway epithelial cells were exposed to 2 μg/ml LPS, astragalin nontoxic at ≤20 μM suppressed cellular induction of Toll-like receptor 4 (TLR4) and ROS production enhanced by LPS. Both LPS and H2O2 induced epithelial eotaxin-1 expression, which was blocked by astragalin. LPS activated and induced PLCγ1, PKCβ2, and NADPH oxidase subunits of p22phox and p47phox in epithelial cells and such activation and induction were demoted by astragalin or TLR4 inhibition antagonizing eotaxin-1 induction. H2O2-upregulated phosphorylation of JNK and p38 MAPK was dampened by adding astragalin to epithelial cells, while this compound enhanced epithelial activation of Akt and ERK. H2O2 and LPS promoted epithelial apoptosis concomitant with nuclear condensation or caspase-3 activation, which was blunted by astragalin.
Conclusions
Astragalin ameliorated oxidative stress-associated epithelial eosinophilia and apoptosis through disturbing TLR4-PKCβ2-NADPH oxidase-responsive signaling. Therefore, astragalin may be a potent agent antagonizing endotoxin-induced oxidative stress leading to airway dysfunction and inflammation.
doi:10.1186/1471-2466-14-122
PMCID: PMC4118077  PMID: 25069610
Asthma; Airway apoptosis; Astragalin; Eotaxin-1; Oxidative stress
20.  Preparation of in situ hardening composite microcarriers: Calcium phosphate cement combined with alginate for bone regeneration 
Journal of Biomaterials Applications  2014;28(7):1079-1084.
Novel microcarriers consisting of calcium phosphate cement and alginate were prepared for use as three-dimensional scaffolds for the culture and expansion of cells that are effective for bone tissue engineering. The calcium phosphate cement-alginate composite microcarriers were produced by an emulsification of the composite aqueous solutions mixed at varying ratios (calcium phosphate cement powder/alginate solution = 0.8–1.2) in an oil bath and the subsequent in situ hardening of the compositions during spherodization. Moreover, a porous structure could be easily created in the solid microcarriers by soaking the produced microcarriers in water and a subsequent freeze-drying process. Bone mineral-like apatite nanocrystallites were shown to rapidly develop on the calcium phosphate cement–alginate microcarriers under moist conditions due to the conversion of the α-tricalcium phosphate phase in the calcium phosphate cement into a carbonate–hydroxyapatite. Osteoblastic cells cultured on the microspherical scaffolds were proven to be viable, with an active proliferative potential during 14 days of culture, and their osteogenic differentiation was confirmed by the determination of alkaline phosphatase activity. The in situ hardening calcium phosphate cement–alginate microcarriers developed herein may be used as potential three-dimensional scaffolds for cell delivery and tissue engineering of bone.
doi:10.1177/0885328213496486
PMCID: PMC4107800  PMID: 23836845
Microcarriers; calcium phosphate cements; alginate; cell culture; bone regeneration
21.  Gelatin-apatite bone mimetic co-precipitates incorporated within biopolymer matrix to improve mechanical and biological properties useful for hard tissue repair 
Journal of Biomaterials Applications  2014;28(8):1213-1225.
Synthetic biopolymers are commonly used for the repair and regeneration of damaged tissues. Specifically targeting bone, the composite approach of utilizing inorganic components is considered promising in terms of improving mechanical and biological properties. We developed gelatin-apatite co-precipitates which mimic the native bone matrix composition within poly(lactide-co-caprolactone) (PLCL). Ionic reaction of calcium and phosphate with gelatin molecules enabled the co-precipitate formation of gelatin-apatite nanocrystals at varying ratios. The gelatin-apatite precipitates formed were carbonated apatite in nature, and were homogeneously distributed within the gelatin matrix. The incorporation of gelatin-apatite significantly improved the mechanical properties, including tensile strength, elastic modulus and elongation at break, and the improvement was more pronounced as the apatite content increased. Of note, the tensile strength increased to as high as 45 MPa (a four-fold increase vs. PLCL), the elastic modulus was increased up to 1500 MPa (a five-fold increase vs. PLCL), and the elongation rate was ∼240% (twice vs. PLCL). These results support the strengthening role of the gelatin-apatite precipitates within PLCL. The gelatin-apatite addition considerably enhanced the water affinity and the acellular mineral-forming ability in vitro in simulated body fluid; moreover, it stimulated cell proliferation and osteogenic differentiation. Taken together, the GAp-PLCL nanocomposite composition is considered to have excellent mechanical and biological properties, which hold great potential for use as bone regenerative matrices.
doi:10.1177/0885328213502100
PMCID: PMC4107824  PMID: 23985536
Composite materials; bone mimetic; bioactive ceramics; polymer matrix; mechanical properties; bone regeneration
22.  Variations in the Hospital Standardized Mortality Ratios in Korea 
Objectives:
The hospital standardized mortality ratio (HSMR) has been widely used because it allows for robust risk adjustment using administrative data and is important for improving the quality of patient care.
Methods:
All inpatients discharged from hospitals with more than 700 beds (66 hospitals) in 2008 were eligible for inclusion. Using the claims data, 29 most responsible diagnosis (MRDx), accounting for 80% of all inpatient deaths among these hospitals, were identified, and inpatients with those MRDx were selected. The final study population included 703 571 inpatients including 27 718 (3.9% of all inpatients) in-hospital deaths. Using logistic regression, risk-adjusted models for predicting in-hospital mortality were created for each MRDx. The HSMR of individual hospitals was calculated for each MRDx using the model coefficients. The models included age, gender, income level, urgency of admission, diagnosis codes, disease-specific risk factors, and comorbidities. The Elixhauser comorbidity index was used to adjust for comorbidities.
Results:
For 26 out of 29 MRDx, the c-statistics of these mortality prediction models were higher than 0.8 indicating excellent discriminative power. The HSMR greatly varied across hospitals and disease groups. The academic status of the hospital was the only factor significantly associated with the HSMR.
Conclusions:
We found a large variation in HSMR among hospitals; therefore, efforts to reduce these variations including continuous monitoring and regular disclosure of the HSMR are required.
doi:10.3961/jpmph.2014.47.4.206
PMCID: PMC4162118  PMID: 25139167
Quality of health care; Outcome assessment; Hospital mortality
23.  The anti-inflammatory role of tissue inhibitor of metalloproteinase-2 in lipopolysaccharide-stimulated microglia 
Background
Tissue inhibitors of metalloproteinases (TIMPs) are known to be endogenous inhibitors of matrix metalloproteinases (MMPs). Our preliminary study showed that TIMP-2 is constitutively expressed in microglia but significantly inhibited by lipopolysaccharide (LPS) treatment. The current study was undertaken to investigate the role of TIMP-2 in microglia.
Methods
The expression of TIMP-2 was evaluated in the BV2 mouse microglial cell line and rat primary cultured microglia. To investigate the role of TIMP-2, a TIMP-2 expression plasmid or small interfering RNA (siRNA) was introduced into BV2 cells by transient transfection, and their effects on LPS-induced inflammatory reactions were examined. We further analyzed the molecular mechanism underlying the anti-inflammatory effects of TIMP-2 by electrophoretic mobility shift assay (EMSA), a reporter gene assay and Western blot analysis.
Results
Overexpression of TIMP-2 significantly inhibited the production of nitric oxide (NO), TNF-α, IL-1β, and reactive oxygen species (ROS), while increasing anti-inflammatory IL-10 production. On the other hand, knockdown of TIMP-2 augmented the production of pro-inflammatory molecules and downregulated IL-10 in LPS-stimulated BV2 cells. The results suggest that endogenously expressed TIMP-2 plays an anti-inflammatory role. Further mechanistic studies revealed that overexpression of TIMP-2 suppresses microglial activation via inhibition of the activity of mitogen-activated protein kinases (MAPKs) and NF-κB with enhancement of the activity of anti-inflammatory Nrf2 and cAMP-response element binding protein (CREB) transcription factors. TIMP-2 also inhibited the activity and expression of LPS-induced MMP-3, -8, and -9. Finally, we demonstrated that TIMP-2 exerts a neuroprotective effect via the inhibition of microglial activation.
Conclusions
Enhancement of TIMP-2 expression may be a potential therapeutic target for neuroinflammatory disorders.
doi:10.1186/1742-2094-11-116
PMCID: PMC4091675  PMID: 24970341
TIMP-2; MMP; microglia; neuroinflammation; neuroprotection
24.  Utilizing PCL Microcarriers for High-Purity Isolation of Primary Endothelial Cells for Tissue Engineering 
Endothelial cells (ECs) are widely used in research, both for fundamental vascular biology research and for exploring strategies to create engineered vascularized tissues. Primary isolation often results in contamination from fibroblasts and vascular smooth muscle cells that can potentially affect function, particularly during the initial expansion period needed to establish the cell culture. In the current study, we explored the use of microcarriers to selectively isolate ECs from the lumen of intact vessels to enhance the purity during the isolation procedure. First, rat aortic explant culture was performed and after 2 weeks of culture, flow cytometry revealed that only 60% of the expanded cell population was positive for the endothelial marker CD31. Then, we employed a strategy to selectively isolate ECs and improve their purity by introducing microcarriers to the lumen of intact aorta. After 10 days, microcarriers were carefully removed and placed in cell culture dishes and at 15 days, a large near confluent layer of primary ECs populated the dish. Flow cytometry revealed that >90% of the expanded cells expressed CD31. Moreover, the cells were capable of forming tubule-like structures when plated onto Matrigel, confirming their function also. The highly modular and transportable nature of microcarriers has significant potential for isolating ECs at high purity, with minimal contamination.
doi:10.1089/ten.tec.2013.0348
PMCID: PMC4152793  PMID: 24552418
25.  Potential of Magnetic Nanofiber Scaffolds with Mechanical and Biological Properties Applicable for Bone Regeneration 
PLoS ONE  2014;9(4):e91584.
Magnetic nanofibrous scaffolds of poly(caprolactone) (PCL) incorporating magnetic nanoparticles (MNP) were produced, and their effects on physico-chemical, mechanical and biological properties were extensively addressed to find efficacy for bone regeneration purpose. MNPs 12 nm in diameter were citrated and evenly distributed in PCL solutions up to 20% and then were electrospun into nonwoven nanofibrous webs. Incorporation of MNPs greatly improved the hydrophilicity of the nanofibers. Tensile mechanical properties of the nanofibers (tensile strength, yield strength, elastic modulus and elongation) were significantly enhanced with the addition of MNPs up to 15%. In particular, the tensile strength increase was as high as ∼25 MPa at 15% MNPs vs. ∼10 MPa in pure PCL. PCL-MNP nanofibers exhibited magnetic behaviors, with a high saturation point and hysteresis loop area, which increased gradually with MNP content. The incorporation of MNPs substantially increased the degradation of the nanofibers, with a weight loss of ∼20% in pure PCL, ∼45% in 10% MNPs and ∼60% in 20% MNPs. Apatite forming ability of the nanofibers tested in vitro in simulated body fluid confirmed the substantial improvement gained by the addition of MNPs. Osteoblastic cells favored the MNPs-incorporated nanofibers with significantly improved initial cell adhesion and subsequent penetration through the nanofibers, compared to pure PCL. Alkaline phosphatase activity and expression of genes associated with bone (collagen I, osteopontin and bone sialoprotein) were significantly up-regulated in cells cultured on PCL-MNP nanofibers than those on pure PCL. PCL-MNP nanofibers subcutaneously implanted in rats exhibited minimal adverse tissue reactions, while inducing substantial neoblood vessel formation, which however, greatly limited in pure PCL. In vivo study in radial segmental defects also signified the bone regeneration ability of the PCL-MNP nanofibrous scaffolds. The magnetic, bone-bioactive, mechanical, cellular and tissue attributes of MNP-incorporated PCL nanofibers make them promising candidate scaffolds for bone regeneration.
doi:10.1371/journal.pone.0091584
PMCID: PMC3976257  PMID: 24705279

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