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1.  Predictive proteomic biomarkers for inflammatory bowel disease-associated cancer: Where are we now in the era of the next generation proteomics? 
World Journal of Gastroenterology : WJG  2014;20(37):13466-12476.
Recent advances in genomic medicine have opened up the possibility of tailored medicine that may eventually replace traditional “one-size-fits all” approaches to the treatment of inflammatory bowel disease (IBD). In addition to exploring the interactions between hosts and microbes, referred to as the microbiome, a variety of strategies that can be tailored to an individual in the coming era of personalized medicine in the treatment of IBD are being investigated. These include prompt genomic screening of patients at risk of developing IBD, the utility of molecular discrimination of IBD subtypes among patients diagnosed with IBD, and the discovery of proteome biomarkers to diagnose or predict cancer risks. Host genetic factors influence the etiology of IBD, as do microbial ecosystems in the human bowel, which are not uniform, but instead represent many different microhabitats that can be influenced by diet and might affect processes essential to bowel metabolism. Further advances in basic research regarding intestinal inflammation may reveal new insights into the role of inflammatory mediators, referred to as the inflammasome, and the macromolecular complex of metabolites formed by intestinal bacteria. Collectively, knowledge of the inflammasome and metagenomics will lead to the development of biomarkers for IBD that target specific pathogenic mechanisms involved in the spontaneous progress of IBD. In this review article, our recent results regarding the discovery of potential proteomic biomarkers using a label-free quantification technique are introduced and on-going projects contributing to either the discrimination of IBD subtypes or to the prediction of cancer risks are accompanied by updated information from IBD biomarker research.
doi:10.3748/wjg.v20.i37.13466
PMCID: PMC4188898  PMID: 25309077
Inflammatory bowel disease; Biomarker; Proteomics; Tailored medicine; Colitic cancer
2.  Large Solid Hemangioblastoma in the Cerebellopontine Angle: Complete Resection Using the Transcondylar Fossa Approach 
Hemangioblastomas (HBMs) in the cerebellopontine angle (CPA) have rarely been reported. When they are within the CPA, they may be misdiagnosed as vestibular schwannoma (VS) or cystic meningioma. Therefore, differential diagnosis is important for the safe treatment of the lesion. Large solid HBMs, similar to intracranial arteriovenous malformations (AVMs), are difficult to surgically remove from an eloquent area because of their location and hypervascularity. We report a case of an HBM in the CPA, which manifested as a hearing impairment or VS. Similar to AVM surgery, the tumor was widely opened and removed en bloc without a new neurological complication using the modified transcondylar fossa approach without resection of the jugular tubercle. Accurate diagnosis, pre-operative embolization, and a tailored approach were essential for the safe treatment of the HBM in the CPA.
doi:10.14791/btrt.2014.2.2.128
PMCID: PMC4231628  PMID: 25408939
Hemangioblastoma; Cerebellopontine angle
3.  Association Factors for CT Angiography Spot Sign and Hematoma Growth in Korean Patients with Acute Spontaneous Intracerebral Hemorrhage : A Single-Center Cohort Study 
Objective
This study was conducted to clarify the association factors and clinical significance of the CT angiography (CTA) spot sign and hematoma growth in Korean patients with acute intracerebral hemorrhage (ICH).
Methods
We retrospectively collected the data of 287 consecutive patients presenting with acute ICH who arrived within 12 hours of ictus. Baseline clinical and radiological characteristics as well as the mortality rate within one month were assessed. A binary logistic regression was conducted to obtain association factors for the CTA spot sign and hematoma growth.
Results
We identified a CTA spot sign in 40 patients (13.9%) and hematoma growth in 78 patients (27.2%). An elapsed time to CT scan of less than 3 hours (OR, 5.14; 95% CI, 1.76-15.02; p=0.003) was associated with the spot sign. A CTA spot sign (OR, 5.70; 95% CI, 2.70-12.01; p<0.001), elevated alanine transaminase (GPT) level >40 IU (OR, 2.01; 95% CI, 1.01-4.01; p=0.047), and an international normalized ratio ≥1.8 or warfarin medication (OR, 5.64; 95% CI, 1.29-24.57; p=0.021) were independent predictors for hematoma growth. Antiplatelet agent medication (OR, 4.92; 95% CI, 1.31-18.50; p=0.019) was significantly associated with hematoma growth within 6 hours of ictus.
Conclusion
As previous other populations, CTA spot sign was a strong predictor for hematoma growth especially in hyper-acute stage of ICH in Korea. Antithrombotics medication might also be associated with hyper-acute hematoma growth. In our population, elevated GPT was newly identified as a predictor for hematoma growth and its effect for hematoma growth is necessary to be confirmed through a further research.
doi:10.3340/jkns.2014.56.4.295
PMCID: PMC4219186  PMID: 25371778
Intracerebral hemorrhage; CT angiography; Spot sign; Hematoma growth; Antithrombotics; Alanine transaminase
4.  Serial Micro-CT Assessment of the Therapeutic Effects of Rosiglitazone in a Bleomycin-Induced Lung Fibrosis Mouse Model 
Korean Journal of Radiology  2014;15(4):448-455.
Objective
The aim of this study was to assess the therapeutic effects of rosiglitazone with serial micro-CT findings before and after rosiglitazone administration in a lung fibrosis mouse model induced with bleomycin.
Materials and Methods
We instilled the bleomycin solution directly into the trachea in twenty mice (female, C57BL/6 mice). After the instillation with bleomycin, mice were closely observed for 3 weeks and then all mice were scanned using micro-CT without sacrifice. At 3 weeks, the mice were treated with rosiglitazone on days 21 to 27 if they had abnormal CT findings (n = 9, 45%). For the mice treated with rosiglitazone, we performed micro-CT with mouse sacrifice 2 weeks after the rosiglitazone treatment completion. We assessed the abnormal CT findings (ground glass attenuation, consolidation, bronchiectasis, reticular opacity, and honeycombing) using a five-point scale at 3 and 6 weeks using Wilcoxon-signed ranked test. The micro-CT findings were correlated with the histopathologic results.
Results
One out of nine (11.1%) mice improved completely. In terms of consolidation, all mice (100%) showed marked decrease from 3.1 ± 1.4 at 3 weeks to 0.9 ± 0.9 at 6 weeks (p = 0.006). At 6 weeks, mild bronchiectasis (n = 6, 66.7%), mild reticular opacity (n = 7, 77.8%) and mild honeycomb patterns (n = 3, 33.3%) appeared.
Conclusion
A serial micro-CT enables the evaluation of drug effects in a lung fibrosis mouse model.
doi:10.3348/kjr.2014.15.4.448
PMCID: PMC4105807  PMID: 25053904
Microcomputed tomography; Bleomycin; Fibrosis; Rosiglitazone; Lung
5.  Paradoxically Augmented Anti-Tumorigenic Action of Proton Pump Inhibitor and GastrininAPCMin/+ Intestinal Polyposis Model12 
Neoplasia (New York, N.Y.)  2014;16(1):73-83.
Though long-term administration of proton pump inhibitor (PPI) imposed the risk of gastrointestinal track tumorigenesis by accompanied hypergastrinemia, no overt increases of colon cancer risk were witnessed after a long-term cohort study. Our recent investigation revealed that PPI prevented colitis-associated carcinogenesis through anti-inflammatory, anti-oxidative, and anti-mutagenic mechanisms in spite of hypergastrinemia. Therefore, we hypothesized that PPI might either antagonize the trophic action of gastrin on gastrointestinal tumorigenesis or synergize to exert augmented anti-tumorigenic actions. We challenged APCMin/+ mice with gastrin, PPI, PPI and gastrin together for 10 weeks and counted intestinal polyposis accompanied with molecular changes. Gastrin significantly increased intestinal polyposis, but combination of PPI and gastrin markedly attenuated intestinal polyposis compared to gastrin-promoted APCMin/+ mice (P < .001), in which significant β-catenin phosphorylation and inhibition of β-catenin nuclear translocation were observed with PPI alone or combination of PPI and gastrin, whereas gastrin treatment significantly increased β-catenin nuclear translocation. Significant footprints of apoptosis, G0/G1 accumulation, inactivation of p38 and extracellular signal-regulated kinase, decreased expressions of CD31, and inhibition of tumor necrosis factor-α and cyclooxygenase-2 were noted in the combination group. In vitro investigations were similar to in vivo findings as shown that PPI treatment inhibited the binding of gastrin to its receptor, inactivated β-catenin-associated signaling including Tcf/Lef and glycogen synthase kinase β, and paradoxically inhibited β-catenin-associated proliferative activities. Our investigations explain why colon cancer risk has not increased despite long-term use of PPIs and provide a rationale for using PPI to achieve anti-tumorigenesis beyond acid suppression.
PMCID: PMC3924549  PMID: 24563620
6.  Short-term Intervention to Revert Premalignant Lesions as Strategy to Prevent Gastrointestinal Cancers 
Journal of Cancer Prevention  2013;18(4):289-297.
“Prevention might be better than treatment in cancer treatment” is brief conclusion drawn from war on cancer through National Cancer Act of 1971 by U.S. President Richard Nixon. However, the clinical practice of chemoprevention is still in its infancy in spite of a wealth of data showing its effectiveness in experimental animals as well as in vitro mechanism research. Recent advances in either high throughput analysis including cancer genomes and tailored medicine or molecular targeted therapeutics, preventive strategies also should be changes as previous preventive strategies including phytoceuticals, life-style modification, and some empirical agents. Furthermore, molecular targeted therapeutics achieved high goal of effectiveness under the concept of therapeutic or preventive “synthetic lethality”, of which extended application can be included within the scope of chemoprevention. Here, we will summarize several recent advances in chemopreventive strategy objected to justify optimism that chemoprevention will be an effective approach for the control of human cancer. siTRP (short-term intervention to revert premalignancy) strategy will be introduced for cancers in gastroenterology.
doi:10.15430/JCP.2013.18.4.289
PMCID: PMC4189441  PMID: 25337558
Chemoprevention; siTRP; Phytoceuticals; Human cancer; Synthetic lethality
7.  Omega-3 Polyunsaturated Fatty Acids as Potential Chemopreventive Agent for Gastrointestinal Cancer 
Journal of Cancer Prevention  2013;18(3):201-208.
Omega-3 polyunsaturated fatty acids (n-3 PUFAs), particularly eicosapentanoic acid (EPA) and docosahexanoic acid (DHA), has been acknowledged as essential very long-chain fatty acids contributing to either achieving optimal health or protection against diseases, and even longevity. Recent high impact studies dealing with EPA and DHA have sparked a renewed interest in using n-3 PUFAs for cancer prevention and cancer treatment, for which n-3 PUFAs may exert their anticancer actions by influencing multiple targets implicated in various stages of cancer development, including cell proliferation, cell survival, angiogenesis, inflammation, and metastasis against various cancers. However, gastrointestinal cancers develop implicated with the close connection between inflammation and cancer and n-3 PUFAs especially imposed excellent actions of antiinflammation and antioxidation as well as their restorative actions. In detail, these beneficial lipids can restore or modify inflammation-associated lipid distorsion and alteration of lipid rafts. Although the chemopreventive effect of n-3 PUFAs has been studied in various experimental models, our understanding regarding the underlying mechanisms of n-3 PUFAs against GI cancer is still limited. In this review article, we described the in-detailed perspective and underlying mechanism of n-3 PUFAs application for GI cancers and added in vivo efficacy of n-3 PUFAs with Fat-1 transgenic mice experience. We suggest that future work should consider the n-6/n-3 FA ratio, combination treatment of other nutritions and alteration of lipid rafts to be a key element in experimental design and analysis.
doi:10.15430/JCP.2013.18.3.201
PMCID: PMC4189468  PMID: 25337547
Omega-3 polyunsaturated fatty acids; Gastrointestinal cancer; Chemoprevention; Lipid rafts; Fat-1 transgenic mice
8.  Isolated Sphenoid Sinus Mucocele Presenting as Third Nerve Palsy 
A sphenoid mucocele often presents late due to its deep seated anatomical site. And it has varied presentation due to its loose relationship to the cavernous sinus and the base of the skull. We describe a case of large sphenoid sinus mucocele. A middle aged old man suddenly developed third cranial nerve palsy. Brain imaging study revealed an isolated sphenoid sinus mucocele, compressing right cavernous sinus. Endoscopic marsupialization of the mucocele via transnasal approach led to complete resolution of the third cranial nerve palsy. Involvement of the third cranial nerve in isolated mucocele is rare but important neurosurgical implications which must be excluded. In addition, proper and timely treatment must be performed to avoid permanent neurologic deficit.
doi:10.3340/jkns.2010.48.4.360
PMCID: PMC2982917  PMID: 21113366
Sphenoid sinus mucocele; Third nerve palsy; Transnasal approach
9.  Infranuchal Infrafloccular Approach to the More Vulnerable Segments of the Facial Nerve in Microvascular Decompressions for the Hemifacial Spasm 
Objective
We investigated the locations of compressing vessels in hemifacial spasm. To approach compression sites, we described and evaluated the efficacy of the infranuchal infrafloccular (INIF) approach.
Methods
A retrospective review of 31 consecutive patients who underwent microvascular decompression (MVD) through INIF with a minimum follow-up of 1 year was performed. Along the intracranial facial nerve, we classified the compression sites into the transitional zone (TRZ), the central nervous system (CNS) segment and the peripheral nervous system (PNS) segment. The INIF approach was used to inspect the CNS segment and the TRZ. Subdural patch graft technique was used in order to achieve watertight dural closure. The cranioplasty was performed using polymethylmethacrylate. The outcome and procedure-related morbidities were evaluated.
Results
Twenty-nine patients (93%) showed complete disappearance of spasm. In two patients, the spasm was resolved gradually in 2 and 4 weeks, respectively. Late recurrence was noted in one patient (3%). The TRZ has been identified as the only compression site in 19 cases (61.3%), both the TRZ and CNS segment in 11 (35.5%) and the CNS segment only in 1 (3.2%). There was no patient having a compressing vessel in the PNS segment. Infection as a result of cerebrospinal fluid leak occurred in one patient (3%). Delayed transient facial weakness occurred in one patient.
Conclusion
The TRZ and the CNS segment were more vulnerable area to the compression of vessels. We suggest that surgical avenue with the INIF approach provides early identification of this area.c
doi:10.3340/jkns.2009.46.4.340
PMCID: PMC2773391  PMID: 19893723
Hemifacial spasm; Microvascular decompression; Root exit zone
10.  Microsurgical Experience with Supraorbital Keyhole Operations on Anterior Circulation Aneurysms 
Objective
Conventional pterional approach is a commonly used neurosurgical technique for the treatment of cerebral aneurysms. However, this technique requires more extensive brain exposure than other key hole approaches and is sometimes associated with surgical traumatization or cosmetic problems. The aim of this study was to compare the postoperative outcome between pterional and supraorbital keyhole approaches in the patients with anterior circulation aneurysms.
Methods
The authors reviewed patients with anterior circulation aneurysms who underwent aneurysm clipping via pterional or supraorbital keyhole approach at a single institute over a period of 2 years. Ninety-eight patients harboring 108 aneurysms were included in this study. Various outcomes were recorded, which included clinical grade, cosmetic problems, patients' satisfaction and complications such as chewing discomfort, frontal muscle weakness, hyposmia, infection.
Results
The supraorbital approach exhibited a shorter operation time compared with the pterional approach. Complications such as chewing discomfort occurred less frequently in the supraorbital approach group. Moreover, the cosmetic outcome was significantly better in the supraorbital group than in the pterional group.
Conclusion
The supraorbital keyhole approach reduced intra- and postoperative complications, including chewing discomfort and cosmetic disturbances, compared with the conventional pterional approach.
doi:10.3340/jkns.2009.46.2.103
PMCID: PMC2744018  PMID: 19763211
Pterional approach; Supraorbital approach; Aneurysm; Clipping; Cosmetic outcome
11.  The Clinical Outcomes of Transcatheter Microcoil Embolization in Patients with Active Lower Gastrointestinal Bleeding in the Small Bowel 
Korean Journal of Radiology  2009;10(4):391-397.
Objective
To assess the clinical outcomes of the transcatheter microcoil embolization in patients with active lower gastrointestinal (LGI) bleeding in the small bowel, as well as to compare the mortality rates between the two groups based on the visualization or non-visualization of the bleeding focus determined by an angiography.
Materials and Methods
We retrospectively evaluated all of the consecutive patients who underwent an angiography for treatment of acute LGI bleeding between January 2003 and October 2007. In total, the study included 36 patients who underwent a colonoscopy and were diagnosed to have an active bleeding in the LGI tracts. Based on the visualization or non-visualization of the bleeding focus, determined by an angiography, the patients were classified into two groups. The clinical outcomes included technical success, clinical success (no rebleeding within 30 days), delayed rebleeding (> 30 days), as well as the major and minor complication rates.
Results
Of the 36 patients, 17 had angiography-proven bleeding that was distal to the marginal artery. The remaining 19 patients did not have a bleeding focus based on the angiography results. The technical and clinical success rates of performing transcatheter microcoil embolizations in patients with active bleeding were 100% and 88%, respectively (15 of 17). One patient died from continued LGI bleeding and one patient received surgery to treat the continued bleeding. There was no note made on the delayed bleeding or on the major or minor complications. Of the 19 patients without active bleeding, 16 (84%) did not have recurrent bleeding. One patient died due to continuous bleeding and multi-organ failure.
Conclusion
The superselective microcoil embolization can help successfully treat patients with active LGI bleeding in the small bowel, identified by the results of an angiography. The mortality rate is not significantly different between the patients of the visualization and non-visualization groups on angiography.
doi:10.3348/kjr.2009.10.4.391
PMCID: PMC2702049  PMID: 19568468
Gastrointestinal bleeding; Selective embolization; Angiography, microcoils
12.  Percutaneous Transportal Sclerotherapy with N-Butyl-2-Cyanoacrylate for Gastric Varices: Technique and Clinical Efficacy 
Korean Journal of Radiology  2008;9(6):526-533.
Objective
This study was deigned to evaluate the technique and clinical efficacy of the use of percutaneous transportal sclerotherapy with N-butyl-2-cyanoacrylate (NBCA) for patients with gastric varices.
Materials and Methods
Seven patients were treated by transportal sclerotherapy with the use of NBCA. For transportal sclerotherapy, portal vein catheterization was performed with a 6-Fr sheath by the transhepatic approach. A 5-Fr catheter was introduced into the afferent gastric vein and a microcatheter was advanced through the 5-Fr catheter into the varices. NBCA was injected through the microcatheter in the varices by use of the continuous single-column injection technique. After the procedure, postcontrast computed tomography (CT) was performed on the next day and then every six months. Gastroendoscopy was performed at one week, three months, and then every six months after the procedure.
Results
The technical success rate of the procedure was 88%. In six patients, gastric varices were successfully obliterated with 1-8 mL (mean, 5.4 mL) of a NBCA-Lipiodol mixture injected via a microcatheter. No complications related to the procedure were encountered. As seen on the follow-up endoscopy and CT imaging performed after six months, the presence of gastric varcies was not seen in any of the patients after treatment with the NBCA-Lipiodol mixture and the use of microcoils. Recurrence of gastric varices was not observed during the follow-up period. Worsening of esophageal varices occurred in four patients after transportal sclerotherapy. The serum albumin level increased, the ammonia level decreased and the prothrombin time increased at six months after the procedure (p < 0.05).
Conclusion
Percutaneous transportal sclerotherapy with NBCA is useful to obliterate gastric varices if it is not possible to perform balloon-occluded retrograde transvenous obliteration.
doi:10.3348/kjr.2008.9.6.526
PMCID: PMC2627238  PMID: 19039269
Interventional procedures, technology; Stomach, varices; Stomach, bleeding; Veins, therapeutic blockade
13.  Critical Use of Balloon Angioplasty after Recanalization Failure with Retrievable Stent in Acute Cerebral Artery Occlusion 
Objective
Sudden major cerebral artery occlusion often resists recanalization with currently available techniques or can results in massive symptomatic intracranial hemorrhage (sICH) after thrombolytic therapy. The purpose of this study was to examine mechanical recanalization with a retrievable self-expanding stent and balloon in acute intracranial artery occlusions.
Methods
Twenty-eight consecutive patients with acute intracranial artery occlusions were treated with a Solitaire retrievable stent. Balloon angioplasty was added if successful recanalization was not achieved after stent retrieval. The angiographic outcome was assessed by Thrombolysis in Cerebral Infarction (TICI) and the clinical outcomes were assessed by the National Institutes of Health Stroke Scale (NIHSS) and the modified Rankin Scale (mRS).
Results
At baseline, mean age was 69.4 years and mean initial NIHSS score was 12.5. A recanalization to TICI 2 or 3 was achieved in 24 patients (85%) after stent retrieval. Successful recanalization was achieved after additional balloon angioplasty in 4 patients. At 90-day follow-up, 24 patients (85%) had a NIHSS improvement of ≥4 and 17 patients (60%) had a good outcome (mRS ≤2). Although there was sICH, there was one death associated with the procedure.
Conclusion
Mechanical thromboembolectomy with a retrievable stent followed by additional balloon angioplasty is a safe and effective first-line therapy for acute intracranial artery occlusions especially in case of unsuccessful recanalization after stent thrombectomy.
doi:10.3340/jkns.2013.53.2.77
PMCID: PMC3611063  PMID: 23560170
Acute cerebral artery occlusion; Mechanical recanalization; Retrievable stent; Balloon angioplasty
14.  Therapeutic Effects of Acupuncture through Enhancement of Functional Angiogenesis and Granulogenesis in Rat Wound Healing 
Acupuncture regulates inflammation process and growth factors by increasing blood circulation in affected areas. In this study, we examined whether acupuncture has an effect on wound healing in injured rat. Rats were assigned randomly into two groups: control group and acupuncture group. Acupuncture treatment was carried out at 8 sites around the wounded area. We analyzed the wound area, inflammatory cytokines, proliferation of resident cells, and angiogenesis and induction of extracelluar matrix remodeling. At 7 days after-wounding the wound size in acupuncture-treat group was decreased more significantly compared to control group. In addition, the protein levels of proinflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were significantly decreased compared to the control at 2 and 7 days post-wounding. Also, we analyzed newly generated cells by performing immunostaining for PCNA and using several phenotype markers such as CD-31, α-SMA, and collagen type I. In acupuncture-treated group, PCNA-positive cell was increased and PCNA labeled CD-31-positive vessels, α-SMA- and collagen type I-positive fibroblastic cells, were increased compared to the control group at 7 days post-wounding. These results suggest that acupuncture may improve wound healing through decreasing pro-inflammatory response, increasing cell proliferation and angiogenesis, and inducing extracellular matrix remodeling.
doi:10.1155/2012/464586
PMCID: PMC3529882  PMID: 23304201
15.  Treatment of Malignant Biliary Obstruction with a PTFE-Covered Self-Expandable Nitinol Stent 
Korean Journal of Radiology  2007;8(5):410-417.
Objective
We wanted to determine the technical and clinical efficacy of using a PTFE-covered self-expandable nitinol stent for the palliative treatment of malignant biliary obstruction.
Materials and Methods
Thirty-seven patients with common bile duct strictures caused by malignant disease were treated by placing a total of 37 nitinol PTFE stents. These stents were covered with PTFE with the exception of the last 5 mm at each end; the stent had an unconstrained diameter of 10 mm and a total length of 50-80 mm. The patient survival rate and stent patency rate were calculated by performing Kaplan-Meier survival analysis. The bilirubin, serum amylase and lipase levels before and after stent placement were measured and then compared using a Wilcoxon signed-rank test. The average follow-up duration was 27.9 weeks (range: 2-81 weeks).
Results
Placement was successful in all cases. Seventy-six percent of the patients (28/37) experienced adequate palliative drainage for the remainder of their lives. There were no immediate complications. Three patients demonstrated stent sludge occlusion that required PTBD (percutaneous transhepatic biliary drainage) irrigation. Two patients experienced delayed stent migration with stone formation at 7 and 27 weeks of follow-up, respectively. Stent insertion resulted in acute elevations of the amylase and lipase levels one day after stent insertion in 11 patients in spite of performing endoscopic sphincterotomy (4/6). The bilirubin levels were significantly reduced one week after stent insertion (p < 0.01). The 30-day mortality rate was 8% (3/37), and the survival rates were 49% and 27% at 20 and 50 weeks, respectively. The primary stent patency rates were 85%, and 78% at 20 and 50 weeks, respectively.
Conclusion
The PTFE-covered self-expandable nitinol stent is safe to use with acceptable complication rates. This study is similar to the previous studies with regard to comparing the patency rates and survival rates.
doi:10.3348/kjr.2007.8.5.410
PMCID: PMC2626809  PMID: 17923784
Biliary tract, malignant obstruction; Biliary tract, interventional procedures; Prosthesis, stent
16.  A possible involvement of Nrf2-mediated heme oxygenase-1 up-regulation in protective effect of the proton pump inhibitor pantoprazole against indomethacin-induced gastric damage in rats 
BMC Gastroenterology  2012;12:143.
Background
Proton pump is an integral membrane protein that is ubiquitous ATP binding cassette (ABC) involved in many transport processes in all living organisms, among which a specialized form of pump, so called p-type proton pump, exists in the parietal cells of stomach. Though proton pump inhibitors (PPIs) are frequently prescribed to prevent nonsteroidal anti-inflammatory drugs (NSAIDs)-induced gastric damage, the acid suppressive actions do not suffice to explain.
Methods
In order to document the effects of pantoprazole, one of PPIs, on the NSAIDs-induced gastric damage, in vitro and in vivo studies were performed. Immunocytochemistry, Western blot analysis, electrophoretic mobility shift assay and RT-PCR were conducted to evaluate the induction of heme oxygenase-1 (HO-1) through Nrf2 activation in normal gastric mucosal RGM-1 cells or in vivo stomach tissues from rats treated with indomethacin and/or pantoprazole.
Results
Pantoprazole activated Nrf2 through inactivation of Keap1, after which the expression of HO-1 was significantly increased in a dose-dependent manner in RGM-1 cells. Increased ARE-DNA binding activity was observed maximally at 1 h with 300 μM of pantoprazole. The expression of HO-1 induced by pantoprazole was significantly associated with the increased in vitro tube formation (P < 0.05) and angiogenic factors including VEGF, bFGF, and HIF-1α. Indomethacin markedly increased the expressions of TNF-α, IL-1ß, IL-8, NOX-1, ICAM-1 and VCAM, whereas pantoprazole significantly decreased the expressions of indomethacin-induced these inflammatory mediators in accord with pantoprazole-induced HO-1 (P < 0.05) as documented with HO-1 inhibitor. In vivo model of indomethacin-induced gastric damage could validate in vitro-drawn results that pantoprazole remarkably protected against indomethacin-induced gastric damage, in which zinc protoporphyrin (5 mg/kg, ip) significantly abolished the protective efficacy of pantoprazole.
Conclusion
These results demonstrate that Nrf2-mediated HO-1 induction of PPIs afforded a significant protective effect against NSAIDs-induced gastric damage beyond acid suppressive actions.
doi:10.1186/1471-230X-12-143
PMCID: PMC3548718  PMID: 23066659
Heme oxygenase-1; Proton pump inhibitor; NSAIDs-induced gastropathy; Nrf2
17.  Long-Term Incidence and Predicting Factors of Cranioplasty Infection after Decompressive Craniectomy 
Objective
The predictors of cranioplasty infection after decompressive craniectomy have not yet been fully characterized. The objective of the current study was to compare the long-term incidences of surgical site infection according to the graft material and cranioplasty timing after craniectomy, and to determine the associated factors of cranioplasty infection.
Methods
A retrospective cohort study was conducted to assess graft infection in patients who underwent cranioplasty after decompressive craniectomy between 2001 and 2011 at a single-center. From a total of 197 eligible patients, 131 patients undergoing 134 cranioplasties were assessed for event-free survival according to graft material and cranioplasty timing after craniectomy. Kaplan-Meier survival analysis and Cox regression methods were employed, with cranioplasty infection identified as the primary outcome. Secondary outcomes were also evaluated, including autogenous bone resorption, epidural hematoma, subdural hematoma and brain contusion.
Results
The median follow-up duration was 454 days (range 10 to 3900 days), during which 14 (10.7%) patients suffered cranioplasty infection. There was no significant difference between the two groups for event-free survival rate for cranioplasty infection with either a cryopreserved or artificial bone graft (p=0.074). Intergroup differences according to cranioplasty time after craniectomy were also not observed (p=0.083). Poor neurologic outcome at cranioplasty significantly affected the development of cranioplasty infection (hazard ratio 5.203, 95% CI 1.075 to 25.193, p=0.04).
Conclusion
Neurologic status may influence cranioplasty infection after decompressive craniectomy. A further prospective study about predictors of cranioplasty infection including graft material and cranioplasty timing is necessary.
doi:10.3340/jkns.2012.52.4.396
PMCID: PMC3488651  PMID: 23133731
Decompressive craniectomy; Cranioplasty infection; Neurologic outcome; Graft material; Cranioplasty timing
18.  The Quality of Life of Patients with Good Outcomes after Anterior Circulation Aneurysm Surgery Assessed by the World Health Organization Quality of Life Instrument-Korean Version 
Objective
Even in the patients with neurologically good outcome after intracranial aneurysm surgery, their perception of health is an important outcome issue. This study aimed to investigate the quality of life (QOL) and its predictors of patients who had a good outcome following anterior circulation aneurysm surgery as using the World Health Organization Quality of Life instrument-Korean version.
Methods
We treated 280 patients with 290 intracranial aneurysms for 2 years. This questionnaire was taken and validated by 99 patients whose Glasgow Outcome Scale score was 4 and more and Global deterioration scale 3 and less at 6 months after the operation, and 85 normal persons. Each domain and facet was compared between the two groups, and a subgroup analysis was performed on the QOL values and hospital expenses of the aneurysm patients according to the type of craniotomy, approach, bleeding of the aneurysm and brain injury.
Results
Aneurysm patients showed a lower quality of life compared with control patients in level of independence, psychological, environmental, and spiritual domains. In the environmental domain, there were significant intergroup differences according to the type of craniotomy and the surgical approach used on the patients (p<0.05). The hospital charges were also significantly different according to the type of craniotomy (p<0.05).
Conclusion
Despite good neurological status, patients surgically treated for anterior circulation aneurysm have a low quality of life. The craniotomy size may affect the QOL of patients who underwent an anterior circulation aneurysm surgery and exhibited a good outcome.
doi:10.3340/jkns.2012.52.3.179
PMCID: PMC3483316  PMID: 23115658
Anterior circulation aneurysm; Quality of life; Craniotomy size; Surgical approach
19.  Comparison of Renal Damage by Iodinated Contrast or Gadolinium in an Acute Renal Failure Rat Model Based on Serum Creatinine Levels and Apoptosis Degree 
Journal of Korean Medical Science  2005;20(5):841-847.
This study was undertaken to compare renal damage, as determined by serum creatinine and degree of apoptosis, caused by iodinated contrast or gadolinium in an acute renal failure (ARF) rat model. Rats were divided into three groups; controls (n=3), a CT contrast medium group (n=9), and an MR contrast medium group (n=9). The CT and MR groups were further subdivided into three groups, namely, low, standard, and high dose subgroups. Renal function was evaluated by determining serum creatinine levels; before ARF, and 48 hr after ARF and contrast administration. Apoptosis was assayed by terminal deoxynucleotidyl transferasemediated dUTP nick-end labeling (TUNEL). No significant creatinine level differences were observed between the CT and MR groups (p=0.116). Degrees of apoptosis in the renal cortex and medulla were more severe in the CT contrast medium group than in the control or MR contrast medium group (p<0.05). The study shows that CT contrast medium did not aggravate renal function more so than MR contrast medium in this ARF rat model. However, apoptosis examination in the renal cortex and medulla indicated that CT contrast medium induced more severe apoptosis than MR contrast medium (p<0.05). We conclude that CT contrast medium can be used for renal imaging studies when subjects are well hydrated and preventive medication is administered.
doi:10.3346/jkms.2005.20.5.841
PMCID: PMC2779283  PMID: 16224160
Renal Function; Contrast Media; Kidney Failure, Acute; Animal Experimentation, Apoptosis; Iodopyridones; Gadolinium
20.  A Pilot Study for the Neuroprotective Effect of Gongjin-dan on Transient Middle Cerebral Artery Occlusion-Induced Ischemic Rat Brain 
In this study, we investigated whether gongjin-dan improves functional recovery and has neuroprotective effects on reducing the infarct volume after transient middle cerebral artery occlusion (MCAo). Infarct volume was measured using TTC staining and glucose utilization by F-18 FDG PET. Functional improvement was evaluated with the Rota-rod, treadmill, Garcia score test, and adhesive removal test. At 14 days after MCAo, neuronal cell survival, astrocytes expansion, and apoptosis were assessed by immunohistofluorescence staining in the peri-infarct region. Also, the expression of neurotrophic factors and inflammatory cytokines such as VEGF, BDNF, Cox-2, TNF-α, IL-1β, and IL-1α was measured in ischemic hemisphere regions. The gongjin-dan-treated group showed both reduced infarct volume and increased glucose utilization. Behavior tests demonstrated a significant improvement compared to the control. Also in the gongjin-dan treated group, NeuN-positive cells were increased and number of astrocytes, microglia, and apoptotic cells was significantly decreased compared with the control group in the ischemic peri-infarct area. Furthermore, the expression of VEGF and BDNF was increased and level of Cox-2, TNF-α, IL-1β, and IL-1α was decreased. These results suggest that gongjin-dan may improve functional outcome through the rapid restoration of metabolism and can be considered as a potential neuroprotective agent.
doi:10.1155/2012/682720
PMCID: PMC3375177  PMID: 22719787
21.  Effects of Resveratrol and trans-3,5,4’-Trimethoxystilbene on Glutamate-Induced Cytotoxicity, Heme Oxygenase-1, and Sirtuin 1 in HT22 Neuronal Cells 
Biomolecules & Therapeutics  2012;20(3):306-312.
Resveratrol (trans-3,5,4’-trihydroxystilbene) has received considerable attention recently for the potential neuroprotective effects in neurodegenerative disorders where heme oxygenase-1 (HO-1) and sirtuin 1 (SIRT1) represent promising therapeutic targets. Resveratrol has been known to increase HO-1 expression and SIRT1 activity. In this study, the effects of resveratrol and trans-3,5,4’-trimethoxystilbene (TMS), a resveratrol derivative, on cytotoxicity caused by glutamate-induced oxidative stress, HO-1 expression, and SIRT1 activation have been investigated by using murine hippocampal HT22 cells, which have been widely used as an in vitro model for investigating glutamate-induced neurotoxicity. Resveratrol protected HT22 neuronal cells from glutamateinduced cytotoxicity and increased HO-1 expression as well as SIRT1 activity in a concentration-dependent manner. Cytoprotec-tion afforded by resveratrol was partially reversed by the specific inhibition of HO-1 expression by HO-1 small interfering RNA and the nonspecific blockage of HO-1 activity by tin protoporphyrin IX, but not by SIRT1 inhibitors. Surprisingly, TMS, a resveratrol derivative with methoxyl groups in lieu of the hydroxyl groups, and trans-stilbene, a non-hydroxylated analog, failed to protect HT22 cells from glutamate-induced cytotoxicity and to increase HO-1 expression and SIRT1 activity. Taken together, our findings suggest that the cytoprotective effect of resveratrol was at least in part associated with HO-1 expression but not with SIRT1 activation and, importantly, that the presence of hydroxyl groups on the benzene rings of resveratrol appears to be necessary for cytoprotection against glutamate-induced oxidative stress, HO-1 expression, and SIRT1 activation in HT22 neuronal cells.
doi:10.4062/biomolther.2012.20.3.306
PMCID: PMC3794528  PMID: 24130928
Resveratrol; trans-3; 5; 4'-Trimethoxystilbene; Heme oxygenase-1; Sirtuin 1; Oxidative stress; Neuroprotection
22.  Inhibition of Hydrogen Sulfide-induced Angiogenesis and Inflammation in Vascular Endothelial Cells: Potential Mechanisms of Gastric Cancer Prevention by Korean Red Ginseng 
Journal of Ginseng Research  2012;36(2):135-145.
Previously, we reported that Helicobacter pylori-associated gastritis and gastric cancer are closely associated with increased levels of hydrogen sulfide (H2S) and that Korean red ginseng significantly reduced the severity of H. pylori-associated gastric diseases by attenuating H2S generation. Because the incubation of endothelial cells with H2S has been known to enhance their angiogenic activities, we hypothesized that the amelioration of H2S-induced gastric inflammation or angiogenesis in human umbilical vascular endothelial cells (HUVECs) might explain the preventive effect of Korean red ginseng on H. pylori-associated carcinogenesis. The expression of inflammatory mediators, angiogenic growth factors, and angiogenic activities in the absence or presence of Korean red ginseng extracts (KRGE) were evaluated in HUVECs stimulated with the H2S generator sodium hydrogen sulfide (NaHS). KRGE efficiently decreased the expression of cystathionine β-synthase and cystathionine γ-lyase, enzymes that are essential for H2S synthesis. Concomitantly, a significant decrease in the expression of inflammatory mediators, including cyclooxygenase-2 and inducible nitric oxide synthase, and several angiogenic factors, including interleukin (IL)-8, hypoxia inducible factor-1a, vascular endothelial growth factor, IL-6, and matrix metalloproteinases, was observed; all of these factors are normally induced after NaHS. An in vitro angiogenesis assay demonstrated that NaHS significantly increased tube formation in endothelial cells, whereas KRGE pretreatment significantly attenuated tube formation. NaHS activated p38 and Akt, increasing the expression of angiogenic factors and the proliferation of HUVECs, whereas KRGE effectively abrogated this H2S-activated angiogenesis and the increase in inflammatory mediators in vascular endothelial cells. In conclusion, KRGE was able to mitigate H2S-induced angiogenesis, implying that antagonistic action against H2S-induced angiogenesis may be the mechanism underlying the gastric cancer preventive effects of KRGE in H. pylori infection.
doi:10.5142/jgr.2012.36.2.135
PMCID: PMC3659584  PMID: 23717113
Panax ginseng; Hydrogen sulfide; Helicobacter pylori; Korean red ginseng; Angiogenesis; Cancer prevention
23.  Delayed Colon Perforation after Palliative Treatment for Rectal Carcinoma with Bare Rectal Stent: A Case Report 
Korean Journal of Radiology  2000;1(3):169-171.
In order to relieve mechanical obstruction caused by rectal carcinoma, a bare rectal stent was inserted in the sigmoid colon of a 70-year-old female. The procedure was successful, and for one month the patient made good progress. She then complained of abdominal pain, however, and plain radiographs of the chest and abdomen revealed the presence of free gas in the subdiaphragmatic area. Surgical findings showed that a spur at the proximal end of the bare rectal stent had penetrated the rectal mucosal wall. After placing a bare rectal stent for the palliative treatment of colorectal carcinoma, close follow-up to detect possible perforation of the bowel wall is necessary.
doi:10.3348/kjr.2000.1.3.169
PMCID: PMC2718188  PMID: 11752950
Rectum, interventional procedure; Rectum, stenosis, obstruction; Stents, prosthesis
24.  Acute Upper Limb Ischemia due to Cardiac Origin Thromboembolism: the Usefulness of Percutaneous Aspiration Thromboembolectomy via a Transbrachial Approach 
Korean Journal of Radiology  2011;12(5):595-601.
Objective
To evaluate the usefulness of percutaneous aspiration thromboembolectomy (PAT) via a transbrachial approach in patients with acute upper limb ischemia.
Materials and Methods
From July 2004 to March 2008, eleven patients with acute upper limb ischemia were enrolled in this study. They were initially treated with thrombolysis (n = 1), PAT (n = 6), or both (n = 4) via a femoral artery approach. However, all of the patients had residual thrombus in the brachial artery, which was subsequently managed by PAT via the transbrachial approach for removal of residual emboli.
Results
Successful re-canalization after PAT via a transbrachial approach was achieved in all patients. Two patients experienced early complications: one experienced a massive hematoma of the upper arm due to incomplete compression and was treated by stent deployment. The other patient experienced a re-occlusion of the brachial artery the day after the procedure due to excessive manual compression of the puncture site, but did not show recurrence of ischemic symptoms in the artery of the upper arm. Clinical success with complete resolution of ischemic symptoms was achieved in all patients.
Conclusion
PAT via a transbrachial approach is a safe and effective treatment for patients with acute upper limb ischemia.
doi:10.3348/kjr.2011.12.5.595
PMCID: PMC3168801  PMID: 21927561
Acute limb ischemia; Artery; Endovascular treatment
25.  Motor-Evoked Potential Confirmation of Functional Improvement by Transplanted Bone Marrow Mesenchymal Stem Cell in the Ischemic Rat Brain 
This study investigated the effect of bone marrow mesenchymal stem cells (BMSCs) on the motor pathway in the transient ischemic rat brain that were transplanted through the carotid artery, measuring motor-evoked potential (MEP) in the four limbs muscle and the atlantooccipital membrane, which was elicited after monopolar and bipolar transcortical stimulation. After monopolar stimulation, the latency of MEP was significantly prolonged, and the amplitude was less reduced in the BMSC group in comparison with the control group (P < .05). MEPs induced by bipolar stimulation in the left forelimb could be measured in 40% of the BMSC group and the I wave that was not detected in the control group was also detected in 40% of the BMSC group. Our preliminary results imply that BMSCs transplanted to the ischemic rat brain mediate effects on the functional recovery of the cerebral motor cortex and the motor pathway.
doi:10.1155/2011/238409
PMCID: PMC3134108  PMID: 21772790

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