Background/Aims: While switching strategies of P2Y12 receptor inhibitors (RIs) have sometimes been used in acute myocardial infarction (AMI) patients, the current status of in-hospital P2Y12RI switching remains unknown. Methods: Overall, 8,476 AMI patients who underwent successful revascularization from Korea Acute Myocardial Infarction Registry-National Institute of Health (KAMIR-NIH) were divided according to in-hospital P2Y12RI strategies, and net adverse cardiovascular events (NACEs), defined as a composite of cardiac death, non-fatal myocardial infarction (MI), stroke, or thrombolysis in myocardial infarction (TIMI) major bleeding during hospitalization were compared. Results: Patients with in-hospital P2Y12RI switching accounted for 16.5%, of which 867 patients were switched from clopidogrel to potent P2Y12RI (C-P) and 532 patients from potent P2Y12RI to clopidogrel (P-C). There were no differences in NACEs among the unchanged clopidogrel, the unchanged potent P2Y12RIs, and the P2Y12RI switching groups. However, compared to the unchanged clopidogrel group, the C-P group had a higher incidence of non-fatal MI, and the P-C group had a higher incidence of TIMI major bleeding. In clinical events of in-hospital P2Y12RI switching, 90.9% of non-fatal MI occurred during pre-switching clopidogrel administration, 60.7% of TIMI major bleeding was related to pre-switching P2Y12RIs, and 71.4% of TIMI major bleeding was related to potent P2Y12RIs. Only 21.6% of the P2Y12RI switching group switched to P2Y12RIs after a loading dose (LD); however, there were no differences in clinical events between patients with and without LD. Conclusions In-hospital P2Y12RI switching occurred occasionally, but had relatively similar clinical outcomes compared to unchanged P2Y12RIs in Korean AMI patients. Non-fatal MI and bleeding appeared to be mainly related to pre-switching P2Y12RIs.

Background: The digits-in-noise (DiN) test is a speech-in-noise test to measure speech recognition threshold in noise adaptively. Herein, we aimed to develop the Korean version of the DiN test to provide a useful hearing screening tool for clinical as well as research purposes.Method: Spoken monosyllabic digits from 0 to 9 were recorded by a female speaker. The test list was constructed such that each digit was placed in three different positions. An optimization procedure was conducted to equate the audibility of each digit. After the optimization, the smartphone application for the Korean DiN (K-DiN) test was developed. For the adaptive measurement procedure, 180 new DiN triplets separated into six lists of 30 were created. Mean speech recognition threshold values for each list and session were measured to examine the test-retest and training effects of the test materials. In addition, speech recognition threshold values measured by different devices were compared to determine whether the speech recognition threshold levels differed. Results: Optimization results showed that the mean speech recognition threshold and slope were −11.55 dB signal-to-noise ratio and 10.21%/dB, respectively, which are comparable to levels shown in different-language versions of the DiN test. The results of the test-retest and training effects revealed no significant differences among the test sessions and lists. Additionally, the mean speech recognition threshold values measured by four different devices were not different, indicating the reliability of the test materials. Conclusion We believe this study is the first to attempt to develop a K-DiN test. Our results indicate that this test can be used as a potentially reliable hearing screening tool.

Stress can induce a serious epileptic encephalopathy that occurs during early infancy. Recent studies have revealed that prenatal stress exposure is a risk factor for the development of infantile spasms. Our previous work demonstrates that prenatal stress with betamethasone-induced alterations to the expression of the K⁺/Cl⁻ co-transporter (KCC2) in gamma-aminobutyric acid (GABA) interneurons lowers the seizure threshold in exposed animals. Here, we further investigated the mechanisms involved in this KCC2 dysfunction and explored possible treatment options. We stressed Sprague-Dawley rats prenatally and further treated dams with betamethasone on gestational day 15, which increases seizure susceptibility and NMDA (N-Methyl-D-aspartate)-triggered spasms on postnatal day 15. In this animal model, first, we evaluated baseline calpain activity. Second, we examined the cleavage and dephosphorylation of KCC2. Finally, we checked the effect of a calpain inhibitor on seizure occurrence. The phosphorylated-N-methyl-D-aspartate Receptor 2B (NR2B):non-phosphorylated NR2B ratio was found to be higher in the cortex of the prenatally stressed beta-methasone model. We further found that the betamethasone model exhibited increased phosphorylation of calpain-2 and decreased phosphorylation of KCC2 and Glutamic acid decarboxylase 67 (GAD67). After using a calpain inhibitor in prenatal-stress rats, the seizure frequency decreased, while latency increased. GABAergic depolarization was further normalized in prenatal-stress rats treated with the calpain inhibitor. Our study suggests that calpain-dependent cleavage and dephosphorylation of KCC2 decreased the seizure threshold of rats under prenatal stress. Calpain-2 functions might, thus, be targeted in the future for the development of treatments for epileptic spasms.
Animals ; Betamethasone ; Brain Diseases ; Calpain ; Epilepsy ; gamma-Aminobutyric Acid ; Glutamate Decarboxylase ; Humans ; Infant ; Infant, Newborn ; Interneurons ; Models, Animal ; N-Methylaspartate ; Phosphorylation ; Rats ; Rats, Sprague-Dawley ; Risk Factors ; Seizures ; Spasm ; Spasms, Infantile

Akt (also known as protein kinase B, PKB) has been seen to play a role in astrocyte activation of neuroprotection; however, the underlying mechanism on deregulation of Akt signaling in brain injuries is not fully understood. We investigated the role of carboxy-terminal modulator protein (CTMP), an endogenous Akt inhibitor, in brain injury following kainic acid (KA)-induced neurodegeneration of mouse hippocampus. In control mice, there was a weak signal for CTMP in the hippocampus, but CTMP was markedly increased in the astrocytes 3 days after KA treatment. To further investigate the effectiveness of Akt signaling, the phosphorylation of CTMP was examined. KA treatment induced an increased p-CTMP expression in the astrocytes of hippocampus at 1 day. LPS/IFN-γ-treatment on primary astrocytes promoted the p-CTMP was followed by phosphorylation of Akt and finally upregulation of CTMP and p-CREB. Time-dependent expression of p-CTMP, p-Akt, p-CREB, and CTMP indicate that LPS/IFN-γ-induced phosphorylation of CTMP can activate Akt/CREB signaling, whereas lately emerging enhancement of CTMP can inhibit it. These results suggest that elevation of CTMP in the astrocytes may suppress Akt activity and ultimately negatively affect the outcome of astrocyte activation (astroglisiois). Early time point enhancers of phosphorylation of CTMP and/or late time inhibitors specifically targeting CTMP may be beneficial in astrocyte activation for neuroprotection within treatment in neuroinflammatory conditions.
Animals ; Astrocytes ; Brain Injuries ; Hippocampus* ; Kainic Acid ; Mice* ; Neuroprotection ; Phosphorylation ; Proto-Oncogene Proteins c-akt ; Up-Regulation

PURPOSE: The optimal indications for omitting adjuvant radiation therapy (RT) after breast-conserving surgery are still controversial in ductal carcinoma in situ (DCIS) of the breast. The purpose of this study was to validate the role of postoperative RT in DCIS patients aged ≤50 years and with tumor margin widths of <1 cm, both of which have been proven to be high-risk features for recurrence in cohorts not receiving RT. METHODS: Using two multicenter retrospective studies on DCIS, a pooled analysis was performed among patients aged ≤50 years and with margin widths < 1 cm. All patients underwent breast-conserving surgery. Two hundred thirty-two patients received postoperative RT, while 54 did not. The median follow-up period was 77 months (range, 2–190 months) and 70 months (range, 5–166 months) in the patients who received RT and those who did not, respectively. RESULTS: The patients who received RT had larger tumors (p < 0.001), higher nuclear grade (p < 0.001), closer margin width (p < 0.001), and negative estrogen receptor expression (p=0.010) compared with those who did not receive RT. During the follow-up period, there were 17 ipsilateral breast tumor recurrences (IBTRs) as follows: invasive carcinoma in 10 patients and DCIS in seven. In the univariate analysis, the treatment with RT and human epidermal growth factor receptor 2 (HER2) status were significant risk factors for IBTR. The 7-year IBTR rates with and without postoperative RT were 3.6% and 13.1%, respectively (p=0.008). HER2-positive tumors had a higher IBTR rate than the HER2-negative tumors (7-year rate, 13.6% vs. 3.9%; p=0.003). CONCLUSION: Postoperative RT following breast-conserving surgery significantly reduced the 7-year IBTR rate in the DCIS patients aged ≤50 years and with margin widths < 1 cm. HER2 positivity was associated with increased IBTR in these patients.
Age Factors ; Breast ; Breast Neoplasms ; Carcinoma, Ductal* ; Carcinoma, Intraductal, Noninfiltrating* ; Cohort Studies ; Estrogens ; Follow-Up Studies ; Humans ; Mastectomy, Segmental* ; Radiation Oncology* ; Radiotherapy ; Receptor, Epidermal Growth Factor ; Recurrence ; Retrospective Studies ; Risk Factors

Growth differentiation factor 15 (GDF15) is, a member of the transforming growth factor beta (TGF-beta) superfamily of proteins. Although GDF15 is well established as a potent neurotrophic factor for neurons, little is known about its role in glial cells under neuropathological conditions. We monitored GDF15 expression in astrocyte activation after a kainic acid (KA)-induced neurodegeneration in the ICR mice hippocampus. In control, GDF15 immunoreactivity (IR) was evident in the neuronal layer of the hippocampus; however, GDF15 expression had increased in activated astrocytes throughout the hippocampal region at day 3 after the treatment with KA. LPS treatment in astrocytes dramatically increased GDF15 expression in primary astrocytes. In addition, LPS treatment resulted in the decrease of the IkappaB-alpha degradation and increase of the phosphorylation level of RelA/p65. These results indicate that GDF15 has a potential link to NF-kappaB activation, making GDF15 a valuable target for modulating inflammatory conditions.
Animals ; Astrocytes* ; Growth Differentiation Factor 15* ; Hippocampus* ; Kainic Acid ; Mice* ; Mice, Inbred ICR ; Neuroglia ; Neurons ; NF-kappa B ; Phosphorylation ; Transforming Growth Factor beta

Pioglitazone (PGZ), a synthetic peroxisome proliferator-activated receptor gamma agonist, is known to regulate inflammatory process and to have neuroprotective effects against neurological disorders. In the present study, we examined the effects of 30 mg/kg PGZ on excitotoxic neuronal damage and glial activation in the mouse hippocampus following intracerebroventricular injection of kainic acid (KA). PGZ treatment significantly reduced seizure-like behavior. PGZ had the neuroprotective effect against KA-induced neuronal damage and attenuated the activations of astrocytes and microglia in the hippocampal CA3 region. In addition, MPO and NFkappaB immunoreactivities in the glial cells were also decreased in the PGZ-treated group. These results indicate that PGZ had anticonvulsant and neuroprotective effects against KA-induced excitotocix injury, and that neuroprotective effect of PGZ might be due to the attenuation of KA-induced activation in astrocytes and microglia as well as KA-induced increases in MPO and NFkappaB.
Animals ; Astrocytes ; CA3 Region, Hippocampal ; Hippocampus* ; Kainic Acid ; Mice* ; Microglia ; Nervous System Diseases ; Neuroglia ; Neurons* ; Neuroprotective Agents ; PPAR gamma

BACKGROUND/AIMS: The incidence of duodenal tumors has increased by health surveillance. However, preoperative diagnosis of subepithelial duodenal tumors remains difficult because of the wide variety of pathologies and the location of the tumors. We analyzed endoscopic, radiological, and pathological features of subepithelial benign duodenal tumors (BDTs), which were treated by surgical resection. METHODS: Five patients with subepithelial BDTs treated by surgical resection were analyzed retrospectively. We compared the preoperative and postoperative diagnosis and evaluated the clinical presentations, endoscopic and radiological findings, surgical treatments, pathological results, and outcomes of these patients. RESULTS: All the patients underwent successful surgical resection. There were two cases of gastrointestinal stromal tumors (GISTs) treated with segmental duodenectomy, one case of carcinoid tumor treated with antrectomy, one case of gangliocytic paraganglioma treated with ampullectomy, and a lipoma removed by mass excision. The two GISTs were in the duodenal third and fourth segment close to the pancreas, and it was difficult to exclude pancreatic tumors by imaging studies. All the patients remained healthy for more than three years. CONCLUSIONS: Subepithelial BDTs are rare and difficult to diagnosis. Awareness and preoperative diagnosis of subepithelial BDTs can lead to minimally invasive treatment, including endoscopic or local surgical resection.
Carcinoid Tumor ; Diagnosis ; Duodenum ; Gastrointestinal Stromal Tumors ; Humans ; Incidence ; Lipoma ; Pancreas ; Paraganglioma ; Pathology ; Retrospective Studies

JL1, a specific epitope on CD43, is a potential biomarker for the diagnosis of acute leukemia. Although qualitative assays for detecting leukemia-specific CD43 exist, there is a need to develop quantitative assays for the same. Here, we developed two novel monoclonal antibodies (mAbs), 2C8 and 8E10, recognizing different epitopes on CD43. These clones are capable of pairing with YG5, another mAb against JL1 epitope, because they were selectively obtained using sandwich ELISA. Antigens recognized by 2C8 and 8E10 were confirmed as CD43 by western blotting using the CD43-hFC recombinant protein. When expression on various leukemic cell lines was investigated, 2C8 and 8E10 displayed a disparity in the distribution of the epitope. Enzyme assays revealed that these mAbs recognized a sialic acid-dependent epitope on CD43. Using normal thymus and lymph node paraffin-embedded tissues, we confirmed a difference in the epitopes recognized by the two mAbs that was predicted based on the maturity of the cells in the tissue. In summary, we developed and characterized two mAbs, 2C8 and 8E10, which can be used with YG5 in a sandwich ELISA for detecting leukemia-specific CD43.
Antibodies, Monoclonal ; Blotting, Western ; Cell Line ; Clone Cells ; Diagnosis ; Enzyme Assays ; Enzyme-Linked Immunosorbent Assay ; Epitopes* ; Leukemia ; Lymph Nodes ; Thymus Gland

BACKGROUND AND OBJECTIVES: The ubiquitin-proteasome system is the major intracellular protein degradation pathway in the eukaryotic cells. Bortezomib inhibits 26S proteasome-induced I-kappaBalpha degradation and suppresses nuclear factor-kappa B (NF-kappaB) activation. We examined the effect of bortezomib on neointima formation after of a rat carotid artery balloon injury. MATERIALS AND METHODS: After carotid artery balloon denudation, bortezomib was immediately administered by tail vein injection (systemic treatment) and by using an F-127 pluronic gel (perivascular treatment). Two weeks after the injury, we compared the degree of neointima formation in the carotid artery and the tissue expression patterns of NF-kappaB and I-kappaBalpha. RESULTS: The systemic treatment group exhibited a 29% reduction in neointima volume at two weeks after the balloon injury. On the western blot analysis, the bortezomib group exhibited an increased I-kappaBalpha expression, which suggested the inhibition of I-kappaBalpha degradation. On immunofluorescence analysis, the nuclear import of NF-kappaB was clearly decreased in the systemic bortezomib group. The perivascular bortezomib treatment group exhibited a significant reduction in the neointimal area (0.21+/-0.06 mm2 vs. 0.06+/-0.01 mm2, p<0.05), the neointima/media area ratio (1.43+/-0.72 vs. 0.47+/-0.16, p<0.05) and the % area stenosis (45.5+/-0.72% vs. 14.5+/-0.05%, p<0.05) compared with the control group. In situ vascular smooth muscle cell proliferation at 2 days after the injury was significantly inhibited (24.7+/-10.9% vs. 10.7+/-4.7%, p<0.05). CONCLUSION: Bortezomib suppressed NF-kappaB activation through the inhibition of I-kappaBalpha degradation, and significantly reduced neointima formation in a rat carotid artery injury model. These data suggested that bortezomib represented a new potent therapeutic agent for the prevention of restenosis.
Active Transport, Cell Nucleus ; Angioplasty ; Animals ; Blotting, Western ; Boronic Acids ; Carotid Arteries ; Carotid Artery Injuries ; Cell Proliferation ; Constriction, Pathologic ; Coronary Restenosis ; Eukaryotic Cells ; Fluorescent Antibody Technique ; Hyperplasia ; Muscle, Smooth, Vascular ; Neointima ; NF-kappa B ; Proteasome Endopeptidase Complex ; Proteolysis ; Pyrazines ; Rats ; Veins ; Bortezomib