Identification of novel susceptibility genes associated with bone density and osteoporosis in Korean women

Purpose@#Osteoporosis is a common calcium and metabolic skeletal disease which is characterized by decreased bone mass, microarchitectural deterioration of bone tissue and impaired bone strength, thereby leading to enhanced risk of bone fragility.In this study, we aimed to identify novel genes for susceptibility to osteoporosis and/or bone density. @*Materials and Methods@#To identify differentially expressed genes (DEGs) between control and osteoporosis-induced cells, annealing control primer-based differential display reverse-transcription polymerase chain reaction (RT-PCR) was carried out in pre-osteoblast MC3T3-E1 cells. Expression levels of the identified DEGs were evaluated by quantitative RT-PCR. Association studies for the quantitative bone density analysis and osteoporosis case-control analysis of single nucleotide polymorphism (SNPs) were performed in Korean women (3,570 subjects) from the Korean Association REsource (KARE) study cohort. @*Results@#Comparison analysis of expression levels of the identified DEGs by quantitative RT-PCR found seven genes, Anxa6, Col5a1, Col6a2, Eno1, Myof, Nfib, and Scara5, that showed significantly different expression between the dexamethasontreated and untreated MC3T3-E1 cells and between the ovariectomized osteoporosis-induced mice and sham mice. Association studies revealed that there was a significant association between the SNPs in the five genes, ANXA6, COL5A1, ENO1, MYOF, and SCARA5, and bone density and/or osteoporosis. @*Conclusion@#Using a whole-genome comparative expression analysis, gene expression evaluation analysis, and association analysis, we found five genes that were significantly associated with bone density and/or osteoporosis. Notably, the association P-values of the SNPs in the ANXA6 and COL5A1 genes were below the Bonferroni-corrected significance level.

A Comparative Study of an Anti-Thrombotic Small-Diameter Vascular Graft with Commercially Available e-PTFE Graft in a Porcine Carotid Model

BACKGROUND@#We have designed a reinforced drug-loaded vascular graft composed of polycaprolactone (PCL) and polydioxanone (PDO) via a combination of electrospinning/3D printing approaches. To evaluate its potential for clinical application, we compared the in vivo blood compatibility and performance of PCL/PDO ? 10%DY grafts doped with an antithrombotic drug (dipyridamole) with a commercial expanded polytetrafluoroethylene (e-PTFE) graft in a porcine model. @*METHODS@#A total of 10 pigs (weight: 25–35 kg) were used in this study. We made a new 5-mm graft with PCL/PDO composite nanofiber via the electrospinning technique. We simultaneously implanted a commercially available e-PTFE graft (n = 5) and our PCL/PDO ? 10%DY graft (n = 5) into the carotid arteries of the pigs. No anticoagulant/antiplatelet agent was administered during the follow-up period, and ultrasonography was performed weekly to confirm the patency of the two grafts in vivo. Four weeks later, we explanted and compared the performance of the two grafts by histological analysis and scanning electron microscopy (SEM). @*RESULTS@#No complications, such as sweating on the graft or significant bleeding from the needle hole site, were seen in the PCL/PDO ? 10%DY graft immediately after implantation. Serial ultrasonographic examination and immunohistochemical analysis demonstrated that PCL/PDO ? 10%DY grafts showed normal physiological blood flow and minimal lumen reduction, and pulsed synchronously with the native artery at 4 weeks after implantation. However, all e-PTFE grafts occluded within the study period. The luminal surface of the PCL/PDO ? 10%DY graft in the transitional zone was fully covered with endothelial cells as observed by SEM. @*CONCLUSION@#The PCL/PDO ? 10%DY graft was well tolerated, and no adverse tissue reaction was observed in porcine carotid models during the short-term follow-up. Colonization of the graft by host endothelial and smooth muscle cells coupled with substantial extracellular matrix production marked the regenerative capability. Thus, this material may be an ideal substitute for vascular reconstruction and bypass surgeries. Long-term observations will be necessary to determine the anti-thrombotic and remodeling potential of this device.

A 75 kDa glycoprotein isolated from Cudrania tricuspidata Bureau induces colonic epithelial proliferation and ameliorates mouse colitis induced by dextran sulfate sodium / 中国天然药物

Cudrania tricuspidata Bureau (CTB), a species of the Moraceae plant, has been used as a bruise recovery treatment. This study aimed to determine whether the 75 kDa phytoglycoprotein extracted from CTB has a regulatory effect on the proliferation of human colon epithelial cells and the pathological process of inflammatory bowel disease (IBD). We found that CTB glycoprotein significantly induces the proliferation of human colon epithelial HT-29 cells by activating protein kinase C. CTB glycoprotein stimulated the phosphorylation of c-Jun N-terminal kinase and transcription factor nuclear factor-κB, which are responsible for the expression of cell-cycle-related proteins (CDK2, CDK4, cyclin D1 and cyclin E) during its promotion of cell proliferation. Experimental colitis was induced in mice by adding dextran sulfate sodium to their drinking water at a concentration of 4% (W/V) for seven days. We found that CTB glycoprotein ameliorates the pathological process of IBD and lowers the disease activity index score, which was composed of body weight change, diarrhea, and hematochezia in ICR mice treated with dextran sulfate sodium. Hence, we suggest that CTB glycoprotein has the ability to prevent IBD by promoting cell proliferation signaling events via the activation of PKC, JNK and NF-κB in colon epithelial cells.

Delayed Subclavian Vein Stenosis without Thrombosis Following Clavicle Fracture

Subclavian vein injuries occasionally occur as a sequela of penetrating trauma or vascular access, but have rarely been reported to occur after clavicle fracture. The subclavian vessels are mainly enclosed by the subclavius muscle, the first rib, and the costocoracoid ligament. Therefore, in such cases, subclavian vein injury is rare because of the strcutures surrounding the subclavian vessels. Nevertheless, subclavian vein injuries occasionally show thrombotic manifestations, and thrombosis of the upper limbs constitutes 1–4% of cases of total deep vein thrombosis. Furthermore, to the best of the authors' knowledge, although vessel injuries have been reported after clavicle or rib fractures and nerve injuries to regions such as the brachial plexus, no case involving delayed presentation of isolated subclavian vein stenosis after clavicle fracture due to blunt trauma has yet been reported.

Propofol Suppresses LPS-Induced Inflammation in Amnion Cells via Inhibition of NF-κB Activation

BACKGROUND: Preterm labor is a leading risk factor for neonatal death and long-term impairment and linked closely with inflammation. Non-obstetric surgery is occasionally needed during pregnancy and the anesthetic drugs or surgery itself can give rise to inflammation. Here, we examined the influence of propofol pretreatment on the expression of cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2) after lipopolysaccharide (LPS) stimulation. In addition, we evaluated the expression of pro-inflammatory cytokines and nuclear factor kappa B (NF-κB). METHODS: Human amnion-derived WISH cells were used to investigate the effect of propofol on the LPS-induced expression of inflammatory substances involved in preterm labor. For the experiment, WISH cells were pretreated with various concentrations propofol (0.01–10 µg/ml) for 1 h and then treated with LPS (1 µg/ml) for 24 h. Cytotoxicity was evaluated using MTT assay. PGE2 concentration was assessed by ELISA. Protein expressions of COX-2, PGE2 and NF-κB were analyzed by western blotting analysis. RT-PCR was used for analysis of mRNA expression of COX-2, PGE2, interlukin (IL)-1β and tumor necrosis factor (TNF)-α. RESULTS: Propofol showed no cytotoxicity on the WISH cells. LPS-induced PGE2 production and COX-2 and PGE2 expression were decreased after propofol pretreatment. Propofol also attenuated the LPS-induced mRNA expression of IL-1β and TNF-α. Moreover, the activation of NF-jB was inhibited by propofol pretreatment on LPS-stimulated WISH cells. CONCLUSION: We demonstrated that propofol suppresses the expression of inflammatory substances enhanced by LPS stimulation. Furthermore, this inhibitory effect of propofol on the inflammatory substance expression is mediated by suppression of NF-κB activation.

Erratum: Predictive Value of Procalcitonin for Infection and Survival in Adult Cardiogenic Shock Patients Treated with Extracorporeal Membrane Oxygenation / 전남의대학술지

In the published article, the Figure 4 was published with incorrect y-axis and legend.

Predictive Value of Procalcitonin for Infection and Survival in Adult Cardiogenic Shock Patients Treated with Extracorporeal Membrane Oxygenation / 전남의대학술지

Procalcitonin (PCT) is a predictive marker for the occurrence of bacterial infection and the decision to terminate antibiotic treatment in critically ill patients. An unusual increase in PCT, regardless of infection, has been observed during extracorporeal membrane oxygenation (ECMO) support. We evaluated trends and the predictive value of PCT levels in adult cardiogenic shock during treatment with ECMO. We reviewed the clinical records of 38 adult cardiogenic shock patients undergoing veno-arterial ECMO support between January 2014 and December 2016. The exclusion criteria were age 10 ng/mL during the first week of ECMO support was significantly associated with mortality (p < 0.01). The change in PCT level was not useful in predicting new infection during ECMO support. However, higher PCT levels within the first week of the ECMO run are associated with significantly higher mortality.

Anticoagulation Therapy during Extracorporeal Membrane Oxygenator Support in Pediatric Patients / 전남의대학술지

Extracorporeal membrane oxygenation (ECMO) is a salvage therapy for critically ill patients. Although ECMO is becoming more common, hemorrhagic and thromboembolic complications remain the major causes of death in patients undergoing ECMO treatments. These complications commence upon blood contact with artificial surfaces of the circuit, blood pump, and oxygenator system. Therefore, anticoagulation therapy is required in most cases to prevent these problems. Anticoagulation is more complicated in pediatric patients than in adults, and the foreign surface of ECMO only increases the complexity of systemic anticoagulation. In this review, we discuss the pathophysiology of coagulation, anticoagulants, and monitoring tools in pediatric patients receiving ECMO.

Nosocomial Infection in Adult Patients Undergoing Veno-Arterial Extracorporeal Membrane Oxygenation

Data on the frequency of nosocomial infections during extracorporeal membrane oxygenation (ECMO) in adult populations remain scarce. We investigated the risk factors for nosocomial infections in adult patients undergoing venoarterial ECMO (VA-ECMO) support. From January 2011 to December 2015, a total of 259 patients underwent ECMO. Of these, patients aged 17 years or less and patients undergoing ECMO for less than 48 hours were excluded. Of these, 61 patients diagnosed with cardiogenic shock were evaluated. Mean patient age was 60.6 ± 14.3 years and 21 (34.4%) patients were female. The mean preoperative Sequential Organ Failure Assessment (SOFA) score was 8.6 ± 2.2. The mean duration of ECMO support was 6.8 ± 7.4 days. The rates of successful ECMO weaning and survival to discharge were 44.3% and 31.1%, respectively. There were 18 nosocomial infections in 14 (23.0%) patients. These included respiratory tract infections in 9 cases and bloodstream infections in a further 9. In multivariate analysis, independent predictors of infection during ECMO were the preoperative creatinine level (hazard ratio [HR], 2.176; 95% confidence interval [CI], 1.065–4.447; P = 0.033) and the duration of ECMO support (HR, 1.400; 95% CI, 1.081–1.815; P = 0.011). A higher preoperative creatinine level and an extended duration of ECMO support are risk factors for infection. Therefore, to avoid the development of nosocomial infections, strategies to shorten the length of ECMO support should be applied whenever possible.

Anticoagulation Therapy during Extracorporeal Membrane Oxygenator Support in Pediatric Patients / 전남의대학술지

Extracorporeal membrane oxygenation (ECMO) is a salvage therapy for critically ill patients. Although ECMO is becoming more common, hemorrhagic and thromboembolic complications remain the major causes of death in patients undergoing ECMO treatments. These complications commence upon blood contact with artificial surfaces of the circuit, blood pump, and oxygenator system. Therefore, anticoagulation therapy is required in most cases to prevent these problems. Anticoagulation is more complicated in pediatric patients than in adults, and the foreign surface of ECMO only increases the complexity of systemic anticoagulation. In this review, we discuss the pathophysiology of coagulation, anticoagulants, and monitoring tools in pediatric patients receiving ECMO.

Guidelines for prescribing opioids for chronic non-cancer pain in Korea

As the treatment of chronic non-cancer pain gradually increases, clinicians have more opportunities to encounter opioid prescription. However, guidelines for prescribing opioids for chronic non-cancer pain have never been published in Korea. The present guidelines were prepared by reviewing various research data. In cases in which the data were insufficient, recommendations were presented following discussion among experts affiliated with the Opioids Research Group in the Korean Pain Society. The present guidelines may need to be continuously revised and amended as more clinical evidence is acquired.

Protective effects of remifentanil against H₂O₂-induced oxidative stress in human osteoblasts

BACKGROUND: Bone injury is common in many clinical situations, such as surgery or trauma. During surgery, excessive reactive oxygen species (ROS) production decreases the quality and quantity of osteoblasts. Remifentanil decreases ROS production, reducing oxidative stress and the inflammatory response. We investigated remifentanil's protective effects against H₂O₂-induced oxidative stress in osteoblasts. METHODS: To investigate the effect of remifentanil on human fetal osteoblast (hFOB) cells, the cells were incubated with 1 ng/ml of remifentanil for 2 h before exposure to H2O2. For induction of oxidative stress, hFOB cells were then treated with 200 µM H₂O₂ for 2 h. To evaluate the effect on autophagy, a separate group of cells were incubated with 1 mM 3-methyladenine (3-MA) before treatment with remifentanil and H₂O₂. Cell viability and apoptotic cell death were determined via MTT assay and Hoechst staining, respectively. Mineralized matrix formation was visualized using alizarin red S staining. Western blot analysis was used to determine the expression levels of bone-related genes. RESULTS: Cell viability and mineralized matrix formation increased on remifentanil pretreatment before exposure to H₂O₂-induced oxidative stress. As determined via western blot analysis, remifentanil pretreatment increased the expression of bone-related genes (Col I, BMP-2, osterix, and TGF-β). However , pretreatment with 3-MA before exposure to remifentanil and H₂O₂ inhibited remifentanil's protective effects on hFOB cells during oxidative stress. CONCLUSIONS: We showed that remifentanil prevents oxidative damage in hFOB cells via a mechanism that may be highly related to autophagy. Further clinical studies are required to investigate its potential as a therapeutic agent.

Dexmedetomidine attenuates H₂O₂-induced cell death in human osteoblasts

BACKGROUND: Reactive oxygen species play critical roles in homeostasis and cell signaling. Dexmedetomidine, a specific agonist of the α₂-adrenoceptor, has been commonly used for sedation, and it has been reported to have a protective effect against oxidative stress. In this study, we investigated whether dexmedetomidine has a protective effect against H₂O₂-induced oxidative stress and the mechanism of H₂O₂-induced cell death in normal human fetal osteoblast (hFOB) cells. METHODS: Cells were divided into three groups: control group—cells were incubated in normoxia without dexmedetomidine, hydrogen peroxide (H2O2) group—cells were exposed to H₂O₂ (200 µM) for 2 h, and Dex/H₂O₂ group—cells were pretreated with dexmedetomidine (5 µM) for 2 h then exposed to H₂O₂ (200 µM) for 2 h. Cell viability and apoptosis were evaluated. Osteoblast maturation was determined by assaying bone nodular mineralization. Expression levels of bone-related proteins were determined by western blot. RESULTS: Cell viability was significantly decreased in the H₂O₂ group compared with the control group, and this effect was improved by dexmedetomidine. The Hoechst 33342 and Annexin-V FITC/PI staining revealed that dexmedetomidine effectively decreased H₂O₂-induced hFOB cell apoptosis. Dexmedetomidine enhanced the mineralization of hFOB cells when compared to the H₂O₂ group. In western blot analysis, bone-related protein was increased in the Dex/H₂O₂ group. CONCLUSIONS: We demonstrated the potential therapeutic value of dexmedetomidine in H₂O₂-induced oxidative stress by inhibiting apoptosis and enhancing osteoblast activity. Additionally, the current investigation could be evidence to support the antioxidant potential of dexmedetomidine in vitro.

Transfusion Associated Hyperkalemia and Cardiac Arrest in an Infant after Extracorporeal Membrane Oxygenation / 대한구급학회지

Cardiac arrest associated with hyperkalemia during red blood cell transfusion is a rare but fatal complication. Herein, we report a case of transfusion-associated cardiac arrest following the initiation of extracorporeal membrane oxygenation support in a 9-month old infant. Her serum potassium level was increased to 9.0 mEq/L, soon after the newly primed circuit with pre-stored red blood cell (RBC) was started and followed by sudden cardiac arrest. Eventually, circulation was restored and the potassium level decreased to 5.1 mEq/L after 5 min. Extracorporeal membrane oxygenation (ECMO) priming is a relatively massive transfusion into a pediatric patient. Thus, to prevent cardiac arrest during blood-primed ECMO in neonates and infants, freshly irradiated and washed RBCs should be used when priming the ECMO circuit, to minimize the potassium concentration. Also, physicians should be aware of all possible complications associated with transfusions during ECMO.

Cross-cultural Adaptation and Linguistic Validation of the Korean Version of the Leeds Assessment of Neuropathic Symptoms and Signs Pain Scale

Distinction between neuropathic pain and nociceptive pain helps facilitate appropriate management of pain; however, diagnosis of neuropathic pain remains a challenge. The aim of this study was to develop a Korean version of the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) pain scale and assess its reliability and validity. The translation and cross-cultural adaptation of the original LANSS pain scale into Korean was established according to the published guidelines. The Korean version of the LANSS pain scale was applied to a total of 213 patients who were expertly diagnosed with neuropathic (n = 113) or nociceptive pain (n = 100). The Korean version of the scale had good reliability (Cronbach's alpha coefficient = 0.815, Guttman split-half coefficient = 0.800). The area under the receiver operating characteristic curve was 0.928 with a 95% confidence interval of 0.885-0.959 (P or = 12, sensitivity was 72.6%, specificity was 98.0%, and the positive and negative predictive values were 98% and 76%, respectively. The Korean version of the LANSS pain scale is a useful, reliable, and valid instrument for screening neuropathic pain from nociceptive pain.

Transfusion Associated Hyperkalemia and Cardiac Arrest in an Infant after Extracorporeal Membrane Oxygenation / 대한중환자의학회지

Cardiac arrest associated with hyperkalemia during red blood cell transfusion is a rare but fatal complication. Herein, we report a case of transfusion-associated cardiac arrest following the initiation of extracorporeal membrane oxygenation support in a 9-month old infant. Her serum potassium level was increased to 9.0 mEq/L, soon after the newly primed circuit with pre-stored red blood cell (RBC) was started and followed by sudden cardiac arrest. Eventually, circulation was restored and the potassium level decreased to 5.1 mEq/L after 5 min. Extracorporeal membrane oxygenation (ECMO) priming is a relatively massive transfusion into a pediatric patient. Thus, to prevent cardiac arrest during blood-primed ECMO in neonates and infants, freshly irradiated and washed RBCs should be used when priming the ECMO circuit, to minimize the potassium concentration. Also, physicians should be aware of all possible complications associated with transfusions during ECMO.

Efficacy of Electroencephalographic Monitoring for the Evaluation of Intracranial Injury during Extracorporeal Membrane Oxygenation Support in Neonates and Infants / 대한구급학회지

BACKGROUND: Neurological complications are a serious concern during extracorporeal membrane oxygenation (ECMO) support in neonates and infants. However, evaluating brain injury during ECMO has limitations. Herein, we report our experience with bedside electroencephalographic monitoring during ECMO support and compared this to post-ECMO brain imaging studies and immediate neurologic outcomes. METHODS: We retrospectively reviewed the data for 18 children who underwent ECMO. From these subjects, we reviewed the medical records of 10 subjects who underwent bedside EEG monitoring during ECMO support. We collected data on patient demographics, clinical details of the ECMO course, electroencephalographic monitoring, brain imaging results, and neurologic outcomes. RESULTS: The median age was 4 months (range: 7 days-22 months), the median weight was 5 (3.6-12) kg, and the median length of ECMO therapy was 86 (27-206) hours. Eight patients (80%) were weaned successfully, and seven (70%) survived to discharge. Those with normal to mildly abnormal electroencephalographic findings had non-specific to mildly abnormal brain computed tomography findings and no neurologic impairment. Those patients with a moderately to severely abnormal electroencephalograph had markedly abnormal brain computed tomography findings and remained neurologically impaired. CONCLUSIONS: Normal electroencephalographic findings are closely related to normal or mild neurologic impairment. Our results indicate that electroencephalographic monitoring during ECMO support can be a feasible tool for evaluating brain injury although further prospective studies are needed.

Dissociated Antidepressant and Analgesic Effects of Intravenous Ketamine in Patients with Chronic Pain / 대한정신약물학회지

OBJECTIVE: Recent studies about low-dose ketamine therapy have found significant improvement of depressive symptoms within a few hours or days. This study was designed to investigate the effect of ketamine on mood in patients with chronic pain. METHODS: Forty subjects with chronic pain were recruited from the pain clinic of the Ajou University Hospital. The Beck Depression Inventory was used to evaluate mood in each patient, and then the patients received ketamine hydrochloride (1.2 mg/kg, average) intravenously over the course of 1 hour. Visual Analogue Scale (VAS) for depression, anxiety, and pain were completed by the subjects just before and 3 hours after ketamine infusion. RESULTS: VAS scores for depression, anxiety, and pain were significantly decreased after ketamine infusion. VAS for depression, anxiety, and pain showed significant correlation with each other before ketamine infusion; however, correlations of the VAS scores for pain with the other two visual scale measures were absent at post-ketamine administration while the correlation between depression and anxiety following ketamine infusion was maintained. CONCLUSION: To our knowledge, this is the first report about the antidepressant effect of intravenous ketamine, which is separated from its analgesic effect in patients with chronic pain. This result raises the possibility that the antidepressant effect of ketamine is generated by a mechanism different from that of the analgesic effect in human.

The Prognosis According to Patterns of Mediastinal Lymph Node Metastasis in Pathologic Stage IIIA/N2 Non-Small Cell Lung Cancer

BACKGROUND: The aim of this study is to evaluate prognostic factors for survival in pathologic stage IIIA/N2 non-small-cell lung cancer (NSCLC), to identify the prognostic significance of the metastatic patterns of mediastinal lymph nodes (MLNs) relating to survival and to recurrence and metastasis. METHODS: A total of 129 patients who underwent radical resection for pathologic stage IIIA-N2 NSCLC from July 1998 to April 2011 were retrospectively reviewed. The end points of this study were rates of loco-regional recurrence and distant metastasis, and survival. RESULTS: The overall 5-year survival rate was 47.4%. A univariate analysis showed that age, pathologic T stage, and adjuvant chemotherapy were significant prognostic factors, while in multivariate analysis, pathologic T stage and adjuvant chemotherapy were significant prognostic factors. The metastasis rate was higher in patients with multistation N2 involvement and with more than 3 positive MLNs. Further, non-regional MLN metastasis was associated with a higher loco-regional recurrence rate. CONCLUSION: Pathologic T stage and adjuvant chemotherapy were independent prognostic factors for long-term survival in pathologic stage IIIA/N2 NSCLC. The recurrence and the metastasis rate were affected by the metastatic patterns of MLNs. These results may be helpful for planning postoperative therapeutic strategies and predicting outcomes.

Mixed Squamous Cell and Glandular Papilloma of the Lung in a 64-Year-Old Woman

Mixed squamous cell and glandular papilloma of the lung is an extremely rare benign epithelial tumor showing a mixture of squamous and glandular epithelium. Here, we report a case of mixed squamous cell and glandular papilloma that presented as a solitary nodule in the left lower lobe of a 64-year-old woman. Chest computed tomography demonstrated a lobulated mass in the basal segment of the left lower lobe. The patient underwent a lobectomy under the suspicion of lung malignancy. The histopathological diagnosis was mixed squamous cell and glandular papilloma.