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1.  The EC50 of remifentanil to minimize the cardiovascular changes during head holder pinning in neurosurgery 
Korean Journal of Anesthesiology  2012;63(4):327-333.
During neuroanesthesia, head holder pinning commonly results in sympathetic stimulation manifested by hemodynamic changes, such as increased heart rate and arterial blood pressure. Remifentanil has been used successfully to control acute autonomic responses during neurosurgical procedures. The objective of this study was to determine effect-site concentration of remifentanil for suppressing the hemodynamic response to head holder pinning with the probability of 50% (EC50).
Forty-one ASA physical status I or II patients, between the ages of 20-70, who were scheduled for neurosurgery were recruited into this study. After arrival in the operating room, standard monitoring was applied throughout the study, which included a bispectral index monitor. Both propofol and remifentanil were administered by Target-control infusion device. The Dixon "up-and-down" sequential allocation method was used to determine the EC50 of remifentanil.
The EC50 of remifentanil was 2.19 ± 0.76 ng/ml by the turning point estimate (TPE). In probit analysis, EC50 was 2.42 ng/ml (95% CI : -0.62-4.66) and EC95 was 5.70 ng/ml (95% CI : 4.02-67.53). The EC50 estimator comes from isotonic regression is 2.90 ng/ml (95% CI : 1.78-3.65). The EC95 estimator comes from isotonic regression is 4.28 ng/ml (95% CI : 3.85-4.41).
This study showed that EC50 of remifentanil was 2.19 ± 0.76 ng/ml by TPE. EC50 was 2.42 ng/ml (95% CI -0.62-4.66) in probit analysis, as back up analysis. The EC50 estimator comes from isotonic regression is 2.90 ng/ml (95% CI : 1.78-3.65).
PMCID: PMC3483491  PMID: 23115685
Hemodynamics; Neurosurgery; Propofol; Remifentanil
2.  Efficacy and Safety of Aceclofenac Controlled Release in Patients with Knee Osteoarthritis: A 4-week, Multicenter, Randomized, Comparative Clinical Study 
To evaluate the analgesic effect, efficacy and safety of aceclofenac controlled release (CR) in patients with chronic knee osteoarthritis (OA).
Materials and Methods
A total of 125 subjects with chronic knee OA were randomly divided into two groups: one group (n=62) was administered aceclofenac CR once daily and the other (n=63), aceclofenac immediate release (IR) twice a day for 4 weeks. A 100-mm visual analogue scale (VAS), Knee injury and Osteoarthritis Outcome Score (KOOS) and range of motoin (ROM) were evaluated as the outcome measures. To evaluate the safety of the drug, adverse events, vital signs, physical examination findings, clinical laboratory values and electrocardiographic findings were evaluated.
The VAS, KOOS and ROM were improved after 4 weeks of administration in both groups, but the differences between the two groups were not statistically significant. Significant differences between the two groups were not shown in the evaluation of the adverse events, vital sign, physical examination results, clinical laboratory values, and electrocardiography.
The aceclofenac CR and aceclofenac IR were equally effective in patients with chronic knee OA and the clinical trial results didn't show any significant difference in safety. The new aceclofenac CR formulation was found to be effective and safe with the practical advantage of once daily administration.
PMCID: PMC3953523  PMID: 24639945
Knee; Osteoarthritis; Aceclofenac; Controlled-release preparations
3.  Cytokine signaling-1 suppressor is inducible by IL-1beta and inhibits the catabolic effects of IL-1beta in chondrocytes: its implication in the paradoxical joint-protective role of IL-1beta 
Arthritis Research & Therapy  2013;15(6):R191.
Although IL-1β is believed to be crucial in the pathogenesis of osteoarthritis (OA), the IL-1β blockade brings no therapeutic benefit in human OA and results in OA aggravation in several animal models. We explored the role of a cytokine signaling 1 (SOCS1) suppressor as a regulatory modulator of IL-1β signaling in chondrocytes.
Cartilage samples were obtained from patients with knee OA and those without OA who underwent surgery for femur-neck fracture. SOCS1 expression in cartilage was assessed with immunohistochemistry. IL-1β-induced SOCS1 expression in chondrocytes was analyzed with quantitative polymerase chain reaction and immunoblot. The effect of SOCS1 on IL-1β signaling pathways and the synthesis of matrix metalloproteinases (MMPs) and aggrecanase-1 was investigated in SOCS1-overexpressing or -knockdown chondrocytes.
SOCS1 expression was significantly increased in OA cartilage, especially in areas of severe damage (P < 0.01). IL-1β stimulated SOCS1 mRNA expression in a dose-dependent pattern (P < 0.01). The IL-1β-induced production of MMP-1, MMP-3, MMP-13, and ADAMTS-4 (aggrecanase-1, a disintegrin and metalloproteinase with thrombospondin motifs 4) was affected by SOCS1 overexpression or knockdown in both SW1353 cells and primary human articular chondrocytes (all P values < 0.05). The inhibitory effects of SOCS1 were mediated by blocking p38, c-Jun N-terminal kinase (JNK), and nuclear factor κB (NF-κB) activation, and by downregulating transforming growth factor-β-activated kinase 1 (TAK1) expression.
Our results show that SOCS1 is induced by IL1-β in OA chondrocytes and suppresses the IL-1β-induced synthesis of matrix-degrading enzymes by inhibiting IL-1β signaling at multiple levels. It suggests that the IL-1β-inducible SOCS1 acts as a negative regulator of the IL-1β response in OA cartilage.
PMCID: PMC3979110  PMID: 24238405
4.  How Much Are Upper or Lower Extremity Disabilities Associated with General Health Status in the Elderly? 
Musculoskeletal complaints influence general health status, but the relative contribution of concurrent upper and lower extremity disabilities on patient perceptions of general health is unclear.
We evaluated whether two regional instruments (DASH and WOMAC) reflect a patient’s perception of general health measured using the SF-36 and determined whether general health components are explained by upper and lower extremity disabilities.
We recruited 272 randomly chosen participants 65 years or older without a history of surgery for musculoskeletal disease or trauma who participated in the Korean Longitudinal Study on Health and Aging. Upper extremity disability was determined with the DASH score and lower extremity disability with the WOMAC; as a measure of general health, we obtained SF-36 scores. Multivariate regression modeling was used to assess the relative contributions made by upper and lower extremity disabilities to general health.
The DASH and WOMAC each was correlated with the physical component summary (PCS) scale and with the mental component summary (MCS) scale to differing extents. Multivariate regression analyses revealed that WOMAC alone, DASH alone, and WOMAC and DASH accounted for 24%, 19%, and 26% of the variance in the PCS scale. However, only the DASH was associated with the MCS scale but accounted for only 2% of the variance.
We found that in a community-based elderly population, perceived general physical health is associated with upper and lower extremity disabilities, whereas perceived general mental health is associated with only upper extremity disabilities, but to a small extent.
Level of Evidence
Level II, prognostic study. See Guidelines for Authors for a complete description of levels of evidence.
PMCID: PMC3462850  PMID: 22689096
5.  The Impact of High Sensitivity C-Reactive Protein Level on Coronary Artery Spasm as Assessed by Intracoronary Acetylcholine Provocation Test 
Yonsei Medical Journal  2013;54(6):1299-1304.
High sensitive C-reactive protein (hs CRP) is well known as a strong risk factor of cardiovascular disease (CVD). The aim of this study is to evaluate the impact of elevated hs CRP on coronary artery spasm (CAS) as assessed by intracoronary acetylcholine (ACh) provocation test.
Materials and Methods
A total of 1729 consecutive patients without significant CVD who underwent coronary angiography and intracoronary ACh test between November 2004 and August 2010 were analyzed. The patients were divided into five groups according to quintiles of hs CRP levels.
At baseline, the prevalence of elderly, hypertension, diabetes mellitus, current smoking, and lipid levels were higher in patients with higher hs CRP. During ACh test, the incidences of significant CAS, ischemic electrocardiography (EKG) change, multivessel, and diffuse CAS were higher in patients with higher hs CRP. Multivariate analysis showed that the old age (OR=1.01, CI; 1.0-1.02, p=0.0226), myocardial bridge (OR=3.34, CI; 2.16-5.17, p<0.001), and highest quintile hs CRP (OR=1.54, CI; 1.12-2.18, p=0.008) were independent predictors of ACh induced CAS. However, there was no difference in clinical outcomes up to 12 months.
In conclusion, higher hs CRP was associated with higher incidence of CAS, worse angiographic characteristics and ischemic EKG change, but was not associated with clinical outcomes.
PMCID: PMC3809884  PMID: 24142631
C-reactive protein; acetylcholine; coronary artery spasm
6.  Does Ramosetron Reduce Postoperative Emesis and Pain after TKA? 
Current pain management protocols involving many anesthetic and analgesic drugs reportedly provide adequate analgesia after TKA. However, control of emetic events associated with the drugs used in current multimodal pain management remains challenging.
We determined (1) whether ramosetron prophylaxis reduces postoperative emetic events; and (2) whether it influences pain levels and opioid consumption in patients managed with a current multimodal pain management protocol after TKA.
We randomized 119 patients undergoing TKA to receive either ramosetron (experimental group, n = 60) or no prophylaxis (control group, n = 59). All patients received regional anesthesia, preemptive analgesic medication, continuous femoral nerve block, periarticular injection, and fentanyl-based intravenous patient-controlled analgesia. We recorded the incidence of emetic events, rescue antiemetic requirements, complete response, pain level, and opioid consumption during three periods (0–6, 6–24, and 24–48 hours postoperatively). The severity of nausea was evaluated using a 0 to 10 VAS.
The ramosetron group tended to have a lower incidence of nausea with a higher complete response and tended to have less severe nausea and fewer rescue antiemetic requirements during the 6- to 24-hour period. However, the overall incidences of emetic events, rescue antiemetic requirements, and complete response were similar in both groups. We found no differences in pain level or opioid consumption between the two groups.
Ramosetron reduced postoperative emetic events only during the 6- to 24-hour postoperative period and did not affect pain relief. More efficient measures to reduce emetic events after TKA should be explored.
Level of Evidence
Level I, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.
PMCID: PMC3348324  PMID: 22161082
7.  Low glibenclamide concentrations affect endoplasmic reticulum stress in INS-1 cells under glucotoxic or glucolipotoxic conditions 
β-Cell apoptosis caused by increased endoplasmic reticulum (ER) stress is an important pathogenic component of type 2 diabetes mellitus. In theory, sulfonylureas, used for the treatment of diabetes, can contribute to ER stress. We assessed changes in ER stress in pancreatic β-cells under glucotoxic or glucolipotoxic conditions using low concentrations of the sulfonylurea, glibenclamide (GB).
Low concentrations of GB (10 or 100 nM) were added to INS-1 cells cultured under glucotoxic or glucolipotoxic conditions. The degree of viability, level of apoptosis and levels of markers associated with ER stress were measured.
Apoptosis decreased in response to low concentrations of GB under glucolipotoxic but not glucotoxic conditions. Most ER stress markers decreased upon the addition of GB. Under glucotoxic conditions, changes in the levels of ER stress markers were not consistent. However, all decreased significantly under glucolipotoxic conditions.
Low concentrations of GB exerted antiapoptotic effects through the attenuation of ER stress under glucolipotoxic conditions.
PMCID: PMC3654132  PMID: 23682228
Glyburide; Insulin-secreting cells; Endoplasmic reticulum stress; Glucotoxicity; Glucolipotoxicity
8.  Prediction of Chronicity of Anterior Cruciate Ligament Tear Using MRI Findings 
Clinics in Orthopedic Surgery  2013;5(1):19-25.
The estimation of anterior cruciate ligament (ACL) tear is required in certain cases involving legal and financial administration, such as the worker's compensation and/or insurance. The aim of this study is to propose and evaluate a quantitative evaluation instrument to estimate the chronicity of the ACL tear, based on the four magnetic resonance imaging (MRI) findings.
One hundred and fifty one cases of complete ACL tear confirmed by arthroscopy were divided into 4 groups according to the time from ACL injury to MRI acquisition: acute (< 6 weeks), subacute (6 weeks to 3 months), intermediate (3 months to 1 year), and chronic (> 1 year). The four MRI findings including ACL morphology, joint effusion, posterior cruciate ligament angle, and bone bruise were analyzed for temporal changes among the 4 groups. Binary logistic regression equations were formulated using the MRI findings to estimate the chronicity of ACL tear in a quantitative manner, and the accuracy of the formulated regression equations was evaluated.
The four MRI findings showed substantial temporal correlation with the time-limits of ACL injury to be included in the estimation model. Three predictive binary logistic equations estimated the probability of the ACL injury for the three cutoff time-limits of 6 weeks, 3 months, and 1 year with accuracies of 82.1%, 89.4%, and 89.4%, respectively.
A series of predictive logistic equations were formulated to estimate the chronicity of ACL tear using 4 MRI findings with chronological significance.
PMCID: PMC3582867  PMID: 23467216
Anterior cruciate ligament; Chronicity; Magnetic resonance imaging; Predictive model
9.  A Submucosal Tumor-Like Recurrence of Early Esophageal Cancer after Endoscopic Submucosal Dissection 
Clinical Endoscopy  2013;46(2):182-185.
Early esophageal cancer is defined as a tumor invading the mucosa with or without lymph node or distant organ metastasis. In the current guidelines for early esophageal cancer, absolute indication for endoscopic resection include lesions limited to the epithelium or lamina propria mucosa not exceeding two-thirds of the circumference, and relative indications include lesions limited to the muscularis mucosa or the upper third of the submucosal layer and not accompanied by clinical evidence of lymph node metastasis. After endoscopic submucosal dissection for early esophageal cancer, locally recurrent cancer can occur, especially in the case of incomplete resection. Here, we report a rare case of a submucosal tumor-like recurrence after endoscopic resection of early esophageal cancer.
PMCID: PMC3630314  PMID: 23614130
Esophageal neoplasms; Endosonography; Endoscopic resection; Recurrence
10.  Eruptive Penile Syringomas Spreading to the Pubic Area and Lower Abdomen 
Annals of Dermatology  2013;25(1):116-118.
PMCID: PMC3582913  PMID: 23463834
11.  Relation of Absolute or Relative Adiposity to Insulin Resistance, Retinol Binding Protein-4, Leptin, and Adiponectin in Type 2 Diabetes 
Diabetes & Metabolism Journal  2012;36(6):415-421.
Central fat mass (CFM) correlates with insulin resistance and increases the risk of type 2 diabetes and cardiovascular complications; however, peripheral fat mass (PFM) is associated with insulin sensitivity. The aim of this study was to investigate the relation of absolute and relative regional adiposity to insulin resistance index and adipokines in type 2 diabetes.
Total of 83 overweighted-Korean women with type 2 diabetes were enrolled, and rate constants for plasma glucose disappearance (KITT) and serum adipokines, such as retinol binding protein-4 (RBP4), leptin, and adiponectin, were measured. Using dual X-ray absorptiometry, trunk fat mass (in kilograms) was defined as CFM, sum of fat mass on the lower extremities (in kilograms) as PFM, and sum of CFM and PFM as total fat mass (TFM). PFM/TFM ratio, CFM/TFM ratio, and PFM/CFM ratio were defined as relative adiposity.
Median age was 55.9 years, mean body mass index 27.2 kg/m2, and mean HbA1c level 7.12±0.84%. KITT was positively associated with PMF/TFM ratio, PMF/CFM ratio, and negatively with CFM/TFM ratio, but was not associated with TFM, PFM, or CFM. RBP4 levels also had a significant relationship with PMF/TFM ratio and PMF/CFM ratio. Adiponectin, leptin, and apolipoprotein A levels were related to absolute adiposity, while only adiponectin to relative adiposity. In correlation analysis, KITT in type 2 diabetes was positively related with HbA1c, fasting glucose, RBP4, and free fatty acid.
These results suggest that increased relative amount of peripheral fat mass may aggravate insulin resistance in type 2 diabetes.
PMCID: PMC3530712  PMID: 23275935
Adiponectin; Adiposity; Insulin resistance; Leptin; Retinol binding protein-4
12.  The median effective effect-site concentration of remifentanil for minimizing the cardiovascular changes to endotracheal intubation during desflurane anesthesia in pediatric patients 
Korean Journal of Anesthesiology  2012;63(4):314-320.
Desflurane has the most rapid onset and offset of action among the volatile anesthetic agents used for general anesthesia, but it can cause airway reactivity, tachycardia, and hypertension during induction, especially in pediatric patients. This study was designed to determine a median effective effect-site concentration (EC50) of remifentanil to prevent the cardiovascular changes due to tracheal intubation during the 1 minimum alveolar concentration (MAC) desflurane inhalation, which was required to prevent movement in response to a noxious stimulus in 50% of subjects, in pediatric patients.
Twenty-four pediatric patients between the ages 5-15 years were enrolled in this study. We injected thiopental intravenously, at the same time remifentanil was infused by Target Controlled Infusion (TCI) device. When the target effect-site concentration (Ce) of remifentanil reached a preset level, desflurane was administrated through the facial mask. Then, we assessed the signs of desflurane related airway reactivity and cardiovascular changes for 2 min. The up-and-down criteria was a 20% change in systolic blood pressure (SBP) and a heart rate (HR) between just prior to intubation and 1 min after intubation. The EC50 of remifentanil was calculated from 8 independent pairs using Dixon's up-and-down method.
We studied 24 pediatric patients in range of 1-5 ng/ml of the Ce of remifentanil. No patient showed airway reactivity during the study. The EC50 of remifentanil to suppress the hemodynamic changes after tracheal intubation during desflurane anesthesia was calculated as 3.4 ± 0.9 ng/ml.
In pediatric anesthesia, the EC50 of remifentanil to minimize the cardiovascular changes due to tracheal intubation during 1 MAC desflurane anesthesia was 3.4 ± 0.9 ng/ml.
PMCID: PMC3483489  PMID: 23115683
Child; Desflurane; Endotracheal intubation; Heart rate; Remifentanil; Systolic pressure
13.  Clinical significance of standardized uptake value and maximum tumor diameter in patients with primary extranodal diffuse large B cell lymphoma 
The Korean Journal of Hematology  2012;47(3):207-212.
Maximum standardized uptake value (SUVmax) and maximum tumor diameter (MTD) have been shown to reflect survival outcome in diffuse large B cell lymphoma (DLBCL). However, applying these values to primary extranodal DLBCL is difficult because they are separate nosological entities with differences in genetic origin. We therefore decided to evaluate whether SUVmax and MTD on 2-[fluorine-18]-fluoro-2-deoxy-D-glucose (18-FDG) positron emission tomography (PET) would affect the survival outcome in primary extranodal DLBCL.
From October 2005 to November 2010, 76 primary extranodal DLBCL patients receiving R-CHOP therapy were analyzed. All patients had undergone an initial 18-FDG PET/CT and conventional computed tomography (CT) of the neck, chest, abdomen, and pelvis for staging. Median follow-up period was 35 months.
The SUVmax and MTD cut-off values were 11.0 and 7.5 cm, respectively. SUVmax≥11.0 predicted a short progression free survival (PFS, P=0.002) and overall survival (OS, P=0.002). MTD≥7.5 cm was associated with poor PFS (P=0.003) and OS (P=0.003). High International Prognostic Index (IPI) was also associated with the survival outcome (PFS, P=0.046; OS, P=0.030). Multivariate analysis revealed that SUVmax≥11.0 (PFS, hazard ratio [HR]=10.813, P=0.024; OS, HR=6.312, P=0.015); MTD≥7.5 cm (PFS, HR=5.631, P=0.008; OS, HR=4.072, P=0.008); and high IPI (PFS, P=0.027; OS, P=0.046) were independent prognostic factors.
It appears that both MTD and SUVmax can be independent prognostic factors in primary extranodal DLBCL.
PMCID: PMC3464338  PMID: 23071476
Lymphoma; Large B-cell; Extranodal
14.  Evaluation of an Experimentally Designed Stereotactic Guidance System for Determining Needle Entry Point during Uniplanar Fluoroscopy-guided Intervention 
The Korean Journal of Pain  2012;25(2):81-88.
In discography performed during percutaneous endoscopic lumbar discectomy (PELD) via the posterolateral approach, it is difficult to create a fluoroscopic tunnel view because a long needle is required for discography and the guide-wire used for consecutive PELD interrupts rotation of fluoroscope. A stereotactic system was designed to facilitate the determination of the needle entry point, and the feasibility of this system was evaluated during interventional spine procedures.
A newly designed stereotactic guidance system underwent a field test application for PELD. Sixty patients who underwent single-level PELD at L4-L5 were randomly divided into conventional or stereotactic groups. PELD was performed via the posterolateral approach using the entry point on the skin determined by premeasured distance from the midline and angles according to preoperative magnetic resonance imaging (MRI) findings. Needle entry accuracy provided by the two groups was determined by comparing the distance and angle measured by postoperative computed tomography with those measured by preoperative MRI. The duration and radiation exposure for determining the entry point were measured in the groups.
The new stereotactic guidance system and the conventional method provided similarly accurate entry points for discography and consecutive PELD. However, the new stereotactic guidance system lowered the duration and radiation exposure for determining the entry point.
The new stereotactic guidance system under fluoroscopy provided a reliable needle entry point for discography and consecutive PELD. Furthermore, it reduced the duration and radiation exposure associated with determining needle entry.
PMCID: PMC3324745  PMID: 22514774
equipment design; fluoroscopy; needle; percutaneous discectomy; stereotactic technique
15.  The changes of mitochondrial cytochrome c and GABAergic neuron in neuropathic pain model 
Korean Journal of Anesthesiology  2012;62(4):365-370.
Role of cytochrome c (Cyt c) is an apoptogenic agent under certain conditions. The mitochondrial permeability transition pore (MPTP) plays an important role in cell death since it opens, leading to mitochondrial swelling and release of Cyt c, which initiates apoptosis. By inhibiting the opening of MPTP, cyclosporine A (CSA) may contribute to maintaining mitochondrial homeostasis. We investigate the effects of the partial sciatic nerve injury (PSNI)-induced neuropathic pain model on mitochondrial Cyt c release and the effects of CSA on neuroprotection by mitochondrial stabilizing activity in PSNI rats.
Rats were assigned to two groups that received different operations (Group P; PSNI operation, Group S; sham operation). The changes of cyt c and GABAergic neuron were evaluated in the spinal cord tissue. After which, PSNI rats randomly received CSA (Group C) or saline (Group S), and the changes of mechanical thresholds with Cyt c and GABAergic neuron were checked.
PSNI in rats increased the release of cytosolic Cyt c. However, GABAergic cells were not decreased in the spinal cord level on the ipsilateral side to the PSNI. The second experiment reveal a reduction in Cyt c release, using CSA in PSNI model. Rats receiving CSA were afforded the antiallodynia without decrease of GABAergic cell.
The Cyt c probably contributes to nerve dysfunction after PSNI. PSNI induced neuropathic pain was profoundly linked to mitochondrial stabilization. Thus, the potent neuroprotector, CSA, might produce antiallodynia through its capability to inhibit the opening of MPTP.
PMCID: PMC3337384  PMID: 22558504
Allodynia; Cyclosporine A; Cytochrome c; Mitochondrial permeability transition pore; Neuropathic pain
16.  Severe airway obstruction in an infant with congenital tracheal stenosis and congenital heart disease -A case report- 
Korean Journal of Anesthesiology  2012;62(3):285-288.
Congenital tracheal stenosis (CTS), though rare, is important because the mortality and morbidity rates are high in infants. Especially, associated congenital heart disease (CHD) in these infants may compound the effects of airway pathology. A 3-week-old patient with long-segmental tracheal stenosis below an anomalous right-upper lobe (RUL) bronchus had undergone a total correction of double outlet right ventricle. On third postoperative day, hypercarbia developed, and severe airway obstruction and atelectasis were detected. An emergency slide tracheoplasty was performed under cardiopulmonary bypass (CPB). The patient recovered well after the surgery. Thus, special attention needs to be paid during the postoperative intensive care of patients with congenital tracheal anomalies. Early detection and prompt diagnosis of airway obstruction can help reduce the morbidity and mortality rates. Further, it is important to select the suitable treatment of CTS associated with CHD.
PMCID: PMC3315662  PMID: 22474559
Airway obstruction; Congenital; Heart disease; Tracheal stenosis
17.  The Effects of Glyburide on Apoptosis and Endoplasmic Reticulum Stress in INS-1 Cells in a Glucolipotoxic Condition 
Diabetes & Metabolism Journal  2011;35(5):480-488.
β-cell death due to endoplasmic reticulum (ER) stress has been regarded as an important pathogenic component of type 2 diabetes. The possibility has been suggested that sulfonylurea, currently being used as one of the main oral hypoglycemic agents of type 2 diabetes, increases ER stress, which could lead to sulfonylurea failure. The authors of the present study examined ER stress of β-cells in a glucolipotoxic condition using glyburide (GB) in an environment mimicking type 2 diabetes.
Apoptosis was induced by adding various concentrations of GB (0.001 to 200 µM) to a glucolipotoxic condition using 33 mM glucose, and the effects of varied concentrations of palmitate were evaluated via annexin V staining. The markers of ER stress and pro-apoptotic markers were assessed by Western blotting and semi-quantitative reverse transcription-polymerase chain reaction. Additionally, the anti-apoptotic markers were evaluated.
Addition of any concentration of GB in 150 µM palmitate and 33 mM glucose did not increase apoptosis. The expression of phosphorylated eukaryotic initiation factor (eIF-2α) was increased and cleaved caspase 3 was decreased by adding GB to a glucolipotoxic condition. However, other ER stress-associated markers such as Bip-1, X-box binding protein-1, ATF-4 and C/EBP-homologous protein transcription factor and anti-apoptotic markers phosphor-p85 phosphatidylinositol 3-kinase and phosphorylation of Akt did not change significantly.
GB did not show further deleterious effects on the degree of apoptosis or ER stress of INS-1 cells in a glucolipotoxic condition. Increased phosphorylation of eIF-2α may attenuate ER stress for adaptation to increased ER protein load.
PMCID: PMC3221023  PMID: 22111039
Apoptosis; Endoplasmic reticulum stress; Glyburide; Insulin-secreting cells
18.  The effects of sevoflurane and propofol anesthesia on cerebral oxygenation in gynecological laparoscopic surgery 
Korean Journal of Anesthesiology  2011;61(3):225-232.
Both the Trendelenburg position and pneumoperitoneum with carbon dioxide have been reported to increase intracranial pressure (ICP) and to alter cerebral blood flow or cerebral blood volume. Also anesthetic agents have variable effects on cerebral hemodynamics and ICP. The present study was conducted to determine whether regional cerebral oxygen saturation (rSO2) values differ between propofol and sevoflurane anesthesia during laparoscopic surgery in the Trendelenburg position.
Thirty-two adult women undergoing gynecological laparoscopic surgery were divided into sevoflurane and propofol groups. rSO2 values were recorded at 10 min after induction in the neutral position (Tpre), 10 min after the pneumoperitoneum in the Trendelenburg position (Tpt) and 10 min after desufflation in the neutral position (Tpost). For analysis of rSO2, we did ANOVA and univariate two-way ANCOVA with covariates being mean arterial pressure and end tidal carbon dioxide tension.
Between sevoflurane and propofol groups, the change in rSO2 was significantly different even after ANCOVA. rSO2 at Tpt (76.3 ± 5.9% in sevoflurane vs 69.4 ± 5.8% in propofol) and Tpost (69.5 ± 7.1% in sevoflurane vs 63.8 ± 6.6% in propofol) were significantly higher in the sevoflurane group compared with the propofol group. In the propofol group, rSO2 at Tpost was significantly lower than at Tpre (71.1 ± 4.8%) and cerebral oxygen desaturation occurred in two patients (14.3%).
Significantly lower rSO2 values were observed in the propofol group during gynecological laparoscopic surgery. The possibility of cerebral oxygen desaturation should not be overlooked during propofol anesthesia even after desufflation of the abdomen in the neutral position.
PMCID: PMC3198184  PMID: 22025945
Cerebral hypoxia; Head-down tilt; Near-infrared spectroscopy; Pneumoperitoneum; Propofol; Sevoflurane
19.  Subcutaneous versus Intraarticular Indwelling Closed Suction Drainage after TKA: A Randomized Controlled Trial 
TKA can involve substantial bleeding, and the issue regarding whether vacuum drainage should be used during TKA continues to be debated as both methods have disadvantages.
We therefore asked whether subcutaneous indwelling vacuum drainage is advantageous over intraarticular indwelling vacuum drainage in terms of blood drainage, bleeding-related complications, and functional outcomes in primary TKA.
Patients and methods
We randomized 111 patients undergoing TKAs to have either a subcutaneous indwelling or an intraarticular indwelling catheter and compared the two groups for blood loss (hemoglobin decrease, transfusion requirements, hypotension episode), incidence of wound problems (requirements for dressing reinforcement, oozing, hematoma, hemarthrosis, ecchymosis, infection), and functional outcomes (recovery of motion arc, American Knee Society, WOMAC, and SF-36 scores) at 12 months after surgery.
The mean vacuum drainage volume was less in the subcutaneous indwelling group than in the intraarticular indwelling group (140 mL versus 352 mL). The groups were similar in terms of decreases in hemoglobin after 2 and 5 days (3.0 versus 3.3 g/dL and 3.3 versus 3.7 g/dL, respectively), allogenic transfusion requirements (4% versus 11%), incidence of wound problems, and functional scores.
The data suggest subcutaneous indwelling closed-suction drainage is a reasonable alternative to intraarticular indwelling closed-suction drainage and to no suction drainage.
Level of Evidence
Level I, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.
PMCID: PMC2895852  PMID: 20127212
20.  The proper effect site concentration of remifentanil for prevention of myoclonus after etomidate injection 
Korean Journal of Anesthesiology  2011;61(2):127-132.
Etomidate frequently induces myoclonus when administered intravenously with bolus injection during anesthetic induction. This can be bothersome for the anesthesiologist. The dose of remifentanil appropriate for preventing myoclonus without side effects was investigated.
All patients with American Society of Anesthesiologists (ASA) physical status I-III were divided into three groups (n = 33 per group) according to the pretreatment effect site concentration of remifentanil (Ultiva, Glaxo-Wellcome, München, Germany) of 0, 2 or 4 ng/ml (Group N: 0 ng/ml, Group R: 2 ng/ml, Group Q: 4 ng/ml) by a target controlled infusion (TCI) system. After a 0.3 mg/kg dose of etomidate was injected intravenously for over 1 minute for anesthetic induction, myoclonus was observed. Before the etomidate injection, the patients were pretreated with remifentanil and their side effects were monitored.
The number of patients showing myoclonus was significantly different among the groups. The incidence of myoclonus was 81%, 12% and 0% (groups N, R, and Q, respectively, P < 0.01). Side effects including bradycardia and hypotension did not occur in either Group R or Q. Chest wall rigidity occured in 45% of patients in Group Q.
Administration with a 2 ng/ml effect site concentration of remifentanil could reduce the incidence of myoclonus caused by etomidate bolus injection without chest wall rigidity.
PMCID: PMC3167131  PMID: 21927682
Etomidate; Myoclonus; Remifentanil
21.  Gender Differences in the Correlation between Symptom and Radiographic Severity in Patients with Knee Osteoarthritis 
The effects of gender on the relationship between symptom manifestations and radiographic grades of knee osteoarthritis are not well understood.
We therefore determined the increments of symptom progression with regard to radiographic grades of knee osteoarthritis and asked if those increments differed by gender and whether symptom severity was differentially manifested by gender within the same grade.
We recruited 660 community residents; 368 (56%) women and 292 (44%) men. The mean subject age was 71.5 years (range, 65–91 years). Severity of symptoms was measured using the WOMAC and SF-36 scales, and the radiographic severity using Kellgren–Lawrence grades. Incremental changes in WOMAC and SF-36 scores were compared between adjacent Kellgren–Lawrence grades separately in men and women, and in the overall population. We compared symptom severity between men and women with the same radiographic grade.
For the entire cohort, the mean incremental change in symptom severity was not gradual between the adjacent radiographic grades but was greater between Kellgren–Lawrence Grades 1 and 2 and Grades 2 and 3 than between Grades 0 and 1 or Grades 3 and 4. The patterns of incremental changes in symptom severity differed between men and women: women had more severe symptom progression between Kellgren–Lawrence Grades 2 and 3 and Grades 3 and 4 than men. Furthermore, women had worse mean WOMAC and SF-36 scores than men with the same radiographic grade of knee osteoarthritis.
These data suggest symptom progression is not gradual between adjacent radiographic grades, and for the same radiographic grade, symptoms are worse in women.
Level of Evidence
Level III, diagnostic study. See Guidelines for Authors for a complete description of levels of evidence.
PMCID: PMC2881984  PMID: 20204559
22.  Animal Models of Periventricular Leukomalacia 
Laboratory Animal Research  2011;27(2):77-84.
Periventricular leukomalacia, specifically characterized as white matter injury, in neonates is strongly associated with the damage of pre-myelinating oligodendrocytes. Clinical data suggest that hypoxia-ischemia during delivery and intrauterine or neonatal infection-inflammation are important factors in the etiology of periventricular leukomalacia including cerebral palsy, a serious case exhibiting neurobehavioral deficits of periventricular leukomalacia. In order to explore the pathophysiological mechanisms of white matter injury and to better understand how infectious agents may affect the vulnerability of the immature brain to injury, novel animal models have been developed using hypoperfusion, microbes or bacterial products (lipopolysaccharide) and excitotoxins. Such efforts have developed rat models that produce predominantly white matter lesions by adopting combined hypoxia-ischemia technique on postnatal days 1-7, in which unilateral or bilateral carotid arteries of animals are occluded (ischemia) followed by 1-2 hour exposure to 6-8% oxygen environment (hypoxia). Furthermore, low doses of lipopolysaccharide that by themselves have no adverse-effects in 7-day-old rats, dramatically increase brain injury to hypoxic-ischemic challenge, implying that inflammation sensitizes the immature central nervous system. Therefore, among numerous models of periventricular leukomalacia, combination of hypoxia-ischemia-lipopolysaccharide might be one of the most-acceptable rodent models to induce extensive white matter injury and ensuing neurobehavioral deficits for the evaluation of candidate therapeutics.
PMCID: PMC3145996  PMID: 21826166
Periventricular leukomalacia; white matter injury; cerebral palsy; hypoperfusion (hypoxia-ischemia); inflammation (lipopolysaccharide); premyelinating oligodendrocytes
23.  Different Antiulcer Activities of Pantoprazole in Stress, Alcohol and Pylorus Ligation-Induced Ulcer Models 
Laboratory Animal Research  2011;27(1):47-52.
Antiulcer effects of pantoprazole, a proton-pump inhibitor, on water-immersion restraint stress (WIRS)-, alcohol (ethanol)- and pylorus ligation-induced gastric ulcers were investigated in male rats. Rats were orally administered with pantoprazole 30 min prior to exposure to various types of ulcer inducers. In stress-induced ulcer model, rats were subjected to WIRS at 22℃ for 4 hours, and the degree of ulcer (in mm) was evaluated. In alcohol-induced ulcer model, rats were orally administered with pure (100%) ethanol (1 mL/kg), and the ulcer lesions were measured 1 hour after ethanol challenge. In pylorus ligation-induced ulcer model, rats were subjected to pylorus ligation, and the degree of erosions and ulcers was scored 17 hours after the operation. Pantoprazole attenuated the ulcer lesions induced by WIRS in a dose-dependent manner, exhibiting a median effective dose (ED50) value of 0.78 mg/kg. By comparison, pantoprazole was effective at relatively-high doses for the improvement of ethanol-induced ulcers, showing an ED50 value of 20.5 mg/kg. Notably, pantoprazole was practically ineffective (ED50>50.0) in pylorus ligation model. Taken together, it was confirmed that pantoprazole showed inhibitory activity on gastric ulcers induced by stress and alcohol, but was ineffective on pylorus ligation-induced ulcer. Therefore, the results indicate that proton-pump inhibitors including pantoprazole might reveal highly-different effects according to the type of ulcer inducers, and that the prescription of antiulcer agents should be carefully selected.
PMCID: PMC3145982  PMID: 21826160
Pantoprazole; gastric ulcer; stress; alcohol; pylorus ligation
24.  Increased Nephrotoxicity after Combined Administration of Melamine and Cyanuric Acid in Rats 
Laboratory Animal Research  2011;27(1):25-28.
Renal toxicity by melamine in combination with cyanuric acid (1:1) was investigated. Male rats were orally administered melamine plus cyanuric acid (5, 50 or 400 mg/kg each) for 3 days. In contrast to a negligible effect by melamine alone (50 mg/kg, a no-observed-adverse-effect-level: NOAEL), co-administration with cyanuric acid markedly increased the concentrations of blood urea nitrogen and creatinine, as well as kidney weight. A high dose (400 mg/kg) of melamine plus cyanuric acid induced more severe kidney toxicity. The increased blood parameters for kidney toxicity and organ weight lasted longer than 4 days. Combined treatment with melamine and cyanuric acid (50-400 mg/kg each) resulted in many gold-brown crystals and toxic lesions in renal tubules, which were not observed in animals treated with melamine alone (50 mg/kg). These results indicate that only a 3-day exposure to melamine in combination with cyanuric acid causes severe renal damage, even at a NOAEL for melamine found in a 13-week toxicity study. Therefore, it is suggested that the tolerable daily intake or regulatory/management levels of melamine need to be re-considered for cases of co-exposure with cyanuric acid.
PMCID: PMC3145992  PMID: 21826156
Melamine; cyanuric acid; nephrotoxicity; renal crystal
25.  Adiponectin is a potential catabolic mediator in osteoarthritis cartilage 
Arthritis Research & Therapy  2010;12(6):R231.
Adiponectin has been implicated in the pathogenesis of osteoarthritis (OA). We studied the effects of adiponectin on the OA cartilage homeostasis.
Immunohistochemical analysis was performed to evaluate differential expression of adiponectin receptors (AdipoRs) in nonlesional and lesional areas of OA cartilage. Cartilage and chondrocytes from the knee joints of primary OA patients were cultured in the presence of adiponectin (0~30 μg/ml). The levels of total nitric oxide (NO), matrix metalloproteinase (MMP)-1, -3, and -13, and tissue inhibitor of metalloproteinase (TIMP)-1 were measured in the conditioned media. The levels of inducible NO synthase (iNOS) and MMPs were determined with the quantitative real-time reverse transcription-polymerase chain reaction. The concentrations of collagenase-cleaved type II collagen neoepitope (C1-2C) were determined in the supernatant of adiponectin-stimulated OA cartilage explants. The effects of kinase and NOS inhibitors were evaluated in the adiponectin-stimulated chondrocytes.
The expression levels of both AdipoR1 and AdipoR2 were significantly higher in lesional than in nonlesional areas of OA cartilage. The increased rate of AdipoR1-positive chondrocytes was twice that of AdipoR2-positive chondrocytes when compared between nonlesional and lesional areas. Adiponectin-stimulated OA chondrocytes showed increased total NO and MMP-1, -3, and -13 levels compared with nonstimulated cells. The TIMP-1 level was not affected. The C1-2C levels were increased by adiponectin in OA cartilage explant culture. AMP-activated protein kinase (AMPK) and c-Jun N-terminal kinase (JNK) inhibitors (compound C and SP600125) significantly suppressed adiponectin-induced production of total NO and MMP-1, -3, and -13. Inducible NOS inhibitors enhanced the expression of the adiponectin-induced MMPs.
Adiponectin causes matrix degradation in OA cartilage and increases MMPs and iNOS expression via the AMPK and JNK pathways in human OA chondrocytes. The catabolic effects of adiponectin may be counteracted by NO.
PMCID: PMC3046544  PMID: 21194467

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