Functional Characterization of Pharmcogenetic Variants of Human Cytochrome P450 2C9 in Korean Populations

Human cytochrome P450 2C9 is a highly polymorphic enzyme that is required for drug and xenobiotic metabolism. Here, we studied eleven P450 2C9 genetic variants—including three novel variants F69S, L310V, and Q324X—that were clinically identified in Korean patients. P450 2C9 variant enzymes were expressed in Escherichia coli and their bicistronic membrane fractions were prepared The CO-binding spectra were obtained for nine enzyme variants, indicating P450 holoenzymes, but not for the M02 (L90P) variant. The M11 (Q324X) variant could not be expressed due to an early nonsense mutation. LC-MS/MS analysis was performed to measure the catalytic activities of the P450 2C9 variants, using diclofenac as a substrate. Steady-state kinetic analysis revealed that the catalytic efficiency of all nine P450 2C9 variants was lower than that of the wild type P450 2C9 enzyme. The M05 (R150L) and M06 (P279T) variants showed high k(cat) values; however, their K(m) values were also high. As the M01 (F69S), M03 (R124Q), M04 (R125H), M08 (I359L), M09 (I359T), and M10 (A477T) variants exhibited higher K(m) and lower k(cat) values than that of the wild type enzyme, their catalytic efficiency decreased by approximately 50-fold compared to the wild type enzyme. Furthermore, the novel variant M07 (L310V) showed lower k(cat) and K(m) values than the wild type enzyme, which resulted in its decreased (80%) catalytic efficiency. The X-ray crystal structure of P450 2C9 revealed the presence of mutations in the residues surrounding the substrate-binding cavity. Functional characterization of these genetic variants can help understand the pharmacogenetic outcomes.

Adipogenic and Lipolytic Effects of Ascorbic Acid in Ovariectomized Rats

PURPOSE: Ascorbic acid has been reported to have an adipogenic effect on 3T3-L1 preadipocytes, while evidence also suggests that ascorbic acid reduces body weight in humans. In this study, we tested the effects of ascorbic acid on adipogenesis and the balance of lipid accumulation in ovariectomized rats, in addition to long-term culture of differentiated 3T3-L1 adipocytes. MATERIALS AND METHODS: Murine 3T3-L1 fibroblasts and ovariectomized rats were treated with ascorbic acid at various time points. In vitro adipogenesis was analyzed by Oil Red O staining, and in vivo body fat was measured by a body composition analyzer using nuclear magnetic resonance. RESULTS: When ascorbic acid was applied during an early time point in 3T3-L1 preadipocyte differentiation and after bilateral ovariectomy (OVX) in rats, adipogenesis and fat mass gain significantly increased, respectively. However, lipid accumulation in well-differentiated 3T3-L1 adipocytes showed a significant reduction when ascorbic acid was applied after differentiation (10 days after induction). Also, oral ascorbic acid administration 4 weeks after OVX in rats significantly reduced both body weight and subcutaneous fat layer. In comparison to the results of ascorbic acid, which is a well-known cofactor for an enzyme of collagen synthesis, and the antioxidant ramalin, a potent antioxidant but not a cofactor, showed only a lipolytic effect in well-differentiated 3T3-L1 adipocytes, not an adipogenic effect. CONCLUSION: Taking these results into account, we concluded that ascorbic acid has both an adipogenic effect as a cofactor of an enzymatic process and a lipolytic effect as an antioxidant.

Effects of a Mindfulness-Based Mind-Body Intervention Program using Marine Resources on the Improvement of Sleep Quality and Mood Symptoms in Korean Female Emotional Labor Workers : A Pilot Study / 수면정신생리

OBJECTIVES: The purpose of this pilot study was to examine the effects of a mindfulness-based Body-Mind Intervention Program using marine resources on the improvement of quality of sleep, mood symptoms, and cognitive function in Korean female emotional labor workers. METHODS: Twelve female workers who experienced excess emotional labor participated at the training camp program for five days in Danghangpo-ocean park, Goseung-gun, Gyeongnam Province in South Korea. Participant sleep quality, mood symptoms, and cognitive functioning before, after, and 1.5 months later were evaluated and analyzed. RESULTS: After participating in the marine resource program, participants reported significantly decreased sleep latency. Global sleep quality, cognitive functions (attention, flexibility, and inhibition control), and mood states, including depression, tension, anger, fatigue, were also improved. These effects were generally maintained after 1. 5 months (PSQI t = 2.63, p = 0.02 ; HAM-D t = 5.92, p < 0.001). CONCLUSION: A Body-Mind Intervention Program using marine resources was effective in relaxing emotion-related tension and improving cognitive function. To advance this pilot study, it is necessary to carry out further research to investigate the use of marine resources in mental health interventions.

Prognostic Scoring Index for Patients with Metastatic Pancreatic Adenocarcinoma / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: This study focused on implementation of a prognostic scoring index based on clinico-laboratory parameters measured routinely on admission in metastatic pancreatic cancer patients. MATERIALS AND METHODS: Records from 403 patients of metastatic disease were analyzed retrospectively. Continuous variables were dichotomized according to the normal range or the best cut-off values statistically determined by Contal and O’Quigley method, and then analyzed in association with prognosis—overall survival (OS), using Cox's proportional hazard model. Scores were calculated by summing the rounded chi-square scores for the factors that emerged in the multivariate analysis. RESULTS: Performance status, hemoglobin, leucocyte count, neutrophil-lymphocyte ratio, and carcinoembryonic antigen were independent factors for OS. When patients were divided into three risk groups according to these factors, median survival was 11.7, 6.2, and 1.3 months for the low, intermediate, and high-risk groups, respectively (p < 0.001). Palliative chemotherapy has a significant survival benefit for low and intermediate-risk patients (median OS; 12.5 months vs. 5.9 months, p < 0.001 and 8.0 months vs. 2.0 months, p < 0.001, respectively). CONCLUSION: We advocate the use of a multivariable approach with continuous variables for prognostic modeling. Our index is helpful in accurate patient risk stratification and may aid in treatment selection.

Clinical and Pathological Heterogeneity of Korean Patients with CAPN3 Mutations

PURPOSE: This study was designed to investigate the characteristics of Korean patients with calpainopathy. MATERIALS AND METHODS: Thirteen patients from ten unrelated families were diagnosed with calpainopathy via direct or targeted sequencing of the CAPN3 gene. Clinical, mutational, and pathological spectra were then analyzed. RESULTS: Nine different mutations, including four novel mutations (NM_000070: c.1524+1G>T, c.1789_1790inA, c.2184+1G>T, and c.2384C>T) were identified. The median age at symptom onset was 22 (interquartile range: 15-28). Common clinical findings were joint contracture in nine patients, winged scapula in four, and lordosis in one. However, we also found highly variable clinical features including early onset joint contractures, asymptomatic hyperCKemia, and heterogeneous clinical severity in three members of the same family. Four of nine muscle specimens revealed lobulated fibers, but three showed normal skeletal muscle histology. CONCLUSION: We identified four novel CAPN3 mutations and demonstrated clinical and pathological heterogeneity in Korean patients with calpainopathy.

Non-syndromic hearing loss caused by the dominant cis mutation R75Q with the recessive mutation V37I of the GJB2 (Connexin 26) gene

GJB2 alleles containing two cis mutations have been rarely found in non-syndromic hearing loss. Herein, we present a Korean patient with non-syndromic hearing loss caused by the R75Q cis mutation with V37I, which arose de novo in the father and was inherited by the patient. Biochemical coupling and hemichannel permeability assays were performed after molecular cloning and transfection of HEK293T cells. Student's t-tests or analysis of variance followed by Tukey's multiple comparison test was used as statistical analysis. Biochemical coupling was significantly reduced in connexin 26 (Cx26)-R75Q- and Cx26-V37I-transfected cells, with greater extent in Cx26-R75Q and Cx26-R75Q+V37I cells. Interestingly, our patient and his father with the mutations had more residual hearing compared with patients with the dominant mutation alone. Although the difference in hemichannel activity between R75Q alone and R75Q in combination with V37I failed to reach significance, it is of note that there is a possibility that V37I located upstream of R75Q might have the ability to ameliorate R75Q expression. Our study emphasizes the importance of cis mutations with R75Q, as the gene effect of R75Q can be modulated depending on the type of additional mutation.

A Patient with Repeated Catastrophic Multi-Vessel Coronary Spasm after Zotarolimus-Eluting Stent Implantation

Drug-eluting stents (DES) have gained great popularity because of extraordinarily low rates of restenosis. Despite these superior clinical outcomes, several cases regarding the severe multi-vessel coronary spasm, although rare, after the placement of first generation DES have been reported. We report a case of severe, multi-vessel coronary spasm that occurred two occasions after placement of a zotarolimus-eluting stent, one of the second generation DES, in a 42-year-old man with unstable angina. The first incidence was relieved by intracoronary nitroglycerin alone, and second incident, which had combined fixed stenosis was treated with intracoronary nitroglycerin and everolimus-eluting stent.

Genetic Variations of ABCC2 Gene Associated with Adverse Drug Reactions to Valproic Acid in Korean Epileptic Patients

The multidrug resistance protein 2 (MRP2, ABCC2) gene may determine individual susceptibility to adverse drug reactions (ADRs) in the central nervous system (CNS) by limiting brain access of antiepileptic drugs, especially valproic acid (VPA). Our objective was to investigate the effect of ABCC2 polymorphisms on ADRs caused by VPA in Korean epileptic patients. We examined the association of ABCC2 single-nucleotide polymorphisms and haplotype frequencies with VPA related to adverse reactions. In addition, the association of the polymorphisms with the risk of VPA related to adverse reactions was estimated by logistic regression analysis. A total of 41 (24.4%) patients had shown VPA-related adverse reactions in CNS, and the most frequent symptom was tremor (78.0%). The patients with CNS ADRs were more likely to have the G allele (79.3% vs. 62.7%, p = 0.0057) and the GG genotype (61.0% vs. 39.7%, p = 0.019) at the g.-1774delG locus. The frequency of the haplotype containing g.-1774Gdel was significantly lower in the patients with CNS ADRs than without CNS ADRs (15.8% vs. 32.3%, p = 0.0039). Lastly, in the multivariate logistic regression analysis, the presence of the GG genotype at the g.-1774delG locus was identified as a stronger risk factor for VPA related to ADRs (odds ratio, 8.53; 95% confidence interval, 1.04 to 70.17). We demonstrated that ABCC2 polymorphisms may influence VPA-related ADRs. The results above suggest the possible usefulness of ABCC2 gene polymorphisms as a marker for predicting response to VPA-related ADRs.

Is Myocardial Infarction in Patients without Significant Stenosis on a Coronary Angiogram as Benign as Believed? / 전남의대학술지

The present study aimed to investigate the clinical characteristics and 1-year outcomes of acute myocardial infarction (AMI) patients without significant stenosis on a coronary angiogram comparison with the clinical characteristics and outcomes of patients with significant coronary artery stenosis. A total of 1,220 patients with AMI were retrospectively classified into Group I (> or =50% diameter stenosis, n=1,120) and Group II (<50%, n=100). Group II was further divided into two subgroups according to the underlying etiology: cryptogenic (Group II-a, n=54) and those with possible causative factors (Group II-b, n=46). Patients in Group II were younger, were more likely to be women, and were less likely to smoke and to have diabetes mellitus than were patients in Group I. The levels of cardiac enzymes, LDL-cholesterol levels, and the apo-B/A1 ratio were lower in Group II. However, 1-month and 12-month rates of major adverse cardiac events (MACE) were not significantly different between the two groups. The Group II-b subgroup comprised 29 patients with vasospasm, 11 with myocardial bridge, and 6 with spontaneous thrombolysis. Left ventricular ejection fraction and creatinine clearance were lower and levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) and high-sensitivity C-reactive protein (hs-CRP) were higher in Group II-a than in Group II-b. However, outcomes including MACE and mortality at 12 months were not significantly different between the two subgroups. The 1-year outcomes of patients in Group II were similar to those of patients in Group I. The clinical outcomes in Group II-a were also similar to those of Group II-b, although the former group showed higher levels of NT-proBNP and hs-CRP.

Recurrent Stent Thrombosis and Pulmonary Thromboembolism Associated with Hyperhomocysteinemia

Stent thrombosis is a fatal complication that can cause sudden cardiac death in patients implanted coronary stent. Also, pulmonary thromboembolism is associated with increased mortality. Usually, these vascular thromboembolic diseases did not occured simultaneously. If this circumstance develops, possible mechanisms and causes should be described. Here, we report a case of patient underwent percutaneous coronary intervention under diagnosis of ST-segment elevation myocardial infarction with recurrent stent thrombosis and pulmonary thromboembolism associated with hyperhomocysteinemia despite optimal medical therapy.

A Rapid Improvement of Heart Failure after Treatment of Hyperthyroidism

BACKGROUND: Heart failure is a rare condition of thyrotoxicosis. We report a case of thyrotoxicosis-inducing heart failure. CASE REPORT: A 29-year old female had been suffered from thyrotoxicosis for 3 years without proper medication. She complained progressive dyspnea and palpitation with atrial fibrillation with rapid ventricular response. Marked cardiomegaly, and severe right ventricular dysfunction with biatrial enlargements were found on Two-dimensional (2D) echocardiography. We treated her with medications for heart failure and thyrotoxicosis, and the patient's symptoms and objective cardiac functions are improved after two weeks. CONCLUSION: Severe heart failure caused by thyrotoxicosis could be reversible with proper management. Patients who have thyrotoxicosis should be assessed closely, and suitable treatment can markedly improve the patient's prognosis.

Comparison of Drug-Eluting Stents in Acute Myocardial Infarction Patients with Chronic Kidney Disease

BACKGROUND/AIMS: To determine which drug-eluting stents are more effective in acute myocardial infarction (MI) patients with chronic kidney disease (CKD). METHODS: This study included a total of 3,566 acute MI survivors with CKD from the Korea Acute Myocardial Infarction Registry who were treated with stenting and followed up for 12 months: 1,845 patients who received sirolimus-eluting stents (SES), 1,356 who received paclitaxel-eluting stents (PES), and 365 who received zotarolimus-eluting stents (ZES). CKD was defined as an estimated glomerular filtration rate < 60 mL/min/1.73 m2 calculated by the modification of diet in renal disease method. RESULTS: At the 12-month follow-up, patients receiving ZES demonstrated a higher incidence (14.8%) of major adverse cardiac events (MACEs) compared to those receiving SES (10.1%) and PES (12%, p = 0.019). The ZES patients also had a higher incidence (3.9%) of target lesion revascularization (TLR) compared to those receiving SES (1.5%) and PES (2.4%, p = 0.011). After adjusting for confounding factors, ZES was associated with a higher incidence of MACE and TLR than SES (adjusted hazard ratio [HR], 0.623; 95% confidence interval [CI], 0.442 to 0.879; p = 0.007; adjusted HR, 0.350; 95% CI, 0.165 to 0.743; p = 0.006, respectively), and with a higher rate of TLR than PES (adjusted HR, 0.471; 95% CI, 0.223 to 0.997; p = 0.049). CONCLUSIONS: Our findings suggest that ZES is less effective than SES and PES in terms of 12-month TLR, and has a higher incidence of MACE due to a higher TLR rate compared with SES, in acute MI patients with CKD.

Successful Primary Percutaneous Coronary Intervention for Acute Myocardial Infarction in a Patient with Dextrocardia and Hypertrophic Cardiomyopathy

We report a case of a 69-year-old man presenting with acute right chest pain radiating to the right shoulder. Physical examination revealed a right sided apex beat with a palpable liver on the left side. Reversed normalizing electrocardiogram are presented, allowing for correct diagnosis of an acute anterior myocardial infarction. Dextrocardia with situs inversus is an uncommon congenital condition, the patient also diagnosed hypertrophic cardiomyopathy by two dimensional echocardiography. Successful percutaneous coronary intervention was performed and the patient was discharged after uneventful recovery.

Relation between Anemia and Vulnerable Coronary Plaque Components in Patients with Acute Coronary Syndrome: Virtual Histology-Intravascular Ultrasound Analysis

The aim of the present study was to evaluate the plaque components and the predictors of thin-cap fibroatheroma (TCFA) in anemic patients with acute coronary syndrome using virtual histology-intravascular ultrasound (VH-IVUS). Anemia was defined according to criteria of the World Health Organization, (i.e. , hemoglobin levels < 13 g/dL in men and < 12 g/dL in women) and we compared VH-IVUS findings between anemia group (171 patients, 260 lesions) and non-anemia group (569 patients, 881 lesions). Anemia group had greater % necrotic core (NC) volume (21% +/- 9% vs 19% +/- 9%, P = 0.001) compared with non-anemia group. Hemoglobin level correlated negatively with absolute NC volume (r = -0.235, P < 0.001) and %NC volume (r = -0.209, P < 0.001). Independent predictors of TCFA by multivariate analysis were diabetes mellitus (odds ratio [OR], 2.213; 95% confidence interval [CI], 1.403-3.612, P = 0.006), high-sensitivity C-reactive protein (OR, 1.143; 95% CI, 1.058-1.304, P = 0.012), microalbuminuria (albumin levels of 30 to 300 mg/g of creatinine) (OR, 2.124; 95% CI, 1.041-3.214, P = 0.018), and anemia (OR: 2.112; 95% CI 1.022-3.208, P = 0.028). VH-IVUS analysis demonstrates that anemia at the time of clinical presentation is associated with vulnerable plaque component in patients with acute coronary syndrome.

Low Density Lipoprotein-Cholesterol/High Density Lipoprotein-Cholesterol Ratio Predicts Plaque Vulnerability in Patients With Stable Angina

BACKGROUND AND OBJECTIVES: The relationship between lipid profile and coronary plaque tissue characteristics in patients with stable angina pectoris (SAP) is unclear. The aim of this study was to evaluate the relationship between tissue characteristics and lipid profile and predictors of unstable plaques (UPs) in patients with SAP by virtual histology intravascular ultrasonography (VH-IVUS). SUBJECTS AND METHODS: VH-IVUS was performed for target lesions in patients with SAP (61.7+/-9.2 years, 174 males, n=266) at the time of coronary angiography. UPs are characterized by thin-cap fibroatheroma, ruptured plaque, or remaining thrombus with VH-IVUS. RESULTS: The present study showed that 34 SAP patients had UPs (61.6+/-9.2 years, 24 males, 12.8%). The percentage of plaque area in the minimum luminal area in high low density lipoprotein-cholesterol (LDL-C)/high density lipoprotein-cholesterol (HDL-C) ratio patients was significantly higher than in low LDL-C/HDL-C ratio patients (72.7+/-9.5% vs. 69.9+/-9.3%, p=0.035). An LDL-C/HDL-C ratio >2.0 was an independent predictor for UPs in SAP patients (odds ratio 5.252, 95% confidence interval 1.132-24.372, p=0.034). CONCLUSION: An elevated LDL-C/HDL-C ratio is a positive predictor for coronary plaque vulnerability in patients with SAP.

Successful Primary Percutaneous Coronary Intervention in a Patient With Acute Myocardial Infarction and Single Coronary Artery Ostium

One of the single anomalous origins of coronary artery that has rarely been reported is a congenital anomaly of coronary circulation that occurs in the left coronary artery originating from the right coronary sinus of valsalva. We report a 49-year-old male patient with non-ST segment elevated myocardial infarction that was identified to have an anomalous origin of the left coronary artery from the right coronary artery (RCA) with thrombotic total occlusion of RCA by coronary angiography and cardiac computed tomography. The patient underwent successful percutaneous coronary intervention in total occlusion of the RCA and was discharged after uneventful recovery.

Clinical Impact of Non-High Density Lipoprotein-Cholesterol and Apolipoprotein B on Clinical Outcomes in Metabolic Syndrome Patients With Acute Myocardial Infarction Undergoing Percutaneous Coronary Intervention

BACKGROUND AND OBJECTIVES: Non-high density lipoprotein-cholesterol (non-HDL-C) and apolipoprotein B (ApoB) are markers of atherosclerotic risk and predictors of cardiovascular events. The aim of this study was to evaluate clinical impact of non-HDL-C and ApoB on clinical outcomes in metabolic syndrome (MS) patients with acute myocardial infarction (AMI) undergoing percuatneous coronary intervetion. SUBJECTS AND METHODS: We analyzed 470 MS patients (64.4+/-12.0 years, 53.6% male) with AMI who were followed-up for 12-month after percutaneous coronary intervention (PCI) from December 2005 to January 2008 in a single center. These patients were divided into 2 groups based on median values of non-HDL-C and ApoB. We studied their baseline and follow-up relation with 12-month clinical outcomes, all-cause death and major adverse cardiac events (MACE). RESULTS: Mean values of baseline non-HDL-C and ApoB were 141.2+/-43.1 mg/dL and 99.3+/-29.0 mg/dL respectively. During 12-month follow-up 32 MACE (6.8%) and 12 deaths (2.5%) occurred. We observed significant correlation between non-HDL-C and ApoB. Twelve-month MACE and all-cause death after PCI showed no significant relation as non-HDL-C or ApoB levels increased. Follow-up patients (n=306, rate 65%) also did not show significant relation with clinical outcomes. Twelve-month MACE decreased as non-HDL-C and ApoB reduction rates increased. CONCLUSION: There was no significant association between higher non-HDL-C or ApoB and 12-month clinical outcomes in MS patients with AMI undergoing PCI. ApoB was found to be a better predictor of 12-month MACE than non-HDL-C based on their reduction rates.

Endovascular Stent in Traumatic Thoracic Aortic Dissection

Traumatic thoracic aortic injury is typically fatal. However, recent improvements in pre-hospital care and diagnostic modalities have resulted in an increased number of patients with traumatic aortic injury arriving alive at the hospital. Also, the morbidity and mortality associated with endovascular repair are significantly lower than with conventional open surgery in traumatic thoracic aorta injury. We experienced two cases of successful management of traumatic thoracic aortic dissection with endovascular stents caused by traffic accidents.

Successful Percutaneous Coronary Intervention in a Centenarian Patient With Acute Myocardial Infarction

Despite an increasing prevalence and burden of disease in the elderly, little is known about the management and outcomes of acute coronary syndromes in this group. We report the case of a 101-year-old female patient with a non-ST segment elevation myocardial infarction. Coronary angiography showed a total occlusion of the proximal right coronary artery (RCA), and a significant stenosis in the proximal to mid left anterior descending artery (LAD). Despite a very poor initial clinical status, a percutaneous coronary intervention was successfully performed for the total occlusion in the RCA. The LAD lesion was treated with medical therapy only, on account of the age and general condition of the patient. She was discharged after recovering to a good health status, free of chest pain or dyspnea.

Is Myocardial Infarction in Patients without Significant Stenosis on a Coronary Angiogram as Benign as Believed? / 전남의대학술지

The present study aimed to investigate the clinical characteristics and 1-year outcomes of acute myocardial infarction (AMI) patients without significant stenosis on a coronary angiogram comparison with the clinical characteristics and outcomes of patients with significant coronary artery stenosis. A total of 1,220 patients with AMI were retrospectively classified into Group I (> or =50% diameter stenosis, n=1,120) and Group II (<50%, n=100). Group II was further divided into two subgroups according to the underlying etiology: cryptogenic (Group II-a, n=54) and those with possible causative factors (Group II-b, n=46). Patients in Group II were younger, were more likely to be women, and were less likely to smoke and to have diabetes mellitus than were patients in Group I. The levels of cardiac enzymes, LDL-cholesterol levels, and the apo-B/A1 ratio were lower in Group II. However, 1-month and 12-month rates of major adverse cardiac events (MACE) were not significantly different between the two groups. The Group II-b subgroup comprised 29 patients with vasospasm, 11 with myocardial bridge, and 6 with spontaneous thrombolysis. Left ventricular ejection fraction and creatinine clearance were lower and levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) and high-sensitivity C-reactive protein (hs-CRP) were higher in Group II-a than in Group II-b. However, outcomes including MACE and mortality at 12 months were not significantly different between the two subgroups. The 1-year outcomes of patients in Group II were similar to those of patients in Group I. The clinical outcomes in Group II-a were also similar to those of Group II-b, although the former group showed higher levels of NT-proBNP and hs-CRP.