A common cause of drug hypersensitivity reactions is iodinated contrast media (ICM). ICM-induced hypersensitivity had been considered to be a non-immunological reaction, but evidence for an immunological mechanism has increased recently. Thus, we evaluated whether HLA-A, -B, and -C alleles were associated with ICM-induced hypersensitivity. In total, 126 patients who underwent contrast-enhanced computed tomography studies through outpatient clinics at a tertiary referral hospital between 2008 and 2012 were assessed. Sixty-one patients experienced ICM-induced hypersensitivity and the remainder, 65, were ICM-tolerant patients (control). ICM-induced hypersensitivity patients showed 51 with immediate, 7 with non-immediate, 3 with both or mixed type. HLA-A, -B, and -C genotyping was performed using a PCR sequence-based typing method. Four kinds of ICM were used: iopromide, iohexol, iobitridol, and iodixanol. The most used ICM among the hypersensitivity patients was iopromide. Significant difference in the frequency of HLA-B*58:01 (odds ratios [OR], 3.90; p = 0.0200, 95% confidence interval [CI], 1.16–13.07) was observed between ICM-induced immediate hypersensitivity and control. There were statistically significant differences in the frequencies of the HLA-B*38:02 (OR, 10.24; p = 0.0145; 95% CI, 1.09–96.14) and HLA-B*58:01 (OR, 3.98; p = 0.0348; 95% CI, 1.03–15.39) between iopromide-induced immediate hypersensitivity and control. The mechanism of ICM-induced hypersensitivity remains unknown, but this study showed associations, although weak, with HLA-B*58:01 alleles for ICM-induced immediate hypersensitivity and HLA-B*38:02 and HLA-B*58:01 for iopromideinduced immediate hypersensitivity as risk predictors. Further studies are needed to validate the associations in larger samples and to identify the functional mechanism behind these results.

While phosphodiesterase type 5 inhibitors have been used for erectile dysfunction with acceptable safety profile, they can induce orthostatic hypotension in patients taking antihypertensive drugs with blood pressure lowering effect. This study evaluated the hemodynamic effects of 100 mg mirodenafil in hypertensive patients taking an amlodipine. Thirteen hypertensive patients who were taking 5 or 10 mg of amlodipine once daily participated in a randomized, double-blind, placebo-controlled, crossover study. A single oral dose of mirodenafil 100 mg or placebo was administered at 4.5 hour after administration of amlodipine. The maximal change in systolic and diastolic blood pressure (ΔmaxSBP and ΔmaxDBP) and pulse rate (ΔmaxPR) were compared between mirodenafil and placebo periods. Twelve patients completed this study and were included analysis. The values of ΔmaxPR in standing and supine position were significantly greater in the mirodenafil period (13.25±7.12 and 11.17±4.86 beats/minute) when compared to the placebo (8.50±4.72 and 6.58±3.90 beats/minute). The ΔmaxSBP and ΔmaxDBP in standing position appeared to be lower in the mirodenafil period, but they were not statistically different from those in the placebo period (ΔmaxSBP = -7.42±5.6 vs -4.42±5.37 mmHg and ΔmaxDBP = -7.17±5.72 vs -3.50±3.37 mmHg). Both ΔmaxSBP and ΔmaxDBP in standing and supine position were not significantly different between mirodenafil and placebo. This study demonstrated that mirodenafil exerted minimal hemodynamic effects in the patients taking amlodipine, that is unlikely associated with a clinically significant hypotensive event.
Amlodipine* ; Antihypertensive Agents ; Blood Pressure ; Cross-Over Studies ; Erectile Dysfunction ; Heart Rate ; Hemodynamics* ; Humans ; Hypotension, Orthostatic ; Male ; Phosphodiesterase 5 Inhibitors ; Posture ; Supine Position

p21-activated kinases (PAKs) are key regulators of actin dynamics, cell proliferation and cell survival. Deregulation of PAK activity contributes to the pathogenesis of various human diseases, including cancer and neurological disorders. Using an ELISA-based screening protocol, we identified naphtho(hydro)quinone-based small molecules that allosterically inhibit PAK activity. These molecules interfere with the interactions between the p21-binding domain (PBD) of PAK1 and Rho GTPases by binding to the PBD. Importantly, they inhibit the activity of full-length PAKs and are selective for PAK1 and PAK3 in vitro and in living cells. These compounds may potentially be useful for determining the details of the PAK signaling pathway and may also be used as lead molecules in the development of more selective and potent PAK inhibitors.
Actins ; Cell Proliferation ; Cell Survival ; Humans ; In Vitro Techniques ; Mass Screening ; Nervous System Diseases ; p21-Activated Kinases ; Phosphotransferases* ; rho GTP-Binding Proteins

p21-activated kinases (PAKs) are key regulators of actin dynamics, cell proliferation and cell survival. Deregulation of PAK activity contributes to the pathogenesis of various human diseases, including cancer and neurological disorders. Using an ELISA-based screening protocol, we identified naphtho(hydro)quinone-based small molecules that allosterically inhibit PAK activity. These molecules interfere with the interactions between the p21-binding domain (PBD) of PAK1 and Rho GTPases by binding to the PBD. Importantly, they inhibit the activity of full-length PAKs and are selective for PAK1 and PAK3 in vitro and in living cells. These compounds may potentially be useful for determining the details of the PAK signaling pathway and may also be used as lead molecules in the development of more selective and potent PAK inhibitors.
Actins ; Cell Proliferation ; Cell Survival ; Humans ; In Vitro Techniques ; Mass Screening ; Nervous System Diseases ; p21-Activated Kinases ; Phosphotransferases* ; rho GTP-Binding Proteins

BACKGROUND: For more effective and safer usage of antibiotics, the dosing strategy should be individualized based on the patients’ characteristics, including race. The aim of this study was to investigate the population pharmacokinetic (PK) profiles of piperacillin and tazobactam in Korean patients with acute infections. MATERIALS AND METHODS: At least four consecutive 2/0.25 g or 4/0.5 g doses of piperacillin/tazobactam (TZP) were intravenously infused over 1 h every 8 h for patients with creatinine clearance (CL(cr)) ≤50 ml/min or CL(cr) >50 mL/min, respectively. Blood samples from 33 patients at a steady-state were taken pre-dose and at 0 min, 30 min, and 4-6 h after the fourth infusion. The population PK analysis was conducted using a non-linear mixed-effects method. A likelihood ratio test was used to select significant covariates, with significance levels of P <0.05 for selection and P <0.01 for elimination. RESULTS: Both piperacillin PK and tazobactam PK were well described by a two-compartment model with first-order elimination. Creatinine clearance and body weight, as covariates on clearance (CL) and volume of central compartment (V1), were selected among the covariates possibly affecting PK parameters of both drugs. CL was defined as CL = 2.9 + 4.03 × CL(cr)/47 for piperacillin and CL = 1.76 + 4.81 × CL(cr)/47 for tazobactam. V1 was defined as V1 = 19.5 × weight/60 for piperacillin and V1 = 22.6 × weight/60 for tazobactam. CONCLUSION: The PK profiles of TZP at a steady-state in Korean patients with acute infections were well described by a two-compartment model with first-order elimination. Both piperacillin and tazobactam clearances were significantly influenced by creatinine clearance.
Anti-Bacterial Agents ; Body Weight ; Continental Population Groups ; Creatinine ; Humans ; Methods ; Piperacillin

PURPOSE: To assess the risk factors for developing urinary retention after removal of the urethral catheter on postoperative day 1 in benign prostatic hyperplasia patients who underwent Greenlight HPS laser photoselective vaporization prostatectomy (PVP). MATERIALS AND METHODS: The study included 427 men who underwent Greenlight HPS laser PVP between 2009 and 2012, excluding patients in whom a catheter was maintained for more than 1 day because of urethral procedures. In all patients, a voiding trial was performed on postoperative day 1; if patients were unable to urinate, the urethral catheter was replaced before hospital discharge. The patients were divided into two groups: early catheter removal (postoperative day 1) and late catheter removal (urethral catheter reinsertion). Preoperative and perioperative parameters were compared between the groups. RESULTS: Catheters were successfully removed in 378 (88.6%) patients on postoperative day 1. In 49 patients, the catheters were reinserted and removed a mean of 6.45+/-0.39 days after surgery. In a multivariate analysis, a history of diabetes was the most significant predictor (p=0.028) of failure of early catheter removal, followed by operative time (p=0.039). There were no significant differences in age, prostate volume, International Prostate Symptom Score, or urodynamic parameters between the two groups. CONCLUSIONS: It is feasible, safe, and cost-effective to remove the urethral catheter on postoperative day 1 after Greenlight HPS laser PVP, but the procedure should be done carefully in patients who have history of diabetes or an extended operative time.
Catheters ; Humans ; Laser Therapy ; Male ; Multivariate Analysis ; Operative Time ; Prostate ; Prostatectomy ; Prostatic Hyperplasia ; Risk Factors ; Urinary Catheterization ; Urinary Catheters ; Urinary Retention ; Urodynamics ; Volatilization

BACKGROUND: Bovine pericardium is one of the most widely used materials in bioprosthetic heart valves. Immunologic responses have been implicated as potential causes of limited durability of xenogenic valves. This study aimed to determine the effectiveness of decellularization and alpha-galactosidase (alpha-gal) to remove major xenoreactive antigens from xenogenic tissues. MATERIALS AND METHODS: Recombinant Bacteroides thetaiotaomicron (B. thetaiotaomicron) alpha-gal or decellularization, or both were used to remove alpha-gal from bovine pericardium. It was confirmed by alpha-gal-bovine serum albumin-based enzyme-linked immunosorbent assay (ELISA), high-performance anion exchange chromatography, flow cytometry, 3,3'-diaminobenzidine-staining, and lectin-based ELISA. The mechanical properties of bovine pericardium after decellularization or alpha-gal treatment were investigated by tests of tensile-strength, permeability, and compliance. Collagen fiber rearrangement was also evaluated by a 20,000x transmission electron microscope (TEM). RESULTS: Recombinant B. thetaiotaomicron alpha-gal could effectively remove alpha-gal from bovine pericardium B. thetaiotaomicron (0.1 U/mL, pH 7.2) while recombinant human alpha-gal removed it recombinant human alpha-gal (10 U/mL, pH 5.0). There was no difference in the mechanical properties of fresh and recombinant alpha-gal-treated bovine pericardium. Furthermore, the TEM findings demonstrated that recombinant alpha-gal made no difference in the arrangement of collagen fiber bundles with decellularization. CONCLUSION: Recombinant B. thetaiotaomicron alpha-gal effectively removed alpha-gal from bovine pericardium with a small amount under physiological conditions compared to human recombinant alpha-gal, which may alleviate the harmful xenoreactive immunologic responses of alpha-gal. Recombinant alpha-gal treatment had no adverse effects on the mechanical properties of bovine pericardium.
alpha-Galactosidase ; Bacteroides ; Bioprosthesis ; Chromatography ; Collagen ; Compliance ; Electrons ; Enzyme-Linked Immunosorbent Assay ; Epitopes ; Flow Cytometry ; Heart Valves ; Humans ; Hydrogen-Ion Concentration ; Pericardium ; Permeability ; Tissue Engineering

BACKGROUND: Bioprostheses for cardiovascular surgery have limitations in their use following as calicification. alpha-galactosidase epitope is known as a stimulant of immune response and then shows a progressing calcification. The objective of this study was to evaluate histologic characteristics and mechanical properties of decellularization and treated with alpha-galactosidase. MATERIALS AND METHODS: Bovine pericardial tissues were allocated into three groups: fixation only with glutaraldehyde, decellularization with sodium dodesyl sulfate and decellularization plus treatment with alpha-galactosidase. We confirmed immunohistological characteristics and mechanical properties as fatigue test, permeability test, compliance test, tensile strength (strain) test and thermal stability test. RESULTS: Decellularization and elimination of alpha-gal were confirmed through immunohistologic findings. Decellularization had decreased mechanical properties compared to fixation only group in permeability (before fatigue test p=0.02, after fatigue test p=0.034), compliance (after fatigue test p=0.041), and tensile strength test (p=0.00). The group of decellularization plus treatment with alpha-galactosidase had less desirable mechanical properties than the group of decellularization in concerns of permeability (before fatigue test p=0.043) and strain test (p=0.001). CONCLUSION: Favorable decellularization and elimination of alpha-gal were obtained in this study through immunohistologic findings. However, those treatment including decellularization and elimination of alpha-gal implied the decreased mechanical properties in specific ways. We need more study to complete appropriate ioprosthesis with decellularization and elimination of alpha-gal including favorable mechanical properties too.
alpha-Galactosidase ; Bioprosthesis ; Compliance ; Fatigue ; Glutaral ; Pericardium ; Permeability ; Sodium ; Sprains and Strains ; Tensile Strength

BACKGROUND AND OBJECTIVES: Glutaraldehyde (GA) has been used as a representative method of tissue preservation in cardiovascular surgery. However, GA has showed limited durability including calcification, mechanical failure and toxicity. To overcome those unsolved problems, we analyzed the crosslinking differences of primary amines, GA and genipin in their mechanical and biochemical properties with a single or double crosslinking agent for clinical application. MATERIALS AND METHODS: Samples were divided into 3 groups; control, single crosslinking fixation and double crosslinking fixation after decellurarization using bovine pericardium. For analysis of the biochemical and mechanical properties of each crosslinking method, tensile strength, percentage strain, thermal stability, resistance to pronase, nynhydrin and cytotoxicity test were studied. RESULTS: Combined hexamethylene diamine and suberic acid in the carbodiimide hydrochloride/N-hydroxysucinimide solution (EDC/NHS) after decellurarization, tensile strength and strain percentage were not statistically significant compared to the single crosslinking treated groups (p>0.05). Tissue crosslinking stability was weak in single treatment of diphenylphosphoryl azide, suberic acid, low concentration of EDC, hexamethylene diamine and procyanidin groups, but thermal stability and resistance to the pronase and ninhydrin were markedly increased in concentrated EDC/NHS or after combined double treatment with low concentration of GA or genipin (p<0.001). CONCLUSION: Single or double crosslinking with low concentration of carbodiimide, diphenylphosphonyl azide, procyanidin, suberic acid and hexane diamine were not as effective in mechanical, biochemical, cytotoxic and crosslinking properties compared to GA or genipin fixation, but their mechanical and chemical properties were much improved when combined with low concentrations of GA or genipin in the double crosslinking process.
Amines ; Azides ; Biflavonoids ; Bioprosthesis ; Caprylates ; Catechin ; Dicarboxylic Acids ; Glutaral ; Iridoids ; Ninhydrin ; Pericardium ; Proanthocyanidins ; Pronase ; Sprains and Strains ; Tensile Strength ; Tissue Preservation

BACKGROUND AND OBJECTIVES: We hypothesized that fetal echocardiography (echoCG) is an accurate diagnostic tool reflecting well postnatal echoCG findings and outcomes. SUBJECTS AND METHODS: We reviewed the medical records of 290 pregnant women, including 313 fetuses, who were examined by fetal echoCG at the Seoul National University Children's Hospital from January 2008 through April 2011. RESULTS: The mean gestational age at diagnosis was 26.2+/-5.2 weeks. The mean age of mothers at diagnosis was 31.7+/-3.8 years. We identified indications for fetal echoCG in 279 cases. The most common indication was abnormal cardiac findings in obstetrical screening sonography (52.0%). Among the 313 echoCG results, 127 (40.6%) were normal, 13 (4.2%) were minor abnormalities, 35 (11.2%) were simple cardiac anomalies, 50 (16.0%) were moderate cardiac anomalies, 60 (19.2%) were complex cardiac anomalies, 16 (5.1%) were arrhythmias, and 12 (3.8%) were twin-to-twin transfusion syndrome. The most common congenital heart disease was tetralogy of Fallot (23 fetuses, 15.9%). One hundred forty-eight neonates were examined by echoCG. We analyzed differences between fetal echoCG and postnatal echoCG. In 131 (88.5%) cases, there was no difference; in 15 (10.1%), there were minor differences; and in only 2 (1.4%) cases, there were major differences. CONCLUSION: There is a recent increase in abnormal cardiac findings of obstetric ultrasonography screenings that indicate fetal echoCG. Fetal echoCG is still a good, accurate diagnostic method for congenital heart disease.
Arrhythmias, Cardiac ; Echocardiography ; Female ; Fetofetal Transfusion ; Fetus ; Gestational Age ; Heart ; Heart Defects, Congenital ; Heart Diseases ; Humans ; Infant, Newborn ; Mass Screening ; Medical Records ; Mothers ; Pregnancy ; Pregnant Women ; Prenatal Diagnosis ; Tetralogy of Fallot ; Ultrasonography, Prenatal