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.

Antiepileptic drugs (AEDs) can induce severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome. We performed HLA genotyping and lymphocyte activation tests (LATs) for five AED-induced SCAR patients (three males and two females; aged 40–66 years old). Three patients were treated with carbamazepine (CBZ) for pain control, one was treated with phenytoin (PHT) for seizure prevention, and one was treated with valproic acid (VPA) for seizure prevention. One patient was diagnosed with CBZ-induced DRESS syndrome and the remaining patients were diagnosed with SJS. All patients recovered from SCARs after stopping suspicious drugs and supportive care. LATs were conducted to confirm the culprit drug responsible for inducing SCARs; and LAT results were positive for the suspected culprit drugs, in all except in one case. HLA-A,
Alleles ; Anticonvulsants ; Carbamazepine ; Cicatrix ; Drug Hypersensitivity Syndrome ; Female ; HLA-A Antigens ; Humans ; Long-Acting Thyroid Stimulator ; Lymphocyte Activation ; Lymphocytes ; Male ; Methods ; Phenytoin ; Seizures ; Stevens-Johnson Syndrome ; Valproic Acid

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: 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/AIMS: The aim of this study was to identify changes in left ventricular (LV) performance in patients with a myocardial bridge (MB) in the left anterior descending coronary artery during resting and in an inotropic state. METHODS: Myocardial strain measurement by speckle-tracking echocardiography and conventional LV wall-motion scoring was performed in 18 patients with MB (mean age, 48.1 +/- 1.7 years, eight female) during resting and intravenous dobutamine challenge (10 and 20 microg/kg/min). RESULTS: Conventional LV wall-motion scoring was normal in all patients during resting and in an inotropic state. Peak regional circumferential strain increased dose dependently upon dobutamine challenge. Longitudinal strains of the anterior and anteroseptal segments were, however, reduced at 20 microg/kg/min and showed a dyssynchronous pattern at 20 microg/kg/min. Although there were no significant differences in radial strain and displacement of all segments at rest compared with under 10 microg/kg/min challenge, radial strain and displacement of anterior segments at 20 microg/kg/min were significantly reduced compared with posterior segments at the papillary muscle level (44.8 +/- 14.9% vs. 78.4 +/- 20.1% and 5.3 +/- 2.3 mm vs. 8.5 +/- 1.8 mm, respectively; all p < 0.001), and showed plateau (40%) or biphasic (62%) patterns. CONCLUSIONS: Reduced LV strain of patients with MB after inotropic stimulation was identified. Speckle-tracking strain echocardiography identified a LV myocardial dyssynchrony that was not demonstrated by conventional echocardiography in patients with MB.
Adrenergic beta-1 Receptor Agonists/*diagnostic use ; Adult ; Aged ; Chest Pain ; Coronary Angiography ; Diastole ; Dobutamine/*diagnostic use ; Echocardiography, Stress/instrumentation/*methods ; Female ; Humans ; Male ; Middle Aged ; *Myocardial Contraction ; *Myocardium ; Physical Exertion ; Systole ; *Ventricular Dysfunction, Left ; Ventricular Function, Left/*drug effects

Angiotensin II (Ang II) stimulates migration of vascular smooth muscle cell (VSMC) in addition to its contribution to contraction and hypertrophy. It is well established that Rho GTPases regulate cellular contractility and migration by reorganizing the actin cytoskeleton. Ang II activates Rac1 GTPase, but its upstream guanine nucleotide exchange factor (GEF) remains elusive. Here, we show that Ang II-induced VSMC migration occurs in a betaPIX GEF-dependent manner. betaPIX-specific siRNA treatment significantly inhibited Ang II-induced VSMC migration. Ang II activated the catalytic activity of betaPIX towards Rac1 in dose- and time-dependent manners. Activity reached a peak at 10 min and declined close to a basal level by 30 min following stimulation. Pharmacological inhibition with specific kinase inhibitors revealed the participation of protein kinase C, Src family kinase, and phosphatidylinositol 3-kinase (PI3-K) upstream of betaPIX. Both p21-activated kinase and reactive oxygen species played key roles in cytoskeletal reorganization downstream of betaPIX-Rac1. Taken together, our results suggest that betaPIX is involved in Ang II-induced VSMC migration.
1-Phosphatidylinositol 3-Kinase/metabolism ; Angiotensin II/*metabolism ; Animals ; *Cell Movement ; Cells, Cultured ; Guanine Nucleotide Exchange Factors/genetics/*metabolism ; Muscle, Smooth, Vascular/cytology ; Myocytes, Smooth Muscle/*cytology ; NADPH Oxidase/metabolism ; Protein Kinase C/metabolism ; RNA, Small Interfering/genetics ; Rats ; Rats, Sprague-Dawley ; p21-Activated Kinases/metabolism ; rac1 GTP-Binding Protein/metabolism ; src-Family Kinases/metabolism

PURPOSE: Post-lumbar puncture headache is common complaint. A study of post-diagnostic lumbar puncture headache in children is rare. Various factors that might influence the occurrence of post- diagnostic lumbar puncture headache in children exist. The purpose of this prospective study was to assess the frequency and risk factors for post-diagnostic lumbar puncture headache in children. METHODS: From March 2005 to February 2006, 44 patients with suspected meningitis were enrolled. Patients were received diagnostic lumbar puncture at the Chosun University Hospital, Gwangju, Korea. We evaluated age, sex, previous headache history, number of puncture attempts, volume of cerebrospinal fluid (CSF), pressure of CSF, cell count in CSF, final diagnosis, and the frequency and duration of headaches. RESULTS: Of the 44 patients (mean age 7.36+/-2.04, range 4-13 years), 16 patients (36.4%, male 13/33, 39.4%, female 3/11, 27.2%) had headache. The frequency of headaches was significantly higher in patients with previous headache history compare to those without previous headache history (P= 0.037). The mean of cell count of CSF was significantly higher in patients with post-lumbar puncture headache (P=0.012). The other factors did not influence the post-diagnostic lumbar puncture headache. CONCLUSION: Post-diagnostic lumbar puncture headache in children was more common than other studies. The factors that influence post-diagnostic lumbar puncture headache in children are previous headache history and cell count in CSF.
Cell Count ; Cerebrospinal Fluid ; Child* ; Diagnosis ; Female ; Gwangju ; Headache* ; Humans ; Korea ; Male ; Meningitis ; Post-Dural Puncture Headache ; Prospective Studies ; Punctures ; Risk Factors ; Spinal Puncture*

Purpose:The purpose of this study was to determine the incidence and potential predictors of weight gain in older children and teens treated with valproate (VPA) for epilepsy. Methods:Sixty-five subjects aged 8 to 17 years of age, who began VPA treatment between January 1, 2001, and December 31, 2004, and who had documented weight and height measurements at medication initiation and at least one follow-up visit were retrospectively identified. Exclusion criteria were follow-up <6 months, discontinuation of VPA within 6 months, and concurrent therapy with medication known to affect weight (such as topiramate, carbamazepin). Body mass index (BMI) was calculated at initiation and either discontinuation of VPA or last follow-up and stratified into four categories: group 1, underweight <5%; group 2, appropriate 5-85%; group 3, potentially overweight 85-95%; group 4, overweight >95%. Results:Twenty-eight subjects (77.8%) remained within their same category and eight (22.2%) moved up at least one category. Weight gain (increase in BMI difference) was observed in 72.2% of the 36 subjects treated with VPA. Three factors, neurocognitive status (P=0.017), seizure type (P=0.001) and duration of VPA treatment (P=0.035) were identified to be significant predictors of BMI difference. Conclusion:VPA induces weight gain in children and teens with epilepsy. These factors which are normal neurocognitive status, primary generalized type and duration of VPA treatment over the 12 months were predictors for an increase of weight gain. Therefore potential weight gain should be discussed with patients before the initiation of therapy and BMI should be monitored closely.
Adolescent ; Body Mass Index ; Child* ; Epilepsy* ; Follow-Up Studies ; Humans ; Incidence ; Overweight ; Retrospective Studies ; Seizures ; Thinness ; Valproic Acid ; Weight Gain*

We examined lymphocyte subpopulations of peripheral blood from BLV infected and noninfected Holstein-Friesian dairy cattle reared in Korea by flow cytometry using monoclonal antibodies specifically reactive with bovine leukocyte differentiation marker. Lymphocyte subpopulations expressing BoCD11b, B-B2, CD5, B, MHC II-DP, MHC II-DQ, and MHC II-DR antigens were significantly abundant in the BLV(+) group than the BLV(-) group (p<0.01). On double staining, subpopulation of B-1a(BoCD5+ BoCD11b+) lymphocytes was significantly increased in leukemic group. However, T-lymphocyte lineage expressing BoCD2, BoCD4, BoCD8, and WC1 antigens was significantly lower than in the BLV(+) group (p<0.01). However the absolute number of T-lymphocytes expressing BoCD2, BoCD4, BoCD8, and WC1 antigens in BLV(+) group remained with in the normal range. Furthermore mean ratio of BoCD4/BoCD8 in the BLV(+) groups was higher than that in the BLV(-) group. Taken together, cellular immune responses did not seem to significantly be decreased in the leukemic cattle.
Animals ; Antibodies, Monoclonal ; Cattle* ; Enzootic Bovine Leukosis* ; Flow Cytometry ; Immunity, Cellular ; Korea ; Leukemia Virus, Bovine* ; Leukocytes ; Lymphocyte Subsets* ; Lymphocytes* ; Reference Values ; T-Lymphocytes