Bioanalytical methods for the detection of duloxetine and thioctic acid in plasma using ultra performance liquid chromatography with tandem mass spectrometry (UPLC-MS/MS)

Duloxetine and thioctic acid (TA) are standard drugs for treating diabetic neuropathy, a primary complication associated with diabetes. In this study, ultra performance liquid chromatography coupled with tandem mass spectrometry methods was successfully developed and validated for quantifying duloxetine and TA in biological samples. The protein precipitation method was used to extract duloxetine, TA and their internal standards from beagle dog plasma. A Hypersil Gold C18 column (150 × 2.1 mm, 1.9 μm) was used for the experiment. Isocratic elution with 0.1% formic acid in acetonitrile (A) and 0.1% formic acid (B) was used for duloxetine, whereas a gradient elution with 0.03% acetic acid (A) and acetonitrile (B) was used for TA. The validated parameters included linearity, sensitivity, accuracy, precision, selectivity, matrix effect, stability, and recovery under different conditions. The linear ranges of the calibration curves for duloxetine and TA were 5–800 ng/mL and 5–1,000 ng/mL, respectively. An intra- and inter-run precision of ± 15% can be observed in all quality control samples. These methods were successfully used for pharmacokinetics (PKs) studies in beagle dogs to compare PK differences in a fixed-dose combination including duloxetine and TA and co-administration of the 2 drugs.

Dual regulatory effects of PI(4,5)P2 on TREK-2 K+ channel through antagonizing interaction between the alkaline residues (K330. and R355-357 ) in the cytosolic C-terminal helix

TWIK-related two-pore domain K+ channel-2 (TREK-2) has voltageindependent activity and shows additional activation by acidic intracellular pH (pH i ) via neutralizing the E332 in the cytoplasmic C terminal (Ct). We reported opposite regulations of TREK-2 by phosphatidylinositol 4,5-bisphosphate (PIP2 ) via the alkaline K330 and triple Arg residues (R355-357) inhibition and activation, respectively. The G334 between them appeared critical because its mutation (G334A) endowed hTREK-2 with tonic activity, similar to the mutation of the inhibitory K330 (K330 A). To further elucidate the role of putative bent conformation at G334 ,we compared the dual mutation forms, K330 A/G334 A and G334 A/R 355-7 A, showing higher and lower basal activity, respectively. The results suggested that the tonic activity of G334 A owes to a dominant influence from R355-7. Since there are additional triple Arg residues (R 377-9 ) distal to R355-7 , we also examined the triple mutant (G334A/R355-7 A/R377-9 A) that showed tonic inhibition same with G334 A/R 355-7 A. Despite the state of tonic inhibition, the activation by acidic pH i was preserved in both G 334 A/R355-7 A and G334 A/R 355-7A/R377-9 A, similar to the R355-7 A.Also, the inhibitory effect of ATP could be commonly demonstrated under the activation by acidic pH i in R355-7A, G334 A/R355-7 A, and G334 A/R355-7 A/R377-9 A. These results suggest that the putative bent conformation at G334 is important to set the tug-of-war between K330 and R355-7 in the PIP2 -dependent regulation of TREK-2.

Dual regulatory effects of PI(4,5)P2 on TREK-2 K+ channel through antagonizing interaction between the alkaline residues (K330. and R355-357 ) in the cytosolic C-terminal helix

TWIK-related two-pore domain K+ channel-2 (TREK-2) has voltageindependent activity and shows additional activation by acidic intracellular pH (pH i ) via neutralizing the E332 in the cytoplasmic C terminal (Ct). We reported opposite regulations of TREK-2 by phosphatidylinositol 4,5-bisphosphate (PIP2 ) via the alkaline K330 and triple Arg residues (R355-357) inhibition and activation, respectively. The G334 between them appeared critical because its mutation (G334A) endowed hTREK-2 with tonic activity, similar to the mutation of the inhibitory K330 (K330 A). To further elucidate the role of putative bent conformation at G334 ,we compared the dual mutation forms, K330 A/G334 A and G334 A/R 355-7 A, showing higher and lower basal activity, respectively. The results suggested that the tonic activity of G334 A owes to a dominant influence from R355-7. Since there are additional triple Arg residues (R 377-9 ) distal to R355-7 , we also examined the triple mutant (G334A/R355-7 A/R377-9 A) that showed tonic inhibition same with G334 A/R 355-7 A. Despite the state of tonic inhibition, the activation by acidic pH i was preserved in both G 334 A/R355-7 A and G334 A/R 355-7A/R377-9 A, similar to the R355-7 A.Also, the inhibitory effect of ATP could be commonly demonstrated under the activation by acidic pH i in R355-7A, G334 A/R355-7 A, and G334 A/R355-7 A/R377-9 A. These results suggest that the putative bent conformation at G334 is important to set the tug-of-war between K330 and R355-7 in the PIP2 -dependent regulation of TREK-2.

correlation between the first heart sound and cardiac output as measured by using digital esophageal stethoscope under anaesthesia

The use of an esophageal stethoscope is a basic heart sounds monitoring procedure performed in patients under general anesthesia. As the size of the first heart sound can express the left ventricle function, its correlation with cardiac output should be investigated. The aim of this study was to investigate the effects of cardiac output [CO] on the first heart sound [S1] amplitude. Six male beagles were chosen. The S1 was obtained with the newly developed esophageal stethoscope system. CO was measured using NICOM, a non-invasive CO measuring device. Ephedrine and beta blockers were administered to the subjects to compare changes in figures, and the change from using an inhalation anesthetic was also compared. The S1 amplitude displayed positive correlation with the change rate of CO [r = 0.935, p < 0.001]. The heart rate measured using the esophageal stethoscope and ECG showed considerably close figures through the Bland-Altman plot and showed a high positive correlation [r = 0.988, p < 0.001]. In beagles, the amplitude of S1 had a significant correlation with changes in CO in a variety of situations

Comparable bone healing capacity of different bone graft matrices in a rabbit segmental defect model

We compared the bone healing capacity of three different demineralized bone matrix (DBM) products applied using different carrier molecules (hyaluronic acid [HA] vs. carboxymethylcellulose [CMC]) or bone compositions (cortical bone vs. cortical bone and cancellous bone) in a rabbit segmental defect model. Overall, 15-mm segmental defects in the left and right radiuses were created in 36 New Zealand White rabbits and filled with HA-based demineralized cortical bone matrix (DBX), CMC-based demineralized cortical bone matrix (DB) or CMC-based demineralized cortical bone with cancellous bone (NDDB), and the wound area was evaluated at 4, 8, and 12 weeks post-implantation. DBX showed significantly lower radiopacity, bone volume fraction, and bone mineral density than DB and NDDB before implantation. However, bone healing score, bone volume fraction, bone mineral density, and residual bone area at 4, 8, and 12 weeks post-implantation revealed no significant differences in bone healing capacity. Overall, three DBM products with different carrier molecules or bone compositions showed similar bone healing capacity.

Chronic Non-Social Stress Affects Depressive Behaviors But Not Anxiety in Mice

The etiology of most psychiatric disorders is still incompletely understood. However, growing evidence suggests that stress is a potent environmental risk factor for depression and anxiety. In rodents, various stress paradigms have been developed, but psychosocial stress paradigms have received more attention than non-social stress paradigms because psychosocial stress is more prevalent in humans. Interestingly, some recent studies suggest that chronic psychosocial stress and social isolation affects mainly anxiety-related behaviors in mice. However, it is unclear whether chronic non-social stress induces both depression- and anxiety-related phenotypes or induces one specific phenotype in mice. In the present study, we examined the behavioral consequences of three chronic non-social stress paradigms: chronic predictable (restraint) stress (CPS), chronic unpredictable stress (CUS), and repeated corticosterone-HBC complex injection (RCI). Each of the three paradigms induced mild to severe depression/despair-like behaviors in mice and resulted in increased immobility in a tail suspension test. However, anxiety-related phenotypes, thigmotaxis and explorative behaviors, were not changed by the three paradigms. These results suggest that depression- and anxiety-related phenotypes can be dissociated in mouse stress models and that social and non-social stressors might affect brain circuits and behaviors differently.

Takayasu's Disease in a Patient with Ulcerative Colitis

A 35-year-old Korean man with a 10-year history of ulcerative colitis (UC) presented with pain and swelling of the right neck. The patient was diagnosed with Takayasu's arteritis (TA) and had human leukocyte antigen (HLA) B-52, which is frequently found in patients having both UC and Takayasu's disease concurrently on HLA analysis. This case is the first report of a patient with both TA and UC in Korea, to the best of our knowledge.

Takayasu's Disease in a Patient with Ulcerative Colitis

A 35-year-old Korean man with a 10-year history of ulcerative colitis (UC) presented with pain and swelling of the right neck. The patient was diagnosed with Takayasu's arteritis (TA) and had human leukocyte antigen (HLA) B-52, which is frequently found in patients having both UC and Takayasu's disease concurrently on HLA analysis. This case is the first report of a patient with both TA and UC in Korea, to the best of our knowledge.

A case of Morgagni hernia with intestinal obstruction / 대한내과학회지

Although Morgagni hernias are rarely symptomatic, an 88-year-old woman presented with severe abdominal pain and distension due to large bowel obstruction. The transverse colon and omentum were herniated through an anterior medial diaphragmatic defect in the right thorax. The plain abdominal X-rays indicated intestinal obstruction and the plain chest X-ray showed hazy mass-like densities. The multi-detector row computed tomography (MDCT) findings were compatible with a Morgagni hernia. This diagnosis of a Morgagni hernia was confirmed at immediate surgery.

Transvaginal Ultrasonographic Assessment of Cervical Length for Prediction of Preterm Delivery within 7 Days in Patients with Preterm Labor / 대한주산의학회잡지

PURPOSE: To investigate the usefulness of transvaginal ultrasonographic measurement of cervical length in patients with preterm labor for prediction of preterm delivery within 7 days. METHODS: Cervical length was measured by transvaginal ultrasound in 140 women with singleton pregnancies presenting with preterm labor and intact membranes from 24(+0) to 33(+6) weeks of gestation. Other potential predictive factors, such as Bishop score, previous history of preterm delivery, and parity were assessed. RESULTS: The mean gestational age at presentation was 30.5+/-14.7 (range, 24.0 to 33.6) weeks and the mean cervical length was 29.0+/-0.9 (range, 31.0 to 52.1) mm. Delivery within 7 days occurred in 7.9% (11/140). Receiver-operating characteristics (ROC) curves established a cervical length of 25 mm as the most relevant cut off level for prediction of delivery within 7 days. Interval between admission and delivery was significantly short when ultrasonographic cervical length was less than or equal to 25 mm. Logistic regression analysis demonstrated that the significant independent risk factors were cervical length < or =25 mm (OR: 24.64, 95% Cl: 2.97~204.20, P=0.003). CONCLUSION: Ultrasonographic cervical length measurement is a useful tool for prediction of progression to preterm delivery within 7 days with patients with preterm labor.

Anti-Tuberculosis Agents Induced Pseudomembranous Colitis Treated with Maintaining Anti-Tuberculosis Drugs / 대한소화기내시경학회지

Tuberculosis is one of the main infectious health problems in Korea, and a combination of antibiotics is required to treat this illness. The combination therapy with rifampicin, isoniazid, ethambutol and pyrazinamide has many adverse reactions and there have been several case reports about pseudomembranous colitis (PMC) after anti- tuberculosis treatment. Rifampicin is regarded as a main cause of anti-tuberculosis induced PMC because of its bacteriocidal effect, and interruption of the offending drug, such as rifampicin, is usually necessary to treat the PMC. However, in patents with uncompensated tuberculosis, the discontinuance of anti-tuberculosis medication accentuates the disease severity, and continuance of the anti-tuberculosis medication is necessary to overcome the tuberculosis. We report here on a case in which the anti- tuberculosis agents induced PMC in 32 year old female who was diagnosed with active pulmonary tuberculosis. She was treated with maintenance of the anti-tuberculosis medication and also the addition of both oral metronidazole and probiotics.

A case of primary transitional cell carcinoma of the ovary / 대한산부인과학회지

Primary ovarian transitional cell carcinoma (TCC) is extremely rare type of tumor and resembles transitional cell carcinoma of the bladder. Primary ovarian TCC has been classified as a different subtype from malignant Brenner tumor for it's histologic and clinical characteristics. It usually presents at an advanced stage .Though more aggressive than malignant Brenner tumor, it shows more favorable prognosis because of better response to the chemotherapy than other epithelial ovarian carcinomas. We experienced a case of primary ovarian transitional cell carcinoma in a premenopausal woman who underwent staging operation and chemotherapeutic treatment, and herein report the case with a brief review of related literatures.

Clinical study on obstetric variables affecting perinatal mortality in placental abruption / 대한산부인과학회지

OBJECTIVE: To evaluate obstetric variables in the placental abruption that affect on perinatal mortality. METHODS: We reviewed clinical data of all singleton deliveries complicated with placental abruption between January 2000 and December 2007, in Department of Ob. & Gyn., Sanggye Paik Hospital. RESULTS: Placental abruption complicated 54 cases (0.55%) of all deliveries (n=9,903) from January 2000 to December 2007. The peak age was 26-30 years (42.1%). The most common symptom was vaginal bleeding (57.4%) and intrauterine fetal death had already occurred in 9.3%. Perinatal mortality rate was 13.0% and there was no maternal death. 38.9% of placental abruption occurred between 33 to 36weeks of gestational age. 38.9% of placental abruption was diagnosed before delivery with ultrasonography and 9.3% was chronic placental abruption. 33.3% of placental abruption was associated with preeclampsia, and then associated with PPROM (24.1%), uterine myoma (3.7%), chronic hypertension (1.9%) and smoking (1.9%). When the hypertensive disorders were associated, fetal distress rate was higher than normotensive pregnancy (63.2% vs 20.0%, P-value: 0.005). Mean gestational age (days) (194+/-32.8 vs 248.12+/-28.0, P-value<0.001) and the severity of placental abruption (P-value: 0.005) affect perinatal mortality in placental abruption. The most common complication of placental abruption was DIC (16 cases, 29.6%), followed by Couvelaire uterus (4 cases, 7.4%) and uterine rupture (1 case, 1.9%). CONCLUSION: Obstetric variables that affect perinatal mortality were gestational age at the diagnosis and the severity of placental abruption.

A Case of Esophageal and Gastric Foreign Bodies Induced by Cyanoacrylate Ingestion / 대한소화기내시경학회지

Foreign bodies of the upper gastrointestinal tract are found in all age groups, and the foreign bodies can be ingested incidentally or intentionally. They are usually common in children, but they have also been discovered in adults with esophageal disease, artificial teeth, mental retardation, in patients seeking secondary gains and in alcoholics. The types of foreign bodies vary for different social and cultural conditions, and can include coins, corks, toys, fish bones, toothbrushes, needles, nails and pens. Foreign bodies of the upper gastrointestinal tract are usually passed into the intestinal tract spontaneously, but sometimes intervention is required. We report a case of an 80-year-old man with a past medical history of depressive disorder that had ingested adhesives. The adhesives present in the esophagus were removed by the use of therapeutic endoscopy. However, the adhesives in the stomach were too large to remove by the use of an endoscopic procedure, and gastrotomy was performed.

A Case of Choledochocele with Parapapillary Diverticulum Presenting as Pancreatitis / 대한소화기내시경학회지

Choledochocele, classified as choledochal cyst: type III, is a rare cystic or diverticular dilatation of the terminal biliary tree that causes abdominal pain, recurrent pancreatitis, and obstructive jaundice. It is the rarest of the choledochal cysts and has lower malignant potential than any other type of choledochal cyst. Although its anatomic structure does not fit the criteria for pancreatobiliary maljunction, pancreaticobiliary reflux may occur in patients with choledochocele. Herein, we report the case of a 63-year-old woman with recurrent episodes of acute pancreatitis that were caused by a choledochocele with two parapapillary diverticula. She was successfully treated by endoscopic needle-knife sphincterotomy without severe complications and remained asymptomatic at the 6-month follow-up.

Endoscopic Papillary Balloon Dilation with Large Balloon after Limited Sphincterotomy for Retrieval of Choledocholithiasis

Endoscopic papillary balloon dilation (EBD) for choledocholithiasis is known to be comparable to endoscopic sphincterotomy (EST) especially in cases of small stones. With larger stones, EBD with conventional balloon, which have a diameter of 6-8 mm, was reported as less effective for extraction of stones. We evaluated the efficacy and complications of EBD with large balloons (10-15 mm) after limited EST for retrieval of choledocholithiasis. From February 2005, we have performed EBD with limited EST for retrieval of common bile duct (CBD) stones. The patients who admitted with hyperamylasemia and gallstone pancreatitis were excluded. In cases without CBD dilation, EPBD with 12 mm for 40 seconds was performed. And in cases with CBD dilation, we dilated the sphincters with 15 mm sized balloon for 40 seconds. Total 22 patients (11 of male) were performed EBD with limited EST for retrieval of CBD stones. The median diameter of the stones was 10 mm (5-25 mm). Ten cases had multiple stones and 6 cases periampullary diverticuli. Successful stone removal in the initial session of ERCP with EBD was accomplished in 16 patients (72.7%). And complete retrieval of bile duct stones was achieved in all patients with repeated ERCP. In the aspect of complications, any episodes of perforation, bleeding was not developed. Only one case of mild grade of post-procedural pancreatitis was noted. However, post-procedural hyperamylasemia was developed in 16 cases (68.2%). EBD with larger balloon seems to be a feasible and safe alternative technique for conventional EST in CBD stone extraction.

Endoscopic Papillectomy for Tumors of the Duodenal Major Papilla / 대한소화기내시경학회지

BACKGROUND/AIMS: A surgical resection has traditionally been used to treat tumors of the duodenal major papilla. However, radical surgery may cause significant morbidity and mortality. Endoscopic papillectomy has been reported in patients with benign papillary tumors. We evaluated the safety and outcomes of endoscopic papillectomy in patients with a papillary tumor. METHODS: Between January 1994 and December 2003, fifteen patients with ampullary tumors underwent an endoscopic papillectomy using a snare resection. Endoscopic papillectomy was performed in 13 patients diagnosed with an adenoma and in 2 patients diagnosed with an adenocarcinoma, who were contraindicated for surgery. RESULTS: Endoscopic papillectomy was performed in fifteen patients (11 men, 4 women: median age 61.7 years). All the tumors were removed either "en bloc" (14 tumors) or in a "piecemeal" fashion (one tumor). Ten patients were available for follow-up (median, 20.9 months: range, 1~62 months). The procedure-related complications were bleeding (n=1), pancreatitis (n=3), and a duodenal perforation (n=1). The follow-up endoscopy revealed a recurrent adenocarcinoma in 2 patients after 13 months (20%). CONCLUSIONS: Endoscopic papillectomy is a useful alternative for treating a papillary adenoma. The relatively high incidence of pancreatitis this study suggests that stenting into the pancreatic duct will be needed to prevent postprocedure pancreatitis.

Partial agenesis of dorsal pancreas with Castleman's disease in pancreatic tail area / 대한내과학회지

Agenesis of dorsal pancreas is a very rare congenital anomaly which comes from the failure of development of the body and tail of pancreas in embryogenesis. Castleman's disease is a rare lymphoid tumor which usually occurred in the mediastinum, but it is very uncommon in the retroperitoneal pancreatic tail area. We report a case of partial agenesis of dorsal pancreas with Castleman's disease in pancreatic tail area, mimicking a pancreatic tumor. A 46-year-old woman was admitted to our hospital with intermittent abdominal discomfort for 2 months. Computed tomography, magnetic resonance imaging, and endoscopic retrograde cholangiopancreatography (ERCP) revealed a tumor at distal pancreatic tail area, short pancreatic duct, and absence of pancreatic body and tail. The surgical excision of the tumor revealed hyaline-vascular type Castleman's disease.

Comparison of Rifaximin and Lactulose for the Treatment of Hepatic Encephalopathy: A Prospective Randomized Study

Rifaximin has been reported to be effective for the treatment of hepatic encephalopathy (HE) in Europe. However, it is unknown whether Rifaximin is effective for the treatment of HE in Koreans, therefore we conducted a open-label prospective randomized study to evaluate the efficacy of rifaximin versus lactulose in Korean patients. Fifty-four patients with liver cirrhosis and hepatic encephalopathy were enrolled. Thirty-two patients were randomized to receive rifaximin and 22 to receive lactulose both over a 7-day periods. Before and at the end of treatment, gradation of blood ammonia, flapping tremor, mental status, number connection test (NCT) were performed and estimation of HE indexes determined. Both rifaximin and lactulose were effective in the majority of patients (84.4% and 95.4%, respectively, p=0.315). Blood NH3, flapping tremor, mental status, and NCT was significantly improved by rifaximin and lactulose, and the post- treatment levels of these measures were similar for the rifaximin and lactulose-treated groups, as was the HE index (rifaximin group (10.0-->> 4.2, p=0.000) ; lactulose group (11.3-->> 5.0, p=0.000) ). One patient treated with rifaximin complained of abdominal pain, which was easily controlled. There was no episode of renal function impairment in either treatment group. Rifaximin proved to be as safe and as effective as lactulose for the treatment of Korean patients with hepatic encephalopathy.

Evaluation of NeonatalImmature Reticulocyte Fraction in Small-for-gestational Age Infant in Umbilical Cord Blood / 대한산부인과학회잡지

OBJECTIVE: To evaluate the immature reticulocyte fraction (IRF) by automated calculator that have played a role of predicting marker for hematopoiesis induced by perinatal asphyxia. METHODS: Hospital charts of 40 neonates with diagnosis of small for gestational age (SGA: birth weight <10 percentile) and 47 babies of appropriate for gestational age (AGA) who were delivered vaginally between May 8, 2000 and March 2, 2002 at department of Obstetric and Gynecology, Sanggye Paik Hospital, Inje university. About 5 cc in cord blood was collected immediately after delivery, the calculation of nucleated RBC (N-RBC)/100WBC by macroscopic exam and the evaluation of reticulocyte maturation by automated reticulocyte calculator (Sysmex SE 9000, TOA Medical Electronics Co., Ltd, Kobe, Japan) were performed, and made a comparative study of apgar score. RESULTS: The comparison between AGA and SGA infants, the mean values of cord blood sampling parameter N-RBC (3.53 +/- 4.89 vs 7.92 +/- 10.06, P=0.016), middle fluorescence ratio reticulocyte (MFR) (0.21 +/- 0.02 vs 0.23 +/- 0.03, P<0.001), high fluorescence ratio reticulocyte (HFR) (0.08 +/- 0.03 vs 0.12 +/- 0.03, P<0.001), IRF (0.28 +/- 0.03 vs 0.35 +/- 0.05, P<0.001) were obtained. All of the parameters were significantly different between SGA infants and normal infants and IRF was more valuable marker than N-RBC in evaluation of hematopoietic activity in SGA infants (multiple logistic regression analysis: P value 0.282 vs <0.001). CONCLUSION: Immature reticulocyte fraction by automated calculator is more accurate and confident marker better than N-RBC/100WBC by manual countingin evaluation of the fetal hypoxic induced hematopoiesis.