Effects of CYP2C19 Genetic Polymorphisms on PK/PD Responses of Omeprazole in Korean Healthy Volunteers

The aim of this study was to examine the effects of CYP2C19*2 and *3 genetic polymorphisms on omeprazole pharmacokinetic (PK) and pharmacodynamic (PD) responses. Twenty-four healthy Korean volunteers were enrolled and given 20 mg omeprazole orally once daily for 8 days. The genotypes of CYP2C19 single nucleotide polymorphisms (SNPs) (*2, *3, and *17) were screened. The plasma concentrations of omeprazole, omeprazole sulfone, and 5-hydroxy (5-OH) omeprazole were determined by liquid chromatography with tandem mass spectrometry (LC-MS/MS). The noncompartmental method was used for the determination of PK parameters. Change of mean pH and proportion (%) of time of gastric pH above 4.0 were estimated. The poor metabolizer (PM) group had the lowest metabolic ratio and exhibited the highest area under the curve (AUC) for omeprazole among the CYP2C19 phenotype groups. The PM group showed the greatest change of mean pH and the highest % time of gastric pH above 4.0. The relationship between AUC of omeprazole and % time of gastric pH above 4.0 was confirmed. The study demonstrates that CYP2C19*2 and *3 influence the PKs and PDs of omeprazole in Korean healthy volunteers. Clinical trial registry at the U.S. National Institutes of Health (https://clinicaltrials.gov), number NCT02299687.

Altered Cortical Thicknesses of Left Pars Opercularis and Left Lateral Occipital Gyrus Can Be Associated with Psychotic Symptoms in Patients with Alzheimer's Disease

OBJECTIVE: The aims of this study was to present an association between the presence of psychotic symptoms and cortical thicknesses/subcortical volumes in patients with Alzheimer's disease (AD). METHODS: Fourteen AD patients with psychotic symptoms and 41 without psychotic symptoms underwent 3T MRI scanning. After adjusting the effects of confounding variables, the cortical thicknesses were compared between the AD patients with and without psychotic symptoms in multiple regions, across the continuous cortical surface. In addition, the subcortical volumes were compared with a structure-by-structure manner. RESULTS: AD patients with psychotic symptoms were characterized by significant smaller cortical thickness of left pars opercularis (F=4.67, p=0.02) and left lateral occipital gyrus (F=6.05, p=0.04) rather than those without psychotic symptoms, after adjusting the effects of age and scores on the Stroop test, non-psychotic items of Neuropsychiatry Inventory and Clinical Dementia Rating, triglyceride level and total intracranial volume. However, there were no significant differences in the subcortical volume between the two groups. CONCLUSION: These results suggest that AD psychosis may reflect more severe deterioration of neuropathologic change in specific brain region.

The Correlation of Levels of Serum Lipid, Homocysteine, and Folate with Volumes of Hippocampus, Amygdala, Corpus Callosum, and Thickness of Entorhinal Cortex in Patients with Amnestic Mild Cognitive Impairment or Dementia of Alzheimer's Type

OBJECTIVES: In this study, the authors evaluated the correlation between levels of serum lipid, homocysteine, and folate with volumes of hippocampus, amygdala, corpus callosum, and in patients with amnestic mild cognitive impairment (aMCI) or Alzheimer's disease (AD) type. METHODS: The study recruited patients who visited the dementia clinic of Haeundae Paik Hospital in Korea between March 2010 and June 2014. Among those, patients who had taken the neurocognitive test, brain magnetic resonance imaing, tests for serum lipid, homocysteine, folate, and apolipoprotein E (APOE) genotyping and diagnosed with aMCI or AD were included for analysis. Bilateral hippocampus, entorhinal cortex, amygdala and corpus callosum were selected for region of interest (ROI). The cross-sectional relationships between serum lipid, homocysteine, folate and ROI were assessed by partial correlation analysis and multiple linear regression analysis. RESULTS: In patients with aMCI, old age (> 80) and APOE epsilon4 carrier were associated with AD [odds ration (OR) : 12.80 ; 95% confidence interval (CI) : 2.25-72.98 and OR : 4.48 ; 95% CI : 1.58-12.67, respectively]. In patients with aMCI or AD, volumes and thickness of ROI were inversely correlated with levels of serum lipid and homocysteine. In multiple linear regression analyses, higher total cholesterol level was related to lower left, right hippocampus volume and left amygdala volume ; higher low-density lipoprotein cholesterol was related to lower right entorhinal cortex thickness ; higher homocysteine level was related to lower corpus callosum volume. CONCLUSIONS: Higher serum lipid and homocysteine levels are associated with decreased volume of hippocampus, amygdala, corpus callosum and entorhinal cortex thickness in patients with aMCI or AD. These findings suggest that serum lipid and homocysteine levels are associated with AD as a modifiable risk factor.

Detection of HBV in Blood and Blood Products by PCR

The aim of this study was to establish a PCR for detecting of the hepatitis B virus (HBV) in blood and blood products. A primer pair set was designed to amplify a 513 bp fragment in the S-region of the HBV genome in the first PCR and a 233 bp fragment of first PCR amplicon in the second PCR with Rubisco (internal control). In order to assess the specificity of the PCR results, all the samples were tested cross-reactivity or interference in the assay. This method did not result in cross-reactivity with the non-HBV (HAV, HCV, HIV, CMV, HPV 18&6b, parvovirus B19/ or HSV 1&2) positive samples and was unaffected. In case of the HBV spiked blood products such as the immunogloubulin and coagulation factors, the lower detection limit of this method for the HBV DNA is 62.5 IU/ml. The PCR method is fully established in this study and will be a valuable method for the detection of the HBV in a variety of blood products, particularly, those derived from starting materials with a high titer of virus.

Immune Tolerance in Murine Islet Transplantation Across HY Disparity

BACKGROUND: Minor histocompatibility HY antigen, as a transplantation antigen, has been known to cause graft rejection in MHC (major histocompatibility complex) matched donor-recipient. The aim of our study is to investigate the role of male antigen (HY) disparity on MHC matched pancreatic islet transplantation and to examine the mechanism of the immune reaction. METHODS: Pancreatic islets were isolated and purified by collagen digestion followed by Ficoll gradient. The isolated islets of male C57BL6/J were transplanted underneath the kidney capsule of syngeneic female mice rendered diabetic with streptozotocine. Blood glucose was monitored for the rejection of engrafted islets. After certain period of time, tail to flank skin transplantation was performed either on mouse transplanted with HY mismatched islets or on sham treated mouse. The rejection was monitored by scoring gross pathology of the engrafted skin. RESULTS: HY mismatched islets survived more than 300 days in 14 out of 15 mice. The acceptance of second party graft (male B6 islets) and the rejection of third party graft (male BALB/c islets) in these mice suggested the tolerance to islets with HY disparity. B6 Skin with HY disparity was rejected on day 25 +/- 7. However, HY mismatched skin transplanted on the mice tolerated to HY mismatched islets survived more than 240 days. Tetramer staining in these mice indicated the CTL recognizing MHC Db/Uty was not deleted or anergized. CONCLUSION: The islet transplantation across HY disparity induced tolerance to HY antigen in C57BL6 mouse, which in turn induced tolerance to HY mismatched skin, which otherwise would be rejected within 25 days. The MHC tetramer staining suggested the underlying mechanisms would not be clonal deletion or anergy.

Pena Operation as a Redo Procedure for Anorectal Malformation

The aim of this study was to evaluate the posterior sagittal anorectoplasty (PSARP) as a re-do operation in patients who failed initial repair of anorectal malformation. Nine patients (4 boys and 5 girls) who had previous failed surgery for anorectal malformation underwent secondary operations through posterior sagittal approach. The main reasons of surgery were constipation (n=3) and persistent anatomical derangement in spite of previous correction surgery (n=6). In addition to constipation, the former group (n=3) had various anatomical defects, and the latter group (n=6), of course, had constipation in some degrees. Patients ranged in age from 2 to 19 years (median 3 years) with only one over the age of 6 years. The primary procedures included PSARP (n=8) and anoplasty (n=1). The rectum was mobilized from surrounding structures through posterior sagittal approach and anatomical defects were corrected. The rectum underwent reconstruction, which involved relocation of the rectum and anus within the limits of the intact muscle complex. Patients underwent follow-up for periods ranging from 6 to 77 months (mean 37 months) after surgery. Anatomical corrections of all the defects were successfully fulfilled in 9 patients. All the patients were satisfied with the functional results after redo-PSARP compared with the preoperative defecatory function. This study suggests that (1) some of the patients with troublesome constipation may have anatomical defects, prominent or hidden, (2) surgeons should suspect the possibility of anatomical defect as the cause of incontinence and (3) preoperative thorough investigation to reveal the anatomical defects should be included in estimating patients with severe incontinence after previous surgery and planning the correction for failed previous surgery as well.

Spatial changes of the maxillofacial complex following maxillary protraction of human dry skull / 대한치과교정학회지

The purpose of this investigation was to study the spatial changes of the maxillofacial complex following maxillary protraction transmitted to the center of resistance of a dry juvenile human skull by a modified maxillary protraction appliance. Four dry juvenile human skulls (without mandible) with well aligned upper deciduous dentition and early mixed dentition were used as experimental samples. A modified protraction headgear was fabricated from a Delare's facemask, and following an alginate impression, an orthodontic resin maxillary splint was made for each dry skull. Protraction force level was maintained at approximately 1000gm per side for 6 hours. Cephalometric radiographs were taken pre- and post-protraction, and nine reference markers with 1.5 mm length of .017 x .025 TMA wire were placed on the right side of the skull for an accurate superimposition of serial cephalometric radiographs. The present investigation demonstrated that vertical changes associated with an anterior displacement of the maxillary complex was observed, and the most prominent effect of protraction headgear was a counterclockwise rotation of the maxilla, that is, a forward and downward tipping around the palatomaxillary region.

The Predisposing Factors in Recurrenct Inguinal Hernias in Infants and Children

Inguinal hernia is a major surgical disease in pediatric surgery, occurring in 3.5% to 5% of all mature newborns and 9% to 11% of all premature babies. The objective of this study is to analyze the predisposing factors in association with recurrences of inguinal hernias in infants and children. In the period from January 1995 to September 2001, 1,575 infants and children who had primary inguinal hernias and recurrent inguinal hernias operated on at the Department of Pediatric Surgery at Seoul National University Hospital were evaluated retrospectively. We evaluated the data by medical records and by telephone interview. The sex, age, location of hernia, comorbidity, prematurity, incarceration, interval to operation after incarceration, postoperative complications were analyzed as predisposing factors in associated with hernia recurrence. Operative findings of recurrent inguinal hernia were reviewed. The data were statistically analyzed with Pearson Chi-Square test and Fisher-exact test. A total of eighteen (1.14%) out of 1,575 patients underwent an operation due to recurrent inguinal hernia. In 5 (27.8%) out of 18 recurred patients, institution of the primary herniorrhaphy was our hospital and in the other 13 (72.2%) was outside hospital. No impact on the development of recurrences was seen for sex, age, interval to operation after incarceration, and postoperative complications. The significant predisposing factors of recurrent inguinal hernias were left inguinal hernias (p=0.002), comorbidity (p=0.002), prematurity (p=0.006), incarceration (p=0.017) and technical error of first herniorrhaphy. We expect that knowledge for predisposing factors of recurrent inguinal hernias and experienced skill of pediatric surgeons will decrease recurrence rate in primary inguinal hernia.

Detection of Chlamydia pneumoniae by Use of the Nested Polymerase Chain Reaction in Children with Lower Respiratory Tract Infection / 감염

BACKGROUND: Chlamydia pneumoniae is a common cause of respiratory tract infection in adults, but little is known about its role in acute respiratory tract infection in children. The aim of this study was to detect C. pneumoniae by use of the nested polymerase chain reaction (nPCR) in Korean children with acute lower respiratory tract infection. METHODS: This study included 95 nasal aspirates obtained from children of 3 years of age or older with acute lower respiratory tract infection admitted to the Seoul National University Children's Hospital from January 1993 through December 1997. They were all negative by culture for RSV, adenovirus, influenza A and B, parainfluenza 1, 2, and 3. The nPCR was performed by use of two primer pairs (HL-1/HR-1, HM-1/HR-2). After amplification, PCR products were digested with Rsa I to confirm the sequence. RESULTS: C. pneumoniae was detected in one sample taken from an 11-year-old girl. She was referred with fever and productive cough for 10 days and she was revealed to have systemic lupus erythematosus and pneumonia. Her chest radiograph showed a left lower lobe infiltrate. Her fever and cough resolved slowly over 15 days without proper antibiotic therapy for C. pneumoniae. CONCLUSION: This study reveals C. pneumoniae as a cause of pneumonia in Korean children. Further studies are required to reveal the epidemiology and the role of C. pneumoniae in respiratory infection in Korean children.

Clinical Analysis of Malignant Pheochromocytoma / 대한암학회지

PURPOSE: There are no specific clinical and histopathologic characteristics of malignant pheochromocytoma and the optimal treatment modality has not been established yet. We analyzed the clinical and histopathologic features of malignant pheochromocytoma and treatment results. MATERIALS AND METHODS: We reviewed the clinical records of 10 patients with malignant pheochromocytoma diagnosed at Seoul National University Hospital from March 1987 to June 1998. RESULTS: Nine of 10 (90%) patients had functional tumors. The biochemical laboratory findings showed elevated 24-hour urine VMA level in nine patients available. The median size of the tumors was 11x11 cm. Six of 10 (60%) patients were initially diagnosed as malignant tumors because of direct invasions to adjacent tissues or distant metastases. On the other hand, remaining 4 patients were initially diagnosed as benign, but the distant metastases developed metachronously after resection of the primary lesion. The median duration between the initial operation and the detection of metastases was 57 months (range: 47~72 months) in these patients. The liver was the most common site of metastases (60%). With regards to the histopathological features, most of the tumors (87.5%) showed capsulation, necrosis and hemorrhage. The findings of lymphatic invasion, angio-invasion, and mitosis were found in 62.5% of the cases. All but 2 patients were initially treated with radical operation for the primary lesions. The disease recurrences or metastases occurred in 7 out of 10 patients. Of these, 4 patients were treated with chemotherapy or interferon- a after recurrences. Overall, the median survival for all patients was 82 months (range: 37~143 months). Two patients is alive and only one patient is alive without recurrence. CONCLUSION: The careful follow-up for at least 5 years and the aggressive multi-disciplinary therapy may be needed for the diagnosis and the management of malignant pheochromocytoma.

Metabolic Abnormalities in Patients with Mitochondrial Myopathy Evaluated by In Vivo 31P Magnetic Resonance Spectroscopy

PURPOSE: To investigate the phosphorus metabolic abnormalities in skeletal muscle of patients with mitochondrial myopathy using in vivo 31P magnetic resonance spectroscopy(MRS). MATERIAL AND METHODS: Patients with mitochondrial myopathy(N=10) and normal control subjects (N=10) participated. All in vivo 31P MRS examinations were performed on 1.5T whole-body MRI/MRS system by using an image selected in vivo spectroscopy (ISIS) pulse sequence that provided a 4 X 4 X 4 cm3 volume of interest (VOI) in the right thigh muscle tissue. Peak areas for each phophorus methabolite were measured using a Marquart algorithm. RESULTS: The specific features in patients with mitochondrial myopathy were a significant increase of Pi/PCr ratio (p=0.003) and a significant decrease of ATP/PCr ratio (p=0.004) as compared with normal controls. In particular, the beta-ATP/PCr ratio between controls and patients with mitochondrial myopathy was predominantly altered. CONCLUSIONS: In vivo 31P MRS may be a useful modality in the clinical evaluation of patients with mitochondrial myopathy based on ATP/PCr and Pi/PCr ratios in skeletal muscle tissue and provides a valuable information in further understanding disorders of muscle metabolism.

A Case of Bilateral Adrenal Cortical Adenomas Causing Cushing's Syndrome and Primary Aldosteronism

A 38-year old female was admitted to our hospital for further evaluation of an incidentally found cardiac murmur. She had been in a hypertensive state for 5 years but had taken antihypertensive drugs intermittently on her own. Her history revealed that she had become amenorrheic for 7 months and had, had headaches for a few months. Physical examination revealed central obesity and a moon face, but no hirsuitism. When she first visited our hospital, her blood pressure was 260/170 mmHg and grade 2 systolic murmur was audible along the left sternal border. Laboratory studies revealed high levels of 24-hour urine-free cortisol and plasma aldosterone, but a very low level of plasma adrenocorticotropic hormone and plasma renin activity. A low-dose and a high-dose dexamethasone suppression tests, adrenal venous sampling, inferior petrosal sinus sampling, and a renin stimulation test were performed. Bilateral adrenal masses were found on computerized tomographic scanning and magnetic resonance imaging but there was no abnormality of the pituitary gland. The uncontrollable blood pressure and the elevated 24-hour urine-free cortisol and plasma aldosterone levels were corrected by a right-total and left-subtotal adrenalectomy. Pathologic findings were bilateral adrenal cortical adenomas of different cell types. These findings indicate that the adrenal cortical adenomas were tumors that functioned differently, causing Cushing's syndrome and primary aldosteronism in the same patient. A review of, the literature published in English showed that this is the first reported case, of bilateral adrenal adenomas functioning differently.

Prophylactic Effect of Diazepam to Prevent Recurrent Febrile Seizure

No abstract available.