Effects of the ABCG2 and ABCB1 drug transporter polymorphisms on the pharmacokinetics of bicalutamide in humans.

BACKGROUNDS: Bicalutamide is an oral non-steroidal anti-androgen used in the treatment of prostate cancer. Drug transporters P-glycoprotein encoded by ABCB1 and breast cancer resistance protein (BCRP) encoded by ABCG2 are involved in the transportation of bicalutamide and its treatment failure. We evaluated the roles of ABCB1 and ABCG2 genetic polymorphisms in the pharmacokinetics of bicalutamide in humans. METHODS: After a single oral dose of 150mg bicalutamide was administered, plasma concentrations of bicalutamide were measured, and pharmacokinetic analyses were performed in 27 healthy subjects according to ABCB1 (c.1236C>T, c.2677G>T/A, and c.3435C>T) and ABCG2 (c.34G>A and c.421C>A). RESULTS: ABCB1 polymorphisms did not affect the plasma levels of bicalutamide and the pharmacokinetic parameters did not differ among ABCB1 genotype groups. However, the ABCG2 c.421C>A polymorphism significantly influenced the plasma levels and pharmacokinetics of bicalutamide gene dose-dependently. CONCLUSIONS: The ABCB1 genetic polymorphisms did not influence the pharmacokinetics of bicalutamide. However, ABCG2 c.421C>A significantly and gene dose-dependently influenced its pharmacokinetics, but c.34G>A did not.

Clinical Significance of Fecal Lactoferrin and Multiplex Polymerase Chain Reaction in Patients with Acute Diarrhea.

BACKGROUND/AIMS: The diagnostic yield of fecal leukocyte and stool cultures is unsatisfactory in patients with acute diarrhea. This study was performed to evaluate the clinical significance of the fecal lactoferrin test and fecal multiplex polymerase chain reaction (PCR) in patients with acute diarrhea. METHODS: Clinical parameters and laboratory findings, including fecal leukocytes, fecal lactoferrin, stool cultures and stool multiplex PCR for bacteria and viruses, were evaluated prospectively for patients who were hospitalized due to acute diarrhea. RESULTS: A total of 54 patients were included (male, 23; median age, 42.5 years). Fecal leukocytes and fecal lactoferrin were positive in 33 (61.1%) and 14 (25.4%) patients, respectively. Among the 31 patients who were available for fecal pathogen evaluation, fecal multiplex PCR detected bacterial pathogens in 21 patients, whereas conventional stool cultures were positive in only one patient (67.7% vs 3.2%, p=0.000). Positive fecal lactoferrin was associated with presence of moderate to severe dehydration and detection of bacterial pathogens by multiplex PCR (21.4% vs 2.5%, p=0.049; 100% vs 56.5%, p=0.032, respectively). CONCLUSIONS: Fecal lactoferrin is a useful marker for more severe dehydration and bacterial etiology in patients with acute diarrhea. Fecal multiplex PCR can detect more causative organisms than conventional stool cultures in patients with acute diarrhea.

Multiplex pyrosequencing method to determine CYP2C9*3, VKORC1*2, and CYP4F2*3 polymorphisms simultaneously: its application to a Korean population and comparisons with other ethnic groups.

Warfarin is an anticoagulant that is difficult to administer because of the wide variation in dose requirements to achieve a therapeutic effect. CYP2C9, VKROC1, and CYP4F2 play important roles in warfarin metabolism, and their genetic polymorphisms are related to the variability in dose determination. In this study we describe a new multiplex pyrosequencing method to identify CYP2C9*3 (rs1057910), VKORC1*2 (rs9923231), and CYP4F2*3 (rs2108661) simultaneously. A multiplex pyrosequencing method to simultaneously detect CYP2C9*3, VKORC1*2, and CYP4F2*3 alleles was designed. We assessed the allele frequencies of the polymorphisms in 250 Korean subjects using the multiplex pyrosequencing method. The results showed 100 % concordance between single and multiplex pyrosequencing methods, and the polymorphisms identified by pyrosequencing were also validated with the direct sequencing method. The allele frequencies of these polymorphisms in this population were as follows: 0.040 for CYP2C9*3, 0.918 for VKORC1*2, and 0.416 for CYP4F2*3. Although the allele frequencies of the CYP2C9*3 and VKROC1*2 were comparable to those in Japanese and Chinese populations, their frequencies in this Korean population differed from those in other ethnic groups; the CYP4F2*3 frequency was the highest among other ethnic populations including Chinese and Japanese populations. The pyrosequencing methods developed were rapid and reliable for detecting CYP2C9*3, VKORC1*2, and CYP4F2*3. Large ethnic differences in the frequency of these genetic polymorphisms were noted among ethnic groups. CYP4F2*3 exhibited its highest allele frequency among other ethnic populations compared to that in a Korean population.

A comparative study of the effects of inhibitory cytokines on human natural killer cells and the mechanistic features of transforming growth factor-beta.

The major factors and mechanisms by which natural killer (NK) cells are inhibited in cancer patients have not yet been well defined. In this study, we conducted a comparative analysis of the effects of TGF-ß, IL-10, and IL-4 on primary NK cells, and it was demonstrated that (1) TGF-ß most potently inhibited the overall function of NK cells. (2) It appears that TGF-ß reduced the tyrosine phosphorylation of Syk and the expression of c-myc. (3) It was also found that the IL-2-induced promoter-binding activities of C-myb, AP-1, CREB, and AR were also completely suppressed upon TGF-ß treatment. Interestingly, TGF-ß also completely suppressed other transcription factors, which are constitutively activated. Among these factors, we further confirmed roles of AP-1 in NK-92 cell activation through c-jun and MEK1 inhibitor assay. Our study provides insight into the effects of TGF-ß in modulating NK cell functions.

Brief education on microvasculature and pit pattern for trainees significantly improves estimation of the invasion depth of colorectal tumors.

Objectives. This study was performed to evaluate the effectiveness of education for trainees on the gross findings identified by conventional white-light endoscopy (CWE), the microvascular patterns identified by magnifying narrow-band imaging endoscopy (MNE), and the pit patterns identified by magnifying chromoendoscopy (MCE) in estimation of the invasion depth of colorectal tumors. Methods. A total of 420 endoscopic images of 35 colorectal tumors were used. Five trainees estimated the invasion depth of the tumors by reviewing the CWE images before education. Afterwards, the trainees estimated the invasion depth of the same tumors after brief education on CWE, MNE and MCE images, respectively. Results. The initial diagnostic accuracy for deep submucosal invasion before education and after education on CWE, MNE, and MCE findings was 54.3%, 55.4%, 67.4%, and 76.6%, respectively. The diagnostic accuracy increased significantly after MNE education (P = 0.028). The specificity for deep submucosal invasion before education and after education on CWE, MNE, and MCE findings was 47.9%, 45.7%, 65.0%, and 80.7%, respectively. The specificity increased significantly after MNE (P = 0.002) and MCE (P = 0.005) education. Conclusion. Brief education on microvascular pattern identification by MNE and pit pattern identification by MCE significantly improves trainees' estimations of the invasion depth of colorectal tumors.

Influence of ABCB1 and CYP3A5 genetic polymorphisms on the pharmacokinetics of quetiapine in healthy volunteers.

BACKGROUND AND OBJECTIVES: Quetiapine is an atypical antipsychotic drug used to treat schizophrenia and acute episodes of mania. Quetiapine is metabolized by CYP3A enzymes including CYP3A5 and is a substrate of P-glycoprotein, an efflux drug transporter encoded by the ABCB1 gene. We assessed the effects of ABCB1 [c.1236C>T (rs1128503), c.2677G>T/A (rs2032582), c.3435C>T (rs1045642)] and CYP3A5*3 (6986A>G) (rs776746) polymorphisms on the pharmacokinetics of quetiapine in humans. MATERIALS AND METHODS: Forty healthy male individuals were enrolled, and their ABCB1 and CYP3A5 polymorphisms were assessed. After a single dose of 100 mg quetiapine was administered, plasma concentrations of quetiapine were measured for 24 h and pharmacokinetic analysis was carried out. RESULTS: The ABCB1 polymorphisms including c.1236C>T, c.2677G>T/A, and c.3435C>>T did not affect plasma levels of quetiapine, and its pharmacokinetic parameters did not differ among ABCB1 genotype groups. However, the CYP3A5*3 polymorphism significantly affected the plasma level of quetiapine and its pharmacokinetics. The peak plasma concentration of quetiapine was 208.39 ng/ml for CYP3A5*1/*1, 243.46 ng/ml for CYP3A5*1/*3, and 332.94 ng/ml for CYP3A5*3/*3 (P=0.0118). The mean AUC(inf) (area under the time vs. concentration curve from 0 to infinity) value was 627.3, 712.77, and 1045.29 ng h/ml, respectively (P=0.0017). CONCLUSION: The results indicated that the genetic polymorphism of CYP3A5*3 but not ABCB1 significantly influences the plasma level of quetiapine and its pharmacokinetics. These findings suggest that the CYP3A5 genetic polymorphism affects the disposition of quetiapine and provide a plausible explanation for interindividual variation in the disposition of this drug.

Fluid balance in late preterm infants with prenatal gastrointestinal pathology -a report of two cases-.

Intestinal obstruction was diagnosed in two fetuses at maternal antenatal care. Both received emergency surgery on the day of their birth, at about 35 weeks gestational age. The disease progressed for a long time in both cases because prompt diagnosis and surgery are difficult to perform in utero. As a result, severe adhesion and distorted anatomy were observed in both cases. Massive third space losses and bleeding were predicted during the surgery. However, the accurate ongoing losses were difficult to anticipate. The assessment of fluid deficits cannot be based on measured losses alone, but hemodynamic status including blood pressure, heart rate, urine output, capillary refill, and/or central venous pressure should be evaluated additionally.

The comparison of feasibility and safety on fiberoptic guided intubation under conscious sedation with remifentanil and propofol.

BACKGROUND: Oropharyngeal manipulation is problematic when patients have a gag reflex. Sedation can suppress gag reflex, but can cause serious airway problems. We compared remifentanil (Group R) and propofol (Group P) in terms of cooperation and loss of gag reflex, while drugs were administered incrementally using target controlled infusion (TCI). METHODS: Fifty seven patients who required awake fiberoptic intubation were randomized to Group R or Group P. After measurement of baseline gag trigger point index (GTPI), TCI was set to effect-site concentration (Ce) of 1 ng/ml (Group R) or 1 µg/ml (Group P), then titrated by 0.5 increment until GTPI score reached 0. The incidence of drop-out and decreased cooperation, Ramsay sedation scale (RSS) and Ce at loss of GR, and complications were assessed. RESULTS: Seven patients were dropped out in Group P due to deep sedation and disobedient behavior, but none in Group R (P = 0.015). Gag reflex suppressed as RSS increased in both groups (P < 0.001), however, the incidence of elimination of gag reflex clustered at RSS 2 in Group R (P < 0.001), whereas it was evenly distributed in Group P (P = 0.20). The incidence of patients who were spontaneously roused (gag reflex elimination at RSS 1 and 2) were higher in Group R than in Group P (P = 0.002). CONCLUSIONS: Deep sedation and impaired cooperation were observed only in Group P and spontaneously roused patients were higher in Group R, suggesting that remifentanil is more suitable for cooperative elimination of GR.

SLCO2B1 genetic polymorphisms in a Korean population: pyrosequencing analyses and comprehensive comparison with other populations.

SLCO2B1, also known as OATP2B1 (Organic Anion Transporter) or OATP-B or SLC21A9, is an organic anion uptake transporter that is encoded by the SLCO2B1 gene. In this study we assessed the frequencies of SLCO2B1 polymorphisms in a Korean population using newly developed pyrosequencing methods and compared their frequencies with those in other ethnic groups. We developed pyrosequencing methods to identify the following six SLCO2B1 non-synonymous polymorphisms: c.1175C > T (rs1621378), c.1457C > T (rs2306168), c.43C > T (rs56837383), c.935G > A (rs12422149), c.601G > A (rs35199625) and c.644A > T (rs72559740). The allele frequencies of these polymorphisms were analyzed in 227 Korean subjects. The allele frequencies of SLCO2B1 polymorphisms in the population tested were as follows: 0.0 for c.1175C > T, c.43C > T and c.644A > T; 0.2687 for c.1457C > T; 0.4273 for c.935G > A; and 0.0727 for c. 601G > A. Even though the allele frequencies of the c.1175C > T and c.1457C > T polymorphisms were comparable to those in Japanese subjects, the frequencies in this Korean population differed from those in other ethnic groups. The developed pyrosequencing methods are rapid and reliable for detecting non-synonymous SLCO2B1 polymorphisms. Large ethnic differences in the frequency of SLCO2B1 genetic polymorphisms were noted among ethnic groups. The SLCO2B1 polymorphisms at c.1175C > T, c.43C > T and c.644A > T were not found in the Korean population while c.1457C > T, c.935G > A and c.601G > A exhibited mostly higher frequencies in Koreans compared with Finnish, Caucasian and African-American populations.

Crohn's Disease Initially Accompanied by Deep Vein Thrombosis and Ulnar Neuropathy without Metronidazole Exposure.

Extraintestinal manifestations are not uncommon in Crohn's disease, and a thromboembolic event is a disastrous potential complication. Deep vein thrombosis is the most common manifestation of a thromboembolic event and typically occurs in association with active inflammatory disease. Peripheral neuropathy in Crohn's disease has rarely been reported and is considered an adverse effect of metronidazole therapy. Here, we describe a patient who was initially diagnosed with Crohn's disease complicated with deep vein thrombosis and ulnar neuropathy without metronidazole exposure. The simultaneous occurrence of these complications in the early stage of Crohn's disease has never been reported in the English literature.

Single-molecule surface-enhanced Raman spectroscopy: a perspective on the current status.

This perspective presents an overview of single-molecule surface-enhanced Raman scattering (sm-SERS). Our overview is organized as a brief theoretical background, discussion of the factors that enhance SERS, various experimental preparations for inserting a single molecule in a hot spot, recent sm-SERS experiments, and a perspective. Although, there have been numerous review papers on sm-SERS, we mainly concentrated on the logical development of sm-SERS on the basis of the fundamental concepts and their physical significance, so that readers outside this field can understand the motivation and the underlying physics when describing current sm-SERS measurements. Indeed, understanding such current sm-SERS experiments conducted by representative groups would be very helpful for readers to answer for themselves the fundamental and practical questions surrounding sm-SERS: (1) what information can sm-SERS provide? (2) Which factors based on the SERS mechanism should be considered to significantly amplify the SERS signal? (3) What kinds of related microscopy techniques could be combined with sm-SERS to attain more meaningful results? (4) Which statistical approaches can be used and how they can be applied to properly analyze sm-SERS data? We hope that this review article can help readers answer these questions.

High-precision measurement-based correlation studies among atomic force microscopy, Rayleigh scattering, and surface-enhanced Raman scattering at the single-molecule level.

We investigated the correlations among the structure, Rayleigh scattering, and single-molecule surface-enhanced Raman scattering (SERS) of DNA-tethered Au-Ag core-shell nanoparticles, especially in dimer and trimer forms. For the optimal correlation measurements, accurate information on the position of the nanoparticle is crucial for locating the nanoparticle at the center of the excitation source for the optical measurements. To achieve this, we developed a multistep correlation strategy that enables us to unambiguously correlate the AFM images with optical images within a few nanometers. We also newly defined the correlation accuracy in this paper as a useful concept for the correlation measurements. With this reliable correlation accuracy, we performed various statistical analyses to thoroughly elucidate the relationships between particle structure, Rayleigh scattering and SERS in terms of the incident polarization and scattering intensity ratio.

An acute postoperative intractable hyperventilation after an endoscopic third ventriculostomy.

This report describes a rare case of postoperative hyperventilation attack after an endoscopic third ventriculostomy in a 46-year-old woman. About 60 min after the termination of the operation, an intractable hyperventilation started with respiratory rate of 65 breaths/min and EtCO(2), 16.3 mm Hg. Sedation with benzodiazepine, thiopental sodium, fentanyl, and propofol/remifentanil infusion was tried under a rebreathing mask at a 4 L/min of oxygen. With aggressive sedative challenges, ventilation pattern was gradually returned to normal during the 22 hrs of time after the surgery. A central neurogenic hyperventilation was suspected due to the stimulating central respiratory center by cold acidic irrigation solution during the neuroendoscopic procedure.

Anesthetic management of non-cardiac surgery with adult onset type of cor triatriatum sinister -A case report-.

A 45-year-old woman with cor triatriatum sinister was admitted for laparoscopic resection of an ovarian tumor. Her medical history was benign with the exception of a single episode of syncope one year ago. A 1.5-cm membrane fenestration was found on echocardiography, but there were no other cardiac structural anomalies. General anesthesia was established with etomidate, sevoflurane, and remifentanil; no notable events occurred during the anesthesia. As cor triatriatum shows a clinical picture of mitral stenosis (MS), careful anesthetic management is required.

Functional MRI findings showing cortical reorganization in a patient with type 2 complex regional pain syndrome: A case report.

The patients suffering with complex regional pain syndrome (CRPS) reveal sensory, motor and autonomic abnormalities. The pathogenesis of CRPS is poorly understood. Some recent studies have reported that the functional magnetic resonance image (fMRI) findings support that cortical reorganization occurred in the patients with CRPS. We compared the cortical responses on fMRI in a 54-year-old right-handed male patient who suffered with type 2 CRPS on his left hand following an injury 4 years ago. He complained of severe pain and allodynia on the left hand that spread up to the left chest, and he showed abnormal involuntary movement and significant hypothermia on the left hand. The fMRI findings, when a mechanical stimulus was applied on both hands with a brush, showed significantly increased abnormal cortical responses on the primary and secondary somatosensory areas and the distinct parietal association area on the contra-lateral side of the brain to the stimuli on the affected painful hand relative to the stimuli on the unaffected hand. We report on the fMRI findings showing the cortical reorganization in a patient with type 2 CRPS.