Laser-driven neutron source and nuclear resonance absorption imaging at ILE, Osaka University: review.

Here, we present an overview on the recent progress in the development of the laser-driven neutron source (LDNS) and nuclear resonance absorption (NRA) imaging at the Institute of Laser Engineering (ILE), Osaka University. The LDNS is unique because the number of neutrons per micro pulse is very large, and the source size and the pulse width are small. Consequently, extensive research and development of LDNSs is going on around the world. In this paper, a typical neutron generation process by the laser-driven ion beam, called the pitcher-catcher scheme, is described. The characteristics of the LDNS are compared with those of the accelerator-driven neutron source (ADNS), and unique application of the LDNS, such as NRA imaging, is presented. In the LDNS, NRA imaging is possible with a relatively short beam line in comparison with that of the ADNS since the neutron pulse width and the source size of the LDNS are small. Future prospects in research and development of NRA imaging with the LDNS at ILE Osaka University are also described.

Oncological outcome of neoadjuvant low-dose estramustine plus LHRH agonist/antagonist followed by extended radical prostatectomy for Japanese patients with high-risk localized prostate cancer: a prospective single-arm study.

BACKGROUND: Patients with advanced high-risk prostate cancer (PCa) are prone to have worse pathological diagnoses of positive surgical margins and/or lymph node invasion, resulting in early biochemical recurrence (BCR) despite having undergone radical prostatectomy (RP). Therefore, it is controversial whether patients with high-risk PCa should undergo RP. The purpose of this study was to evaluate the efficacy of neoadjuvant chemohormonal therapy (NAC) followed by "extended" RP. METHODS: A total of 87 patients with high-risk PCa prospectively underwent extended RP after NAC; most of the patients underwent 6 months of estramustine phosphate (EMP) 140 mg twice daily, along with a luteinizing hormone-releasing hormone agonist/antagonist. We developed our surgical technique to reduce the rate of positive surgical margins. We aimed to approach the muscle layer of the rectum by dissecting the mesorectal fascia and continuing the dissection through the mesorectum until the muscle layer of the rectum was exposed. RESULTS: More than 1 year had elapsed after surgery in all 86 patients, with a median follow-up period of 37.7 months. The 3-year BCR-free survival was 74.9%. Multivariate Cox-regression analysis revealed that a positive core ratio of 50% or greater and pathological stage of pT3 or greater were independent predictors for BCR. About 17 of 23 cases received salvage androgen deprivation therapy and concurrent external beam radiotherapy, and showed no progression after the salvage therapies. CONCLUSIONS: NAC concordant with extended RP is feasible and might provide good cancer control for patients with high-risk PCa.

Validation of prognostic impact of number of extrathoracic metastases according to the eighth TNM classification: a single-institution retrospective study in Japan.

BACKGROUND: In the eighth edition of the TNM classification of lung cancer, the M1b and M1c descriptors are newly defined by the number of extrathoracic metastases. To verify the prognostic value of these descriptors in Japan, we reclassified our cases and re-evaluated prognosis in M1b and M1c patients. METHODS: All non-small cell lung cancer (NSCLC) patients with extrathoracic metastases who visited Saitama Medical Center from 2010 to 2016 were evaluated, divided according to the eighth edition of the TNM classification criteria into two groups (M1b, patients with single extrathoracic metastasis, and M1c, patients with multiple extrathoracic metastases), and followed up until December 31, 2017. Survival time analysis was performed using the Kaplan-Meier method, and between-group differences in overall survival time (OS) were evaluated by the log-rank test. RESULTS: A total of 231 NSCLC patients were divided into 57 patients with M1b and 174 with M1c. Median OS was 15.2 months (95% confidence interval [CI]: 9.3-19.9) and 7.3 months (95% CI 5.7-10.7) for M1b and M1c, respectively, with no significant between-group difference (P = 0.239). However, after excluding patients with epidermal growth factor receptor (EGFR) mutation or echinoderm microtubule-associated protein-like 4 and anaplastic lymphoma kinase (EML4-ALK) fusion gene, median OS was 12.9 months (95% CI 7.2-19.9) for M1b and 5.4 months (95% CI 3.8-6.3) for M1c, respectively, showing a significant difference (P = 0.029). CONCLUSIONS: The effect of therapy directed toward EGFR mutation or EML4-ALK fusion gene might obscure the significant prognostic difference between M1b and M1c.

Long-term desensitization for ABO-incompatible living related kidney transplantation recipients with high refractory and rebound anti-blood type antibody: case report.

BACKGROUND: ABO-incompatible living related kidney transplantation (ABO-iLKT) has increased the possibilities for kidney transplantation in patients with end stage renal disease. Due to advancements in immunosuppressive agents and the identification of immunological conditions following ABO-iLKT, this transplantation technique has achieved the same success rate as ABO-compatible LKT. However, some patients continue to generate anti-blood type antibodies, despite conventional immunosuppressant treatment. CASE PRESENTATION: A 60-year-old man was referred to our hospital for kidney transplantation. The proposed transplant was ABO incompatible, from a donor with blood-type A to a recipient with blood-type O. The recipient's anti-A blood-type IgG antibody titer was measured at 4096-fold dilution. Following desensitization therapy, including mycophenolate mofetil (MMF) 750 mg/day for 3 months, intravenous Rituximab 200 mg, and two sessions of double filtration plasmapheresis, the anti-A blood-type IgG antibody titer decreased to only 516-fold dilution and did not meet our target of less than 128-fold dilution. MMF was thus continued for an additional 4 months and four additional sessions of plasmapheresis were undertaken. Following these interventions, antibody titers decreased to 128-fold dilution and ABO-iLKT was performed. Following transplant, antibody-mediated rejection was not observed and renal function was preserved. However, a post-operative renal biopsy 1.5 months later showed evidence of T-cell-mediated rejection IB. The patient was treated with steroids, with no increase in serum creatinine. CONCLUSION: Our findings suggest that the long-term single MMF desensitization therapy could be a suitable option for ABO-iLKT with high refractory and rebound anti-blood type antibody. Further studies are required to establish the optimal immunosuppression regimen to control B cell- mediated immunity in ABO-iLKT.

Immunoadsorption plasmapheresis treatment for the recurrent exacerbation of neuromyelitis optica spectrum disorder with a fluctuating anti-aquaporin-4 antibody level.

The pathogenesis in the exacerbation of neuromyelitis optica spectrum disorder (NMOSD) involves mainly the serum anti-aquaporin-4 (AQP4) immunoglobulin G antibody (anti-AQP4 antibody). If high-dose corticosteroid treatment is not achieved during remission, rescue plasmapheresis is recommended. However, there are few reports on the therapeutic efficacy of repetitive immunoadsorption plasmapheresis (IAPP) for the recurrent exacerbation of NMOSD with a fluctuating anti-AQP4 antibody level. A 36-year-old man presented with a reduction of visual acuity (VA) on the right eye (OD) to 20/250. At this reduction of VA OD, magnetic resonance imaging (MRI) showed right optic nerve swelling without cerebral, brainstem, or spinal cord lesions. The anti-AQP4 antibody was detected in the serum. We diagnosed the patient with NMOSD and treated him with high-dose corticosteroid therapy. To prevent exacerbation with this treatment, the sixth session of the first IAPP course was adopted and VA OD improved to 20/100. Seven months later, VA OD deteriorated to 20/125 and ocular pain occurred. At that time, the anti-AQP4 antibody was not detected, although MRI revealed the recurrence of right optic neuritis. A second IAPP course with seven sessions was conducted with a concomitant administration of 1000 mg methylprednisolone every 10 days for 30 days. Ocular pain improved, although VA OD had continued to decline during these treatments and was eventually preserved at 20/400. In conclusion, IAPP is effective for the treatment of exacerbated NMOSD with a seropositive anti-AQP4 antibody. However, further study is necessary to develop treatments for relapsing NMOSD with a seronegative anti-AQP4 antibody.

In vitro identification of human cytochrome P450 isoforms involved in the metabolism of Geissoschizine methyl ether, an active component of the traditional Japanese medicine Yokukansan.

1. Yokukansan (YKS) is a traditional Japanese medicine also called kampo, which has been used to treat neurosis, insomnia, and night crying and peevishness in children. Geissoschizine methyl ether (GM), a major indole alkaloid found in Uncaria hook, has been identified as a major active component of YKS with psychotropic effects. Recently, GM was reported to have a partial agonistic effect on serotonin 5-HT1A receptors. However, there is little published information on GM metabolism in humans, although several studies reported the blood kinetics of GM in rats and humans. In this study, we investigated the GM metabolic pathways and metabolizing enzymes in humans. 2. Using recombinant human cytochrome P450 (CYP) isoforms and polyclonal antibodies to CYP isoforms, we found that GM was metabolized into hydroxylated, dehydrogenated, hydroxylated+dehydrogenated, demethylated and water adduct forms by some CYP isoforms. 3. The relative activity factors in human liver microsomes were calculated to determine the relative contributions of individual CYP isoforms to GM metabolism in human liver microsomes (HLMs). We identified CYP3A4 as the CYP isoform primarily responsible for GM metabolism in human liver microsomes. 4. These findings provide an important basis for understanding the pharmacokinetics and pharmacodynamics of GM and YKS.

Metabolic profiling of the Uncaria hook alkaloid geissoschizine methyl ether in rat and human liver microsomes using high-performance liquid chromatography with tandem mass spectrometry.

Geissoschizine methyl ether (GM) is an indole alkaloid found in Uncaria hook, which is a galenical constituent of yokukansan, a traditional Japanese medicine. GM has been identified as the active component responsible for anti-aggressive effects. In this study, the metabolic profiling of GM in rat and human liver microsomes was investigated. Thirteen metabolites of GM were elucidated and identified using a high-performance liquid chromatography with tandem mass spectrometry method, and their molecular structures were proposed on the basis of the characteristics of their precursor ions, product ions, and chromatographic retention times. There were no differences in the metabolites between the rat and human liver microsomes. Among the 13 identified metabolites, there were two demethylation metabolites, one dehydrogenation metabolite, three methylation metabolites, three oxidation metabolites, two water-adduct metabolites, one di-demethylation metabolite, and one water-adduct metabolite followed by oxidation. The metabolic pathways of GM were proposed on the basis of this study. This study will be helpful in understanding the metabolic routes of GM and related Uncaria hook alkaloids, and provide useful information on the pharmacokinetics and pharmacodynamics. This is the first report that describes the separation and identification of GM metabolites in rat and human liver microsomes.

Plasma Pharmacokinetics of Polyphenols in a Traditional Japanese Medicine, Jumihaidokuto, Which Suppresses Propionibacterium acnes-Induced Dermatitis in Rats.

Most orally administered polyphenols are metabolized, with very little absorbed as aglycones and/or unchanged forms. Metabolic and pharmacokinetic studies are therefore necessary to understand the pharmacological mechanisms of polyphenols. Jumihaidokuto (JHT), a traditional Japanese medicine, has been used for treatment of skin diseases including inflammatory acne. Because JHT contains various types of bioactive polyphenols, our aim was to clarify the metabolism and pharmacokinetics of the polyphenols in JHT and identify active metabolites contributing to its antidermatitis effects. Orally administered JHT inhibited the increase in ear thickness in rats induced by intradermal injection of Propionibacterium acnes. Quantification by LC-MS/MS indicated that JHT contains various types of flavonoids and is also rich in hydrolysable tannins, such as 1,2,3,4,6-penta-O-galloyl glucose. Pharmacokinetic and antioxidant analyses showed that some flavonoid conjugates, such as genistein 7-O-glucuronide and liquiritigenin 7-O-glucuronide, appeared in rat plasma and had an activity to inhibit hydrogen peroxide-dependent oxidation. Furthermore, 4-O-methylgallic acid, a metabolite of Gallic acid, appeared in rat plasma and inhibited the nitric oxide reaction. JHT has numerous polyphenols; it inhibited dermatitis probably via the antioxidant effect of its metabolites. Our study is beneficial for understanding in vivo actions of orally administered polyphenol drugs.

Effects of blood purification therapy on a patient with ifosfamide-induced neurotoxicity and acute kidney injury.

Ifosfamide combined with other antineoplastic agents has been effective in the treatment of osteosarcoma, although adverse effects are reported in the increasing use of ifosfamide. The most serious complications among the ifosfamide intoxications are neurotoxicity and nephrotoxicity. We report on a patient who suffered from ifosfamide-induced neurotoxicity and nephrotoxicity and rhabdomyolysis after chemotherapy, and was successfully treated with blood purification therapy. The patient had osteosarcoma with multiple lung metastases, wherein the chemotherapy included ifosfamide (3 g/m(2)) and VP-16 (60 mg/m(2)) per day for 3 days. The first day after chemotherapy, the patient experienced impaired consciousness and renal function. Based on the clinical course and laboratory data, the diagnosis was ifosfamide-induced neurotoxicity and the acute kidney injury caused by ifosfamide-induced nephrotoxicity and rhabdomyolysis. As a detoxification treatment, blood purification procedures were performed daily for 3 days. Thirty-six hours after the first hemodialysis session, the symptoms of neurotoxicity disappeared. In the lead-up to the 10th day following intoxication, the serum creatinine recovered to the baseline level. Serum ifosfamide concentration decreased from 41.9 to 12.1 ng/ml by the second session of blood purification. Despite the absence of an established detoxification method when complications present simultaneously, blood purification therapy should be considered for treating severe concurrent neurotoxicity and nephrotoxicity and rhabdomyolysis.

Novel GNE compound heterozygous mutations in a GNE myopathy patient.

INTRODUCTION: Molecular studies have revealed that some patients with myopathies with rimmed vacuoles have pathogenic mutations in the UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase (GNE) and Z-band alternatively spliced PDZ motif-containing protein (ZASP) genes. METHODS: We investigated a patient with distal myopathy with rimmed vacuoles by muscle biopsy and sequenced 6 candidate genes. RESULTS: The patient carried GNE compound heterozygous missense mutations (p.V421A and p.N635K) and a ZASP variant (p.D673N). This patient also presented with distal weakness sparing the quadriceps muscles and had atypical results for Z-band-associated protein immunostaining. This finding indicates that the GNE mutations are pathogenic, and the diagnosis is compatible with GNE myopathy. CONCLUSIONS: By combining pathological studies and candidate gene screening, we identified a patient with GNE myopathy due to novel GNE compound heterozygous mutations.

Combination treatment using percutaneous transluminal angioplasty and low-density lipoprotein apheresis in a patient with peripheral arterial disease and a history of chronic hemodialysis.

Peripheral arterial disease (PAD) is very common in dialysis patients, who tend to have diffuse calcification and severe peripheral arterial stenosis that make it difficult to treat limbs using only surgical or endovascular interventions. Better ways to treat this condition are therefore required and also follow-up studies to evaluate the effects of these treatments on the microcirculation. A 59-year-old man who had a cadaveric kidney transplant five years previously after 25 years of regular hemodialysis complained of pain at rest in his right lower limb and subsequently developed an intractable decubitus ulcer on his right fifth toe (Fontaine IV). Digital subtraction angiography revealed a severe obstruction of the right femoral artery and diffuse stenosis of the right superficial femoral artery. The patient underwent percutaneous transluminal angioplasty (PTA) and six sessions of low-density lipoprotein apheresis (LDL apheresis). At the end of these sessions his complaints were almost completely alleviated. The mean elevation in skin temperature after each session was (1.58 ± 0.99)°C [mean ± SD] over the right dorsalis pedis artery and (1.52 ± 0.88)°C at the tip of the right fifth toe. Ultrasound-measured blood flow rates in the right dorsalis pedis artery were 9.2 cm/s before PTA and 20.2 cm/s one month after PTA. Hemodialysis was resumed 3 days after the PTA due to contrast-induced nephropathy. The combination of PTA and LDL apheresis is useful for treating PAD in hemodialysis patients, with the changes in peripheral artery patency are able to be evaluated effectively by measuring skin temperature.

Simultaneous quantitative analyses of indole and oxindole alkaloids of Uncaria Hook in rat plasma and brain after oral administration of the traditional Japanese medicine Yokukansan using high-performance liquid chromatography with tandem mass spectrometry.

Uncaria Hook (UH) alkaloids are involved in the beneficial effects of Yokukansan. However, the pharmacokinetics of UH alkaloids after oral administration of Yokukansan has not yet been sufficiently investigated. Therefore, we developed and validated a sensitive and specific high-performance liquid chromatography with tandem mass spectrometry (LC/MS/MS) method for the simultaneous quantitation of seven UH alkaloids (corynoxeine, isocorynoxeine, rhynchophylline, isorhynchophylline, hirsutine, hirsuteine and geissoschizine methyl ether) in rat plasma and brain. After protein precipitation with acetonitrile, chromatographic separation was performed using an Ascentis Express RP-amide column, with gradient elution with 0.2% formic acid and acetonitrile at 0.3 mL/min. All analytes in the plasma and brain showed good linearity over a wide concentration range (r > 0.995). Intra-day and inter-day variations of each constituent were 8.6 and 8.0% or less in the plasma, and 14.9 and 15.0% or less in the brain, respectively. The validated LC/MS/MS method was applied in the pharmacokinetic studies of UH alkaloids after oral administration of Yokukansan to rats. In the plasma, rhynchophylline, hirsutine, hirsuteine and geissoschizine methyl ether were detected, but only geissoschizine methyl ether was detected in the brain. These results suggest that geissoschizine methyl ether is an important constituent of the pharmacological effects of Yokukansan.

Inguinal Lymphadenopathy After Renal Transplantation Leading to the Diagnosis of Prostate Cancer: A Case Report.

It is extremely rare for a patient with prostate cancer (PCa) to have palpable lymph nodes at the initial presentation. In fact, only 4 case reports of palpable superficial lymph nodes at the first visit led to the diagnosis of PCa. Moreover, no such cases are reported in kidney transplantation (KT) patients. A 72-year-old man who started hemodialysis due to diabetic nephropathy was referred to our hospital for a KT in 2018. Before the KT, he had a negative screen for cancer, including PCa. The postoperative course was good. He felt a lump in the left inguinal region three years after the KT. A computed tomography scan revealed abdominal and left inguinal lymphadenopathy, which was consistent with a post-transplant lymphoproliferative disorder. However, a biopsy of an inguinal lymph node revealed adenocarcinoma with positive prostate-specific antigen (PSA) staining, suggesting lymph node metastasis of PCa. The blood PSA level was 1674.23 ng/mL. A prostate biopsy was performed, the pathologic diagnosis of which was PCa, with a Gleason score of 10. In conclusion, even though the standardized incidence ratio of PCa is not known to increase in KT patients, PCa should be included in the differential diagnosis, along with the possibility of post-transplant lymphoproliferative disorder. We also suggest the importance of regular screening for malignant tumors after organ transplantation.

Impact of Locoregional Therapies for Brain Lesions on Survival in Patients With Non-small Cell Lung Cancer With Multiple Extrathoracic Metastases.

BACKGROUND/AIM: The treatment of brain metastases in patients with non-small cell lung cancer (NSCLC) typically involves surgery, irradiation, and chemotherapy (single or combination therapy). However, the impact of these therapies on the survival of patients with NSCLC with multiple extrathoracic metastases has not yet been determined. Therefore, in the present study, we examined the prognostic effect of multimodal treatment for brain metastases in patients with NSCLC with multiple extrathoracic metastases in the absence of driver mutations. PATIENTS AND METHODS: Patients with NSCLC with multiple extrathoracic metastases (including at least one brain metastasis), who visited Saitama Medical Center, Saitama Medical University from January 1, 2010 to December 31, 2016, were enrolled in this study; follow-up was conducted until December 31, 2021. RESULTS: A total of 56 patients were enrolled, including 12 and 44 patients with single and multiple brain metastases, respectively. The median overall survival (OS) for all patients was 4.9 months, and did not differ significantly between patients with single and multiple brain metastases (3.0 vs. 4.9 months, respectively). The selection of locoregional treatment for brain metastases did not depend on Karnofsky performance status (p=0.0862). Among patients with multiple brain metastases, the OS for those who underwent craniotomy followed by whole brain radiation therapy (WBRT), those who received only WBRT, and those treated without locoregional therapy was 47.7, 3.9, and 15.9 months, respectively (p=0.00382). CONCLUSION: Surgical resection followed by radiation therapy is an effective treatment option for brain metastases in patients with multiple metastases. However, WBRT alone did not improve prognosis.

Total synthesis of hydroxy-α- and hydroxy-ß-sanshool using Suzuki-Miyaura coupling.

Here, we describe the first total synthesis of hydroxyl-α- and hydroxyl-ß-sanshool, which involves Suzuki-Miyaura coupling (SMC). Hydroxy-α-sanshool (1) was synthesized by SMC of bromoalkyne 4 with boronate 3 followed by (Z)-selective reduction of the triple bond in the coupling product. Hydroxy-ß-sanshool (2) was synthesized by regio- and (E)-selective conversion of 4 to iodoalkene 11 followed by SMC with 3.

Laparoscopic Surgery for Pheochromocytoma in Hemodialysis Patients.

Objectives: We analyzed the clinical outcomes of laparoscopic adrenalectomy for pheochromocytomas in hemodialysis compared with nonhemodialysis patients. Methods: Fifty-seven patients (7 hemodialysis and 50 nonhemodialysis) were included in the study. We analyzed the differences in clinical parameters and outcomes between the hemodialysis patient groups and nonhemodialysis patient groups as well as identified predictors for an intraoperative hypertensive spike. Results: The increasing intravascular volume before surgery in hemodialysis patients made perioperative hemodynamic management safer. No significant difference in clinical parameters between the two groups was observed except for the length of hospitalization that was significantly longer in the hemodialysis patients (9 vs. 6 days, P=0.005). An increase in systolic blood pressure at CO2 insufflation was an independent predictor of a hypertensive spike with a cutoff value of 22.5 mmHg (odds ratio 1.038, 95% confidence interval 1.012-1.078). Conclusion: Laparoscopic adrenalectomy for pheochromocytomas in hemodialysis was safe and feasible. An increase in systolic blood pressure at CO2 insufflation was a predictor of the intraoperative hypertensive spike. The research in this manuscript is not registered. This is a retrospective study.

Nintedanib induces gene expression changes in the lung of induced-rheumatoid arthritis-associated interstitial lung disease mice.

Nintedanib is a multi-tyrosine kinase inhibitor widely used to treat progressive fibrosing interstitial lung diseases because it slows the reduction in forced vital capacity. However, the prognosis for patients treated with nintedanib remains poor. To improve nintedanib treatment, we examined the effects of nintedanib on gene expression in the lungs of induced-rheumatoid arthritis-associated interstitial lung disease model mice, which develop rheumatoid arthritis and subsequent pulmonary fibrosis. Using next-generation sequencing, we identified 27 upregulated and 130 downregulated genes in the lungs of these mice after treatment with nintedanib. The differentially expressed genes included mucin 5B and heat shock protein 70 family genes, which are related to interstitial lung diseases, as well as genes associated with extracellular components, particularly the myocardial architecture, suggesting unanticipated effects of nintedanib. Of the genes upregulated in the nintedanib-treated lung, expression of regulatory factor X2, which is suspected to be involved in cilia movement, and bone morphogenetic protein receptor type 2, which is involved in the pathology of pulmonary hypertension, was detected by immunohistochemistry and RNA in situ hybridization in peripheral airway epithelium and alveolar cells. Thus, the present findings indicate a set of genes whose expression alteration potentially underlies the effects of nintedanib on pulmonary fibrosis. It is expected that these findings will contribute to the development of improved nintedanib strategies for the treatment of progressive fibrosing interstitial lung diseases.

Gender differences in plasma pharmacokinetics and hepatic metabolism of geissoschizine methyl ether from Uncaria hook in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Geissoschizine methyl ether (GM), an indole alkaloid from Uncaria hook, is an active ingredient in the traditional Japanese Kampo medicine yokukansan, which is used to treat neurosis, insomnia, irritability, and night crying in children. AIM OF THE STUDY: Recent our pharmacokinetic studies suggested that there may be gender differences in the plasma concentrations of GM in rats, but not in humans. However, the details of this difference remain unverified. The purpose of this study was to clarify the reasons for the gender differences in rats. MATERIALS AND METHODS: GM plasma pharmacokinetics was compared in male and female rats orally administered yokukansan (4 g/kg). To confirm the involvement of cytochrome P450 (CYP) in GM liver metabolism, GM was incubated with male and female rat liver S9 fraction in the absence or presence of 1-aminobenzotriazole (a nonspecific CYP inhibitor). CYP isoforms involved in GM metabolism were estimated using recombinant rat CYP isoforms and anti-rat CYP antibodies. RESULTS: The maximum GM plasma concentrations were significantly higher in female than in male rats. When GM was incubated with rat liver S9 fractions, GM reduction was more striking in male S9 (69.3%) than that in female S9 (10.0%) and was completely blocked with nonspecific CYP inhibitor 1-aminobenzotriazole. Screening experiments using recombinant rat cytochrome P450 (CYP) isoforms showed that CYP1A1, CYP2C6, CYP2C11, CYP2D1, and CYP3A2 were involved in GM metabolism. Of these CYP isoforms, the use of anti-rat CYP antibodies indicated that male-dependent CYP2C11 and CYP3A2 were predominantly involved in the liver microsomal GM metabolism with gender differences. CONCLUSIONS: These results suggest that the cause of gender differences in plasma GM pharmacokinetics in rats is most likely because of male-dependent CYP2C11 and CYP3A2, and provide also useful information to further evaluate the pharmacological and toxicological effects in future. This study is the first to demonstrate that the gender differences in plasma GM pharmacokinetics in rats are caused by the gender-dependent metabolism of GM.

Significance of preoperative screening of deep vein thrombosis and its indications for patients undergoing urological surgery.

PURPOSE: Preoperative deep vein thrombosis (pre-DVT) is a risk of symptomatic venous thromboembolism (VTE) and a serious postoperative surgical complication. However, little is known about pre-DVT in patients undergoing surgery. This study aimed to investigate the incidence and screening criteria of pre-DVT in patients undergoing urological surgery. MATERIALS AND METHODS: Between 2015 and 2017, 320 patients admitted to our hospital for urological surgery were included in this retrospective study. All patients underwent preoperative D-dimer testing. Patients with elevated D-dimer (≥1.0 µg/mL) levels underwent lower-limb compression ultrasonography (CUS). Clinical parameters were analyzed as predictors of pre-DVT, and modest cutoff value of D-dimer to predict pre-DVT were evaluated. RESULTS: Of 320 patients, preoperative elevated D-dimer levels and DVT were found in 81 (25.3%) and 20 (6.3%) patients, respectively. The positive predictive value (PPV) was 24.7% (20/81). ROC curve analysis revealed a cutoff D-dimer level of 1.8 µg/mL, yielding a PPV of 40.7% for pre-DVT among patients with elevated D-dimer levels. Preoperative DVT was detected in 16 (7.6%, n=210) patients with malignancy, 3 (5.7%, n=53) with adrenal tumors, and in 1 (1.8%, n=57) kidney donor. An age of >70 years was significantly associated with risk for pre-DVT (odds ratio, 2.81; 95% confidence interval, 1.12-7.19; p=0.0270). During a postoperative follow-up period of 90 days, no patient developed symptomatic VTE. CONCLUSIONS: The incidence of pre-DVT was 6.3% in patients undergoing urological surgery. Elderly patients and/or a cutoff D-dimer level of 1.8 µg/mL might be good indications for pre-DVT screening by CUS.