Genetic effects of demographic bottleneck and recovery in Kinkazan Island and mainland populations of Japanese macaques (Macaca fuscata).

Populations of Japanese macaques were significantly reduced in most areas from the 1900s to the 1960s and then recovered mainly in the northeastern part of Honshu. A drastic reduction in population size reduces genetic variability through a bottleneck effect. Demographic expansion after the reduction that accumulates new mutations can reduce the bottleneck effects or drive the recovery of genetic variability. We examined the genetic status of a small island population (Kinkazan Island) and a larger mainland population (southern Tohoku) of Japanese macaques that experienced recent demographic bottlenecks and recovery using eight microsatellite loci. The two populations were significantly genetically different from each other. The Kinkazan population exhibited lower genetic variability, remarkable evidence of bottleneck (i.e., significant heterozygosity excess and lower frequency of rare alleles), and a considerably smaller effective population size based on genetic data than based on the current census size. These results indicate that the genetic status has not completely recovered from the demographic bottleneck despite a full recovery in census size on Kinkazan Island. New mutations might rarely have accumulated because of the small carrying capacity of the island. Therefore, the genetic variability of the population would have been restrained by the severe bottleneck size, small carrying capacity, and long-term isolation. On the other hand, the bottleneck effect seems to be limited in the southern Tohoku population considering higher genetic variability, non-significant heterozygosity excess in many mutation conditions, and the highest frequency of rare alleles.

Effect of baseline urinary glucose levels on the relationship between sodium-glucose cotransporter 2 inhibitors and serum uric acid in Japanese patients with type 2 diabetes mellitus.

In patients with type 2 diabetes mellitus (T2DM), controlling serum uric acid (SUA) and blood glucose levels is important. Moreover, sodium-glucose cotransporter 2 (SGLT2) inhibitors decrease SUA levels by accelerating urinary uric acid excretion. We investigated the effect of baseline urinary glucose levels on the relationship between SGLT2 inhibitors and SUA levels. We conducted a retrospective observational study using the electronic medical records of patients with T2DM of Kindai University Nara Hospital (April 2013 to March 2022). We divided the patients into two groups according to their baseline urinary glucose levels: the N-UG group, which included patients with negative urinary glucose strip test results (-), and the P-UG group, which included patients with positive urinary glucose strip test results (± or more). The changes in SUA levels before and after SGLT2 inhibitor administration were investigated. For comparison, the changes in SUA levels before and after the prescription of antidiabetic agents, excluding SGLT2 inhibitors, were also investigated. Our results revealed that SGLT2 inhibitors significantly decreased the SUA levels in patients in the N-UG group but tended to decrease its levels in those in the P-UG group. Regardless of the urinary glucose status at baseline, the administration of SGLT2 inhibitors may be useful for patients with T2DM to prevent the complications of hyperuricemia.

MR Imaging Findings of Carcinoma Ex Pleomorphic Adenoma Related to Extracapsular Invasion and Prognosis.

BACKGROUND AND PURPOSE: MR imaging can reflect the pathologic progression of carcinoma ex pleomorphic adenoma (CXPA). This study aimed to identify the imaging findings related to extracapsular invasion of CXPA. Additionally, the pathologic background of these findings was investigated. MATERIALS AND METHODS: This retrospective study included 37 patients with histologically confirmed CXPA. Three radiologists independently evaluated whether the CXPA showed the following characteristic MR imaging findings: border, capsule, the corona sign on fat-saturated T2WI and contrast-enhanced fat-saturated T1WI, and the black ring sign. The corona sign appeared larger on fat-saturated and/or contrast-enhanced fat-saturated T1WI than on T1WI. The black ring sign was defined as an intratumoral nodule with a thick low-intensity rim on T2WI. Interreader agreement of the visual assessment was performed using κ analysis, and MR imaging and histopathologic findings were also correlated. Kaplan-Meier survival and the log-rank test were used to estimate the 3-year disease-free survival. RESULTS: MR imaging findings, especially peritumoral findings, showed a significant difference between invasive and noninvasive CXPA. The reliability was poor for the border and capsule. In contrast, it was good for the corona sign on fat-saturated and contrast-enhanced fat-saturated T1WI and the black ring sign. Pathologically, the corona sign reflected the invasiveness of the tumor and inflammatory cells, while the black ring sign reflected hyalinization or fibrosis. The corona sign also showed a significant difference in the 3-year disease-free survival. CONCLUSIONS: MR imaging findings, including the corona and black ring signs, reliably differentiated invasive and noninvasive CXPA. The corona sign can be used as a prognostic factor for CXPA.

Anxiety relaxation during MRI with a patient-friendly audiovisual system.

INTRODUCTION: Many patients experience anxiety, not limited to claustrophobia, before magnetic resonance imaging (MRI) examination. We performed a non-randomized controlled trial to evaluate whether a patient-friendly audiovisual (AV) system in the MR scanner room reduces patient anxiety. METHODS: We randomly selected 61 participants from outpatients who required brain MRI examination. Patients were informed that they could choose to undergo an MRI examination with a patient-friendly AV system (Ambient Experience, Philips Healthcare, Best, The Netherlands) or the standard system. To complete the MRI examination without affecting clinical practice, all patients who preferred the patient-friendly AV system were assigned to the preferring AV group. Patients who indicated that either system was acceptable were randomly assigned to the no preference but allocated AV group or control (using the standard system) groups. In both groups, state anxiety using the State-Trait Anxiety Inventory (STAI) was assessed before and after the MRI examination (A-State-before and A-State-after MRI, respectively). The changes in A-State-before and A-State-after MRI were categorized as follows: relieved high-state anxiety, no change in high-state anxiety, stable easiness, and intensified anxiety. RESULTS: Among the 61 included patients, 19 were assigned to the preferring AV group, 20 to the no preference but allocated AV group, and 22 to the control group. There were no significant differences between the group. However, in patients with high-state anxiety before MRI, the preferring AV group and the no preference but allocated AV group, which used the patient-friendly AV system, relieved high-state anxiety by 63.6% (7 of 11 patients) and 81.8% (9 of 11 patients), respectively. In contrast, the control group using the standard system relieved high-level anxiety by only 42.9% (three out of seven patients). CONCLUSION: The patient-friendly AV system may reduce anxiety in patients undergoing MRI examinations. IMPLICATIONS FOR PRACTICE: The patient-friendly AV system may reduce anxiety in patients undergoing MRI examination by providing a more patient-centered MRI examination environment. These findings may help ameliorate negative perceptions associated with MRI examination.

Identification of Vortex Cores in Cerebral Aneurysms on 4D Flow MRI.

BACKGROUND AND PURPOSE: The complexity and instability of the vortex flow in aneurysms are factors related to the rupture risk of unruptured cerebral aneurysms. We identified aneurysm vortex cores on 4D flow MR imaging and examined the relationship of these factors with the characteristics of cerebral aneurysms. MATERIALS AND METHODS: We subjected 40 aneurysms (37 unruptured, 3 ruptured) to 4D flow MR imaging. We visualized streamlines with velocities below the threshold-that is, a percentage value of the aneurysm maximum inflow velocity-and progressively decreased the threshold to identify vortex cores as thin, streamline bundles with minimum velocities. Complexity and stability were compared in aneurysms with a smooth surface and those with blebs or daughter sacs. RESULTS: The threshold for visualizing vortex cores ranged from 3% to 13% of the maximum inflow velocity. Vortex cores could be visualized in 38 aneurysms; in 2, they were not visualized through the cardiac cycle. A simple flow pattern (single vortex core) was identified in 27 aneurysms; the other 13 exhibited a complex flow pattern. The cores were stable in 32 and unstable in 8 aneurysms. Significantly more aneurysms with-than-without blebs or daughter sacs had a complex flow pattern (P = .006). Of the 3 ruptured aneurysms, 1 aneurysm had an unstable vortex core; in the other 2, the vortex core was not visualized. CONCLUSIONS: The identification of vortex cores on 4D flow MR imaging may help to stratify the rupture risk of unruptured cerebral aneurysms.

Results of a multi-institutional, randomized, non-inferiority, phase III trial of accelerated fractionation versus standard fractionation in radiation therapy for T1-2N0M0 glottic cancer: Japan Clinical Oncology Group Study (JCOG0701).

Background: We assessed the non-inferiority of accelerated fractionation (AF) (2.4 Gy/fraction) compared with standard fractionation (SF) (2 Gy/fraction) regarding progression-free survival (PFS) in patients with T1-2N0M0 glottic cancer (GC). Patients and methods: In this multi-institutional, randomized, phase III trial, patients were enrolled from 32 Japanese institutions. Key inclusion criteria were GC T1-2N0M0, age 20-80, Eastern Cooperative Oncology Group performance status of 0-1, and adequate organ function. Patients were randomly assigned to receive either SF of 66-70 Gy (33-35 fractions), or AF of 60-64.8 Gy (25-27 fractions). The primary end point was the proportion of 3-year PFS. The planned sample size was 360 with a non-inferiority margin of 5%. Results: Between 2007 and 2013, 370 patients were randomized (184/186 to SF/AF). Three-year PFS was 79.9% (95% confidence interval [CI] 73.4-85.4) for SF and 81.7% (95% CI 75.4-87.0) for AF (difference 1.8%, 91% CI-5.1% to 8.8%; one-sided P = 0.047 > 0.045). The cumulative incidences of local failure at 3 years for SF/AF were 15.9%/10.3%. No significant difference was observed in 3-year overall survival (OS) between SF and AF. Grade 3 or 4 acute and late toxicities developed in 22 (12.4%)/21 (11.5%) and 2 (1.1%)/1 (0.5%) in the SF/AF arms. Conclusion: Although the non-inferiority of AF was not confirmed statistically, the similar efficacy and toxicity of AF compared with SF, as well as the practical convenience of its fewer treatment sessions, suggest the potential of AF as a treatment option for early GC. Clinical trials registration: UMIN Clinical Trial Registry, number UMIN000000819.

MR Imaging of the Superior Cervical Ganglion and Inferior Ganglion of the Vagus Nerve: Structures That Can Mimic Pathologic Retropharyngeal Lymph Nodes.

BACKGROUND AND PURPOSE: The superior cervical ganglion and inferior ganglion of the vagus nerve can mimic pathologic retropharyngeal lymph nodes. We studied the cross-sectional anatomy of the superior cervical ganglion and inferior ganglion of the vagus nerve to evaluate how they can be differentiated from the retropharyngeal lymph nodes. MATERIALS AND METHODS: This retrospective study consists of 2 parts. Cohort 1 concerned the signal intensity of routine neck MR imaging with 2D sequences, apparent diffusion coefficient, and contrast enhancement of the superior cervical ganglion compared with lymph nodes with or without metastasis in 30 patients. Cohort 2 used 3D neurography to assess the morphology and spatial relationships of the superior cervical ganglion, inferior ganglion of the vagus nerve, and the retropharyngeal lymph nodes in 50 other patients. RESULTS: All superior cervical ganglions had homogeneously greater enhancement and lower signal on diffusion-weighted imaging than lymph nodes. Apparent diffusion coefficient values of the superior cervical ganglion (1.80 ± 0.28 × 10-3mm2/s) were significantly higher than normal and metastatic lymph nodes (0.86 ± 0.10 × 10-3mm2/s, P < .001, and 0.73 ± 0.10 × 10-3mm2/s, P < .001). Ten and 13 of 60 superior cervical ganglions were hypointense on T2-weighted images and had hyperintense spots on both T1- and T2-weighted images, respectively. The latter was considered fat tissue. The largest was the superior cervical ganglion, followed in order by the retropharyngeal lymph node and the inferior ganglion of the vagus nerve (P < .001 to P = .004). The highest at vertebral level was the retropharyngeal lymph nodes, followed, in order, by the inferior ganglion of the vagus nerve and the superior cervical ganglion (P < .001 to P = .001). The retropharyngeal lymph node, superior cervical ganglion, and inferior ganglion of the vagus nerve formed a line from anteromedial to posterolateral. CONCLUSIONS: The superior cervical ganglion and the inferior ganglion of the vagus nerve can be almost always differentiated from retropharyngeal lymph nodes on MR imaging by evaluating the signal, size, and position.

Localization of an Aldo-Keto Reductase (AKR2E4) in the Silkworm Bombyx mori (Lepidoptera: Bombycidae).

The aldo-keto reductase AKR2E4 reduces 3-dehydroecdysone to ecdysone in the silkworm Bombyx mori L. In this study, a quantitative polymerase chain reaction analysis revealed that the level of AKR2E4 mRNA was higher in the testes than in other tissues, and a western immunoblot analysis revealed that the AKR2E4 content in the testes was stage-specific from the fifth larval instar to the pupal stage. Immunohistochemical analysis showed that the AKR2E4 protein was present in cyst cells associated with sperm cells and spermatocytes. These results indicate that AKR2E4 plays an important role in 3-dehydroecdysone conversion to ecdysone and spermatogenesis in silkworm testes.

Associations of three-dimensional T1 rho MR mapping and three-dimensional T2 mapping with macroscopic and histologic grading as a biomarker for early articular degeneration of knee cartilage.

T1 rho and T2 mapping are magnetic resonance imaging (MRI) techniques to detect early degenerative changes in cartilage. Recent advancements have enabled 3D acquisition for both techniques. The objective of the present study was to examine the correlation of 3D T1 rho and 3D T2 mapping with macroscopic and histological characteristics of knee cartilage. Twenty-one patients who underwent total knee arthroplasty due to osteoarthritis with involvement of the medial compartment but with minimum involvement of the lateral compartment were enrolled. Prior to surgery, five series of MRI were acquired with a 3-T scanner. 3D T1 rho/T2 analyses were performed following determination of regions to be assessed using in-house software that incorporated three series of MRI acquisitions data (3D-MERGE, 3D-SPGR, and 3D-CUBE). During surgery, the cartilage of the lateral compartment was macroscopically assessed with the International Cartilage Research Society (ICRS) articular classification system. The extracted specimens were histologically assessed using the OARSI histology score. Three regions of interest (ROI) were assessed for each slice (two slices per knee): the central lateral femoral condyle (cLFC), the posterior portion of the lateral femoral condyle (pLFC), and the lateral tibia plateau (LTP). For each ROI, the mean T1 rho and T2 relaxation time, the ICRS grade, and the OARSI score were compared. Neither the T1 rho nor the T2 reflected the macroscopic grading. The T1 rho could discriminate between histological grades 1 and 2. However, the T2 could not. The T1 rho relaxation time was higher in the pLFC than in the cLFC even in the same grade. Compared to T2 mapping, T1 rho mapping may have an advantage in differentiating grades I and II cartilage degeneration on OARSI histological grading system.

A phase I, open-label, dose-escalation, multicenter study of the JAK2 inhibitor NS-018 in patients with myelofibrosis.

NS-018 is a Janus-activated kinase 2 (JAK2)-selective inhibitor, targeting the JAK-signal transducer and activator of transcription (STAT) pathway that is deregulated in myelofibrosis. In this phase I, dose-escalation portion of a phase I/II study, patients with myelofibrosis received oral NS-018 in continuous 28-day cycles. The primary study objective was to evaluate safety, tolerability and clinically active dose of NS-018. Forty-eight patients were treated; 23 (48%) had previously received a JAK inhibitor (JAKi). The most common drug-related adverse events were thrombocytopenia (27%)/anemia (15%) for hematologic events, and dizziness (23%)/nausea (19%) for non-hematologic events. Once daily NS-018 at 300 mg was chosen as the phase II study dose based on improved tolerability compared with higher doses. A ⩾50% reduction in palpable spleen size was achieved in 56% of patients (47% of patients with prior JAKi treatment), and improvements were observed in myelofibrosis-associated symptoms. Bone marrow fibrosis grade (local assessment) improved from baseline in 11/30 evaluable patients (37%) after 3 cycles of NS-018. JAK2 allele burden was largely unchanged. Changes in cytokine/protein levels were noted after 4 weeks of treatment. NS-018 reached peak plasma concentration in 1-2 h and did not accumulate with multiple dosing. NS-018 will be assessed in patients with previous JAKi exposure in the phase II portion.

Multiple inductive effects of carbamazepine on combined therapy with paliperidone and amlodipine.

WHAT IS KNOWN AND OBJECTIVE: Carbamazepine is a potent inducer of cytochrome P450 3A and P-glycoprotein. However, there are no reports of the effects of carbamazepine on more than one co-administered drug. CASE SUMMARY: A 53-year-old female patient with schizophrenia and hypertension was on paliperidone 12 mg/day and amlodipine 5 mg/day. When carbamazepine was added to this prescription, the plasma concentrations of both drugs decreased dramatically in a dose-dependent manner. Although the patient's psychotic symptoms did not change, as a result, her mean blood pressure increased to 160·1/103·6 mmHg from 138·4/91·4 mmHg at a carbamazepine dose of 600 mg/day. WHAT IS NEW AND CONCLUSION: Theses cases show the effect of carbamazepine induction on two drugs simultaneously. Care is required when carbamazepine is added to drug regimens including paliperidone or amlodipine alone or together.

Effects of multiple-dose rifampicin 450 mg on the pharmacokinetics of fexofenadine enantiomers in Japanese volunteers.

WHAT IS KNOWN AND OBJECTIVE: Rifampicin is a potent inducer of P-glycoprotein (P-gp) and inhibitor of organic anion-transporting polypeptides (OATPs), with fexofenadine acting as a substrate for both mechanisms. Simultaneous administration of single- or multiple-dose rifampicin 600 mg significantly increases the concentrations of fexofenadine enantiomers by inhibiting OATP transporters. However, the effects of rifampicin 450 mg are unknown. Here, we evaluated the effects of multiple doses of rifampicin 450 mg on the pharmacokinetics of fexofenadine enantiomers in healthy Japanese volunteers. METHODS: In this randomized, two-phase, double-blind crossover study, 10 healthy volunteers received rifampicin 450 mg/day or placebo for 7 days. On day 7, fexofenadine 60 mg was co-administered simultaneously. RESULTS AND DISCUSSION: Rifampicin significantly increased the mean area under the plasma concentration-time curve (AUC) of (R)- and (S)-fexofenadine (3.10-fold and 3.48-fold, respectively) and decreased the renal clearance of (R)- and (S)-fexofenadine (0.40-fold and 0.47-fold, respectively), causing marked differences in the mean amounts of these enantiomers excreted into the urine in the rifampicin phase (P < 0.001). These results indicated that multiple doses of rifampicin 450 mg may be sufficient to inhibit the renal influx transporter and OATP-mediated hepatic uptake of both enantiomers. Moreover, these effects may be greater than the P-gp-inductive effects of rifampicin. Therefore, the interactive mechanism of multidose rifampicin may occur through a combination of OATP and P-gp transporters, thereby altering the pharmacokinetics of fexofenadine enantiomers. WHAT IS NEW AND CONCLUSIONS: In this study of rifampicin 450 mg, the interactive magnitude of the mean AUC values of fexofenadine enantiomers was higher than that observed in the previous study of rifampicin 600 mg, and no dose-dependent inhibitory effects of rifampicin were observed. These effects may be clinically significant in patients receiving fexofenadine and rifampicin.

Conjugation of a TLR7 agonist and antigen enhances protection in the S. pneumoniae murine infection model.

Next generation vaccine adjuvants include Toll like receptor agonists, which are mostly extracted from microorganisms, but synthetic small molecule TLR agonists have also been identified. However, their delivery systems have not been optimized for effective administration in conjunction with antigens. Here, we describe a novel approach in which a small molecule TLR agonist was directly conjugated to antigen to ensure effective co-delivery. We describe the conjugation of a recombinant protective antigen from Streptococcus pneumoniae linked to a TLR7 agonist. Following thorough characterization to ensure no aggregation, the conjugate was evaluated in a murine infection model. Results showed that the conjugate extended the animals' survival after lethal challenge with S. pneumoniae. Comparable results were obtained with a dose 10-fold lower than that of the native unconjugated antigen. Notably, the animals immunized with the same dose of unconjugated TLR7 agonist and antigen showed no adjuvant effect. The increased immunogenicity was likely a consequence of the co-localization of TLR7 agonist and antigen by chemical binding and was more effective than simple co-administration. This approach can be adopted to increase potency of a broad variety of antigens and reduce the dose of antigen required to induce protective immunity.

Subarachnoid hyperattenuation on flat panel detector-based conebeam CT immediately after uneventful coil embolization of unruptured intracranial aneurysms.

BACKGROUND AND PURPOSE: Flat panel detector-based CBCT can provide CT-like images of the brain without transferring patients from the angiography suite to a conventional CT facility. Conventional brain CT after uneventful endovascular treatment sometimes shows focal subarachnoid hyperattenuation with contrast leakage, mimicking SAH. Differentiating this finding from SAH is important for immediate postprocedural medical management. We investigated CBCT for detecting subarachnoid hyperattenuation immediately after coil embolization of unruptured cerebral aneurysms. MATERIALS AND METHODS: Thirty-six patients with unruptured cerebral aneurysms undergoing CBCT immediately after uncomplicated coil embolization were included. The relationship between the presence of subarachnoid hyperattenuation and total volume of contrast medium injected, aneurysm size and location, and balloon and stent assistance during embolization was investigated. Statistical analyses were performed with the χ(2) test (P < .05). RESULTS: Nine of the 36 patients (25.0%) showed focal subarachnoid hyperattenuation within the relevant parent artery territory harboring the aneurysm. Subarachnoid hyperattenuation locations included the ipsilateral superior frontal sulcus (n = 5), the bilateral superior frontal sulcus (n = 1), and the ipsilateral superior frontal and precentral sulci (n = 3). Statistically significant differences were observed between the presence of a subarachnoid hyperattenuation and the total volume of contrast medium injected (P < .001) and aneurysm size (P < .05). CONCLUSIONS: Subarachnoid hyperattenuation can be detected by CBCT immediately after coil embolization for unruptured aneurysms. The increased amounts of contrast medium to be given before CBCT and the specific location of the hyperattenuation may help differentiate benign subarachnoid contrast leakage from SAH.

Living-donor liver transplantation in 126 patients with biliary atresia: single-center experience.

OBJECTIVES: To describe our experience with 126 consecutive living-donor liver transplantation (LDLT) procedures performed because of biliary atresia and to evaluate the optimal timing of the operation. PATIENTS AND METHODS: Between May 2001 and January 2010,126 patients with biliary atresia underwent 130 LDLT procedures. Mean (SD) patient age was 3.3 (4.2) years, and body weight was 13.8 (10.7) kg. Donors included 64 fathers, 63 mothers, and 3 other individuals. The left lateral segment was the most commonly used graft (75%). Patients were divided into 3 groups according to body weight: group 1, less than 8 kg (n = 40); group 2,8 to 20 kg (n = 63); and group 3, more than 20 kg (n = 23). Medical records were reviewed retrospectively. Follow up was 4.5 (2.7) years. RESULTS: All group 3 donors underwent left lobectomy, and all group 1 donors underwent left lateral segmentectomy. No donors required a second operation or died. Comparison of the 3 groups demonstrated that recipient Pediatric End-Stage Liver Disease score in group 1 was highest, operative blood loss in group 2 was lowest (78 mL/kg), and operative time in group 3 was longest (1201 minutes). Hepatic artery complications occurred more frequently in group 1 (17.9%), and biliary stenosis (43.5%) and gastrointestinal perforation (8.7%) occurred more frequently in group 3. The overall patient survival rates at 1, 5, and 9 years was 98%, 97%, and 97%, respectively. Five-year patient survival rate in groups 1,2, and 3 were 92.5%, 100%, and 95.7%, respectively. Gastrointestinal perforation (n = 2) was the primary cause of death. CONCLUSIONS: Living-donor liver transplantation is an effective treatment of biliary atresia, with good long-term outcome. It seems that the most suitable time to perform LDLT to treat biliary atresia is when the patient weighs 8 to 20 kg.

Rapid detection of Acanthamoeba cysts in frozen sections of corneal scrapings with Fungiflora Y.

AIMS: To evaluate the usefulness of serial frozen sections of corneal scrapings stained with Fungiflora Y (FFY) to diagnose Acanthamoeba keratitis (AK). METHODS: Eight patients with suspected AK were studied. Serial frozen sections were made from part of the corneal epithelial scrapings and stained with FFY. The remaining corneal epithelial scrapings were submitted for laboratory culture. RESULTS: The FFY stained frozen sections were completed within an hour, and Acanthamoeba cysts were detected under a fluorescence microscope in all eight patients. The same sections were examined with a light microscope, and Acanthamoeba cysts were confirmed to be present from their morphological characteristics. Five of the eight patients had positive laboratory cultures for Acanthamoeba. CONCLUSION: FFY staining of frozen sections of corneal scrapings is a rapid and reliable technique which can be used to make an early diagnosis of AK.

Oral administration of cilnidipine to patients with hypertensive intracerebral hemorrhage in the acute stage: significance and role of an N-type calcium channel blocker.

BACKGROUND: Elevated blood pressure (BP) causes rebleeding or enlargement of intracerebral hematomas. AIMS: How a long-acting oral calcium channel blocker, cilnidipine, could control BP in the acute stage of cerebral hemorrhage was evaluated. METHODS AND RESULTS: Cilnidipine given within 3 days of hospitalization has more benefit than cilnidipine given after 4 days of hospitalization; it can reduce the amount of intravenous nicardipine, and it can help to maintain the BP below 80% of the initial BP. Surgical removal of the hematoma has no benefit in reducing the amount of intravenous nicardipine and maintaining the BP below 80% of the initial BP. CONCLUSION: In order to reduce the total amount of intravenous nicardipine and to maintain the BP below 80% of the initial BP, oral administration of a long-acting N-type calcium channel blocker, cilnidipine, is useful and important, independent of whether the hematomas are surgically removed.

The effect of CYP2C19 genotypes on the pharmacokinetics of warfarin enantiomers.

The aim of this study was to elucidate the pharmacokinetics and pharmacodynamics of warfarin enantiomers in relation to cytochrome P450 2C19 (CYP2C19) genotypes. Fourteen subjects, of whom seven were homozygous extensive metabolizers (hmEMs) and seven were poor metabolizers (PMs) for CYP2C19, were enrolled. After a single oral 10 mg dose of racemic warfarin, the plasma concentrations of the warfarin enantiomers and prothrombin time expressed as international normalized ratio (PT-INR) were measured over the course of 120 h. The mean plasma concentrations and elimination half-life of (R)-warfarin of all the subjects were about 2-fold greater than those of (S)-warfarin. Additionally, the area under the plasma concentration-time curve from zero to infinity (AUC(0-infinity)) and the elimination half-life of (R)-warfarin in PMs were significantly greater than those in hmEMs (P = 0.0005 and P = 0.0101 respectively). The S/R ratios of AUC of warfarin enantiomers were 0.51 in hmEMs and 0.37 in PMs (P = 0.0052). Whereas no difference was found in all pharmacokinetic parameters of (S)-warfarin in hmEMs compared with PMs. No significant difference in PT-INR, used as a measure of anticoagulant effect, was found between the hmEMs and PMs. These results show that CYP2C19 activity is important in the pharmacokinetics of (R)-warfarin. However, when warfarin is administered as a racemate, this difference is not translated into any significant effect in the pharmacodynamics of warfarin.

Concurrent daily cisplatin and extended-field radiation therapy for carcinoma of the cervix.

The aim of this study was to assess acute toxicities of concurrent low-dose daily cisplatin and extended-field radiation therapy (EFRT) for carcinoma of the uterine cervix. Fifteen women with cervical cancer who were treated with concurrent daily low-dose cisplatin and EFRT were analyzed. Daily cisplatin dose was fixed to 8 mg/m(2), which was determined in the preceding phase I study using pelvic radiotherapy. Twelve patients underwent either combined external beam radiation therapy and intracavitary brachytherapy or external beam radiation therapy alone. Three other patients were treated with adjuvant chemoradiotherapy after surgery. A total dose of EFRT ranged from 40 to 45 Gy, with an additional boost to the gross tumor volume up to 50.4-55 Gy. A median total dose of cisplatin during entire radiation therapy course was 224 mg/m(2) (range, 200-240 mg/m(2)). In 14 of 15 patients (93%), daily cisplatin could be delivered continuously as planned without any modification. Administration of cisplatin had to be interrupted in only one patient for only 3 days. Fourteen patients developed grade 2 or worse leukopenia including five after treatment, grade 2 in four, grade 3 in eight, and grade 4 in two. Grade 3 thrombocytopenia was observed in three patients. Grade 2 or worse anemia was observed in 12. Three patients had grade 3 nonhematologic toxicities, diarrhea in two, and nausea/vomiting in one. Although moderate to severe hematologic toxicities are common, this study suggests that concurrent low-dose daily cisplatin and EFRT are feasible. A cumulative cisplatin dose of greater than 200 mg/m(2) during radiation therapy could be achieved by using daily cisplatin dose of 8 mg/m(2).

Long-term interleukin-1alpha treatment inhibits insulin signaling via IL-6 production and SOCS3 expression in 3T3-L1 adipocytes.

Proinflammatory cytokines are well-known to inhibit insulin signaling to result in insulin resistance. IL-1alpha is also one of the proinflammatory cytokines, but the mechanism of how IL-1alpha induces insulin resistance remains unclear. We have now examined the effects of IL-1alpha on insulin signaling in 3T3-L1 adipocytes. Prolonged IL-1alpha treatment for 12 to 24 hours partially decreased the protein levels as well as the insulin-stimulated tyrosine phosphorylation of IRS-1 and Akt phosphorylation. mRNA for SOCS3, an endogenous inhibitor of insulin signaling, was dramatically augmented 4 hours after IL-1alpha treatment. Concomitantly, the level of IL-6 in the medium and STAT3 phosphorylation were increased by the prolonged IL-1alpha treatment. Addition of anti-IL-6 neutralizing antibody to the medium or overexpression of dominant-negative STAT3 decreased the IL-1alpha-stimulated STAT3 activation and SOCS3 induction, and ameliorated insulin signaling. These results suggest that the IL-1alpha-mediated deterioration of insulin signaling is largely due to the IL-6 production and SOCS3 induction in 3T3-L1 adipocytes.